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Introduction and Principles of
Pharmacology
General Principles
―To administer a drug safely, one must

know its usual dose frequency, route of
administration, indications,
contraindications, significant adverse
reactions, and major drug interactions.‖
Pharmacology
• Pharmacology: the study of drugs and
their actions and effects in body systems
• Pharmacodynamics: the study of
biochemical and physiologic drug effects,
and the mechanisms of drug action
• Pharmacokinetics: the study of drug
absorption, distribution, metabolism, and
excretion
Other Pharmacologic Terms
• Pharmacognosy: the study of drugs

derived from herbal or natural sources
• Pharmacotherapeutics: the study of how
drugs are best used and which drug is
appropriate for a specific disease
• Toxicology: the study of poisons and
poisonings
Pharmacokinetics
Absorption, distribution, metabolism, and

excretion of drugs are related to:
– Concentration of drug
– Drug’s chemical by-products in various body
sites
– Time required for drug concentrations to
develop or change
Figure 1-1
The four processes of pharmacokinetics (that is, movement)
are absorption, metabolism, distribution, and excretion.
Pharmacodynamics
Describes all matters concerned with

pharmacologic actions of a drug,
including:
– Therapeutic effects (effects that are meant
to treat a disease or disorder)
– Adverse effects (harmful effects)
Dose-Effect Relationship
Pharmacokinetics and
pharmacodynamics determine the dose-
effect relationship:
– Relationship between dose of a drug that
produces harmful effects and severity of
effects on client
– Body’s response to a drug or toxic agent
increases as overall exposure to substance
increases
Figure 1-2A
The dose-effect relationship. Along the x-axis is the drug dose, which increases from left to right.
Along the y-axis is the maximum response for each drug (%). (A)These curves show drug potency.
Drug A’s curve is to the left of drug B’s curve, which indicates that drug A has a higher potency.
This means that a smaller dose of drug A will produce the same effect as a larger dose of drug B.
Figure 1-2B
(B) These curves show drug efficacy (or effectiveness).
Drug A reaches a maximum response of 100% at the same dose as drug B,
which reaches a maximum response of about 60%.
Therefore, drug A’s efficacy (or effectiveness) is greater than that of drug B.
Mechanism of Drug Actions
• Drugs work by altering normal cell and

tissue function.
• Specific groups of drugs have affinity
(attractive force) for specific target cells,
known as receptors.
• Binding of drugs to a particular receptor
type produces pharmacologic effect—
either agonist or antagonist actions.
Agonists and Antagonists
Two types of chemical substances bind
to receptors:
– Agonists: drugs that bind to receptors and
produce stimulatory responses that are
similar to that produced by endogenous
chemicals
– Antagonists: drugs that prevent agonists
from binding to receptors, thus blocking their
effects
Agonist and Antagonist
Animation
Click here to view an animation showing an agonist and antagonist.
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Receptor Selectivity
Some receptors have subtypes, for which

certain chemicals have some selectivity.
– For example, beta (β)-adrenoreceptors have
two subtypes, β1 and β2.
– The drug propranolol (Inderal) is an
antagonist at both β1 and β2, whereas
atenolol (Tenormin) is selective for β1.
Drug Half-Life
• Half-life (t1/2): time taken for the drug’s

blood or plasma concentration to
decrease from full to one-half (50%)
• The longer the half-life, the longer the
drug remains in the body.
Figure 1-3
Plasma concentration of a drug versus time. The onset of action occurs at 2 hours;
the duration of action is 6 hours; peak plasma concentration is 10 mcg/mL;
and the time to reach peak drug effect is 5 hours.
Factors Affecting Drug Action
• Age: affects metabolic rates, requiring

dosage adjustments.
• Gender: responses to drugs sometimes
differ.
• Body weight: dosages may require
adjusting for body weight and body
surface area.
Factors Affecting Drug Action
(continued)
• Diurnal rhythms: intensity of response to

drug may be affected by when it is given.
• Disease: dosages may need to be
adjusted in persons with kidney or liver
disease.
Drug Elimination
in Elderly Patients
• Acute or chronic diseases that affect liver

architecture or function also affect
hepatic metabolism of some drugs.
• Elderly patients may therefore have
markedly affected drug elimination and
require dosage adjustment.
Pharmacokinetics:
Absorption
Absorption: movement of drug into systemic
circulation
– Depends on drug’s ability to cross cell
membranes and resist presystemic metabolism
(enzymes in GI tract begin to break down drug
before it is absorbed)
– Presystemic metabolism affects drug’s
bioavailability—amount of drug that reaches
systemic circulation intact and its speed
Factors That Affect
Absorption
• Acidity of the stomach

• Physiochemical properties: dissolution,
solubility, thermodynamics
• Presence of food in stomach or intestine
• Routes of administration: PO, IV, IM,
subcutaneous, transdermal, sublingual,
buccal, rectal, vaginal
Pharmacokinetics:
Distribution
• Distribution: passage of agent through

blood or lymph to various body sites
• Many drugs are bound to circulating
proteins, affecting their ability to bind to
receptors; cross tissue membranes; and
be distributed, metabolized, and
excreted.
Pharmacokinetics:
Metabolism
• Most drug metabolism occurs in the liver.
• First-pass effect (metabolism of drug by
liver enzymes before it reaches systemic
circulation) influences metabolism.
• Substances that are absorbed across the
intestinal wall enter blood vessels and
are carried directly to the liver (hepatic
portal circulation).
Pharmacokinetics:
Metabolism (continued)
• End-products of metabolism are

metabolites.
Figure 1-4
First-pass effect. Oral drugs are absorbed through the intestinal wall
and enter the hepatic portal circulation. They are taken directly to the liver for metabolism
before reaching the heart and circulating throughout the body.
Biotransformation
• Biotransformation is the conversion of

drugs in four stages:
– Oxidation: combining with oxygen
– Reduction: gaining electrons
– Hydrolysis: cleaving into simpler compounds
– Conjugation: combining with glucuronic or
sulfuric acid, terminating biologic activity
Pharmacokinetics: Excretion
• The main route of excretion is via the
kidneys.
• Kidney diseases can prolong the duration
of drug action.
• Other routes of excretion include:
– Lungs
– Breast milk
– Sweat, tears, urine, feces
– Bile
– Saliva
Other Pharmacologic Principles
• Toxicity: refers to drug’s ability to poison

the body.
• Overdose: dose of drug that causes
harm.
• Adverse drug reaction (ADR): any
response to drug that is noxious,
unintended, and occurs at doses
normally used for prophylaxis, diagnosis,
or therapy.
Other Pharmacologic Principles
(continued)
• Side effect: an unintended drug effect;

this can be beneficial
Drug Interactions
• Occur when the effects of one drug are

altered by those of another drug
• Occasionally, the effects of both drugs
are altered.
• Drug interactions usually result in an
adverse drug reaction, though some
interactions may be beneficial.
Idiosyncratic Reactions
• Idiosyncratic reaction: a unique, strange,
or unpredicted reaction to a drug
• Allergic reaction: hypersensitivity to drug
that occurs after previous exposure to
similar or same drug, and develops
rapidly after reexposure
• Anaphylactic shock: idiosyncratic,
sudden, and life-threatening allergic
reaction
Allergy History
• Ask all patients if they have a history of

allergies, such as hay fever, rashes or
asthma, or have had unusual reactions to
any drugs taken orally or by injection.
Tolerance
• Tolerance: development of resistance to

drug’s effects, such that dose must be
continually raised to elicit desired
response.
• Drugs that commonly produce tolerance
are:
– Opiates – Nitrates
– Barbiturates – Alcohol
– Tobacco
Other Drug Effects
• Cumulative effect: occurs when body

cannot completely metabolize and
excrete one drug dose before next dose
is given
• Synergism: occurs when combined
action of two or more agents produces a
greater effect than expected from agents
acting separately
Other Drug Effects (continued)
• Potentiation: a greater effect than

expected caused from additive properties
of two or more drugs
Using Drugs
Therapeutically
Introduction
• The effect a drug exerts is directed toward

– prevention
– diagnosis
– treatment
• Can exert other undesirable effects
Copyright ©2010 by Pearson Education, Inc.

Understanding Pharmacology for Health Professionals, Fourth Edition Upper Saddle River, New Jersey 07458
Susan M. Turley All rights reserved.
Introduction
• Drug effects can be altered by interaction

with
– drugs
– food

Basis of Drug Effects
• Drug effects are initiated through receptors
– special protein molecules
– located on cell membrane of every cell
– specifically designed to interact with natural
body chemicals
 hormones
 enzymes
 neurotransmitters
– also interact with drugs

• Lock and key
– receptors are the lock
– drugs are the key
 certain drugs can unlock (activate) receptor
 chemically similar drugs activate same receptor
• produce similar effects
• Agonist drug
– a drug that is able to unlock and activate a
receptor and produce an effect

• Antagonist and blocker drugs

– some drugs fit, but cannot unlock (activate),
certain receptors
– therapeutic action is to occupy receptor site
– block hormones, neurotransmitters, other
drugs from activating the receptor

Figure 5-1 Agonist and antagonist drugs. An agonist drug (key) unlocks and activates a receptor
(lock). An antagonist drug (key) occupies and blocks a receptor (lock), but does not activate it. An
antagonist drug also keeps an agonist drug from unlocking and activating the receptor.

Receptor Theory
• Classic theory referring to the cellular

mechanism by which most drugs can
change body processes.
• Agonists are drugs capable of binding with
receptors and causing a cellular response;
these are facilitators of cellular action.
When they are present in the bloodstream,
agonists cause the tissue to respond,
resulting in a therapeutic action.
Receptor Theory
• Antagonists are drugs that inhibit or block

the responses of agonists. Antagonists are
called blockers.

Figure 4.4 Cellular receptors: (a) A neurotransmitter or hormone binds to the receptor. A drug is a close ―mimic‖ of the
neurotransmitter or hormone and initiates a response by binding to the same receptor site. (b) An agonist is a drug that
facilitates the pharmacologic response. (c) An antagonist is a drug that temporarily blocks or depresses the
pharmacologic response.

• One drug can act as a master key

– unlocks several different receptors in different
organs and tissues
– accounts for
 therapeutic effect of drug
 various side effects of drug

• Types of receptors
– adrenergic receptors
– cholinergic receptors
– H1 and H2 receptors

• Adrenergic receptors
– α – adrenergic receptors
 alpha1
 alpha2
 respond to
• norepinephrine (sympathetic nervous system
neurotransmitter)
• drugs that act in a similar way

• Adrenergic receptors
– β – adrenergic receptors
 beta1
 beta2
 respond to
• epinephrine (sympathetic nervous system
neurotransmitter)
• drugs that act in a similar way

• Cholinergic receptors
– respond to
 acetylcholine (parasympathetic neurotransmitter)
 certain drugs
– H1 and H2 receptors
– respond to histamine

Local and Systemic Effects of
Drugs
• Drugs have one of two effects
– local effect
 limited to site of administration
 tissues immediately surrounding it
– systemic effect
 felt throughout the body

Drugs
• Always local
– vaginally administered drugs
• Always systemic
– orally administered drugs (usually)
 exception: some drugs not absorbed exert local
effect on GI tract
– intramuscularly administered drugs
– intravenously administered drugs

Drugs
• Either local or systemic
– depends on the type of drug administered
 inhaled drugs
 subcutaneously administered drugs
 rectally administered drugs

Therapeutic Effect
• Therapeutic effect
– drug’s main action for which it was prescribed
– selected to
 prevent a disease
 diagnose a disease
 treat a disease by controlling, improving, or curing
the symptoms

Therapeutic Effect
• Therapeutic effect
– can be directed toward a specific area of the
body
 target organ
– not always directed towards a target organ
 antibiotic drugs
– sometimes therapeutic effect actually a side
effect
 antihistamines
 insomnia
Side Effects
• Drug effects other than the therapeutic
effect
– mild and temporary
– moderate and annoying
– severe
 FDA may not approve the drug

Side Effects
• Common side effects listed as drug is
tested
• No drug is entirely safe and without
potential side effects

―I stopped taking the medicine because I prefer the original disease to the side effects.‖
© ScienceCartoonsPlus.com.

Side Effects
• Examples of side effects vary widely

– some drugs produce few side effects
– most drugs are associated with at least one or
two side effects

Side Effects
• Gastrointestinal side effects
– anorexia
– nausea
– vomiting
– diarrhea
– constipation (narcotic drugs)

Side Effects
• Central nervous system drugs
– drowsiness
– excitement
– depression
• Antidepressant drugs
– blurred vision
– dry mouth
– fatigue

Side Effects
• Chemotherapy drugs
– nausea
– vomiting
– chills
– fever
– loss of hair
– depression of bone marrow
– FDA does not take the drug off the market
because of the treatment (life-threatening
cancer)
Side Effects
• Once FDA approved, must list side effects

– advertisements
– informational literature
– prescribing information
– package inserts

Adverse Effects
• Severe side effects often referred to as

adverse effects
– not as commonly observed as side effects
– become apparent only after a drug is on the
market
– can cause the FDA to remove a drug from the
market even after approval

Focus on Healthcare Issues
In 2000, the FDA proposed regulations to make
the prescribing information provided with drugs
easier for doctors to use. The FDA acknowledged
that too few doctors read these lengthy, fine-print
information sheets. The newly revised drug
information begins with a section describing the
most important warnings for not prescribing a drug
for particular types of patients and ends with a
patient-counseling checklist that the doctor can
review with the patient.
Focus on Healthcare Issues
Seven of the eleven drugs taken off the market by
the FDA from 1997 to 2000 were taken off
because doctors kept prescribing certain drugs to
particular patients despite warnings to the contrary
in the drug information.

Historical Notes
In 1997, the FDA removed from the market one of
the two drugs in the widely popular ―fen-phen‖
combination drug for weight control. Fenfluramine
(Pondimin) was removed from the market; the
other drug, phenteramine (Fastin), was allowed to
remain on the market as an appetite suppressant.

Historical Notes
At the same time, the chemically related drug
dexfenfluramine (Redux) was also taken off the
market. Both fenfluramine (Pondimin) and
dexfenfluramine (Redux) were linked to cases of
patients developing primary pulmonary arterial
hypertension and damage to the heart valves.
Before it was taken off the market, Redux had
already been prescribed for 2 million people.

Clinical Applications
Isotretinoin (Accutane) is a vitamin A–type
(retinoid) drug that was first approved by the FDA
in 1982 for the treatment of severe cystic acne
vulgaris of the skin. It was not until 2001 that the
FDA required patients to sign a consent form prior
to taking Accutane because of a possible link to
suicide.

Pramipexole (Mirapex) was approved by the FDA
in 1997 to treat the symptoms of Parkinson’s
disease. More recently it was approved to treat
restless legs syndrome. However, even the
television advertisements warn of the adverse
reactions of compulsive gambling and sexual
activity.

Adverse Effects
• Incidence of death or adverse reactions to

drugs more than doubled between 1998
and 2005

Adverse Effects
• Adverse drug reactions

– account for 1.5 million hospitalizations each
year (4000 a day)
– after being admitted to the hospital, an
additional 770,000 patients develop and
adverse drug reaction
– as many as 100,000 Americans die each year
as a result of adverse drug reactions

Adverse Effects
• Estimated that every dollar spent on
prescription drugs, another dollar is spent
to treat reactions caused by those drugs
• Physicians and pharmacists can report
adverse drug effects to the FDA
• FDA’s phone number must be published in
bold type on all drug information
• FDA maintains the national Adverse Event
Reporting System (AERS)
Toxic Effects
• Toxic effects: when a drug’s serum levels

rises above therapeutic level
• Before FDA approval, drug company must
show that a drug does not produce toxic
effects when administered in therapeutic
doses

Toxic Effects
• Therapeutic index
– narrow margin of safety between therapeutic
dose and toxic dose
– when a drug with a low therapeutic index is
administered it is not uncommon to see toxic
symptoms

Toxic Effects
• When toxic symptoms occur

– physician may elect to
 decrease the dose of a drug
 lengthen the time between doses
 discontinue the drug altogether
– patients on drugs known to frequently cause
toxic effects
 scheduled for blood tests to monitor drug levels
 other laboratory tests to monitor the function of
particular organs affected
Figure 5-2 Pharmacists. Pharmacists check each patient’s list of prescribed drugs, watching for
drugs that might cause an adverse effect or interact with other drugs. Pharmacists also consult with
physicians. This collaborative communication is one way to avoid adverse drug effects. Corbis—Brand
X Pictures.
Allergic Reactions
• Type of side effect but differs from other
side effects
– has specific underlying cause
– release of histamine
– occurs when body’s immune system identifies
a foreign substance (antigen)
– initiates an antibody response against it
– antigen does not provoke an allergic reaction
in everyone, only in certain hypersensitive
people
Allergic Reactions
• Histamine
– produces mild-to-severe allergic symptoms
– depends on amount released
– Mild-to-severe to life-threatening reactions
– most severe symptoms of an allergic reaction
are collectively known as anaphylaxis or
anaphylactic shock

Allergic Reactions
• Mild allergic reaction • Severe to life-
– itching threatening allergic
– swelling reaction
– redness – bronchospasm
– sneezing – edema
– shock
– death

Drug Alert!
Anaphylactic shock is not common, but is often
associated with antibiotic drugs, although other
drugs may also produce it. Interestingly, a patient
may take several courses of an antibiotic drug over
the years without any reaction, but then the next
course of the drug will cause an allergic reaction.
Once a patient is sensitized to a particular drug,
even a small dose can trigger an allergic reaction.

Drug Alert!
In addition, some drugs show cross allergies to
other drug groups because of similarities in their
molecular structures. For example, patients
allergic to penicillin should avoid other drugs in the
penicillin group, such as ampicillin, and may also
exhibit hypersensitivity to cephalosporin antibiotic
drugs (Keflex, Velosef, Ceclor) because of their
similar chemical structure.

• Drug idiosyncrasy
– drug reaction not a side effect
– not based on an allergic reaction
– individual’s unique reaction
– has basis in the genetic makeup of the
individual
– genetic factors are responsible for variations
in
 metabolism of drug
 action of drug
• Certain ethnic groups have well-studied

idiosyncratic reactions
– Asian
– Jewish
– African descent
• Pharmacogenetics
– study of how the genetic makeup of different
people affects their response to certain drugs

• Malignant Hyperthermia (uncontrolled

elevated body temperature)
– occurs in 1 out of 20,000 patients given the
inhaled anesthetic drug halothane
– can also occur in some patients given
succinylcholine prior to surgery
– caused by a genetic variation in one known
gene

• Malignant Hyperthermia (uncontrolled

elevated body temperature)
– may involve up to six different genes
– can result in death

Drug-Drug Interactions
• Many patients take more than one drug

daily
• Elderly
– make up 15% of population
– take 33% of the prescription drugs

• Polypharmacy
– patients may take both prescription drugs and
over-the-counter drugs
– increases the likelihood of a drug-drug
interaction
• When administered simultaneously some
drugs interact with each other
– accentuates action of each
– diminished action of each
• Types of drug-drug interactions

– synergism
– antagonism
• Synergism
– occurs when the two drugs combine to
produce an effect
– effect is greater than the independent effect of
each drug

• Synergism
– in many cases, synergism is beneficial
 Tylenol taken with codeine
 potassium-wasting diuretic taken with a potassium-
sparing diuretic

• Synergism
– in some cases synergism is undesirable
 combination of tranquilizers and alcohol or
antihistamines and alcohol
• side effect of drowsiness is heightened
• sedative effect of alcohol
• often has a fatal result

The way to optimize the therapeutic effect of a
drug and minimize the occurrence of adverse or
toxic effects is to take the drug exactly as
prescribed. For many elderly people, this is easier
said than done. The multiple drugs they take are
on varying schedules, given several times a day,
or daily, or only weekly—and this can be
confusing.

Add to that the common problems of memory and
vision loss, and this increases the possibility of
noncompliance (missed drug doses) or toxicity
(overdoses). A drug dose container purchased at a
drug store (see FIGURE 5-3) can be an
inexpensive solution.

A new FDA-approved computerized unit the size of
a bread box and known as EMMA (Electronic
Medication Management Assistant) holds
individualized doses of a month’s worth of drugs.
EMMA plugs into a regular outlet and has a
wireless connection to the Internet to access the
patient’s electronic medication administration
record. When it is time for a drug dose, an audible
alert sounds. The patient then pushes a button on
the touch screen, and the drug dose is dispensed.
Figure 5-3 Polypharmacy. Elderly patients often take multiple prescription and over-the-counter
drugs each day. Drug dose containers help organize the patient’s various drugs. This container has
sections for each day of the week, for both A.M. and P.M. drug doses. The patient is getting ready to
take his Wednesday P.M. drugs. The use of a drug dose container helps remind the patient to take all
of the drugs at the correct time each day, but it does not prevent the occurrence of a drug-drug
interaction. Polypharmacy increases the likelihood of a drug-drug interaction.

Did You Know?
Although Elvis Presley officially died of a heart
attack in 1977, the State Board of Medical
Examiners found that he had been prescribed
some 12,000 pills—tranquilizers, stimulants,
sedatives, and painkillers—in the 18 months prior
to his death.

Did You Know?
According to the Washington Post newspaper,
Prozac (an antidepressant drug) and alcohol taken
by the chauffeur driving Princess Diana may have
contributed to the car accident in which she was
tragically killed in 1997.

Historical Notes
In 1988, astemizole (Hismanal) and terfenadine
(Seldane) antihistamine drugs were hailed as
superior to older antihistamine drugs because they
did not cause sedation. After they had been on the
market for 10 years, the FDA required them to
carry a warning label that they should not be used
by patients taking the antibiotic drug erythromycin
or the antifungal drugs ketoconazole or
itraconazole.

Historical Notes
Taking just a little more than the prescribed dose
of either of these antihistamine drugs in
combination with the antibiotic or antifungal drug
could cause a fatal cardiac arrhythmia. In 1999,
the FDA removed both of these antihistamine
drugs from the market.

• Antagonism
– occurs when two drugs combine to produce
an effect
– effect is less than the intended effect of either
drug
– example
 tetracycline taken with an antacid

Figure 5-4 Warning labels on prescription bottles. The pharmacist applies labels to the
prescription bottle to warn the patient of a possible drug-drug interaction, drug–food interaction, side
effects, and so forth. These two prescription bottles have a total of seven warning labels on them. On
the bottle on the left, the patient is warned (1) that it might cause dizziness (a side effect), (2) that it
should not be chewed or crushed, (3) that it should not be taken with other drug without checking first
with the doctor or pharmacist (drug-drug interaction of antagonism), and (4) that it should be taken
exactly as directed. On the bottle on the right, the patient is warned (1) not to take it with aspirin
(drugdrug interaction of synergism), (2) to take it with food (to avoid the side effect of stomach
irritation), and (3) not to drink alcoholic beverages with it (drug–drug interaction).
Drug-Food Interactions
• Synergistic drug-food interactions also

occur
– examples
 tetracycline cannot be taken with milk
 MAO inhibitors cannot be given with foods rich in
tyramine

Figure 5-5 Grapefruit and grapefruit juice. This delicious, nutritious, and healthful fruit and its juice
can cause serious adverse effects and even toxic effects when taken together with certain drugs.

Drug Alert!
The beneficial effects of drinking grapefruit juice
may turn into toxic effects if you are taking certain
drugs. This is because grapefruit juice blocks an
enzyme in the intestine that normally breaks down
part of a drug dose before it even enters the blood.
With decreased levels of this enzyme, much more
active drug enters the blood, and this can result in
a toxic level of the drug.

Drug Alert!
• Example: An antihistamine drug taken with
grapefruit juice can cause the adverse effect of a
heart arrhythmia.
• Example: A cholesterol-lowering drug taken with
grapefruit juice can result in toxicity with blood
levels 15 times higher than normal.

Systems of Drug Measurement
• Apothecary System
• Metric System
• Other Systems
– unit
– inch
– drop
– milliequivalent
– percentage
– ratio
– household
Apothecary System
• Some apothecary measurements are still
used today
– liquid measurements of
 pint
 quart
 gallon
• Apothecary drug doses measurement has
been discontinued
• Variation of roman numerals often used
with measurements
Figure 5-6 Roman numerals for drug doses. Special Roman numerals are often used for drug
doses in handwritten prescriptions. Note: These do not represent fractions, although they do resemble
them to some extent.

Metric System of Drug Measurement
• Invented by the French in 1790

• Officially known as the International
System of Units (SI)
• Adopted as the exclusive unit of
measurement by the AMA
• Based on
– meter (for length measurements)
– kilogram (for weight measurements)
– liter (for volume measurements)
Metric System of Drug
Measurements
• Metric length measurements include the
meter and centimeter
– a centimeter is equivalent to 1/100 of a meter
– when a cube is formed, 1 cm long on each
side
 measurement of volume know as cubic centimeter
(cm3 or cc)
 equivalent to the volume in a milliliter (mL and cc)
 often used to express volume of liquid drug doses

Measurements
• Drug weight measurements are not
expressed in terms of kilograms
• Kilograms are used to measure a person’s
weight
– can be important in calculating correct drug
doses
– 50-kilograms equals 110 pounds)
• Most drugs are measured in milligrams,
ocassionally micrograms
Measurements
• Metric volume measurements include the
liter and milliliter
• 1 liter equals 1000 milliliters
• Drugs are not prescribed by the liter, by
the milliliter (mL)
• Drug measurements in the metric system
are never expressed in fractions.
• Drug doses with number less than 1 is
written with a decimal and always has a
zero added to the left of the decimal point
Other Drug Measurements
• Unit
– some drugs are never measured by the metric
system, but instead by a special designation
called a unit
 some penicillins (1 unit is 0.6 mcg of penicillin G)
 all types of insulin (defined on weight basis of pure
insulin)
• manufactured with 100 units per milliliter
• abbreviated as U-100
– exact value varies from drug to drug
Figure 5-7 Insulin syringe. An insulin syringe is used to administer liquid insulin, and its calibrations
are in units, not in milliliters as are other syringes. This system of measurement (units) is clearly
marked at the base of the syringe. This syringe can administer up to 100 units of liquid insulin. It
cannot be used to administer liquid drugs that are measured in milliliters. Photo reprinted courtesy of
BD (Becton, Dickinson and Company).
• Inches
– only one common medication measured in
inches
– nitroglycerin ointment (Nitro-Bid)
 pad of specially marked paper
 ointment squeezed onto the paper
 prescribed dose may range from ½ inch to 4
inches

• Drops
– abbreviated gtt
– eye and ear liquid drugs prescribed as drops
to be given

• Milliequivalents
– an equivalent is the molecular weight of an
ion divided by the number of hydrogen ions it
reacts with
– a milliequivalent is 1/1000 of an equivalent
– abbreviated mEq

• Percentage
– one part in relationship to the whole
– based on a total of 100
– a 10% solution would be composed of 10 mL
of drug in 100 mL of liquid

• Ratio
– relationship between the concentrations of
two substances together in a solution
– expressed as two numbers with a colon mark
between them

• Household
– unofficial system
– used by people at home measuring drugs
– includes measuring spoons and silverware
– inaccurate measurement system because of
no standardized size

The Five Rights of Drug
Administration
• Every year, 1.5 million people are harmed
by drug errors
• Institute of Medicine (IOM) recommends
– all prescriptions should be created
electronically & drug information and inserts
be standardized
– each patient has approximately one
medication error per day

Administration
• Archives of Internal Medicine found that
drug errors occur in 1 of every 5 doses
administered in the hospital

Administration
1. The right patient
2. The right drug
3. The right dose
4. The right route
5. The right time

Administration
• The right patient
– in home situations, dispensing to yourself is
not difficult
– in healthcare facilities many patients receive
drugs
– patient identification becomes crucial

Administration
• The right drug
– generic drug names are often complex
– trade name drugs can have similar-sounding
names
– check the drug name against the medication
order
 when the drug is taken from the cart or shelf
 as it is being poured or placed in a paper cup
 before giving it to the patient
– never administer a drug prepared by another
person
Administration
• The right dose
– calculating drug dose is an extremely
important process
– standard adult dosage is appropriate for most
adults
 preset by the drug company during clinical trials
 patients who fall outside adult dosage range may
need to have dose adjusted (elderly, thin, obese)

Administration
• The right dose
– pediatric dosages
 especially for infants and premature babies
 must be calculated with great accuracy
 based on the total weight of the patient not the age
 expressed as mg/kg/day (milligrams of drug per
kilogram of body weight per 24-hour period)

Administration
• The right dose
– chemotherapy drug doses
 calculated based on the patient’s total body
surface area
 customizes the dose for each patient to maximize
the effectiveness of drug
 minimizes side effects
 expressed as mg/m2 (milligrams of drug per meter
squared of body surface area)

Administration
• The right route
– important to check the prescribed route of
administration
– make sure the drug form is compatible with
that route

Administration
• The right time
– measured in frequency of dosage
– number of commonly used abbreviations that
indicate frequency
 based on Latin phrases

Table 5-1 Common abbreviations for frequency of drug administration

Routes of Administration
and the Drug Cycle
Introduction
• Before final FDA approval, the drug

company must state what routes of
administration are safe and effective
• Different forms for different routes
• Some drugs ineffective, or may seriously
injure the patient, with the wrong route

• Various routes of administration

• Some drugs
– approved for various routes
– manufactured in different drug forms
• Each route has advantages and
disadvantages

• Topical • Gastrostomy and

• Transdermal jejunostomy
• Oral • Vaginal
• Sublingual and buccal • Rectal
• Nasal • Parenteral
• Inhalation • Intradermal
• Nasogastric • Other routes of
administration

• Topical
– applied to the skin, eyes, or ears
– local therapeutic effect

Figure 4-1 Topical route of administration. The nurse is administering a topical ophthalmic
antibiotic ointment to the patient’s eye by pulling down the lower eyelid so that a ribbon of ointment
can be laid in the sac between the eye and the lower eyelid. As the patient blinks, the ointment is
distributed across the eye. Topical ophthalmic ointment is specially formulated to be nonirritating to the
eye; it is not interchangeable with other topical ointments that are used on the skin. Jenny Thomas
Photography.
Table 4-1 Abbreviations for topical administration

• Transdermal
– different than topical route
– applied to skin
– systemic therapeutic effect
– delivered through a patch
– drug slowly released

• Oral
– most convenient route
– most commonly used
– tablets, capsules, liquids
– absorbed in the stomach or small intestine
– PO, p.o. (Latin per os, through the mouth)

Figure 4-2 Oral route of administration. This is the most common route of drug administration.
Drugs can be given as tablets, capsules, or liquids. Many pediatric drugs are in a liquid form. For oral
administration of a drug to an infant, the liquid drug is mixed with a small amount of formula and given
orally through the nipple which has been removed from the bottle of formula. David Young-Wolff ©
PhotoEdit Inc.
• Disadvantages of oral route

– difficult for some patients to swallow
– cannot be used in unconscious patients
– cannot be used in patients who are vomiting
– some drugs are inactivated by stomach acid
– some drugs are metabolized too quickly by the liver
– some drugs cannot be taken with certain foods or
beverages

Figure 4-3 Oral route of administration. Some patients have difficulty swallowing very large tablets
or capsules. Their physicians can prescribe an alternate drug form, such as a liquid. © Abbott Labs

• Sublingual
– placing medication under the tongue
– provides faster therapeutic effect than oral
route
• Buccal
– placing medication in the pocket between the
cheek and lower teeth
– few drugs are administered by buccal route

• Sublingual and buccal

– medication slowly disintegrates
– dissolved drug is absorbed quickly
 through oral mucous membranes
 into large blood vessels

• Nasal
– spraying a drug into the nasal cavity
– usually done topically
– some nasal spray drugs work systemically

• Inhalation
– inhaling of a drug in a gas, liquid, or powder
form
– absorbed through the alveoli

Figure 4-4 Inhalation route of administration. This patient is receiving a drug in the form of an
anesthetic gas to produce unconsciousness prior to having surgery. John Greim/Science Photo
Library © Photo Researchers, Inc.

• Nasogastric (NG)
– used for patients who cannot take oral
medications
– accomplished through a nasogastric tube
 inserted through the nose
 through the esophagus
 into the stomach
– any liquid drug that can be given orally

Did You Know?
The first nasogastric tube, developed in the
late 1700s, was constructed from eel skin. It
was used for several weeks to feed a patient
who could not eat.

• Gastrostomy and jejunostomy

– for patients who cannot take oral medications
– surgically implanted feeding tubes
 deliver liquid drugs to the stomach (gastrostomy)
 deliver liquid drugs to the jejunum (jejunostomy)
– any liquid drug that can be given orally

• Vaginal
– used to treat vaginal infections
– creams, ointments, and suppositories
– contraceptive foams are inserted vaginally

• Rectal
– reserved for certain situations
 when patient is vomiting or unconscious
 medication cannot be given by injection
– systemic absorption is slow and unpredictable
– not used often
– preferred to relieve constipation or to treat
hemorrhoids

• Parenteral
– theoretically includes all routes of
administration other than oral
– in clinical use, commonly includes
 intradermal
 intramuscular
 Intravenous
 subcutaneous

• Intradermal
– using a syringe to inject a liquid drug into the
dermis
– used for allergy scratch test and Mantoux test

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Figure 4-5 Intradermal route of administration. The needle is inserted at a 10- to 15-degree angle
so that it does not penetrate too deeply. The epidermis itself is less than 1/20 inch thick; therefore,
when an intradermal injection is positioned correctly, the tip of the needle is still visible through the
epidermis.
Figure 4-6 Syringe. A syringe is used to withdraw a liquid drug from an ampule or vial. This
tuberculin syringe is calibrated to measure liquid drug doses to the hundredth of a milliliter (mL). The
needle on the syringe is used to penetrate the skin to the correct depth to administer the liquid drug.
This type of syringe is used to give either intradermal or subcutaneous injections. A longer needle and
a larger syringe are used to administer liquid drug doses via the intramuscular route. Photo reprinted
courtesy of BD (Becton, Dickinson and Company)
• Subcutaneous (subQ, SQ, subcu)

– using a syringe to inject a liquid drug into the
subcutaneous tissue
– only a few blood vessels in this fatty layer
– drugs are absorbed more slowly than by
intramuscular route

Figure 4-7 Subcutaneous route of administration. The needle is inserted at a 45-degree angle to
reach the fatty subcutaneous tissue, but not penetrate into the muscle layer. Diabetic patients who
inject insulin daily use the subcutaneous route. A subcutaneous injection can also be classified as a
hypodermic injection (hypo- means below and derm/o- means skin).
• Intramuscular (IM, I.M.)

– injection of a liquid drug into the belly of a
muscle
– muscles are well supplied with blood vessels
– absorbed more quickly than subcutaneous
– better able to absorb large amount of liquid
drug
– muscle large enough so as not to injure a
nerve
Figure 4-8 Intramuscular route of administration. The needle is inserted at a 90-degree angle to
reach the muscle layer. An intramuscular injection can also be classified as a hypodermic injection.

Figure 4-9 Newborn intramuscular injection. The vastus lateralis muscle is the preferred site for
giving injections such as infant immunizations, as this is the muscle that has the greatest bulk. Elena
Dorfman © Pearson Education/PH College.

• Intravenous (IV, I.V.)

– injection of liquid drug into a vein
– fluid is hung from an I.V. pole, gravity moves
the fluid through the tubing
– alternatively, an I.V. pump can be used
– therapeutic effect often seen immediately

• Intravenous
– Bolus
 whole amount injected in a short period of time
 often referred to as I.V. push
– I.V. infusion
 injected into the fluid of a large I.V. bag
 administered over several hours
 known as an I.V. drip

• Intravenous
– I.V. piggyback
 injected into the fluid of a small I.V. bag attached to
existing I.V. line

Figure 4-10 I.V. piggyback route of administration. Because I.V. antibiotic drugs are frequently
ordered in the hospital, small I.V. bags often come premixed with the antibiotic drug already in them;
they can be attached quickly to the patient’s existing I.V. line. This I.V. bag contains the trade name
antibiotic drug Zosyn, a combination drug that contains the generic antibiotic drugs piperacillin and
tazobactam; it is used to treat severe infections.
• Central venous line

– used to continuously administer intravenous
fluids or drugs
– special catheter tunneled through the
subcutaneous tissue of the upper chest
– positioned in the superior vena cava

• Endotracheal tube
– used to administer drugs through tube
inserted in the mouth into the trachea
– useful if no established intravenous access
– drug is absorbed through the lung tissue and
into the blood
– NAVEL (naloxone, atropine, Valium,
epinephrine, lidocaine

Figure 4-11 Endotracheal tube route of administration. The paramedic is injecting a liquid drug in
a syringe into the open end of the clear plastic endotracheal tube. After the drug is injected, it will be
absorbed by the lungs and go into the blood. The patient also will receive oxygen and manual
ventilation to assist her breathing until she can be evaluated in the emergency room.

• Implantable port
– special intravenous access
– used to administer chemotherapy drug
– thin metal or plastic reservoir placed in
subcutaneous pocket of tissue
– reservoir attached to a catheter that is
threaded into superior vena cava
– administered by inserting a needle through
the skin overlying the reservoir
• Implantable port
– Ommaya reservoir placed beneath the scalp
– catheter is placed in the ventricle of the brain
– reservoir filled with chemotherapy drug

• Intra-arterial
– used to administer chemotherapy directly into
the area of a cancerous tumor
– catheter inserted into the main artery that
brings blood to organ where cancer is located
– connected to an infusion pump implanted
under the skin and worn externally
– pump administers doses of chemotherapy
drug at preprogrammed intervals
• Intra-articular
– used to administer drugs to a joint
– injected once every few weeks or months
• Intracardiac
– only used during emergency resuscitation
– needle inserted through the chest wall,
between the ribs, and into one of the heart
chambers

• Intrathecal
– used to administer drugs within the meninges
around the spinal cord

• Intraperitoneal
– used to administer drugs or fluids into the
peritoneal cavity
– catheter surgically implanted through the
abdominal wall into peritoneal cavity
– used to administer chemotherapy or dialysis
fluid

• Intravesical
– used for the administration of chemotherapy
drugs into the bladder
– catheter inserted into the urethra

• Umbilical artery or vein

– accessible only in newborn infants before the
umbilical cord has dried
– used to administer fluids and draw blood
– generally not used to give drugs

The Drug Cycle
• After administration, most drugs go

through a well-defined sequence of four
steps before being excreted from the body
– absorption from the site of administration
– distribution via the circulatory system
– metabolism
– excretion from the body

The Drug Cycle
• Pharmacokinetics is the study of how

drugs move through the body in the
processes of absorption, distribution,
metabolism, and excretion

Absorption
• Absorption involves the movement of

drugs from the site of administration
through tissues and into the bloodstream
• For most drugs, absorption involves three
steps
– disintegrate
– dissolve
– absorb

Absorption
• Disintegrate
– must disintegrate before they are absorbed
– this step is omitted when already in a liquid
form or effervescent tablets
• Dissolve
– once in liquid form, dissolves into the
surrounding fluids

Figure 4-12 Disintegration. These two tablets are disintegrating in a glass of water before they can
be taken by the oral route.

Absorption
• Absorb
– from the body fluid, the drug passes through
the walls of nearby capillaries

Absorption
• After topical administration

– drug form does not need to undergo
disintegration
– quickly dissolves into the tissue fluids of the
skin
– do not complete the final step of absorption
– do not go into the blood
– therapeutic action only exerted locally at the
site of administration
Absorption
• After transdermal administration

– drug begins to be released
– because it is in liquid form, does not undergo
disintegration
– quickly dissolves in the tissue fluids on the
skin
– passes through the walls of nearby capillaries
and absorbed into the blood

Absorption
• After oral administration

– drug form disintegrates
– dissolves in the stomach or intestinal fluids
– passes through the mucous membrane lining
– absorbed into the blood
– presence or absence of food can influence
rate of absorption

Absorption
• After oral administration

– some drugs are not absorbed
 this drawback can be overcome by administering
the drug via a different route
 but can also be turned into a therapeutic
advantage
• neomycin
• Carafate
• Metamucil

Absorption
• After inhalation administration

– vaporized liquid or gas does not need to
undergo disintegration
– drug immediately dissolves in the tissue fluids
of the mucous membranes lining the lungs
– some exert a topical effect, while others
produce a systemic effect
Absorption
• After vaginal administration

– drug form disintegrates and releases the drug
topically
– always intended to have a topical effect

Absorption
• After rectal administration

– rate of absorption is rather slow and variable
– usually reserved for drugs that act topically
within the rectum
– patients vomiting, drugs cannot be given
orally and is not manufactured for I.M. or I.V.
administration

Absorption
• After parenteral administration

– intradermal, subcutaneous, intramuscular
injections
– drug is already in liquid form
– quickly dissolves in the tissue fluids of the skin

Absorption
• Intravenous injections
– entirely bypass the step of absorption
– administered directly into the vein
– immediately enters the blood

Distribution
• Distribution
– once a drug has been absorbed into the blood
– distributed via the circulatory system
 some of the drug binds to circulating plasma
proteins
 other portions that do not bind

Figure 4-13 Steps in the drug cycle. Drugs pass through the four steps in the drug cycle:
absorption, distribution, metabolism, and excretion.

Distribution
• Distribution
– some of the drug binds to circulating plasma
proteins
 large molecules have indentations in their
molecular surface
 permit drug molecules to bind to them
 essentially pharmacologically inactive as they are
carried through the blood

Distribution
• Distribution
– other portions that do not bind to plasma
proteins
 moves through circulatory system
 passes through walls of capillaries into body
tissues
 as this portion leaves the blood, some of the bound
drug is released by the plasma proteins so as to
maintain the equilibrium of unbound drug in the
blood

Distribution
• Distribution
– Drugs that move into body tissues come in
contact with a cell membrane where it exerts
an effect by interacting with a receptor

Distribution
• Blood-brain barrier
– one area of the body where drugs are not
readily distributed
– exists between the capillary walls of blood
vessels in the brain and the surrounding brain
tissues
– some drugs are able to pass through and can
exert a therapeutic effect

Distribution
– other drugs are able to pass through and can
cause side effects
– some classes of drugs are unable to cross the
barrier

Distribution
– sometimes the barrier actually blocks drugs
that are needed to treat diseases of the brain
 chemotherapy drugs
• wafer form implanted directly in the brain
 Parkinson’s drugs
• dopamine
• levodopa

Distribution
• Placenta
– thought that it formed a barrier to protect fetus
– allows nearly all drugs to pass from the
maternal circulation to the fetus

Metabolism
• Biotransformation
– the process of metabolism
– drug gradually transformed or metabolized
 from its original active form
 to less active or inactive form
– accomplished in the liver
 principal organ of metabolism
 by action of liver enzymes

Metabolism
• Drugs given orally

– absorbed through the mucous membranes of
the stomach and intestines
– enter blood flowing through the portal vein
– before going into general circulation, portal
vein passes through the liver

Metabolism
• First-pass effect
– initial metabolism by the liver
– drug must first pass through the liver before
entering the general circulation
– for some drugs, most of the drug dose is
immediately metabolized
– drug must be given by a different route in
order to be therapeutic

Metabolism
• Prodrug
– some drugs are administered in an inactive
form and remain inactive until metabolized by
the liver
– metabolite form of the drug that is active and
actually exerts a therapeutic effect
– prodrug form of the drug that comes before
the active drug is produced

Clinical Application
Because the liver is the principal organ for drug
metabolism, a decreased rate of drug metabolism
occurs in patients with chronic liver disease, such
as hepatitis, or in elderly patients with decreased
liver function due to degenerative changes
associated with aging. In these patients, drug
doses need to be reduced to compensate for the
prolonged action of unmetabolized drug in the
blood and to prevent toxicity from high levels of
drug.
Premature infants have very immature livers that
are unable to metabolize drugs efficiently. The
doses of their drugs must be carefully calculated to
avoid toxicity.

Chronotherapy is a method of drug therapy that
attempts to coordinate the administration and
metabolism of a drug to the body’s own biological
rhythms. Certain diseases, such as hypertension or
asthma, tend to be worse at certain times of the
day. If an antihypertensive drug is taken at bedtime,
it is metabolized and reaches its highest therapeutic
level in the early morning, just when the blood
pressure rises dramatically and there is an
increased incidence of heart attacks and strokes.

Excretion
• Necessary step
– in ridding the body of waste products
– removing active drugs that are not
metabolized by the liver
• Principle organ of drug excretion is the
kidney

Excretion
• Other organs involved, to a limited degree

– lungs
– saliva, tears, sweat
– breast milk
• Drug is not automatically excreted just
because it reaches the renal artery

Excretion
• Drug that remains bound to albumin

– cannot pass through the glomerular
membrane
– and is returned to general circulation
• Unbound drug can exist by itself as a
small molecule

Excretion
• Once through the glomerular membrane, a

further distinction is made
– water-soluble drug
 unbound molecule is excreted in the urine
 affinity for the water content of urine

Excretion
• Once through the glomerular membrane, a

further distinction is made
– fat-soluble drug
 attracted to the lipid structure of the renal tubule
 passes through the wall of the renal tubule into a
nearby capillary
 returns to the blood, metabolized by the liver into a
more water-soluble form

Excretion
• Poor renal function

– prolong the effect of some drugs
 renal disease
 elderly patients
 decreased renal function
– prescribed lower doses
– prevents toxic symptoms due to decreased
rates of drug excretion

Drug Design, Testing,
Manufacturing, and
Marketing
Introduction
• The development, testing, manufacturing,

and eventual marketing of any drug is a
time-consuming and expensive process.
• A drug company may evaluate thousands
of different chemicals before finding one
that moves successfully through all
phases of testing and is finally approved
by the FDA for release and marketing.

Introduction
• This chapter traces the steps from a newly

discovered or designed chemical to final
FDA approval and clinical use of a drug.

Drug Discovery and Creation
• Drugs are discovered or created in several

ways
– Ancient sources
– A totally new chemical can be discovered in
the environment, from plants, animals, the
ocean, or the soil
– A totally new chemical can be derived from
molecular manipulation of a drug that is
already in use
• Drugs are discovered or created in several

ways
– a totally new chemical can be created through
genetic manipulation
– stem cell therapy
– gene therapy

Figure 2-1 Derivative chemical structure. In 1957, the first benzodiazepine antianxiety drug was
synthesized: chlordiazepoxide (Librium). Its chemical structure is shown on the left. Working with that
molecule, the same researcher then derived diazepam (Valium). Its chemical structure is shown on the
right. Both drugs are still in use today to treat anxiety and neurosis.
• Ancient sources
– many drugs still in use today were originally
derived from plant, animal, or mineral sources
hundreds or even thousands of years ago.

• A totally new chemical can be discovered

in the environment, from plants, animals,
the ocean, or the soil
– chemotherapy drug Taxol – needles of Pacific
yew tree.
– antituberculosis drug streptomycin – stomach
of sick chickens
– fungus from which cephalosporin antibiotic
drugs were derived
• A totally new chemical can be derived

from molecular manipulation of a drug that
is already in use.
– isomer
 dextrorotary

• In the past
– designing a new drug by changing molecular
structure of an existing drug was a slow
process of trial and error
– using intuition and molecular models made
from wood and wire.
– example
 Penicillin G
 terfenadine (Seldane) = fexofenadine (Allegra)

• Computers
– display the molecular structure of any drug
– With very slight molecular changes, the
original drug may be significantly changed
 absorption
 metabolism
 half-life
 therapeutic effect
 side effects

Figure 2-2 Creating new drugs with computer-aided design (CAD). With computers, researchers
can study any molecule, rotating it in three dimensions on the computer screen. By analyzing the
molecules, researchers can tell if that particular arrangement of atoms is the ―key‖ that will open the
―lock‖—that is, activate a particular receptor on the cell membrane. When a researcher wants to know
why different-looking drugs seem to produce a similar effect on the same receptor, he/she can have
the computer superimpose all of the drugs on the screen to see how their atoms match up. Jacob
Halaska © Photolibrary.com.
• Computers
– identify unsuccessful chemicals before time
and money are invested in extensive testing.
– manipulate chemicals at the molecular level
 design new drugs
 involves molecular pharmacology
 Example: molecular pharmacology

• A totally new chemical can be created

through genetic manipulation
– recombinant DNA technology (RDNA)
 gene splicing
 genetic engineering
 enzymes in test tubes (in vitro)
 gene cloning
 human insulin (Humulin)

• Stem cell therapy

– use of stem cells to repair or replace
damaged body cells
– in 2001 first embryonic stem cell manipulated
– ignited controversy
– umbilical cord blood
– harvesting of adult stem cells

• Gene therapy
– missing specific or have abnormal gene
– normal version linked to harmless virus
– vector
– Human Genome Project
– Connectivity Map database

• Human genome
– pharmacogenetics
– pharmacogenomics
– new area of research: the proteome

Drug Names
• Every drug has a chemical name

– International Union of Pure and Applied
Chemistry (IUPAC) describes molecular
structure
• Generic name
– United States Adopted Names (USAN)
determines a drug’s generic name

Drug Names
• Trade name or Brand name

– created by drug company after FDA approval
– designed to
 be easy for physicians and patients to remember
 suggest how the drug is used
• Accurate spelling of drug name critical
• No linguistic standards

Figure 2-3 Molecular structure and chemical name. The chemical name of this drug actually
describes its molecular structure: 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7- sulfonamide 1,1-
dioxide. The generic name of this drug is hydrochlorothiazide, a diuretic drug. It is also available as the
trade names HydroDIURIL (from the Merck drug company) and Microzide (from the Watson drug
company), among others.
The accurate spelling of drug names is critical. Some trade
name drugs are difficult to spell because drug
manufacturers are not held to any linguistic standards. For
example, the trade name drug Rythmol is used to
normalize the rhythm of the heart, and yet the h found in
rhythm is not in the drug name. The trade name drug
Levothroid is a thyroid hormone replacement, and yet the y
found in thyroid is not in the drug name.

Tip 1 The spellings of generic drugs
belonging to same category often reflect
chemical structure
• beta blocker class • Benzodiazepine class
– acebutolol – clonazepam
– atenolol – diazepam
– betaxolol – lorazepam
– metoprolol – oxazepam
– nadolol
– pindolol
– propanolol

Tip 1 The spellings of generic drugs
belonging to same category often reflect
chemical structure
• penicillin class
– ampicillin
– amoxicillin
– nafcillin
– oxacillin
– penicillin

Tip 2 The drug manufacturer selects a trade
name that indicates what disease condition
or symptom the drug is being used to treat.
• Azmacort – asthma
• Habitrol – nicorette decreases the craving for
nicotine in smokers
• Mucinex – remove mucus
• Pepcid – peptic ulcers
• Rythmol – irregular heart rhythm
name that indicates what part of the body is
being treated.
• Boniva – strengthen bones
• Bronkaid – dilate bronchi
• Dermatop – skin lotion
• Nasalcrom – nasal allergies

name that simplifies the generic name while
retaining its phonetic sound
• Cipro – ciprofloxacin
• Haldol – haloperidol
• Humulin – human recombinant DNA insulin
• Levothroid – thyroid replacement hormone
• Sudafed - pseudoephedrine

name that indicates the ingredients or
source of the drug
• Fer-In-Sol – iron (Fe) in solution
• Kay Ciel –potassium (K) chloride (Cl)
• Premarin – pregnant mares’ urine
• cetuximab – monoclonal antibody

name that indicates the action of the drug.
• Elimite – eliminates mites (scabies)

• Glucotrol – controls the level of glucose
• Lipitor – decreases level of blood lipids
• Restoril – restores rest/sleep to treat
insomnia

name that indicates how often the drug is to
be taken.
• Lithobid – lithium drug given twice a day
• Nitro-Bid – nitroglycerin drug given twice a day
• b.i.d. is a Latin abbreviation that means twice
a day

name that indicates the duration of the
drug's therapeutic effect.
• Cardizem LA – long-acting drug for
hypertension
• Pronestyl-SR – sustained release drug for
heart arrhythmia
• Zyflo CR controlled release – slow-release
potassium (K) supplement
name that indicates the strength of the drug.
• Bactrim DS – double-strength dose of

antibiotic drug
• Cortizone-5 – 0.5% hydrocortisone anti-
inflammatory ointment

Tip 10 The drug manufacturer selects a
trade name that indicates the route of
administration.
• Bactrim IV – intravenous (IV) antibiotic drug
• Transderm-Scop – transdermal skin patch
for motion sickness

trade name that indicates the amount of a
particular active ingredient
• Tylenol w/Codeine No. 2 – contains 15 mg of
codeine
• Tylenol w/Codeine No. 3 – contains 30 mg of
codeine

trade name that reflects the manufacturer’s
identity.
• ED Tuss HC cough syrup – manufactured by
Edwards drug company
• Wytensin for hypertension – manufactured by
Wyeth-Ayerst drug company

Testing of New Drugs
• All drugs must be thoroughly tested

• Tested by the company before marketing
according to FDA guidelines
• Testing to determine:
– drug’s effectiveness
– drug’s safety

• in vitro testing
– in vitro is Latin for in glass
– chemical analysis
– laboratory test tubes
• in vivo testing
– in vivo is Latin for in living
– animal testing
– human testing

• Animal testing
– precedes testing on humans
– drug evaluated and noted for:
 side effects
 toxic effects
 addictions
 cancerous tumors
 fetal deformities
 pharmacodynamics

• Pharmacodynamics
– frequency distribution curve
– half-life
– median effect dose (ED50)
– median toxicity dose (TD50)
– therapeutic index (TI)

―This drug was tested on 2000 white mice, and they had a ball.‖
David W. Harbaugh.

• After completion of animal studies

– company submits an IND (Investigational
New Drug) Application
 contains information about animal trials
 shows drug not a risk to humans
 includes information
• chemistry of drug
• manufacturing process

Testing of New Drug
• Phases of Human Testing (clinical trials)

– Phase I
 10-100 healthy volunteers
 Informed consent mandatory
 evaluate side effects
 establish final, correct dosage
 pharmacokinetics studied
 generally takes 1½ years

Figure 2-4 Newpaper advertisement. A typical newspaper ad seeking volunteers to participate in
clinical trials to test a new drug.

Testing of New Drug

– Phase II
 50-500 patients who have disease drug intended
to treat
 drug given on experimental basis
 determines therapeutic effect
 usually takes 2 years

Drug Alert!
A placebo is a drug form that exerts no
pharmacologic effect, no therapeutic effect, and
has no side effects when administered. The word
placebo means I will please in Latin. Placebos are
used in double-blind research studies in which
neither the researcher nor the patient knows
whether the drug given was the drug being tested
or was a placebo. Placebos are commonly sugar
pills or injections of sterile normal saline solution.

Drug Alert!
Interestingly, while it is physiologically impossible
for a placebo to exert any pharmacologic effect,
patients often report a decrease in certain types of
symptoms and can even experience ‖side effects‖
when given a placebo. These effects are quite real
and demonstrate that, in some situations, the
power of suggestion can produce changes within
the body that closely mimic the pharmacologic
action of an actual drug.

Testing of New Drug

– Phase III
 several hundred or several thousand ill patients
 Administered same way that it will be used on the
market
 performance compared with other drugs that are
currently on the market
 double-blind studies with placebo performed
 usually lasts 3 years

Testing of New Drug

– Phase III
 testing on children
• standardizes pediatric doses
• manufacturer receives 6 month extension on standard 17
year patent

Testing of New Drug
• Completion of Phase III

– drug company submits all documentation to
FDA in a New Drug Application (NDA)
– waits for final FDA decision
 approval
 denial
– only 20% NDA’s receive final FDA approval
for marketing

Did You Know?
The data collected for just one patient in just one
clinical drug trial can exceed 100 pages of
documentation, and the total documentation for all
aspects of the drug testing can exceed 100,000
pages.

Did You Know?
The ulcer drug cimetidine (Tagamet) is a case in
point. After four years of testing, the SmithKline
company had accumulated a stack of documents
17 feet high that had to be taken to the FDA in a
truck. Denise Grady, ―Bottleneck at the FDA,‖
Discover (November 1981), p. 56.

Testing of New Drug
• Once FDA approves

– ingredients, dosage, manufacturing process,
labeling, and packaging cannot change
– can conduct further clinical trials
 expand the drug’s use
 example:
• Propranolol (Inderal)
• Indomethacin (Indocin)

Drug Manufacturing
• In the past pharmacists mixed drugs

• Today the manufacturing process is strictly
regulated
– drug quality
– sanitation
– packaging

Drug Manufacturing
• Generic drugs and trade name drugs,

regardless of who manufactures must:
– have same dose strength
– contain same active ingredient
– be administered in the same way

Drug Manufacturing
• Generic drugs and trade name drugs,

regardless of who manufactures, does not
apply to:
– bioavailability
– inert ingredients
– preservatives
– antioxidants
– buffers

Drug Manufacturing
• Process includes securing drugs in

appropriate containers
– adding a packet of desiccant
– tightly sealing the top to prevent tampering
– placing drugs in individual blister packs

Figure 2-5 Protective packaging. Blister paks protect the integrity of the drug while allowing he
drug form to be seen through a protective plastic window. Access is through a peel-off backing.

Drug Marketing
• Advertising of over-the-counter drugs

– regulated by the FTC (Federal Trade
Commission)
• Advertising of precsription drugs
– regulated by the FDA

Drug Marketing
• Previously, drug companies promoted

prescription drugs by
– direct to physicians by sales reps
– free samples
– literature and videos
• Still the most prevalent form of prescription
drug advertising

Drug Marketing
• Now, direct-to-consumer (DTC) marketing

– magazine ads
 men’s Magazines: erectile dysfunction, enlarged
prostate
 women’s Magazines: birth control, infertility,
menopause, osteoporosis
– television

Drug Marketing
• ―Ask your doctor if [this drug] is right for

you‖
– created consumer-driven shift
– proactively ask for certain prescription drugs
– may not need particular medicine
– pressures physicians to prescribe
 unnecessary medications
 more expensive medications

DTC Marketing Milestones
• 1981 The first direct-to-consumers (DTC)

print advertisement appears for an
analgesic drug.
• 1985 FDA rules that drug ads marketed to
consumers must include risk information.
• 1997 FDA allows drug manufacturers to
direct market their ads to consumers via
TV.
DTC Marketing Milestones
• 2001 More than 100 prescription drugs

are regularly marketed directly to
consumers. Advertising slogans like ―the
little purple pill‖ (for Nexium) become well
known.
• 2004 Cialis, a drug for erectile dysfunction
in men, advertised during TV broadcasts
of the 2004 Super Bowl.

Drug Patents
• Trade name of drug registered with U.S.

Patent Office as a registered trademark ™
• Under patent, right to advertise and
market
• Protected by 17-year patent
– includes testing period before approval
– 1984 law gives back 5 years

Drug Patents
• After expiration, competitors can enter the

market
• Drug’s original trade name can only be
used by the original company
• If generic is manufactured, listed under
different trade names

Table 2-2 Example of generic name and related trade names

Drug Patents
• All drug companies must provide a

complete list of all drugs on the market to
the FDA
• Each drug has a unique identifier
– National Drug Code (NDC)
– multi-digit number (given in three segments)
 first segment: identifies drug company
 second segment: identifies drug’s strength/dose
 third segment: package code
Figure 2-6 National Drug Code. Each prescription drug has a National Drug Code or NDC. The
NDC identifies the drug manufacturer (Eon Labs), drug strength/dose (amiodarone 200 mg), and
package size and type. The NDC may also appear on the label on the prescription bottle or on other
printed labels generated by the pharmacy.

Drug Withdrawals and Recalls
• Drug approval is no guarantee it will stay

on the market
• Post-marketing surveillance
– drug companies and FDA continue to monitor
the drug after approval
– some adverse effects become apparent
– health professional reports
– MedWatch

• Continually evaluates current reports

– especially those involving death
– example: antidepressant drugs changed their
warnings to include risk of suicide in 18-24
year olds
– unexpected adverse effects

• A drug recall can be done for:

– drug does not contain the correct amount of
active ingredient
– drug does not remain stable until its expiration
date
– drug is contaminated with particulate matter
from manufacturing process

• Responsibility of drug manufacturer to

notify physicians, hospitals, and
pharmacies of a drug recall

Receptor-ligand interactions - cell
signaling
No cell lives in isolation
• survival depends on an elaborate
intercellular communication network that
coordinates growth, differentiation and
metabolism
• cells adjacent to one another frequently
communicate through cell-cell contact
• other forms of communication cover larger
distances = extracellular signaling
molecules
Extracellular Signalling
• signaling molecules are released by signaling cells
• the signal is called the ligand
• the ligand binds to its specific receptor on a target cell
• this ligand-receptor interaction induces a conformational
or shape-change in the receptor
• produces a specific response - called the cellular
response
• can include a vast array of compounds
– e.g. small amino acid derivatives, small peptides, proteins
Cell-to-cell communication by extracellular
signaling usually involves six steps
• (1) synthesis of the signaling molecule by the signaling cell
• (2) release of the signaling molecule by the signaling cell
• (3) transport of the signal to the target cell
• (4) detection of the signal by a specific receptor protein –
receptor-ligand specificity
• (5) a change in cellular metabolism, function, or
development = cellular response
– triggered by the receptor-ligand complex – specific to the ligand-
receptor complex
• (6) removal of the signal, which usually terminates the
cellular response – degradation of ligand
Signaling molecules operate over various distances in
animals
-extra cellular signaling can occur over:

1. large distances or endocrine signaling – signaling molecules are called
hormones
- act on target cells distant from their site of synthesis
-usually carried through the bloodstream
2. short distances or paracrine signaling – affects target cells within proximity
to the cell that synthesized the molecule
-usually mediated by neurotransmitters and some growth
factors
Signaling molecules operate over various distances in
animals
-extracellular signaling can occur over:

3. no distance or autocrine signaling – the signal feeds-back and affects
itself
-action of many growth factors
-these compounds generally act on themselves to
regulate proliferation
-seen frequently in tumor cells
-many compounds can act through two or even three types of cell signaling
e.g. growth factors (e.g. EGF) – paracrine and autocrine and endocrine
-epinephrine – endocrine and paracrine
Circulating & Local Hormones
• Circulating
hormones
– act on distant targets
– travel in blood
– endocrine hormones
• Local hormones
– paracrine hormones
& autocrine
hormones
Hormones
• two types
– lipid soluble
– water soluble
Lipid-Soluble Hormones
-lipid-soluble hormones can easily

enter a cell by diffusing through the
plasma membrane
-PROBLEM: how do they travel in the
water-based blood??
-SOLUTION: they are carried by
carrier-proteins
-these hormones then enter their
target cell where they result in a
specific cellular effect or response
Water-soluble Hormones
-water soluble hormones can easily travel within the blood

-PROBLEM: how do they enter a cell and result in a cellular response??
-SOLUTION: binding to specific cell-surface receptors
-this binding activates the receptor and results in a series of cellular events called
the second messenger system
Lipid-soluble Hormones
• Steroids
– lipids derived from cholesterol in SER
– different functional groups attached
to core of structure provide
uniqueness
– interact with specific intracellular
receptors (within the cell) to turn
specific genes on or off
– effective for hours or days
• Thyroid hormones
– tyrosine ring plus attached iodines
are lipid-soluble
– activate enzymes involved in the
catabolism of fats and glucose
– help set our basal metabolic rate
• Retinoids
– vitamin A derivatives
– have dramatic effects on proliferation
and differentiation plus cellular death
(i.e. apoptosis)
Water-soluble Hormones
• Amino acid derivatives,
small peptides and protein
hormones
– modified amino acids or amino
acids put together
• serotonin, melatonin, histamine,
epinephrine
– larger peptide hormones
• insulin and glucagon
• Eicosanoids
– derived from arachidonic acid
(fatty acid)
– prostaglandins or leukotrienes
– prostaglandins despite being
lipidphilic – bind to cell surface
Action of Lipid-Soluble Hormones
• Hormone diffuses
through phospholipid
bilayer & into cell
• Binds to receptor
turning on/off specific
genes
• New mRNA is formed
& directs synthesis of
new proteins
• New protein alters
cell’s activity
Action of Water-Soluble Hormones
• Can not diffuse through plasma
membrane
• Hormone receptors are integral
membrane proteins
– act as first messenger
• Receptor protein activates G-protein in
membrane
• G-protein activates adenylate cyclase to
convert ATP to cAMP in the cytosol
• Cyclic AMP is the 2nd messenger
• Activates kinases in the cytosol to
speed up/slow down physiological
responses
• Phosphodiesterase inactivates cAMP
quickly
• Cell response is turned off unless
new hormone molecules arrive
Cell-surface receptors belong to four major classes
• GPCRs are involved in a range of signaling pathways, including

light detection, odorant detection, and detection of certain
hormones and neurotransmitters
• Many different mammalian cell-surface receptors including
GPCRs are coupled to a trimeric signal-transducing G protein
– made of an alpha, beta and gamma subunit complex
• Ligand binding activates the receptor, which activates the G
protein, which activates an effector enzyme to generate an
intracellular second messenger
– e.g. adenylyl cyclase – converts ATP to cAMP adenylyl cyclase (AC)
• depending on regulation at the effector enzyme – this pathway
can be either activated or inhibited
– by the type of G protein activated by the hormone-receptor
complex
– Gs proteins result in stimulation of the effector enzyme
– Gi proteins result in inhibition of the effector enzyme
Four classes of cell-surface
receptors
-ligand binding changes the confirmation of the receptor so that specific ions flow
through it
-the resultant ion movement alters the electric potential across the plasma
membrane
-found in high numbers on neuronal plasma membranes
e.g. ligand-gated channels for sodium and potassium
-also found on the plasma membrane of muscle cells
-binding of acetylcholine results in ion movement and
eventual contraction of muscle
-lack intrinsic catalytic activity
-binding of the ligand results in the formation of a receptor dimer (2 receptors)
-this dimer then activates a class of protein called tyrosine kinases
-this activation results in the phosphorylation of downstream targets by
these tyrosine kinases (stick phosphate groups onto tyrosines within
the target protein)
Signal
transduction
Cascade
-also called receptor tyrosine kinases OR ligand-triggered protein kinases

-similar to tyrosine-linked receptors - ligand binding results in formation of a dimer
-BUT: they differ from tyrosine-linked receptors – intrinsic catalytic activity
-means that ligand binding activates it and the activated receptor acts as a
kinase
-recognize soluble or membrane bound peptide/protein hormones that act as
growth factors
e.g. NGF, PDGF, insulin
-binding of the ligand stimulates the receptor’s tyrosine kinase activity,
-results in phosphorylation of multiple amino acid residues within its target
– such as serine and threonine residues
-this phosphorylation activates downstream targets
-its targets are generally other protein kinases –which phosphorylate their
own downstream targets (other kinases??)
Signal transduction cascades
Signal
• -the successive p
phosphorylation/activation of multiple KINASE #1
kinases results in a cascade of
phosphorylation/activation
• -this cascade is frequently called a p
signal-transduction cascade KINASE #2
• -this cascade eventually leads to a
specific cellular response
• e.g. changes in cell physiology p
and/or patterns of gene KINASE #3
expression
• -RTK pathways are involved in
regulation of cell proliferation and p
differentiation, promotion of cell TARGET
survival, and
• modulation of cellular metabolism
EFFECT
Second messengers
• produced by the activation of GPCRs and RTKs
• Hormone stimulation of Gs protein-coupled receptors leads to activation
of adenylyl cyclase and synthesis of the second messenger cAMP
– most commonly studied second messenger
– cAMP does not function in signal pathways initiated by RTKs
– cAMP and other second messengers activate specific protein kinases
(cAMP-dependent protein kinases or PKAs)
• cAMP has a wide variety of effects depending on the cell type and the
downstream PKAs and other kinases
– in adipocytes, increased cAMP activates a PKA that stimulates production of
fatty acids
– in ovarian cells another PKA will respond to cAMP by increase estrogen
synthesis
• second messenger systems allow for amplification of an extracellular
signal
– one epinephine molecule can bind one GPCR – this can result in the
synthesis of multiple cAMP molecules which can go on to activate and
amplified number of PKAs
• a blood level as low as 10-10M epinephrine can raise blood glucose levels by 50%
Second messengers
• other second messengers include:
– IP3 and DAG – breakdown products of phosphotidylinositol (PI)
• produced upon activation of multiple hormone receptor types
(GPCRs and RTKs)
– calcium – IP3 production results in the opening of calcium-
channels on the plasma membrane of the ER – release of
calcium
• a rise in calcium in pancreatic beta cells triggers the exocytosis of
insulin
• a rise in intracellular calcium also triggers contraction of muscle
cells
• much study has been done on the binding of calcium to a protein
called calmodulin and the effect of this complex on gene
expression
Common signaling pathways are
initiated by different receptors in a class
• The effects of activation of GPCRs
and RTKs is more complicated than
a simple step-by-step cascade
• Stimulation of either GPCRs or
RTKs often leads to production of
multiple second messengers, and
both types of receptors promote or
inhibit production of many of the
same second messengers
• in addition, RTKs can promote a
signal transduction cascade that
eventually acts on the same target
as the GPCR
• therefore the same cellular
response may be induced by
multiple signaling pathways by
distinct mechanisms
• Interaction of different signaling
pathways permits fine-tuning of
cellular activities
b-adrenergic 2d Messenger System
external
external signal:
signal: nt nt norepinephrine
Receptor b adrenergic -R
trans-
trans- primary
primary adenylyl
ducer effector
effector GS cyclase
ducer
2d
2dmessenger
messenger cAMP
secondary effector
secondary effector protein kinase
b-adrenergic 2d Messenger System
• NT: Norepinephrine
• Membrane-associated components
– Receptor: b-adrenergic
– Transducer: Gs protein
– Primary effector: Adenyly cyclase
• Intracellular components
– 2d messenger: cAMP
– Secondary effector: Protein kinase ~
G protein: Protein Phosphorylation
A
C
R
G
GDP
PK
A
C
R
G
GTP
ATP
cAMP
PK
A
C
R
G
GTP
ATP
cAMP P
PK
A
C
R
G
GTP
ATP
P
cAMP
PK Pore
Specific example: b-adrenergic receptors in
liver and muscle
Signal molecule binds to receptor norepinephrine/

epinephrine
Receptor activates a G protein receptor = b-

adrenergic
Activated G protein activates adenylate cyclase

an effector enzyme
Enzyme produces cyclic AMP (cAMP)

a second messenger
Second messenger molecule glycogen degradation

induces metabolic changes
Adenylate cyclase and cAMP
C. Stimulatory G proteins
How is hormone binding linked
to cAMP production
• Key molecules: trimeric G proteins
– Inhibitory=Gi
– Stimulatory=Gs
Structure of stimulatory trimeric
G protein (Gs)
• Three subunits
termed Gsa, Gb,
and Gg
• Cycles between
inactive and active
states depending
on whether alpha
subunit is bound to
GDP or GTP
Inactive state
• Gsa is complexed
to GDP
• In the inactive
state Gs is a trimer
of Gsa•GDP, Gb,
and Gg
Active state
• Gsa is complexed to
GTP
• In the active state
Gs is dissociated
into a dimer of Gb,
and Gg (Gbg ) plus
dissociated
Gsa•GTP
Back to inactive state
• The active state is

short lived. Gsa
hydrolyzes GTP to
GDP forming
Gsa•GDP
• Gsa•GDP
reassociates with
dimer of Gb, and
Gg (Gbg )
Gs is the signal transducer
• Binding of epinephrine signal is relayed

by Gs to an enzyme that produces cAMP
called adenylate (or adenylyl) cyclase.
• GS activates adenylate cyclase
• Two possibilities:
– Epinephrine binding --> active Gs --> active
adenylate cyclase
– No epinephrine binding --> inactive Gs-->
inactive adenylate cyclase
Signal amplification
• Both receptor and Gs diffuse rapidly in
the plasma membrane
• Receptor-hormone complex can
activate ≈100 inactive Gs molecules
• Each Gsa• GTP activates a single
adenylate cyclase which synthesizes
many cAMP
• Thus, one hormone molecule --> many
hundred cAMP molecules
• 10-10 M epinephrine --> 10-6 M cAMP
How is the signal terminated?
• G protein/receptor interaction - Conversion
of Gsa• GDP --> Gsa• GTP causes the
receptor’s binding site affinity for hormone
to decrease
• Rapid hydrolysis of GTP reversing
activation of adenylate cyclase
• Therefore no adenylate cyclase activity
unless hormone is continuously present
How is the signal terminated?
• Degradation of cAMP
– Hydrolysis via cAMP phosphodiesterase to 5’-
AMP
– This stops the signal
– Control of the phosphodiesterase is via other
hormones that induce increased cytosolic
[Ca++] (Ca++ is another example of a second
messenger)
D. Inhibitory G proteins
Inhibition of adenylate cyclase
via inhibitory G protein (Gi)
• Hormonal control can be stimulatory or
inhibitory
• In liver, epinephrine (as well as glucagon)
activate adenylate cyclase via Gs therefore
[cAMP] is proportional [epinephrine]
• Even more control is exerted in some cell
types
Inhibition of adenylate cyclase
via inhibitory G protein (Gi)
• In adipose tissue, up-regulation of [cAMP]
is via epinephrine and glucagon (also
ACTH) as in liver
• But, there is also down-regulation of
[cAMP] resulting from action of the
hormones, PGE1 and adenosine.
• PGE1 and adenosine regulate adenylate
cyclase via inhibitory G protein (Gi)
Structure of Gi
• Like Gs, Gi is a trimer
• Gb and Gg are the same
• Ga differs and is an inhibitory form, Gia
• Gia•GDP is bound to Gbg
• Gia•GTP is free to dissociate and has an
inhibitory effect on adenylate cyclase
E. Regulation of cellular
metabolism by the second
messenger (cAMP)
Regulation of cellular
metabolism by the second
messenger (cAMP)
• Will discuss cAMP as a specific example
• There are many other second messengers
– Ca++
– Inositol 1,4,5-trisphosphate (IP3)
– 1,2-diacylglycerol (DAG)
Specific example: b-adrenergic receptors in
liver and muscle
Signal molecule binds to receptor norepinephrine/

epinephrine
Receptor activates a G protein receptor=b-adrenergic
Activated G protein activates adenylate cyclase

an effector enzyme
Enzyme produces cyclic AMP

(cAMP)
a second messenger
Second messenger molecule glycogen degradation

induces metabolic changes
The effect of cAMP on cellular
metabolism
• Increased [cAMP] increases glycogen
breakdown
• Phosphorylase (or glycogen
phosphorylase) is a key enzyme involved
in glycogen breakdown
• Increased [cAMP] increases
phosphorylase activity (via a complex
cascade)
Structure of glycogen
• Large, branched polymer of glucose

residues
Glycogen is a
readily mobilized
storage form of
glucose
Active and inactive forms of
phosphorylase
• Phosphorylase b - inactive, not
phosphorylated
• Phosphorylase a - active, phosphorylated
Phosphorylase is activated by
phosphorylase kinase
• Phosphorylase kinase phosphorylates
phosphorylase
• Phosphorylase kinase is in turn activated
by protein kinase A
cAMP activates protein kinase A
How this all fits together:
glycogenolytic cascade
Red=inactive
Green=active
cAMP also inhibits glycogen
synthesis
• Target enzyme is glycogen synthase
– Builds glycogen polymers
– UDP-glucose + glycogen (n residues) --->
UDP + glycogen (n+1 residues)
• Epinephrine causes glycogen synthase to
be inhibited
Effect of cAMP on glycogen
synthase Red = inactive
Green = active
Glycogenolytic cascade
• Huge amplification: 10-10 M epinephrine -->
50% increase in blood glucose
• 10-10 M epinephrine --> 10-6 M cAMP
• Another 104 fold amplification via effects of
cAMP on enzymes.
• Ratio of protein kinase A:phosphorylase
kinase:phosphorylase is 1:10:240 in
skeletal muscle
Coordinate control
• In addition up-regulation of glycogen
breakdown is coupled to down-regulation
of glycogen synthesis
• This occurs at the level of protein kinase A
and is an example of coordinate control
The Autonomic Nervous
System
NEURON
Cell functions
Resting state
Figure 1. Electron microscope images of worm synapses( .A) Ventral nerve cord fixed by classical method using osmium and glutaraldehyde. (B) Ventral nerve cord fixed by
high-pressure freezing. Images in A and B are taken from( Rostaing et al., 2004 )with permission. M, muscle; N, presynaptic terminal; Mit, mitochondria. Yellow arrows, SV;
orange triangles, MT; *, space between nerve processes. Scale: 500nm. (C–E) Images of synapses by classical fixation method: neuron-neuron synapse in the ventral nerve cord
(C), cholinergic neuromuscular junction (D), and GABAergic NMJ (E). M, muscle; N, presynaptic terminal; Mit, mitochondria. (F–G). Images of synapse by high-pressure fixation
procedure. G shows an enlarged view of the presynaptic density (R. Weimer and J-L. Bessereau, personal communication). Yellow arrows, SV; light-blue arrows, dense core
vesicles; dark-blue arrow, large core vesicle; green arrows, postsynaptic density-like structures; pink-purple arrow, presynaptic density; orange triangle, MT. (H). Image of
longitudinal section of ventral nerve cord, showing the sharp transition of SV cluster and MT nearby. Black arrows, presynaptic density; orange triangles, MT; A, axon; M, muscle.
Taken from Hedgecock and Hall (1991 )with permission .
AUTONOMIC NERVOUS SYSTEM
• The Peripheral nervous system is divided
into Afferent and Efferent divisions.
• The section of the efferent division that

controls involuntary bodily functions is
known as the Autonomic Nervous System.
• These functions include cardiac function,

body temperature, smooth muscle, gland
function and arterial blood pressure.
Types of Nerve Fibers
• Visceral afferent (sensory)
– Convey impulses from internal organs to CNS
• Visceral efferent (motor)

– Convey impulses from CNS to internal organs, glands, and
smooth and cardiac muscle
• Somatic afferent (sensory)

– Convey impulses from head, body wall, and extremities to CNS
• Somatic efferent (motor)

– Convey impulses from CNS to striated muscles
ANS similar to somatic reflex arcs except there are two
motor neurons in efferent pathway
ANS continued
Pre- and Postganglionic Neurons
• A two-neuron chain exists in a series
between the CNS and effector organs
– Preganglionic neuron located in the CNS

• Passes between CNS and ganglia
– Postganglionic neuron located in the

periphery
• Passes between ganglia and effector organ
Autonomic Nervous System
• Peripheral nervous system provides a
double set of nerve fibers:
– Sympathetic (adrenergic)
• Exit from thoracic and lumbar regions
– Parasympathetic (cholinergic)
• Exit from cranial and sacral portions
Organization of the Autonomic
Nervous System
• Sympathetic ganglia are located close to the
spinal cord.
• Parasympathetic ganglia are located close to
the effector tissues.
• Sympathetic pathways have short
preganglionic fibers and long postganglionic
fibers.
• Parasympathetic pathways have long
preganglionic and short postganglionic fibers.
Characteristics of sympathetic and
parasympathetic divisions of the ANS
SYMPATHETIC NERVOUS SYSTEM
• Prepares body to deal with stress

– Fight or flight response
• Neurotransmitters are epinephrine and

norepinephrine
– Chemical substances that facilitate
excitation or inhibition of target cells
PARASYMPATHETIC NERVOUS SYSTEM
• Controls vegetative functions

– Constriction of pupils, slowing of heart rate,
constriction of bronchioles, etc.
• Neurotransmitter is Acetylcholine
• A drug that stimulates the system is called a

Parasympathomimetic or cholinergic drug
• A drug that blocks or inhibits the system is

called a Parasympatholytic or anticholinergic
drug
Receptors
Cholinergic Drugs
• Drugs that stimulate the

parasympathetic nervous system (PSNS)
 opposing system to the SNS
 Known as: cholinergic agonists or
parasympathomimetics
 Mimic the effects of the PSNS neurotransmitter:
acetylcholine (Ach)
• Two types of Receptors:
– determined by: Location & Action once stimulated
• Muscarinic receptors
• Nicotinic receptors
Classifications
• Cholinergic (parasympathomimetic)
• Cholinergic blocking (parasympatholytic)
• Adrenergic (sympathomimetic)
• Adrenergic blocking (sympatholytic)

Synthesis of Acetylcholine
Acetyl CoA
Choline
Choline acetylase
Acetylcholine
Acetylcholine and Its Metabolites
hydrolysis
AChE
Acetylcholine
Choline Acetate
Types of cholinergic receptors
The ‘nicotinic’ acetylcholine receptor:
• Activated by nicotine
• A pentameric protein transmembrane channel
• Permeability for small cations
The ‘muscarinic’ acetylcholine receptor:

• Activated by muscarine
• A single chain transmembrane protein, not a channel
• Relays signals through G-proteins
http://www.lookfordiagnosis.com/mesh_info.php?term=Receptors%2C+Choliner
gic&lang=1#
Effects of nicotine (and nicotinic agonists)
1. ‘Preganglionic’ stimulation of both sympathetic and
parasympathetic effectors in the autonomic nervous
system:
• Increased heart rate / blood pressure
• Increased intestinal motility (boy runs for the
bathroom after smoking one of grandpa’s cigars)
2. Stimulation of nicotinic synapses in the brain:

Increased vigilance, heightened mood. Vomiting,
tremor, …
Effects of muscarinic agonists
• Slowed heartbeat
• Stimulation of intestinal and urinary bladder
motility; bronchial constriction
• Secretion of exocrine glands (saliva, intestinal,
sweat, bronchial mucus)
• Miosis; eye accommodation, eased outflow of
humor
Cholinergic Drugs
Mechanism of Action
• Direct-acting cholinergic agonists
– Bind to cholinergic receptors, activating them
• Indirect-acting cholinergic agonists
– Inhibit the enzyme acetylcholinesterase -
prventing, which breaks down ACh - more ACh
is available at the receptors
– Reversible - Bind to cholinesterase for a period
of minutes to hours
– Irreversible - Bind to cholinesterase and form a
permanent covalent bond
• The body must make new cholinesterase to break
these bonds
Cholinergic Drugs
“rest and digest” system
“SLUDGE”
• Salivation
• Lacrimation
• Urinary incontinence
• Diarrhea
• Gastrointestinal cramps
• Emesis
Adverse effects with
cholinergic drugs
Cholinergic Drugs
Drug Effects
• Stimulate intestine and bladder
– Increased gastric secretions
– Increased gastrointestinal motility
– Increased urinary frequency
• Stimulate pupils
– Constriction (miosis)
– Reduced intraocular pressure
• Increased salivation and sweating
• Cardiovascular effects
– Decreased heart rate
– Vasodilation
• Respiratory effects
– Bronchial constriction, narrowed airways
Cholinergic Drugs
Indications
Direct-acting drugs
• Reduce intraocular pressure
• Topical useful for glaucoma and intraocular surgery

– pilocarpine
Cholinergic Drugs
Direct acting:
• Acetylcholine
• Bethanechol : urinary retention
• Carbachol : miosis (glucoma)
• Pilocarpine : Glucoma
Indirect acting: (reversible)
• Physostigmine: reversal of anticholinergic drugs effects
• Pyridostigmine: Myasthenia gravis
• Demecarium
• Edrophonium (diagnosis of MG)
• Tacrine, donepezil, rivastigmine, galantamine (AD)
Physostigmine
Covalent modification
of acetylcholinesterase by
echothiophate;
also shown is the
reactivation of the enzyme
with pralidoxime.
R = (CH3)3N+:CH2:CH2:
Cholinergic antagonists
Antimuscarinic Agents
• e.g. atropine and scopolamine
- Block muscarinic receptors

(inhibition of all muscarinic functions)
- Also block a few sympathetic neurons

(cholinergic; salivary and sweat glands)
- Do not block nicotinic receptors (little or no action at

skeletal neuromuscular junctions or autonomic ganglia)
Atropine
• Tertiary amine belladonna alkaloid
• Competitive Ach antagonist
• Acts both centrally and peripherally
• Actions last about 4 hours
(except when placed topically in the eye,
where the action may last for days)
Atropine
• Pharmacological actions
- Eye; mydriasis (narrow angle glucoma)
- GI; reduce activity (antispasmodic)
- Urinary system; reduce hyper motility
(enuresis)
- Cardiovascular; dose dependent
Atropine
• Cardiovascular effects
- low doses (bradycardia) inh of inh
- High doses (modest increase in HR)
- Toxic doses (dilate the cutaneous

vasculature)
Atropine
• Secretions; blocks the salivary glands
(xerostomia), sweat and lacrimal glands
elevated body temperature?
• Antidote; AchE inhibitors, does cross BBB

Atropine
• Pharmacokinetics; half life is 4 hours
• Adverse effects; dose dependant:

Dry mouth, blurred vision, tachychardia,
confusion, hallucinations …..etc
• Atropine toxicity; physostigmine

Scopolamine
• Greater action on the CNS and a longer duration of
action than atropine
• Pharmacological actions: Anti–motion sickness
blocks short-term memory, produces sedation, and at
higher doses it can produce excitement (may produce
euphoria and is subject to abuse)
• Motion sickness; much more effective prophylactically
• Amnesic action makes it an important adjunct drug in
anesthetic procedures.
• Pharmacokinetics and adverse effects: These
aspects are similar to those of atropine
• Ipratropium; Inhaled:
Positively charged, does not enter the
systemic circulation or the CNS
- Treatment of asthma (unable to take

adrenergic agonists)
- Management of COPD.
• Tropicamide and cyclopentolate
- Used as ophthalmic solutions for similar

conditions as atropine (mydriasis and
cycloplegia). Their duration of action is
shorter than that of atropine; tropicamide
produces mydriasis for 6 hours and
cyclopentolate for 24 hours.
Ganglionic Blockers
• Specifically act on the nicotinic receptors of ANS
Block the entire output of the ANS
• Nondepolarizing competitive antagonists.

Except for nicotine
• Responses are complex and unpredictable,

rarely used therapeutically
• Used in experimental pharmacology.

Ganglionic Blockers
• Nicotine
• Poison? with many undesirable actions and no
therapeutic benefit and is deleterious to health.
• Patches, lozenges, gums, and other forms
• Dose dependent effects, stimulation then in
paralysis of all ganglia.
• ↑ BP and cardiac rate (sympathetic) and ↑
peristalsis and secretions (parasympathetic).
• At higher doses, ganglionic blockade, ↓ BP,
↓ GI and bladder activity
Ganglionic Blockers
Mecamylamine
• Competitive nicotinic blockade of the
ganglia.
• Good oral absorption in contrast to that of
trimethaphan.
• Primarily used to lower blood pressure in
emergency situations like trimethaphan
Neuromuscular Blocking Drugs
• Block cholinergic transmission between motor nerve
endings and the nicotinic receptors on skeletal muscle
- Antagonists (nondepolarizing)
- Agonists (depolarizing)
Uses
• Produce complete muscle relaxation during surgery
• Facilitate intubation
other
Central muscle relaxants:
diazepam, dantrolene, baclofen
Nondepolarizing (competitive)
blockers
• Curare; hunting
• Tubocurarine; 1940
• Significantly increased the safety of

anesthesia
less anesthetic is required to produce muscle
relaxation, allowing patients to recover quickly and
completely after surgery
Nondepolarizing (competitive) blockers
Drug interactions:
• Cholinesterase inhibitors: overcome the action of
nondepolarizing neuromuscular blockers, to a certain
level
• Halogenated hydrocarbon anesthetics: enhance

neuromuscular blockade; halothane
• Aminoglycoside antibiotics: enhance neuromuscular

blockade; gentamicin or tobramycin (inhibit acetylcholine
release)
• Calcium-channel blockers: may increase the

neuromuscular block of tubocurarine and other
competitive blockers as well as depolarizing blockers.
Depolarizing agents
• Succinylcholine; broken down by plasma
cholinesterase (Genetic variants?)
• Rapid endotracheal intubation

(during the induction of anesthesia)
• Phase I; transient twitching of the muscle

fasciculations
• Phase II; resistance to depolarization flaccid

paralysis
Mechanism of action of depolarizing neuromuscular blocking drugs
Adrenergic Agonists
Adrenergic receptors
(adrenoceptors)
• Two families of receptors; α and β
• Respond to the adrenergic agonists epinephrine,
norepinephrine, and isoproterenol
• The α-adrenoceptors;
epinephrine ≥ norepinephrine >> isoproterenol
• α1 and α2 Receptors; based on their affinities for α
agonists and blocking drugs.
• e.g. α1 receptors have a higher affinity for
phenylephrine than do the α2 receptors. Conversely, the
drug clonidine selectively binds to α2 receptors and has
less effect on α1 receptors
• α1 Receptors
- postsynaptic
- Classic (constriction of smooth muscle)
- G protein activation of phospholipase C
• α2 Receptors
- primarily on presynaptic
- Neurons, β cells, smooth muscle cells
- Feedback inhibition
- Parasympathetic ?
- Inhibits adenylyl cyclase; ↓ cAMP.
• Further subdivisions
- α1A, α1B, α1C, and α1D and α2A, α2B, α2C, and α2D
- For selectivity of some drugs
- e.g. tamsulosin is a selective α1A antagonist that is
used to treat benign prostate hyperplasia. α1A receptors
found primarily in the urinary tract and prostate gland.
Second messengers mediate the
effects of α receptors.
DAG = diacylglycerol;
IP3 = inositol trisphosphate;
ATP = adenosine triphosphate;
cAMP = cyclic adenosine monophosphate
β Receptors
• Responses different from α receptors
• Strong response to isoproterenol, less sensitivity to
epinephrine and norepinephrine
• Isoproterenol > epinephrine > norepinephrine
• β1, β2, and β3, based on their affinities for agonists and
antagonists
• β3, involved in lipolysis
• β1 equal affinities for epinephrine and norepinephrine,
• β2 has higher affinity for epinephrine than for
norepinephrine.
• Vasculature of skeletal muscle responsive to adrenaline
(adr. med.), predominance of β2 receptors
• All β receptors results in activation of adenylyl cyclase, ↑
cAMP
β Receptors
Distribution of receptors;
• Predominance of one type of receptor.
e.g. Vasculature to skeletal muscle has both α1 and β2,
β2 predominates
• Some tissues exclusivity to only one. e.g. Heart;
β1 receptors
Characteristic responses mediated by adrenoceptors:

• Physiologic responses according to receptor type
• Many drugs preferentially stimulate or block one type of
receptor
• Stimulation of α1 receptors; vasoconstriction
(particularly in skin and abdominal viscera) ↑ total
peripheral resistance and blood pressure
• Stimulation of β1 receptors; cardiac stimulation
• Stimulation of β2 receptors; vasodilation (in skeletal
vascular beds) and bronchiolar relaxation
Desensitization of receptors
• Prolonged exposure to the catecholamines

reduces the responsiveness of these receptors
• Mechanisms suggested
1) Sequestration of the receptors so that they are
unavailable for interaction with the ligand
2) Down-regulation, destruction or decreased
synthesis
3) Inability to couple to G protein, because the
receptor has been phosphorylated on the
cytoplasmic side by either protein kinase A or
β-adrenergic receptor kinase.
Catecholamines
Epinephrine, norepinephrine, isoproterenol, and dopamine
• High potency; directly activating α or β

receptors
• Rapid inactivation; COMT postsynaptically,

MAO intraneuronally, COMT (gut wall), MAO
(liver and gut wall)
• Poor penetration into the CNS; polar, do

not readily penetrate into the CNS.
(anxiety, tremor, and headaches) CNS?
Noncatecholamines
• No catechol hydroxyl, not inactivated by COMT,
longer half-lives; phenylephrine, ephedrine, and
amphetamine.
• Phenylephrine, epinephrine analog, poor
substrates for MAO, prolonged duration of action
• Increased lipid solubility of many of the
noncatecholamines (due to lack of polar
hydroxyl groups) permits greater access to the
CNS.
Ephedrine and amphetamine may act indirectly by
causing the release of stored catecholamines
Substitutions on the amine nitrogen
• Important in determining the β selectivity

of the adrenergic agonist.
e.g. Epinephrine, with a –CH3 substituent
on the amine nitrogen, is more potent at β
receptors than norepinephrine
Also, Isoproterenol, with an isopropyl
substituent –CH(CH3)2 on the amine
nitrogen is a strong β agonist with little α
activity
Mechanism of action of the adrenergic agonists
• Direct-acting agonists; epinephrine, norepinephrine,

isoproterenol, and phenylephrine.
• Indirect-acting agonists;
- Uptake blockers; cocaine
- Release noradrenaline; tyramine, amphetamines
• Mixed-action agonists; ephedrine, pseudoephedrine

and metaraminol, stimulate adrenoceptors directly and
release norepinephrine
Direct-Acting Adrenergic Agonists
• Second messengers, signal transduction
• Commonly used in therapy: Epinephrine,
norepinephrine, dopamine, and dobutamine
(synthetic)
• Epinephrine released from the adrenal medulla
+ little norepinephrine
• Epinephrine interacts with both α and β
- At low doses, β effects (vasodilation) on the
vascular system
- At high doses, α effects (vasoconstriction) are
strongest
Epinephrine
Pharmacological actions;
• Cardiovascular: increase cardiac output through:
- Stimulation of β1; Positive inotropic & Positive chronotropic effects
- Stimulation of α; Constricts arterioles in the skin, mucous
membranes, and viscera
- Stimulation of β2; Dilates vessels going to the liver and skeletal
muscle
the cumulative effect is an increase in systolic blood pressure,
coupled with a slight decrease in diastolic pressure
• Respiratory:
- Stimulation of β2; Powerful bronchodilation by acting directly on
bronchial smooth muscle → relieves bronchoconstriction
- In acute asthmatic attack,
• Rapidly relieves dyspnea (labored breathing)
• Increases the tidal volume (volume of gases inspired and expired)
• Inhibits the release of allergy mediators such as histamines from
mast cells.
Epinephrine
• Hyperglycemia: cAMP mediated effects
- β2 effect; increased glycogenolysis in the
liver, increased release of glucagon
- α2 effect; decreased release of insulin
• Lipolysis: β receptors of adipose tissue,
↑ cAMP, cAMP stimulates a hormone-
sensitive lipase, which hydrolyzes
triacylglycerols to free fatty acids and
glycerol
Epinephrine
Therapeutic uses
• Bronchospasm: Emergency treatment of bonchoconstriction;
acute asthma and anaphylactic shock. Selective β2 agonists,
such as albuterol, chronic treatment of asthma; longer duration
of action and minimal cardiac stimulatory effect.
• Glaucoma: 2% epinephrine solution topically to reduce

intraocular pressure in open-angle glaucoma (reduces the
production of aqueous humor by vasoconstriction of the ciliary
body blood vessels)
• Anaphylactic shock: Treatment of Type I hypersensitivity
reactions in response to allergens.
• Cardiac arrest: Restores cardiac rhythm in patients with
cardiac arrest regardless of the cause.
• Anesthetics: Produces vasoconstriction at injection site, local
anesthetic persist, ↑ duration of the local anesthesia. 1:100,000
parts epinephrine decrease oozing of capillary blood.
Rapid onset but a brief
duration of action, Only
metabolites are excreted in
the urine
Epinephrine
Adverse effects
• CNS disturbances; anxiety, fear, tension,
headache, and tremor.
• Cerebral hemorrhage; ↑↑ blood pressure.
• Cardiac arrhythmias: particularly if the patient

is receiving digitalis.
• Pulmonary edema
Epinephrine
Interactions
• Hyperthyroidism: ↑ production of adrenergic receptors on the

vasculature, hypersensitive response, ↑ cardio-vascular
actions, so ↓ epinephrine dose
• Cocaine: prevent reuptake of catecholamines, epinephrine. At

receptor site for longer, exaggerated cardiovascular actions
• Diabetes: ↑ release of endogenous stores of glucose, dosages

of insulin may have to be increased
• β-Blockers: unopposed α-receptor stimulation, ↑ peripheral

resistance and ↑ blood pressure
• Inhalation anesthetics: sensitize the heart to the effects of

epinephrine, which may lead to tachycardia
Norepinephrine
• Neuromediator of adrenergic nerves, it
should theoretically stimulate all types of
adrenergic receptors
• In practice, when the drug is given in

therapeutic doses to humans, the α-
adrenergic receptor is most affected
Norepinephrine
Cardiovascular actions
• Vasoconstriction (α1 effect): Norepinephrine >

epinephrine, no compensatory vasodilation (β2 effect)
receptors on blood vessels supplying skeletal muscles, ↑
peripheral resistance. Both systolic and diastolic blood
pressures increase. Asthma…not useful… (weak β2)
• Baroreceptor reflex: stimulates cardiac contractility; not

noted, due to reflex bradycardia that counteract
norepinephrine effects on the heart.
• Effect of atropine pretreatment: block vagal effects,

tachycardia.
Norepinephrine
• Therapeutic uses:
- treat shock, ↑ vascular resistance, ↑ increases blood
pressure.
- Metaraminol is favored, does not reduce blood flow to
the kidney
- It is never used for asthma or in combination with local
anesthetics
- Extravasation? (discharge of blood from vessel into

tissues), blanching and sloughing of skin along injected
vein (due to extreme vasoconstriction)
• Administered IV for rapid onset of action. The duration of

action is 1 to 2 minutes. No SC, no oral
Isoproterenol
• Direct-acting synthetic catecholamine
• Stimulates both β1- and β2 adrinoceptors
• Nonselective, rarely used therapeutically
• Its action on α receptors is insignificant

Isoproterenol
Pharmacological actions:
• Cardiovascular:
- ↑ rate and force of contraction, ↑ cardiac output
- Treatment of AV block or cardiac arrest
- Decreases peripheral resistance through dilating the
arterioles of skeletal muscle (β2 effect)
- ↑ systolic blood pressure slightly, ↓↓ mean arterial and
diastolic BP
• Pulmonary:
- Bronchodilation (β2 action)
- Rapidly alleviates an acute attack of asthma when taken
by inhalation
• Other effects: β receptors, ↑ blood sugar and increased
lipolysis, not clinically significant.
Isoproterenol
• Therapeutic uses:
- Rarely used as a broncho-dilator in asthma
- Stimulate the heart in emergency situations
• Pharmacokinetics:
- Sublingual absorption
- Better if parenterally or as an inhaled aerosol.
- Marginal substrate for COMT and is stable to
MAO
Dopamine
• Immediate metabolic precursor of norepinephrine
• Natural neurotransmitter in the basal ganglia & AM
• Activates α- and β-adrenergic receptors

- ↑doses; vasoconstriction by activating α1 receptors
- ↓doses; inotropic and chronotropic by stimulating β1
• D1 and D2 dopaminergic receptors, in the peripheral

mesenteric and renal vascular beds, where binding of
dopamine produces vasodilation.
• Activation of D2 receptors on presynaptic adrenergic

neurons interferes with norepinephrine release
Dopamine
Therapeutic uses
• Dopamine is the drug of choice for shock and is
given by continuous infusion (β1, α1, D1 & D2)
• ↑blood flow to the kidneys; ↑ glomerular filtration

rate and causes sodium diuresis. dopamine superior
to norepinephrine, which diminishes the blood supply
to the kidney and may cause renal shutdown.
• Adverse effects: sympathetic stimulation. (nausea,

hypertension, arrhythmias)
Abundance of MAO & COMT, short-lived effects
Dobutamine
• Synthetic direct-acting catecholamine, β1-receptor agonist
• Racemic mixture, one stereoisomer has a stimulatory activity
• Increases cardiac rate and output with few vascular effects

congestive heart failure, inotropic support after cardiac surgery
Advantage over other sympathomimetics: increases cardiac

output with little change in heart rate, and does not
significantly elevate oxygen demands of the myocardium
• Caution in atrial fibrillation (↑ AV conduction)
• Tolerance may develop on prolonged use

Oxymetazoline
• Direct-acting synthetic adrenergic agonist; stimulates α1 & α2
• Primarily used locally in the eye or the nose as a vasoconstrictor
• Found in many over-the-counter short-term nasal spray decongestant
• Ophthalmic drops; relief of redness of the eyes (swimming, colds, contact

lens)
• Nervousness, headaches, and trouble sleeping; due to absorption into

systemic circulation
• When administered in the nose, burning of the nasal mucosa and sneezing
may occur
• Rebound congestion is observed with long-term use.

Phenylephrine
• Direct-acting synthetic adrenergic drug
• Primarily α receptors, α1 > α2
• It is not a catechol derivative (X COMT)
• Vasoconstrictor, raises both systolic and diastolic blood
pressures.
• Induces reflex bradycardia when given parenterally
• Topical on the nasal mucous membranes and in
ophthalmic solutions for mydriasis.
• Nasal decongestant; prolonged vasoconstriction
• The drug is used to raise blood pressure and to
terminate episodes of supraventricular tachycardia
• Large doses can cause hypertensive headache and
cardiac irregularities
Methoxamine
• Direct-acting synthetic adrenergic drug
• Primarily α receptors, α1 > α2
• α1 stimulation; vasoconstriction, ↑ total peripheral resistance, ↑BP
• Relieve attacks of paroxysmal supraventricular tachycardia

through acting on the vagus nerve
• Overcome hypotension during surgery involving halothane

anesthetics.
Does not tend to trigger cardiac arrhythmias in the heart,
sensitized by these general anesthetics.
• Adverse effects include hypertensive headache and vomiting

Clonidine
• α 2 agonist
• Acts on the CNS; lower blood pressure, essential

hypertension
• Minimize symptoms accompanying withdrawal from

opiates or benzodiazepines.
• Acts centrally to produce inhibition of sympathetic

vasomotor centers, decreasing sympathetic outflow
to the periphery.
Metaproterenol
• Chemically similar to isoproterenol
• Not a catecholamine (X COMT)
• Administered orally or by inhalation
• Primarily β2, so little effect on the heart
• Bronchodilator, improves airway function,

treatment of asthma, reverse bronchospasm
Albuterol, pirbuterol, and terbutaline
• Short-acting β2 agonists ≈ 3 hours
• Bronchodilators (metered-dose inhaler)
• Produce equivalent bronchodilation to

nonselective β-adrenergic agonists
(metaproterenol) with less cardiac stimulation
• Salbutamol; 4 - 6 hours
Salmeterol and formoterol
• Long-acting β2 selective agonist, over 12 hours
• Bronchodilators (metered-dose inhaler device)
• Salmeterol; delayed onset of action (↑lipophilicity)
• They are used in combination with corticorsteroids
• Agents of choice for treating nocturnal asthma in

symptomatic patients taking other asthma medications
• Formoterol more potent than salmeterol

Indirect-Acting Adrenergic Agonists
Potentiate the effects of norepinephrine

produced endogenously
• Cause norepinephrine release from presynaptic

terminals
or
• Inhibit the uptake of norepinephrine

Amphetamine
• ↑↑ BP
• α-agonist action on the vasculature
• β-stimulatory effects on the heart
• Blocks of norepinephrine uptake and

cellular release of stored catecholamines
Tyramine
• Not a clinically useful drug but it is important
because it is found in fermented foods, such as
ripe cheese and wine
• Normally, it is oxidized by MAO in the GIT, MAO

inhibitors, serious vasopressor episodes
• Enter the nerve terminal and displace stored

norepinephrine
Cocaine
• local anesthetic; blocks the Na+/K+-activated ATPase
(required for cellular uptake of norepinephrine) on the
cell membrane of the adrenergic neuron
• Norepinephrine accumulates in the synaptic space

• Enhanced sympathetic activity
• Small doses of the catecholamines produce greatly

magnified effects in an individual taking cocaine
• The duration of action of epinephrine and norepinephrine

is increased
• Like amphetamines, it can increase blood pressure by α-

agonist actions and β-stimulatory effects
Mixed-Action Adrenergic
Agonists
• Induce the release of norepinephrine from

presynaptic terminals, and they activate
adrenergic receptors on the postsynaptic
membrane
• Ephedrine and pseudoephedrine

Ephedrine and pseudoephedrine
• Plant alkaloids, now made synthetically.
• Not catechols and are poor substrates for COMT and MAO;
long duration of action
• Excellent absorption orally and penetrate into the CNS;
pseudoephedrine has fewer CNS effects
• Ephedrine raises systolic and diastolic blood pressures by
vasoconstriction and cardiac stimulation.
• Ephedrine produces bronchodilation, but it is less potent
than epinephrine or isoproterenol; produces its action more
slowly, prophylactically rather than to treat the acute
asthmatic attack
• Ephedrine enhances contractility and improves motor
function in myasthenia gravis, particularly when used in
conjunction with anticholinesterases
Ephedrine and pseudoephedrine
• Ephedrine produces a mild stimulation of the CNS;
increases alertness, decreases fatigue, and prevents sleep.
It also improves athletic performance.
• Ephedrine has been used to treat asthma, as a nasal
decongestant, and to raise blood pressure
• Pseudoephedrine is primarily used to treat nasal and sinus
congestion or congestion of the eustachian tubes.
• Clinical use of ephedrine is declining due to the availability
of better, more potent agents that cause fewer adverse
effects.
• Ephedrine-containing herbal supplements; banned by FDA
because of life-threatening cardiovascular reactions
• Pseudoephedrine; illegally converted to methamphetamine
Adrenergic Antagonists
Sympatholytic agents
• Bind to adrenoceptors but do not trigger

the usual receptor-mediated intracellular
effects
• Either reversible or irreversible
• Classified according to their relative

affinities for α or β receptors in the
peripheral nervous system.
α-Adrenergic Blocking Agents
• Block α → profoundly affect blood pressure
• Reduces the sympathetic tone of the blood

vessels, resulting in decreased peripheral
vascular resistance. This induces a reflex
tachycardia resulting from the lowered blood
pressure
• e.g. phenoxybenzamine and phentolamine,

have limited clinical applications
Phenoxybenzamine
• Nonselective , links covalently to both α1 & α2
• Block is irreversible and noncompetitive
• Overcome only by synthesizing new

adrenoceptors, which requires a day or more
• Actions of phenoxybenzamine last about 24

hours after a single administration
• Delay of a few hours, biotransformation to the

active form
Covalent inactivation of
α1 adrenoceptor by
phenoxybenzamine
Phenoxybenzamine
• Cardiovascular effects: α- blockade → prevent vasoconstriction of

peripheral blood vessels → decreased peripheral resistance → reflex
tachycardia
• Blockade of presynaptic inhibitory α2 receptors in the heart → increased

cardiac output
• This blockade results in more norepinephrine release → stimulates β

receptors on the heart to increase cardiac output → unsuccessful in
maintaining lowered blood pressure in hypertension → discontinued for
this purpose.
• Reverses the α-agonist actions of epinephrine
• i.e. vasoconstriction (α) is interrupted, but vasodilation (β) is not blocked →

epinephrine + phenoxybenzamine → decrease in systemic BP.
Norepinephrine? Isoproterenol?
Summary of effects of
adrenergic blockers on the
changes in blood pressure
induced by isoproterenol,
epinephrine, and
norepinephrine.
Phenoxybenzamine
• Treatment of pheochromocytoma (catecholamine-secreting tumor of
cells derived from the adrenal medulla)
- Before surgical removal, prevent hypertensive crisis (tissue manipulation)

- Chronic management, tumor is inoperable (diffuse)
• Treatment of Raynaud's disease (phentolamine can also be used)
• Autonomic hyperreflexia, which predisposes paraplegics to strokes
• SE; postural hypotension, nasal stuffiness, nausea, and vomiting. It

can inhibit ejaculation (sexual dysfunction)
• Contraindicated in patients with decreased coronary perfusion

(induces reflex tachycardia, baroreceptor)
Phentolamine
• Competitive blockade of α1 and α2 receptors
• The drug's action lasts for approximately 4 hours
• Produces postural hypotension and causes epinephrine reversal
• Reflex cardiac stimulation and tachycardia (baroreceptor, α2)
• triggers arrhythmias and anginal pain (X decreased coronary perfusion)
• Short-term management of pheochromocytoma
• If injected intracavernosally → vasodilation of penile arteries, treatment of

impotence (rarely used)
Prazosin, terazosin, doxazosin, alfuzosin, and
tamsulosin
• Selective competitive blockers of the α1 receptor
• Prazosin, terazosin, and doxazosin: treatment of

hypertension
• Tamsulosin and alfuzosin: treatment of benign

prostatic hypertrophy/hyperplasia (BPH)
• Metabolism then excreted in the urine, doxazosin (feces)
• Doxazosin is the longest acting of these drugs.

tamsulosin
• Relaxation of both arterial and venous smooth muscle → ↓ peripheral

vascular resistance and ↓ arterial BP
• Cause minimal changes in cardiac output, renal blood flow, and the
glomerular filtration rate
• Tamsulosin has the least effect on blood pressure
• No tolerance to effects on BP
• First dose effect → produces an exaggerated orthostatic hypotensive

response→ syncope (fainting)
• minimized by adjusting the first dose to one-third or one-fourth of the

normal dose and by giving the drug at bedtime
• ↑ risk of CHF when α1-receptor blockers used as monotherapy in

hypertension
tamsulosin
• Used as an alternative to surgery in patients with symptomatic BPH
• Blockade of the α receptors decreases tone in the smooth muscle of the

bladder neck and prostate and improves urine flow
• Tamsulosin is a more potent inhibitor of the α1A receptors found on the

smooth muscle of the prostate (minimal BP effects)
• SE: dizziness, lack of energy, nasal congestion, headache, drowsiness,

and orthostatic hypotension
• Prazosin + diuretic or β-blocker = additive antihypertensive effect → ↓dose
• Prazosin retains sodium and fluid; frequently used with diuretic
• Sexual dysfunction, inhibition of ejaculation

Some adverse effects commonly observed with
nonselective α-adrenergic blocking agents
Yohimbine
• Selective competitive α2 blocker
• Found in the bark of the Yohimbe tree and is sometimes used

as a sexual stimulant
• Acts on CNS to increase sympathetic outflow to the periphery
• Directly blocks α2 receptors and has been used to relieve

vasoconstriction associated with Raynaud's disease
• X CNS and cardiovascular conditions because it is a CNS

and cardiovascular stimulant.
β-Adrenergic Blocking Agents
• All clinically available β-blockers are competitive antagonists
• Nonselective β-blockers act at both β1 and β2 receptors
• Cardioselective β antagonists primarily block β1
• No clinically useful β2 antagonists
• ↓BP in hypertension do not induce postural hypotension (α functional)
• Effective in treating angina, cardiac arrhythmias, myocardial infarction,

congestive heart failure, hyperthyroidism, and glaucoma
• Prophylaxis of migraine headaches
• The names of all β-blockers end in “-olol” except for labetalol and
carvedilol
Propranolol
• The prototype β-adrenergic antagonist
• Nonselective β antagonist; blocks both β1 and β2 receptors
• Diminishes cardiac output; negative inotropic and chronotropic effects
• Directly depresses sinoatrial and atrioventricular activity→ bradycardia →

limits the dose of the drug
• Treatment of angina (β1 blockade ↓Cardiac output, work, and oxygen

consumption)
• Attenuates supraventricular cardiac arrhythmias, not ventricular

arrhythmias (except those induced by exercise).
• Peripheral vasoconstriction: gradual reduction of both systolic and

diastolic blood pressures in hypertensive patients. No postural
hypotension occurs (α1unaffected)
Propranolol
• Isoproterenol, noradrenaline, adrenaline?
• Bronchoconstriction: β-Blockers (specially nonselective) are

contraindicated in patients with COPD or asthma, respiratory
crisis
• Increased Na+ retention: ↓BP →↓renal perfusion→ ↑Na+

retention and plasma volume may ↑BP→ combine with a
diuretic to prevent Na+ retention. By inhibiting β receptors,
renin production is also prevented, contributing to Na+
retention
• Disturbances in glucose metabolism: ↓glycogenolysis and

↓ glucagon secretion
• Type I diabetic + propranolol → very careful monitoring of blood
glucose, to limit pronounced hypoglycemia after insulin injection. β-
Blockers also attenuate the normal physiologic response to
hypoglycemia.
Propranolol
Therapeutic effects
• Hypertension: Decrease cardiac output, inhibit renin release, and decrease sympathetic
outflow from the CNS ↓BP
• Glaucoma: diminish intraocular pressure ↓secretion of aqueous humor, for chronic treatment
e.g. timolol (topical)
• Migraine: block catecholamine-induced vasodilation in the brain vasculature. reduce migraine

episodes (prophylactically) → chronic treatment ↓ severity and number of attacks
• Hyperthyroidism: ↓ widespread sympathetic stimulation that occurs in hyperthyroidism. May

be lifesaving against serious cardiac arrhythmias (acute hyperthyroidism thyroid storm)
• Angina pectoris: decrease oxygen requirement of heart muscle → ↓chest pain on exertion,
chronic not acute.
• Myocardial infarction: protective effect on the myocardium. Immediately following an MI

reduces infarct size and hastens recovery
block the actions of circulating catecholamines which increase the oxygen demand in an already
ischemic heart muscle
• Propranolol also reduces the incidence of sudden arrhythmic death after myocardial infarction
Propranolol
Adverse effects:
• Bronchoconstriction: serious and potentially lethal side effect when administered
to an asthmatic, asphyxiation. Propranolol must never be used in treating any
individual with COPD or asthma.
• Arrhythmias: β-blockers must never be stopped quickly; precipitating cardiac

arrhythmias, tapered off gradually for 1 week (long-term treatment with a β
antagonist leads to up-regulation of the β-receptor)
• Sexual impairment: not α, some men do complain of impaired sexual activity ???
• Disturbances in metabolism: decreased glycogenolysis and glucagon secretion

→ Fasting hypoglycemia
Cardioselective β-blockers are preferred in treating asthmatic patients who use insulin
• Drug interactions: Drugs that interfere with the metabolism of propranolol, such
as cimetidine, fluoxetine, paroxetine, and ritonavir, may potentiate its
antihypertensive effects. Conversely, those that stimulate its metabolism, such as
barbiturates, phenytoin, and rifampin, can decrease its effects.
Timolol and nadolol
• Nonselective β antagonists
• Block β1- and β2- adrenoceptors and are more potent than propranolol
• Nadolol has a very long duration of action
• Timolol; glaucoma, and for systemic treatment of hypertension
Acebutolol, atenolol, metoprolol, and esmolol
• Selective β1 antagonists
• No unwanted bronchoconstrictor effect (β2 effect) in asthmatics
• Acebutolol, atenolol, and metoprolol, antagonize β1 receptors at doses 50-
to 100-fold less than those required to block β2 receptor
• Cardio-selectivity is lost at high doses
• Acebutolol has some intrinsic agonist activity
Acebutolol, atenolol, metoprolol, and esmolol
• ↓BP in hypertension and increase exercise tolerance in angina
• Esmolol has a very short lifetime (metabolism)→ only given IV if

required during surgery or diagnostic procedures (for example,
cystoscopy)
• Little effect on pulmonary function, peripheral resistance, and

carbohydrate metabolism
• Still, asthmatics → carefully monitored
• Useful in hypertensive patients with impaired pulmonary function
• Less coldness of extremities; nonselective β-blocker → ↓ dilation

of peripheral vasculature (β2), coldness of extremities
• Cardioselective β-blockers are useful in diabetic hypertensive

patients who are receiving insulin or oral hypoglycemic agents.
Pindolol and acebutolol
• Antagonists with partial agonist activity
• Weakly stimulate both β1 and β2 receptors
• Stimulate the β receptor to which they are bound and inhibit stimulation by
the more potent endogenous catecholamines, epinephrine and
norepinephrine
• Diminished effect on cardiac rate and cardiac output compared to that of β-

blockers
• Decreased metabolic effects; minimize the disturbances of lipid and

carbohydrate metabolism that are seen with other β-blockers (valuable in
the treatment of diabetics)
• Effective in hypertensive patients with moderate bradycardia, because a

further decrease in heart rate is less pronounced with these drugs
• Not used as antiarrhythmic agents due to their partial agonist effect

Labetalol and carvedilol
• Antagonists of both α- and β- adrenoceptors
• Reversible β-blockers with concurrent α1-blocking actions that

produce peripheral vasodilation, thereby reducing blood
pressure
• Not like other β-blockers which produce peripheral

vasoconstriction → treat hypertensive patients who don’t want
to increase peripheral vascular resistance
• Do not alter serum lipid or blood glucose levels
• Carvedilol decreases lipid peroxidation and vascular wall

thickening, benefit heart failure patients
Labetalol
• Useful for treating the elderly or black hypertensive patient in
whom increased peripheral vascular resistance is undesirable
Black hypertensive patients are not well controlled with β-blockers
• May be employed as an alternative to methyldopa in the

treatment of pregnancy-induced hypertension
• Intravenous labetalol is also used to treat hypertensive

emergencies, because it can rapidly lower blood pressure
• SE: Orthostatic hypotension and dizziness (associated with

α1 blockade)
Elimination half-lives
for some β-blockers
Drugs Affecting Neurotransmitter
Release or Uptake
• Interfere with neurotransmitter release or alter its uptake
• Rarely used therapeutically; newer agents with less side effects
Reserpine
- A plant alkaloid, blocks transport norepinephrine, dopamine, and serotonin

from the cytoplasm into storage vesicles in the adrenergic nerves of all
body tissues causing their depletion
- Impair sympathetic function because of decreased release of

norepinephrine
- Slow onset and long duration of action, and effects persist for many days
after discontinuation
Drugs Affecting Neurotransmitter
Release or Uptake
Guanethidine
- Blocks the release of stored norepinephrine + displaces
norepinephrine from storage vesicles (thus producing a
transient increase in blood pressure)
- Leads to gradual depletion of norepinephrine in nerve
endings except for those in the CNS
- Causes orthostatic hypotension and interferes with male
sexual function
- Supersensitivity to norepinephrine due to depletion of the
amine can result in hypertensive crisis in patients with
pheochromocytoma
Cocaine
- Inhibits norepinephrine uptake → adrenergic agonist
Parkinson's
disease
PARKINSON’S DISEASE
PATHOPHYSIOLOGY
• Degeneration of neurones within nigro-striatal pathway resulting in loss of

dopaminergic activity
THERAPEUTIC RATIONALE
• Imbalance of dopaminergic and cholinergic activity within the extra-pyramidal

system
Thus: reduced dopaminergic activity

Increased cholinergic activity
Results in:
• Clinical Parkinsonism: hypokinesia, muscle rigidity, tremor
• Treatment thus aims to restore dopaminergic activity OR reduce cholinergic

activity
• Imbalance between the excitatory
neurotransmitter Acetylcholine and
inhibitory neurotransmitter Dopamine
in the Basal Ganglia :
DA
ACh
Basal Ganglia
excitatory inhibitory
Nonmotor symptoms
Cognitive impairment, dementia
Psychiatric symptoms, particularly depression
Autonomic disturbances
» Urinary urgency and frequency
» Constipation
» Hypotension with orthostasis
» Sweating disorders
» Sexual dysfunction
Sleep disturbances
Stats and Facts
• Age at onset variable ( 50 – 80 years ) .
• Man and Woman are equally affected.
• Prevalence 100 case Per 100 000 Population .
• Incidence 20 case Per 100 000 People annually.

Stats and Facts
• Progression highly variable. Within 10 – 20 years.
• Patient age at onset affect progression . ( high rate in older )
• Mortality not caused by disease itself , but, due to complications
related to immobility .
Complication such as ( Aspiration Pneumonia , cardiovascular
and cerebrovascular disease (

Causes:
1. Idiopathic due to exposure to :
• Neurotoxins.
• Oxidative reactions.
2. Genetic factors ??
3. Others :
1. Dopaminergic receptor antagonist ( Antipsychotic ) .
2. Destruction of dopaminergic neurons ( MPTP ) .
Drug induce PD :
1. Reserpine ------------ depletion of dopamine storage.
2. Halloperidole, phenothiazin , MPTP.
What is MPTP ?
Stages of PD
• Stage 1 : Unilateral involvement
Minimal or no functional impairment.
• Stage 2 : Bilateral involvement

Without impairment of balance
• Stage 3 : Postural imbalance

Some restriction of activity
Mild – Moderate disability
• Stage 4 : Severely disable

Cannot walk and stand
• Stage 5 : Restricted to the bed

Some neurotransmitters in the CNS
Treatments for PD
• L-Dihydroxyphenylalanine (L-DOPA)
• DOPA Decarboxylase (DDC) inhibitors
• DA agonists
• Amantadine
• MAO-B inhibitors
• Anticholinergics
• Catechol-O-methyl transferase (COMT)
inhibitors
L-DOPA
• High therapeutic index - drug of choice for symptom control especially in
elderly (need DOPA-decarboxylase, DDC, inhibitor to block dopamine in
periphery)
• “L-dopa honeymoon” - early phase of treatment (lasts 5-6 years typically)

dopaminergic neurons still present - L-dopa can be stored in nerve
terminals - produces a physiological concentration without much fluctuation
• Neurotoxicity of L-dopa - DOPA metabolism results in neurotoxic breakdown

products - results in the progression of Parkinson’s? Hence delay L-dopa
use especially in younger patients.
• Chronic use of L-DOPA results in motor fluctuations (on-off dyskinesias) as

remaining NS nerve ending lost
• Other side effects – hallucinations, nausea and postural hypotension (last 2

usually prevented by DDC blockade)
Treatments of PD
L-Dihydroxyphenylalanine (L-DOPA)
• First effective treatment to be used in PD, and is still the mainstay of PD drug
therapy.
• 30-50% of patients suffer unpleasant and potentially disabling drug induced
involuntary movements, this usually happens after 2 to 5 years of using treatment
DOPA Decarboxylase (DDC) inhibitors

• Carbidopa in combination with L-DOPA decreases the peripheral break down of L-
DOPA thus leads to more drug reaching the brain.
• Carbidopa cannot be given alone
• Benserezide
DA agonists
• Mimic the function of DA in the brain and are used primarily as adjuncts
to L-DOPA/carbidopa therapy.
• Can be used as monotherapy but are generally less effective in controlling
symptoms.
• Examples: bromocriptine, pergolide, pramipexole and ropinirole
Treatments of PD
Amantadine (early stages)
• Antiviral drug which has DA agonist properties.
• It increases the release of DA
• Unfortunately, ceases to be effective within 3 to 4 months
MAO-B inhibitors
• Inhibit the oxidation of DA by monoamine oxidase B and thus prolonging its
availability.
• Example is selegiline which inhibits MAO-B and consequently increases the amount
of available DA in the brain.
Anticholinergics
• Reduce the relative over activity of acetylcholine to balance the diminished activity of
DA.
• Most effective in the control of tremor, and they are used as adjuncts to L-DOPA.
• Examples: benztropine mesylate, biperiden, diphenhydramine and
trihydroxyphenidyl
Catechol-O-methyl transferase (COMT) inhibitors

• Inhibit the COMT enzyme which metabolizes L-DOPA before it reaches the brain.
Only effective when used with L-DOPA.
• Examples: entacapone and tolcapone
Experimental approach to treat PD
Vitamin E: Free radical scavenger.
Neurotrophic factor e.g. Glial –derived
neurotrophic factor
Surgical Procedure :
Used in poorly responsive PD patients to
pharmacotherapy ..
• High Frequency Deep Brain Stimulation (Thalamic Stimulation ).
• Transplantation of Dopaminergic tissue

The end
Alzheimer's Disease
Distinguishing features:
1) accumulation of senile plaques (β-amyloid accumulations),
2) formation of numerous neurofibrillary tangles
3) loss of cortical neurons (cholinergic)
Drugs for AD
• Short term benefit
• None alter the underlying neurodegenerative process
• Improve cholinergic transmission within the CNS
• Prevent excitotoxic actions resulting from overstimulation of N-
methyl-D-aspartic acid (NMDA)-glutamate receptors in selected
brain areas.
Increase ACh
• Reversible AChE inhibitors for
mild to moderate Alzheimer's disease.
donepezil, galantamine, rivastigmine (AChE), and
tacrine (hepatotoxicity)
Galantamine (competitive), some selectivity for
AChE in the CNS
Allosteric modulator of the nicotinic receptor in the

CNS, increase cholinergic neurotransmission
NMDA-receptor antagonist
• Binding of glutamate to the NMDA
receptor assists in the opening of an
associated ion channel that allows Na+
and, particularly, Ca2+ to enter the neuron
• Excess intracellular Ca2+ can activate a
number of processes that ultimately
damage neurons and lead to apoptosis
NMDA-receptor antagonist
• Memantine acts by physically blocking the
NMDA receptor
• Blocks excess
• Phencyclidine, occupies and blocks nearly
all channels
Adverse effects of AChE inhibitors
CNS Stimulants
Two groups (CNS)
• Psychomotor stimulants; cause excitement
and euphoria, decrease feelings of fatigue,
and increase motor activity
• Hallucinogens (psychotomimetic); produce

profound changes in thought patterns and
mood
Relative potential for
physical dependance
Psychomotor Stimulants
Methylxanthines
• Theophylline (tea), theobromine (cocoa), and caffeine

(coffee, tea, cola drinks, chocolate candy, and cocoa)
• Mechanism of action:
- Translocation of extracellular calcium
- Increase in cAMP and cGMP caused by inhibition of

phosphodiesterase
- Blockade of adenosine receptors (actions achieved by

the usual consumption of caffeine-containing beverages)
Methylxanthines
• CNS;
- 100–200 mg caffeine; brain (cortex) stimulation, decrease in fatigue and increased
mental alertness
- 1.5 g of caffeine; anxiety and tremors
- 2–5 g of caffeine; spinal cord stimulation
- Tolerance can rapidly develop to the stimulating properties of caffeine
- Withdrawal; feelings of fatigue and sedation.
• Cardiovascular system;
- A high dose of caffeine has positive inotropic and chronotropic effects (harmful to
patients with angina pectoris)
- In others, an accelerated heart rate can trigger premature ventricular contractions
• Diuretic action: Caffeine has a mild diuretic action that increases urinary output of
sodium, chloride, and potassium.
• Gastric mucosa: Because all methylxanthines stimulate secretion of hydrochloric
acid from the gastric mucosa, individuals with peptic ulcers should avoid beverages
containing methylxanthines.
methylxanthines
• Relaxation of smooth muscles of the bronchioles (theophylline)
• Well absorbed orally (caffeine distributes throughout the body,

including the brain
• Crosses the placenta & secreted into milk
• Metabolized in the liver (CYP1A2)
• Adverse effects;
• Moderate doses of caffeine cause insomnia, anxiety, and agitation
• A high dosage is required for toxicity, which is manifested by emesis
and convulsions
• The lethal dose is about 10 g of caffeine (100 cups of coffee),
unlikely, induces cardiac arrhythmias
• Lethargy, irritability, and headache occur in users who have
routinely consumed more than 600 mg of caffeine per day (roughly
six cups of coffee per day) and then suddenly stop
Nicotine
• Active ingredient in tobacco

• Not used therapeutically (only smoking cessation)
• Second to caffeine as most used CNS stimulant
• Second only to alcohol as the most abused drug
• Serious risk factor for lung and cardiovascular
disease, various cancers, and other illnesses
• Dependency is not easily overcome
• At low doses, ganglionic stimulation by
depolarization
• At high doses, ganglionic blockade
Nicotine
- Nicotine is highly lipid soluble and readily crosses the BBB

- Produces some degree of euphoria and arousal as well as
relaxation
- Improves attention, learning, problem solving, and reaction
time
- High doses result in central respiratory paralysis and severe
hypotension
- Nicotine is an appetite suppressant
- Peripheral effects, stimulation of sympathetic ganglia and
adrenal medulla
- increases blood pressure and heart rate
- X hypertensive patients, peripheral vascular disease
Nicotine
• Lethal dose is 60 mg
• Metabolized in lung and liver and excreted in urine
• Tolerance to its toxic effects develop
• Adverse effects; The CNS effects of nicotine include irritability and
tremors
• Intestinal cramps, diarrhea, and increased heart rate and blood
pressure
• Enzyme induction
• Addictive substance, physical dependence by irritability, anxiety,
restlessness, difficulty concentrating, headaches, and insomnia
• Appetite is affected, and gastrointestinal pain often occurs
• Patches and chewing gum reduce nicotine withdrawal symptoms
• Bupropion, an antidepressant, can reduce the craving for cigarettes
Varenicline
• Partial agonist at α4β2 neuronal nicotinic

acetylcholine receptors in the CNS
• Partial agonist → less euphoric than nicotine
• Smoking cessation (withdrawal symptoms)
• Attenuates the rewarding effects of nicotine if
a person relapses and uses tobacco
• Monitor for suicidal thoughts, vivid
nightmares and mood changes
Cocaine
• More than 3 million people abuse (U.S)
• Binds to the monoaminergic reuptake transporters
• Blocks reuptake of the monoamines (norepinephrine,
serotonin, and dopamine)
• Potentiates and prolongs the CNS and peripheral
actions of these monoamines
• Dopaminergic effects in the brain's pleasure system
(limbic system) produces the intense euphoria that
cocaine initially causes
• Chronic intake of cocaine depletes dopamine. This
depletion triggers the vicious cycle of craving for cocaine
that temporarily relieves severe depression
Cocaine
• Powerful stimulation of the cortex and brainstem
• Acutely increases mental awareness and produces a

feeling of well-being and euphoria (like amphetamine)
• Can produce hallucinations and delusions of paranoia

or grandiosity
• Increases motor activity, and at high doses, it causes

tremors and convulsions, followed by respiratory and
vasomotor depression
Cocaine
– SNS; potentiates the action of NA “fight or flight”
– Hyperthermia; death? ↑ in hot weather
– Impairs sweating and cutaneous vasodilatation
– ↓ Perception of thermal discomfort

Cocaine
• Only use; local anesthetic (topically)
• During; eye, ear, nose, and throat surgery
• Block of voltage-activated sodium
channels
• Interaction with potassium channels
- Cardiac arrhythmias
- Necrosis and perforation of the nasal septum
Cocaine
• Chewing, intranasal snorting, smoking, or intravenous (IV) injection
• Rapidly de-esterified and demethylated → urine
Adverse effects:
– Anxiety: hypertension, tachycardia, sweating, and paranoia.
– With alcohol: cocaine metabolite + ethanol → cocaethylene,
psychoactive and believed to contribute to cardiotoxicity.
– Depression: mental and physical depression, agitation
(benzodiazepines, phenothiazines)
– Toxic effects:
• Seizures, treated by IV diazepam
• Fatal cardiac arrhythmias, treated by IV propranolol
Amphetamine
• Noncatecholaminergic sympathetic amine that shows neurologic
and clinical effects quite similar to those of cocaine
• Dextroamphetamine ,methamphetamine (speed) → abuse
• Indirect effect; elevate catecholamine neurotransmitters in synaptic

spaces
• Release intracellular stores of catecholamines
• Inhibit MAO, ↑ catecholamines released into synaptic spaces
• Similar behavioral effects to those of cocaine

Amphetamine
Pharmacological actions:
– CNS: combination of ↑ dopamine and ↑ norepinephrine
– Stimulates the entire cerebrospinal axis, cortex, brainstem, and

medulla. This leads to increased alertness, decreased fatigue,
depressed appetite, and insomnia.
– Hyperactivity in children, narcolepsy, and for appetite control
– At high doses, psychosis and convulsions
– Activate the SNS through ↑ norepinephrine release.

Amphetamine
• Psychological and physiological dependence limit therapeutic use
– Attention deficit hyperactivity disorder (ADHD); Dextroamphetamine and

methylphenidate (DA reuptake Inhibitor), Lisdexamfetamine (prodrug long acting, school
time)
– Atomoxetine is a nonstimulant drug approved for ADHD in children and adults.
• Norepinephrine reuptake inhibitor
• MAO inhibitors X
• Narrow-angle glaucoma X
• Not habit forming and is not a controlled substance
– Narcolepsy: sleep disorder; amphetamine or methylphenidate

– Newer drug, modafinil , and armodafinil
– Fewer psychoactive and euphoric effects as well as, alterations in mood, perception,
thinking, and feelings
– Involves the adrenergic and dopaminergic systems
– Effective orally
– Extensive hepatic metabolism
– SE: Headaches, nausea, and rhinitis are the primary adverse effects, some potential for
abuse
Amphetamine
• Completely absorbed from the GIT, metabolized by the
liver, and excreted in the urine
• Euphoria caused by amphetamine lasts 4-8 times longer

than the effects of cocaine
• Overdoses of amphetamine are treated with chlorpromazine

or haloperidol (α-blocking effects)
• Anorectic effect of amphetamine is due to its action in the

lateral hypothalamic feeding center
Adverse effects of amphetamine
Methylphenidate
• CNS stimulant properties similar to amphetamine, abuse?
• One of the most prescribed medications in children (ADHD, 4 to 6
million USA)
• Dexmethylphenidate is active isomer, ADHD
• ADHD → weak dopamine signals (reward centers), ↓ participation in
interesting activities
• Dopamine transport inhibitor → more dopamine available
• Enters brain slower than cocaine (less potential for abuse)
• Effective in the treatment of narcolepsy (not dexmethylphenidate)
• Readily absorbed on oral administration
• SE; GIT: abdominal pain and nausea
• Anorexia, insomnia, nervousness, and fever
• Increase the seizure frequency, contraindicated in patients with
glaucoma.
• interfere in the metabolism of warfarin, diphenylhydantoin,
phenobarbital, primidone, and the tricyclic antidepressants.
Hallucinogens (psychotomimetic drugs)
• Ability to induce altered perceptual states reminiscent of dreams

• Incapable of normal decision making, interference with rational thought
• Lysergic acid diethylamide (LSD);

- Affects multiple sites in the CNS
- Shows serotonin (5-HT) agonist activity at presynaptic 5-HT1 receptors in
the midbrain, and also stimulates 5-HT2 receptors
- Activates SNS; pupillary dilation, increased blood pressure, piloerection,
and increased body temperature
- Taken orally, low doses; induce hallucinations with brilliant colors, mood
alteration
- Tolerance and physical dependence?
- SE: hyperreflexia, nausea, and muscular weakness
- High doses may produce long-lasting psychosis in some
- Haloperidol and other neuroleptics block the hallucinatory action of LSD
• Tetrahydrocannabinol (THC); The main psychoactive alkaloid

contained in marijuana (THC)
• Can produce euphoria, followed by drowsiness and relaxation
• affects short-term memory and mental activity, decreases muscle

strength and impairs highly skilled motor activity
• Stimulates appetite, xerostomia, visual hallucinations, delusions, and

enhancement of sensory activity
• THC receptors, G protein coupled, CB1 receptors, found on inhibitory

presynaptic nerve terminals that interact synaptically with pyramidal
neurons
• Dronabinol; drug administered orally as appetite-stimulant (acquired

immunodeficiency syndrome)
• Sometimes given for the severe emesis caused by some cancer

chemotherapeutic agents
• SE: increased heart rate, decreased blood pressure, and reddening of the
conjunctiva
• At high doses, a toxic psychosis develops
• Tolerance and mild physical dependence
• Rimonabant; CB1antagonist, effective in the treatment of obesity and has

been found to decrease appetite and body weight in humans
Induces psychiatric disturbances, such as anxiety and depression
Phencyclidine
• PCP, or “angel dust”
• Inhibits the reuptake of dopamine, 5-HT, and norepinephrine
• Mainly works through blocking NMDA receptor
• Prevents the passage of critical ions (particularly Ca2+)
• Anticholinergic activity but, surprisingly, produces
hypersalivation.
• Ketamine analog, causes dissociative anesthesia (insensitivity
to pain, without loss of consciousness) and analgesia
numbness of extremities, staggered gait, slurred speech, and
muscular rigidity. Sometimes, hostile and bizarre behavior
occurs.
• At increased dosages, anesthesia, stupor, or coma result, but
strangely, the eyes may remain open.
• Increased sensitivity to external stimuli exists, and the CNS
actions may persist for a week
• Tolerance often develops with continued use.
Anxiolytic and Hypnotic Drugs
Anxiolytics
• Anxiety is an unpleasant state of tension,
apprehension, or uneasiness
• Symptoms; tachycardia, sweating,
trembling, and palpitations (sympathetic
activation)
• Anxiolytics may have
hypnotic & anticonvulsant activity
• SSRI’s ?
Benzodiazepines
• Most widely used anxiolytic drugs
• Safer and more effective than barbiturates
• Increase the frequency of channel
openings produced by GABA
• Increase the affinity of GABA for the
GABA-binding site
Benzodiazepines
• Have neither antipsychotic activity nor analgesic action
• Reduction of anxiety: At low doses, inhibit neuronal circuits in the limbic

system of the brain.
• Sedative and hypnotic actions: mediated by the α1-GABAA receptors.
• Anterograde amnesia: mediated by the α1-GABAA receptors.
• Anticonvulsant: partially mediated by α1-GABAA receptors.
• Muscle relaxant: At high doses, mediated by α2-GABAA receptors
Baclofen is a muscle relaxant that is believed to affect GABAb

receptors at the level of the spinal cord.
Therapeutic uses of Benzodiazepines
Anxiety symptoms secondary to:
- Panic disorder
- Generalized anxiety disorder
- Social anxiety disorder
- Performance anxiety
- Posttraumatic stress disorder
- Obsessive-compulsive disorder
- Anxiety from specific phobias, such as fear of flying
- Anxiety accompanying depression and schizophrenia
 Potential for addiction, tolerance (sedative and hypnotic effects)

 Ethanol ?
 Long term treatment; clonazepam, diazepam
 Alprazolam; short- & long-term treatment, withdrawal? 30%
• Muscular disorders: (Diazepam)
- Spasms (muscle strain)
- Spasticity (degenerative disorders)
e.g. Multiple Sclerosis and cerebral palsy
• Amnesia; Midazolam (injectable-only, induction of anesthesia)
• Seizures:
- Clonazepam; certain types of epilepsy
- Diazepam and lorazepam; terminate grand mal
epileptic seizures and status epilepticus
- Chlordiazepoxide, clorazepate, diazepam, and
oxazepam; acute treatment of alcohol withdrawal
(related seizures)
• Sleep disorders: Important to balance the sedative

effect needed at bedtime with the residual sedation
(“hangover”) upon awakening.
- long-acting flurazepam t1/2: 85h
- Intermediate-acting temazepam;
frequent wakening. 1 to 2 hours before the desired bedtime
- Short acting triazolam;

difficulty in going to sleep. Tolerance (use intermittently)
• Nonbenzodiazepine drugs, zolpidem, zaleplon, and

eszopiclone, preferred hypnotics
Do not significantly alter the various sleep stages
Benzodiazepines
• Complete absorption and wide distribution
• Metabolized by the liver, active metabolite?
• Benzodiazepines should be used cautiously

in treating patients with liver disease
• Benzodiazepine Antagonist; Flumazenil

Other Anxiolytic Agents
• Buspirone; generalized anxiety disorder
• Mediated by serotonin receptors, dopamine receptors?
• No anticonvulsant or muscle-relaxant properties, little
sedation.
• hypothermia and can increase prolactin and growth
hormone.
• CYP3A4; rifampin? and erythromycin?
• Little adverse effects; headaches, dizziness,
nervousness, and light-headedness.
• Dependence is unlikely
• Slow onset of action (disadvantage)
Other Anxiolytic Agents
• Hydroxyzine;
- Antihistamine with antiemetic activity
- Anxiety with history of drug abuse
- Sedation prior to dental procedures or surgery.
- SE; Drowsiness
• Antidepressants
- long-term symptoms of chronic anxiety disorders
- When concerns for addiction or dependence or a history of addiction
- SSRIs, TCAs, venlafaxine, duloxetine and MAOIs all have potential
usefulness in treating anxiety.
Barbiturates
- Induce tolerance, drug-metabolizing enzymes, physical dependence, and are
associated with very severe withdrawal symptoms.
- Ability to cause coma in toxic doses.
- Thiopental (very short-acting) still used to induce anesthesia
Barbiturates
• Classified according to their duration of action
• Thiopental (30min) induction of anesthesia.
• Phenobarbital (>day) treatment of seizures
• Pentobarbital, secobarbital, and amobarbital :

short-acting barbiturates, sedative and hypnotic
(not antianxiety)
Other Hypnotic Agents
Treatment of insomnia
• Zolpidem; hypnotic with no anticonvulsant or

muscle-relaxing properties, CYP3A4?
• Zaleplon; similar to zolpidem t1/2 is 1h CYP3A4?
• Eszopiclone; t1/2 is 6h CYP3A4?
• Ramelteon; induction of sleep. Low abuse,

dependence or withdrawal; long-term.
• Chloral hydrate; sedative and hypnotic, induces
sleep (30 min), sleeptime (6h)
- Irritates GI, unpleasant taste sensation
- synergizes with ethanol
• Antihistamines Nonprescription,
- diphenhydramine and doxylamine
- mild types of insomnia.
- many undesirable side effects (anticholinergic
effects)
• Ethanol; anxiolytic and sedative
- Alcoholism is a serious medical and social problem
- CNS depressant; hypnosis with increasing dosage
- Metabolized primarily in the liver
- Synergizes with many sedative agents and can produce severe

CNS depression with benzodiazepines, antihistamines, or
barbiturates.
- Chronic consumption can lead to severe liver disease, gastritis, and

nutritional deficiencies.
- The treatment of choice for alcohol withdrawal are the

benzodiazepines
- Carbamazepine is effective in treating convulsive episodes during

withdrawal.
Ethanol
• Disulfiram: flushing, tachycardia,
hyperventilation, and nausea.
disulfiram-induced acetaldehyde accumulation.
• Naltrexone: long-acting opiate antagonist,

treatment of alcohol dependence
• Acamprosate: alcohol dependence treatment,

poorly understood mechanism of action
• The end
Antidepressants
Depression
• Serious disorder; 14 million adults in the US each year
• Prevalence (US): 16% adults (21% of women, 13% of men),

or more than 32 million people
• Symptoms; intense feelings of sadness, hopelessness, and

despair, as well as the inability to experience pleasure in usual
activities, changes in sleep patterns and appetite, loss of
energy, and suicidal thoughts
• Mania is characterized by the opposite behavior—that is,

enthusiasm, rapid thought and speech patterns, extreme self-
confidence, and impaired judgment
Mechanism of Antidepressant Drugs
• Most potentiate, either directly or indirectly, the actions of norepinephrine and/or

serotonin in the brain
• Due to a deficiency of monoamines, such as norepinephrine and serotonin, at
certain key sites in the brain
• Mania is caused by an overproduction of these neurotransmitters
• overly simplistic
• Antidepressant and antimania drug effects on neurotransmission occur
immediately, but therapeutic response occurs over several weeks
• potency of drugs often does not correlate with clinically observed antidepressant
effects
• Decreased uptake of neurotransmitter is only an initial effect of the drugs, which
may not be directly responsible for the antidepressant effects
• It has been proposed that presynaptic inhibitory receptor densities in the brain
decrease over a 2- to 4-week period with antidepressant drug use. This down-
regulation of inhibitory receptors permits greater synthesis and release of
neurotransmitters into the synaptic cleft and enhanced signaling in the
postsynaptic neurons, presumably leading to a therapeutic response
SSRI’s
• Antidepressant drugs that specifically inhibit serotonin reuptake, having
300- to 3000-fold greater selectivity for the serotonin transporter as
compared to the norepinephrine transporter
• Not like tricyclic antidepressants that nonselectively inhibit the uptake of

norepinephrine and serotonin
• Both TCA’s and SSRI’s exhibit little ability to block the dopamine
transporter
• SSRIs have little blocking activity at muscarinic, α-adrenergic, and
histaminic H1 receptors → no orthostatic hypotension, sedation, dry
mouth, and blurred vision (side effects associated with TCA’s)
• Relatively safe even in overdose

• SSRIs are drugs of choice in depression (replaced TCA’s and MAOI’s)
• Fluoxetine (the prototypic drug), citalopram, escitalopram, fluvoxamine,
paroxetine, and sertraline
• Citalopram and fluoxetine are racemic mixtures, of which the respective S-
enantiomers are the more potent inhibitors of the serotonin reuptake pump
Relative receptor
specificity of some
antidepressant
drugs
*Venlafaxine
inhibits
norepinephrine re-
uptake only at high
doses
++++ = very strong

affnity
+++ = strong
affinity
++ = moderate
affinity
+ = weak affinity
0 = little or no
affinity.
SSRI’s
Pharmacological actions
• block the reuptake of serotonin→↑ concentrations of the neurotransmitter in the
synaptic cleft and, ultimately, to greater postsynaptic neuronal activity
• At least 2 weeks to produce significant improvement in mood, and maximum benefit

may require up to 12 weeks or more
• None of the antidepressants are uniformly effective
• ~ 40 percent of depressed patients treated with adequate doses for 4 to 8 weeks do

not respond to the antidepressant agent, may respond to another
• ~ 80 percent or more will respond to at least one antidepressant drug
• SSRI’s do not cause CNS stimulation or mood elevation in normal individuals
• Depression, but also other psychiatric disorders; OCD (fluvoxamine’s only use),
panic disorder, generalized anxiety disorder, posttraumatic stress disorder, social
anxiety disorder, premenstrual dysphoric disorder, and bulimia nervosa (only
fluoxetine approved)
SSRI’s
• Well absorbed after oral administration (food or none, except with sertraline, for which food
increases its absorption)
• Only sertraline undergoes significant first-pass metabolism
• The majority of SSRIs have plasma half-lives that range between 16 and 36 hours
• Deactivation by P450-dependent enzymes and glucuronide or sulfate conjugation
• Fluoxetine:
- Long half-life (50 hours); is available as a sustained-release preparation → once-weekly
dosing
- Metabolite of the S-enantiomer, S-norfluoxetine, is as potent as the parent compound and has
quite long t ½ (10 days)
• Fluoxetine and paroxetine are potent inhibitors of CYP2D6, responsible for the elimination of:
- tricyclic antidepressant drugs
- neuroleptic drugs
- some antiarrhythmic and β-adrenergic–antagonist drugs
• Genomics? 7% Caucasians lack CYP2D6 → metabolize fluoxetine very slowly (poor

metabolizers)
• CYP2C9/19, CYP3A4, and CYP1A2 → SSRI metabolism → inhibited by the SSRIs→ affect
metabolism of multiple medications
• SSRIs → kidney excretion, paroxetine and sertraline → also undergo fecal excretion (35 and
50 percent, respectively)
• Dosages adjusted downward in patients with hepatic impairment
SSRI’s
Adverse effects
• SSRIs; fewer and less severe adverse effects than

TCAs & MAOI
• Headache, sweating, anxiety and agitation,

gastrointestinal effects (nausea, vomiting, diarrhea),
weakness and fatigue, sexual dysfunction, changes in
weight, sleep disturbances (insomnia and
somnolence)
• Potential for drug-drug interactions

SSRI’s
• Sleep disturbances: Paroxetine and fluvoxamine; more sedating than activating → difficulty
sleeping and not for fatigued or complaining of excessive somnolence (may benefit from one
of the more activating antidepressants, such as fluoxetine or sertraline)
• Sexual dysfunction: Loss of libido, delayed ejaculation, and anorgasmia; replace with one
having fewer sexual side effects, such as bupropion or mirtazapine or reduce dose. In men
with erectile dysfunction and depression, treatment with sildenafil, vardenafil, or tadalafil may
improve sexual function
• Use in children and teenagers: used cautiously in children and teenagers, 1 out of 50
children becomes more suicidal as a result of SSRI. Observed for worsening depression and
suicidal thinking
• Overdoses: does not usually cause cardiac arrhythmias (compared to the arrhythmia risk for
TCAs), but seizures are a possibility because all antidepressants may lower the seizure
threshold
• Serotonin syndrome; symptoms of hyperthermia, muscle rigidity, sweating, myoclonus
(clonic muscle twitching), and changes in mental status and vital signs when used in the
presence of a monoamine oxidase inhibitor or another highly serotonergic drug → extended
periods of washout for each drug class should occur prior to the administration of the other
class of drugs
• Discontinuation syndrome: all SSRIs; agents with the shorter half-lives and having inactive
metabolites have a higher risk for such an adverse reaction→ Fluoxetine has the lowest risk
headache, malaise and flu-like symptoms, agitation and irritability, nervousness, and
changes in sleep pattern.
SNRIs
SNRIs
• Venlafaxine and duloxetine selectively inhibit the re-uptake of both
serotonin and norepinephrine
• May be effective in treating depression in patients in whom SSRIs are

ineffective
• Useful for depression accompanied chronic pain symptoms, such as

backache and muscle aches (SSRIs are relatively ineffective)
• SNRIs and TCAs are sometimes effective in relieving physical symptoms of

neuropathic pain, such as diabetic peripheral neuropathy
• SNRIs, unlike TCAs, have little activity at adrenergic, muscarinic, or

histamine receptors and, thus, have fewer of these receptor-mediated
adverse effects
• Venlafaxine and duloxetine may precipitate a discontinuation syndrome if

treatment is abruptly stopped
Venlafaxine
• Potent inhibitor of serotonin reuptake and, at medium to higher doses, is an
inhibitor of norepinephrine re-uptake
• Mild inhibitor of dopamine reuptake at high doses
• Minimal inhibition of the CYP and is a substrate of the CYP2D6 isoenzyme
• half-life of the parent compound plus its active metabolite is approximately
11 hours
• Only 27 percent bound to plasma protein and is not expected to be
involved in protein displacement interactions
• SE; nausea, headache, sexual dysfunction, dizziness, insomnia, sedation,
and constipation. At high doses, there may be an increase in blood
pressure and heart rate.
Duloxetine
• Inhibits serotonin and norepinephrine reuptake at all doses
• Extensively metabolized in the liver → X hepatic insufficiency
• Metabolites are excreted in the urine → X ESRD
• Food delays the absorption of the drug
• T1/2 ~ 12 hours, highly bound to plasma protein
• SE; GIT: nausea, dry mouth, and constipation vomiting, Insomnia,
dizziness, somnolence, and sweating. Sexual dysfunction also occurs
along with the possible risk for an increase in either blood pressure or heart
rate.
Atypical Antidepressants
• Mixed group of agents that have actions at several different
sites: bupropion, mirtazapine, nefazodone, and trazodone
• Not any more efficacious than the tricyclic antidepressants or
SSRIs, but their side effect profiles are different
• Bupropion
- Weak dopamine and norepinephrine reuptake inhibitor
- Short half-life; more than once-a-day dosing or extended-
release formulation
- Assists in decreasing the craving and attenuating the
withdrawal symptoms for nicotine in tobacco users trying to
quit smoking
- SE; dry mouth, sweating, nervousness, tremor, a very low
incidence of sexual dysfunction, and an increased risk for
seizures at high doses
- Metabolized by the CYP2D6 pathway and is considered to
have a relatively low risk for drug-drug interactions
• Mirtazapine
- Enhances serotonin and norepinephrine neurotransmission
via blocking presynaptic α2 receptors + blocks 5-HT2
receptors
- It is a sedative (good; sleeping problems) because of its
potent antihistaminic activity (no antimuscarinic SE like TCAs)
- No interference with sexual functioning like SSRIs
- Increase appetite → weight gain frequently occurs
• Nefazodone and trazodone

- Weak inhibitors of serotonin reuptake
- Therapeutically act by blocking postsynaptic 5-HT2A
receptors
- Chronic use → desensitize 5-HT1A presynaptic autoreceptors
→↑ serotonin release
- Sedating → potent H1-blocking activity
- Trazodone; associated with causing priapism
- Nefazodone; associated with the risk for hepatotoxicity
TCAs
• Block norepinephrine and serotonin reuptake into the neuron
• Tertiary amines; imipramine (the prototype drug), amitriptyline,

clomipramine, doxepin and trimipramine
• Secondary amines; desipramine, nortriptyline and protriptyline
• Tetracyclic; Maprotiline and amoxapine, included to TCAs
• All have similar therapeutic efficacy, and the choice of drug may depend
on such issues as patient tolerance to side effects, prior response,
preexisting medical conditions, and duration of action
• Patients who do not respond to one TCA may benefit from a different drug
in this group
• Valuable alternative for patients who do not respond to SSRIs.

TCAs
Mechanism of action
• Inhibition of neurotransmitter reuptake:

- Potent inhibitors of the neuronal reuptake of norepinephrine and serotonin
into presynaptic nerve terminals
- At therapeutic concentrations, don’t block dopamine transporters
- Cause increased concentrations of monoamines in the synaptic cleft →
antidepressant effects
- Maprotiline and desipramine are selective inhibitors of norepinephrine
reuptake
• Blocking of receptors:
- Block serotonergic, α-adrenergic, histaminic, and muscarinic receptors
- Actions at these receptors are probably responsible for many of the
unwanted SE
- Amoxapine also blocks the D2 receptor
TCAs
• Elevate mood, improve mental alertness, increase physical activity, and
reduce morbid preoccupation in 50 to 70 percent of individuals with major
depression
• Onset of the mood elevation is slow, ≥ 2 weeks
• Do not commonly produce CNS stimulation or mood elevation in normal
individuals
• ↓Physical and psychological dependence, still slow withdrawal to minimize
discontinuation syndromes and cholinergic rebound effects
Therapeutic uses
• Treating moderate to severe major depression.
• Some patients with panic disorder also respond to TCAs
• Imipramine has been used to control bed-wetting in children (older than 6
years) by causing contraction of the internal sphincter of the bladder
• Induces cardiac arrhythmias and other serious cardiovascular problems
(cautiously used)
• TCAs, particularly amitriptyline, have been used to treat migraine headache
and chronic pain syndromes (for example, ―neuropathic‖ pain) in a number
of conditions for which the cause of the pain is unclear
TCAs
Pharmacokinetics
• Well absorbed upon oral administration

• Lipophilic nature → widely distributed and readily penetrate
into the CNS + variable half-lives (4 to 17 hours for
imipramine)
• Variable first-pass metabolism in the liver → low and
inconsistent bioavailability → the patient's response and
plasma levels can be used to adjust dosage
• Initial treatment period is typically 4 to 8 weeks → dosage can
be gradually reduced to improve tolerability unless relapse
occurs
• metabolized by CYP450 (D/D interaction) and conjugated with
glucuronic acid
• Ultimately excreted as inactive metabolites via the kidney
TCAs
Adverse effects
• Blockade of muscarinic receptors leads to blurred vision, xerostomia (dry mouth), urinary
retention, constipation, and aggravation of narrow-angle glaucoma
• Slow cardiac conduction similarly → possible life-threatening arrhythmias (overdose)
• Block α-adrenergic receptors → orthostatic hypotension, dizziness, and reflex tachycardia
(most serious problem in the elderly) → Imipramine most likely and nortriptyline least likely to
cause orthostatic hypotension
• Sedation → block histamine H1 receptors
• Weight gain
• Sexual dysfunction, erectile dysfunction in men and anorgasmia in women, less than SSRIs
• Precautions:
• Known manic-depressive patients, even during their depressed state, because antidepressants
may cause a switch to manic behavior
• Narrow therapeutic index → 5-6 fold the maximal daily dose of imipramine can be lethal
• Depressed patients who are suicidal → limited quantities & monitored closely
• D/D interactions
• May exacerbate certain medical conditions, such as unstable angina, benign prostatic
hyperplasia, epilepsy, and patients with preexisting arrhythmias
• Caution should be exercised with their use in very young or very old patients as well.
MAOIs
• MAO → oxidative deamination (norepinephrine,
dopamine, and serotonin)
• Irreversibly or reversibly inactivate MAO → no or

↓degradation → accumulate within the presynaptic
neuron and leak into the synaptic space → activation
of norepinephrine and serotonin receptors → indirect
antidepressant action
• Phenelzine, tranylcypromine, and selegiline (PD?,

transdermal delivery system)
• Limited use due to the complicated dietary

restrictions required of patients taking MAO inhibitors
MAOIs
Mechanism of action
• Most form stable complexes with the enzyme → irreversible inactivation
(phenelzine) → ↑ stores of norepinephrine, serotonin, and dopamine within the
neuron → diffusion of excess neurotransmitter into the synaptic space
• Inhibit MAO in the brain and also in liver and gut (tyramine?) → high incidence of
drug-drug and drug-food interactions
• Selegiline → transdermal ―patch‖ → less inhibition of hepatic MAO at low doses,
because it avoids first-pass metabolism
• Delayed antidepressant like SSRIs and TCAs (several weeks)
• Selegiline and tranylcypromine have an amphetamine-like stimulant effect that may
produce agitation or insomnia
Therapeutic uses
• Depression in patients who are unresponsive or allergic to TCAs or who experience
strong anxiety
• Patients with low psychomotor activity may benefit from the stimulant properties
• Useful in the treatment of phobic states
• Atypical depression (characterized by labile mood, rejection sensitivity, and appetite
disorders)
• Last-line agents in many treatment venues (D/D & F/D interactions)
MAOIs
Pharmacokinetics
• Well absorbed after oral administration,
• Enzyme regeneration, when irreversibly inactivated, varies, but it usually occurs
several weeks after termination of the drug → minimum of 2 weeks of delay must
be allowed after termination of MAO inhibitor therapy and the initiation of another
antidepressant from any other class (fluoxetine, discontinued at least 6 weeks
before a MAO inhibitor is initiated)
Adverse effects
• Severe & often unpredictable due to D/D & F/D interactions; tyramine (aged
cheeses and meats, chicken liver, pickled or smoked fish such as anchovies or
herring, and red wines) normally inactivated by MAO in the gut → MAOI→ unable to
degrade tyramine → tyramine causes the release of large amounts of stored
catecholamines from nerve terminals →occipital headache, stiff neck, tachycardia,
nausea, hypertension, cardiac arrhythmias, seizures, and possibly, stroke →
educate patients to avoid tyramine-containing foods
• Phentolamine or prazosin;→ management of tyramine-induced hypertension
• Treatment with MAO inhibitors may be dangerous in severely depressed patients
with suicidal tendencies. Purposeful consumption of tyramine-containing foods is a
possibility
• Drowsiness, orthostatic hypotension, blurred vision, dry mouth, dysuria, and
constipation
• MAOIs and SSRIs should not be coadministered due to the risk of the life-
threatening ―serotonin syndrome‖
• Combination of MAO inhibitors and bupropion can produce seizures
Drugs interacting with tricyclic
antidepressants. CNS =
central nervous system; MAO
= monoamine oxidase
Treatment of Mania and Bipolar Disorder
• Lithium salts are used prophylactically for treating manic-depressive patients and in the
treatment of manic episodes and, thus, is considered a ―mood stabilizer‖
• Lithium is effective in treating 60 to 80 percent of patients exhibiting mania and hypomania
• The mode of action is unknown
• Lithium is given orally, and the ion is excreted by the kidney
• Lithium salts can be toxic → safety factor and therapeutic index are extremely low—
comparable to those of digitalis
• Common adverse effects may include headache, dry mouth, polydipsia, polyuria, polyphagia,
gastrointestinal distress (give lithium with food), fine hand tremor, dizziness, fatigue,
dermatologic reactions, and sedation
• Adverse effects due to higher plasma levels may include ataxia, slurred speech, coarse
tremors, confusion, and convulsions
• The diabetes insipidus that results from taking lithium can be treated with amiloride
• Thyroid function may be decreased and should be monitored. Lithium causes no noticeable
effect on normal individuals
• Not a sedative, euphoriant, or depressant.
• Several antiepileptic drugs, including most notably carbamazepine, valproic acid, and
lamotrigine, have been identified and FDA-approved as ―mood stabilizers‖ and have been
successfully utilized in the treatment of bipolar disorder
• Other agents that may improve manic symptoms include the older and newer antipsychotics.
• The atypical antipsychotics (risperidone, olanzapine, ziprasidone, aripiprazole, and quetiapine)
have also received FDA approval for the management of mania
• Benzodiazepines are also frequently used as adjunctive treatments for the acute stabilization
of patients with mania
Neuroleptics
Neuroleptics
• Also called antipsychotic drugs, or major tranquilizers
• Used primarily to treat schizophrenia, also other psychotic states (manic
states with psychotic symptoms such as grandiosity or paranoia and
hallucinations, and delirium)
• All decrease dopaminergic (mainly D2) and/or serotonergic
neurotransmission
• Typical neuroleptic (conventional or first-generation antipsychotics);
competitive blockers of dopamine receptors → vary in potency:
chlorpromazine is a low-potency drug, and fluphenazine is a high-potency
agent → no one drug is clinically more effective than another
• Atypical (second-generation antipsychotics); fewer extrapyramidal SE
• Block both serotonin and dopamine (other?)
• Current antipsychotic therapy: atypical (↓ risk of debilitating movement
disorders (D2)
• Atypicals efficacy ≥ typicals
• Individual patient response and comorbid conditions often used as a guide
in drug selection
• Not curative; do not eliminate the fundamental and chronic thought
disorder → decrease the intensity of hallucinations and delusions → permit
schizophrenics to function in a supportive environment
Schizophrenia
• Particular type of psychosis (mental disorder caused

by some inherent dysfunction of the brain)
• Characterized by delusions, hallucinations (often in
the form of voices), and thinking or speech
disturbances
• Common; 1% of the population
• Starts during late adolescence or early adulthood
• Chronic and disabling disorder
• Has strong genetic component → dysfunction of the
mesolimbic or mesocortical dopaminergic neurons
Neuroleptic Drugs
• Several diverse, heterocyclic structures with
markedly different potencies
• Tricyclic phenothiazine derivative, chlorpromazine,

was the first neuroleptic drug used to treat
schizophrenia
• Subsequent antipsychotics (haloperidol) → 100-fold

as potent as chlorpromazine
- Increased ability to induce parkinson-like and other
extrapyramidal effects
- No more effective than chlorpromazine.
Neuroleptic Drugs
• Dopamine receptor–blocking activity in the brain:
- And in the periphery
- Five types of dopamine receptors: D1 and D5 receptors activate adenylyl cyclase,
often exciting neurons, whereas D2, D3 and D4 receptors inhibit adenylyl cyclase,
or mediate membrane K+ channel opening leading to neuronal hyperpolarization
- Neuroleptics bind these receptors to varying degrees;
- Typical neuroleptics D2 blockade (mesolimbic) → the more effective
- Atypical clozapine has higher affinity for the D4 receptor and lower affinity for the
D2 receptor, → ↓ extrapyramidal side effects (EPS)
- Neuroleptics are antagonized by agents that raise synaptic dopamine
concentrations (L-DOPA & amphetamine) or mimic dopamine at post-synaptic
binding sites (bromocriptine)
• Serotonin receptor–blocking activity in the brain:

- Atypicals; act partially through inhibition 5-HTreceptors (particularly 5-HT2A
receptors)
- Clozapine has high affinity for D1, D4, 5-HT2, muscarinic, and α-adrenergic
receptors, but it is also a dopamine D2-receptor antagonist. Risperidone &
olanzapine block 5-HT2A receptors to a greater extent than D2 receptors
- Atypical aripiprazole; partial agonist at D2 and 5-HT1A receptors as well as a
blocker of 5-HT2A receptors
- Quetiapine weakly blocks D2 receptors (for short time) & 5HT2A receptors (D2 >
5HT2A) → low risk for EPS
Neuroleptics
• Also block cholinergic, adrenergic, and histaminergic receptors (EPS, role in antipsychosis?)
• Reduce schizophrenia associated hallucinations and delusions (positive symptoms) by

blocking dopamine receptors in the mesolimbic system of the brain
• Negative symptoms (blunted affect, anhedonia (not getting pleasure from normally
pleasurable stimuli), apathy, and impaired attention, as well as cognitive impairment are not as
responsive to therapy, particularly with the typical neuroleptics)
• Many atypical agents, such as clozapine, ameliorate the negative symptoms to some extent
• Have a calming effect and reduce spontaneous physical movement
• Do not depress the intellectual functioning of the patient (like CNS depressants; barbiturates)
with minimal motor incoordination
• Antipsychotic effects → several days to weeks → therapeutic effects are related to secondary
changes in the corticostriatal pathways
• Extrapyramidal effects: (nigro-striatal, less with atypicals)

- Dystonias (sustained contraction of muscles leading to twisting distorted postures)
- Parkinson-like symptoms
- Akathisia (motor restlessness)
- Tardive dyskinesia (involuntary movements of the tongue, lips, neck, trunk, and limbs)
Neuroliptics
• Most have antiemetic effects (not aripiprazole and thioridazine) → D2 receptor
blockade of the chemoreceptor trigger zone of the medulla ( X atypicals)
• Cause some Antimuscarinic effects; particularly thioridazine, chlorpromazine,

clozapine, and olanzapine → blurred vision, dry mouth (clozapine ↑salivation),
confusion, and inhibition of gastrointestinal and urinary tract smooth muscle
(constipation & urinary retention). This anticholinergic property may actually
assist in reducing the risk of EPS with these agents
• Orthostatic hypotention & light-headedness (blockade of α-adrenergic receptors)
• Alter temperature-regulating mechanisms → poikilothermia (body temperature

varies with the environment)
• In the pituitary, neuroleptics block D2 receptors, leading to an increase in prolactin

release (less with atypicals)
• Sedation; potent antagonists of the H1-histamine receptor (chlorpromazine,

olanzapine, quetiapine, and clozapine)
• Sexual dysfunction may also occur with the antipsychotics due to various receptor-
binding characteristics
Neuroleptics
• Only efficacious treatment for schizophrenia, not all patients respond, and
complete normalization of behavior is seldom achieved
• Clozapine is reserved for the treatment of individuals who are unresponsive to

other neuroleptics, because its use is associated with blood dyscrasias and other
severe adverse effects
• Can be used as tranquilizers to manage agitated and disruptive behavior

secondary to other disorders
• Used in combination with narcotic analgesics for treatment of chronic pain with
severe anxiety
• Chlorpromazine is used to treat intractable hiccups
• Promethazine (not good antipsychotic); used in treating pruritus because of its

antihistaminic properties
• Pimozide; treatment of the motor and phonic tics of Tourette's disorder (also
risperidone & haloperidol)
• Risperidone; management of disruptive behavior and irritability secondary to

autism
Neuroleptics
• Variable absorption that is unaffected by food (except for
ziprasidone and paliperidone, the absorption of which is
increased with food)
• Readily pass into the brain, have a large volume of distribution,
binds well to plasma proteins
• Liver metabolism, CYP2D6, CYP1A2, and CYP3A4
• Some metabolites are active
• Fluphenazine decanoate, haloperidol decanoate, and
risperidone microspheres are slow-release (up to 2 to 4
weeks) injectable formulations of neuroleptics that are
administered via deep gluteal intramuscular injection
- Outpatients
- Noncompliant with oral medications
- Lower risk of EPS
• The neuroleptic drugs produce some tolerance but little

physical dependence
Maintenance treatment
• Patients who have had two or more psychotic

episodes secondary to schizophrenia should
receive maintenance therapy for at least 5
years, and some experts prefer indefinite
therapy
• Low doses of antipsychotic drugs are not as

effective as higher-dose maintenance therapy
in preventing relapse
Rates of relapse
among patients with
schizophrenia after
maintenance therapy
with either risperidone
or haloperidol.

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Introduction and Principles of

―To administer a drug safely, one must

• Pharmacognosy: the study of drugs

Absorption, distribution, metabolism, and

Describes all matters concerned with

• Drugs work by altering normal cell and

Click here to view an animation showing an agonist and antagonist.

Some receptors have subtypes, for which

• Half-life (t1/2): time taken for the drug’s

• Age: affects metabolic rates, requiring

• Diurnal rhythms: intensity of response to

• Acute or chronic diseases that affect liver

• Acidity of the stomach

• Distribution: passage of agent through

• End-products of metabolism are

• Biotransformation is the conversion of

• Toxicity: refers to drug’s ability to poison

• Side effect: an unintended drug effect;

• Occur when the effects of one drug are

• Ask all patients if they have a history of

• Tolerance: development of resistance to

• Cumulative effect: occurs when body

• Potentiation: a greater effect than

• The effect a drug exerts is directed toward

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• Drug effects can be altered by interaction

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• Antagonist and blocker drugs

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• Classic theory referring to the cellular

• Antagonists are drugs that inhibit or block

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• One drug can act as a master key

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Copyright ©2010 by Pearson Education, Inc.

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Copyright ©2010 by Pearson Education, Inc.

Copyright ©2010 by Pearson Education, Inc.

Copyright ©2010 by Pearson Education, Inc.

Copyright ©2010 by Pearson Education, Inc.

Copyright ©2010 by Pearson Education, Inc.

Copyright ©2010 by Pearson Education, Inc.

Copyright ©2010 by Pearson Education, Inc.

Copyright ©2010 by Pearson Education, Inc.

Copyright ©2010 by Pearson Education, Inc.

• Examples of side effects vary widely

Copyright ©2010 by Pearson Education, Inc.

Copyright ©2010 by Pearson Education, Inc.

Copyright ©2010 by Pearson Education, Inc.

• Once FDA approved, must list side effects

Copyright ©2010 by Pearson Education, Inc.

• Severe side effects often referred to as

Copyright ©2010 by Pearson Education, Inc.

Copyright ©2010 by Pearson Education, Inc.

Copyright ©2010 by Pearson Education, Inc.