El Husseinys Essentials of General Principles

EL Husseiny's Essentials BOOKSTORES
BOOKSTORES EL Husseiny's Essentials

EL Husseiny's Essentials for USMLE step 1 General Principles
General Pathology
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Chapter 1 General Pathology
Cell death
▪ The morphologic hallmark of cell death is loss of the nucleus, which occurs via nuclear condensation
(pyknosis), fragmentation (karyorrhexis), and dissolution (karyolysis).
▪ The two mechanisms of cell death are necrosis and apoptosis.
Necrosis
▪ Death of large groups of cells followed by acute inflammation (unlike apoptosis).
▪ Due to some underlying pathologic process; never physiologic.
▪ Divided into several types based on gross features.
A. Coagulative necrosis:
▪ Necrotic tissue that remains firm; cell shape and organ structure are preserved by coagulation of
proteins, but the nucleus disappears.
▪ Characteristic of ischemic infarction of any organ except the brain.
B. Liquefactive necrosis:
▪ Necrotic tissue that becomes liquefied; enzymatic lysis of cells and protein results in liquefaction.
▪ Characteristic of:
- Brain infarction: Proteolytic enzymes from microglial cells liquefy the brain.
- Abscess: Proteolytic enzymes from neutrophils liquefy tissue.
- Pancreatitis: Proteolytic enzymes from pancreas liquefy parenchyma.
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C. Caseous necrosis:
▪ Soft and friable necrotic tissue with "cottage cheese-like" appearance.
▪ Combination of coagulative and liquefactive necrosis.
▪ Characteristic of granulomatous inflammation due to tuberculous or fungal infection.
D. Fat necrosis:
▪ Necrotic adipose tissue with chalky-white appearance due to deposition of Calcium.
▪ Characteristic of trauma to fat (breast) and pancreatitis-mediated damage of peripancreatic fat.
▪ Fatty acids released by trauma (to breast) or lipase (pancreatitis) join with calcium via a process called
saponification.
▪ Saponification is an example of dystrophic calcification in which calcium deposits on dead tissues. In

dystrophic calcification, the necrotic tissue acts as a nidus for calcification in the setting of normal
serum calcium and phosphate.
E. Fibrinoid necrosis:
▪ Necrotic damage to blood vessel wall.
▪ Leaking of proteins (including fibrin) into vessel wall results in bright pink staining of the wall
microscopically.
▪ Characteristic of malignant hypertension and vasculitis.
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F. Gangrenous necrosis:
▪ Coagulative necrosis that resembles mummified tissue (dry gangrene).
▪ Characteristic of ischemia of lower limb and GI tract.
▪ If superimposed infection of dead tissues occurs, the liquefactive necrosis ensues (wet gangrene).
Apoptosis
▪ ATP-dependent programmed cell death.
▪ Intrinsic or extrinsic pathway; both pathways → activation of cytosolic proteases called caspases that
mediate cellular breakdown → cell shrinkage, chromatin condensation, membrane blebbing, and
formation of apoptotic bodies, which are then phagocytosed.
▪ Characterized by deeply eosinophilic cytoplasm and basophilic nucleus, pyknosis (nuclear shrinkage),
and karyorrhexis (fragmentation caused by endonucleases cleaving at internucleosomal regions).
▪ DNA laddering (fragments in multiples of 180 bp) is a sensitive indicator of apoptosis.
▪ Cell membrane typically remains intact without significant inflammation (unlike necrosis).
A. Intrinsic (mitochondrial) pathway:

- Involved in tissue remodeling in embryogenesis.
- Occurs when a regulating factor is withdrawn from a proliferating cell population (↓ IL-2 after a
completed immunologic reaction → apoptosis of proliferating effector cells).
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- Also occurs after exposure to injurious stimuli (radiation, toxins, hypoxia).
- Regulated by Bcl-2 family of proteins such as BAX and BAK (proapoptotic) and Bcl-2, Bcl-xL
(antiapoptotic).
- BAX and BAK form pores in the mitochondrial membrane → release of cytochrome C from inner
mitochondrial membrane into the cytoplasm → activation of caspases.
- Bcl-2 keeps the mitochondrial membrane impermeable, thereby preventing cytochrome C release. If
Bcl-2 is overexpressed (follicular lymphoma t[14;18]), then APAF-1 is overly inhibited → ↓ caspase
activation and tumorigenesis.
B. Extrinsic (death receptor) pathway:

- 2 pathways:
o Ligand receptor interactions (FasL binding to Fas [CD95] or TNF-α binding to TNF).
o Immune cell (cytotoxic T-cell release of perforin and granzyme B).
- Fas-FasL interaction is necessary in thymic medullary negative selection. Mutations in Fas ↑ numbers
of circulating self-reacting lymphocytes due to failure of clonal deletion. Defective Fas-FasL interactions
cause autoimmune lymphoproliferative syndrome.
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Types of calcification
A. Dystrophic calcification:
▪ Ca deposition in abnormal tissues 2° to injury or necrosis.
▪ Tends to be localized (calcific aortic stenosis).
▪ The figure below shows dystrophic calcification (yellow star), small bony tissue (yellow arrows), and
thick fibrotic wall (red arrows).
▪ Seen in TB (lungs and pericardium), liquefactive necrosis of chronic abscesses, fat necrosis, infarcts,
thrombi, schistosomiasis, Mönckeberg arteriolosclerosis, congenital CMV + toxoplasmosis, psammoma
bodies.
▪ Is not directly associated with serum Ca levels (patients are usually normocalcemic).
B. Metastatic calcification:
▪ Widespread (diffuse, metastatic) deposition of Ca in normal tissue 2° to hypercalcemia (1°
hyperparathyroidism, sarcoidosis, hypervitaminosis D) or high calcium-phosphate product levels
(chronic renal failure with 2° hyperparathyroidism, long-term dialysis, calciphylaxis, warfarin).
▪ The figure below shows metastatic calcifications of alveolar walls in acute pneumonitis (blue arrows).
▪ Ca deposits predominantly in interstitial tissues of kidney, lung, and gastric mucosa (these tissues lose
acid quickly; ↑ pH favors deposition).
▪ Patients are usually not normocalcemic.
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Cell injury
A. Reversible cell injury:

▪ ↓ ATP → ↓ activity of Ca and Na/K pumps → cellular swelling (earliest morphologic manifestation),
mitochondrial swelling.
▪ Ribosomal/polysomal detachment → ↓ protein synthesis.
▪ Plasma membrane changes (blebbing).
▪ Nuclear changes (chromatin clumping).
▪ Rapid loss of function (myocardial cells are noncontractile after 1-2 minutes of ischemia).
B. Irreversible cell injury:

▪ Breakdown of plasma membrane → cytosolic enzymes (troponin) leak into serum, influx of Ca →
activation of degradative enzymes.
▪ Mitochondrial damage/dysfunction → loss of electron transport chain → ↓ ATP.
▪ Rupture of lysosomes → autolysis.
▪ Nuclear degradation: pyknosis (nuclear condensation) → karyorrhexis (nuclear fragmentation caused

by endonuclease-mediated cleavage) → karyolysis (nuclear dissolution).
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Ischemia
▪ Inadequate blood supply to meet demand.
▪ Mechanisms include ↓ arterial perfusion (atherosclerosis), ↓ venous drainage (testicular torsion,

Budd-Chiari syndrome), and shock.
▪ Regions most vulnerable to hypoxia/ischemia and subsequent infarction:

Organ Region
Brain ACA/MCA/PCA boundary areas
Heart Subendocardium (LV)
Kidney Straight segment of proximal tubule

(medulla)
Thick ascending limb (medulla)
Liver Area around central vein (zone III)
Colon Splenic flexure, rectuma
▪ Watershed areas (border zones) receive blood supply from most distal branches of 2 arteries with
limited collateral vascularity. These areas are susceptible to ischemia from hypoperfusion.
▪ Neurons most vulnerable to hypoxic-ischemic insults include Purkinje cells of the cerebellum and
pyramidal cells of the hippocampus and neocortex (zones 3, 5, 6).
Infarcts: red vs pale
A. Red infarct:
▪ Occurs in venous occlusion and tissues with multiple blood supplies (liver, lung, intestine, testes), and
with reperfusion (after angioplasty).
▪ Reperfusion injury is due to damage by free radicals. Red = reperfusion
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B. Pale infarct:
▪ Occurs in solid organs with a single (endarterial) blood supply (heart, kidney).
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Free radical injury
▪ Free radicals damage cells via membrane lipid peroxidation, protein modification, and DNA breakage.
▪ Initiated via radiation exposure (cancer therapy), metabolism of drugs (phase I), redox reactions, nitric
oxide, transition metals, WBC (neutrophils, macrophages) oxidative burst.
▪ Free radicals can be eliminated by scavenging enzymes (catalase, superoxide dismutase, glutathione
peroxidase), spontaneous decay, antioxidants (vitamins A, C, E), and certain metal carrier proteins
(transferrin, ceruloplasmin).
▪ Examples:
- Oxygen toxicity: retinopathy of prematurity (abnormal vascularization), bronchopulmonary dysplasia,
reperfusion injury after thrombolytic therapy.
- Drug/chemical toxicity: acetaminophen overdose (hepatotoxicity), carbon tetrachloride (converted

by cytochrome P-450 into CCl3 free radical → fatty liver [cell injury → ↓ apolipoprotein synthesis →
fatty change], centrilobular necrosis)
- Metal storage diseases: hemochromatosis (iron) and Wilson disease (copper)
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Inflammation
▪ Response to eliminate initial cause of cell injury, to remove necrotic cells resulting from the original
insult, and to initiate tissue repair.
▪ Divided into acute and chronic.
▪ The inflammatory response itself can be harmful to the host if the reaction is excessive (septic
shock), prolonged (persistent infections such as TB), or inappropriate (autoimmune diseases such
as SLE).
▪ Cardinal signs of inflammation:
Sign Mechanism Mediators

Rubor (redness), calor Vasodilation (relaxation of Histamine,
(warmth) arteriolar smooth muscle) → ↑ prostaglandins,
blood flow. bradykinin, NO.
Tumor (swelling) Endothelial contraction/disruption Endothelial
(from tissue damage) → ↑ vascular contraction:
permeability → leakage of protein- leukotrienes (C4, D4,
rich fluid from postcapillary venules E4), histamine,
into interstitial space (exudate) → serotonin.
↑ interstitial oncotic pressure.
Dolor (pain) Sensitization of sensory nerve Bradykinin, PGE2,
endings. histamine.
Functio laesa (loss of Cardinal signs above impair
function) function (inability to make fist with
hand that has cellulitis).
▪ Systemic manifestations (acute-phase reaction):

A. Fever:
- Pyrogens (LPS) induce macrophages to release IL-1 and TNF → ↑ COX activity in perivascular cells of
hypothalamus → ↑ PGE2 → ↑ temperature set point.
B. Leukocytosis:
- Elevation of WBC count.
- Type of cell that is predominantly elevated depends on the inciting agent or injury (bacteria → ↑
neutrophils).
C. ↑ plasma acute-phase proteins:

- Factors whose serum concentrations change significantly in response to inflammation.
- Produced by the liver in both acute and chronic inflammatory states. Notably induced by IL-6.
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▪ Acute phase reactants [More FFiSH in the C (sea):

A. Positive (upregulated):
- Ferritin: Binds and sequesters iron to inhibit microbial iron scavenging.
- Fibrinogen: Coagulation factor; promotes endothelial repair; correlates with ESR.
- Serum amyloid A: Prolonged elevation can lead to amyloidosis.
- Hepcidin: ↓ iron absorption (by degrading ferroportin) and ↓ iron release (from macrophages) →
anemia of chronic disease.
- C-reactive protein: Opsonin; fixes complement and facilitates phagocytosis. Measured clinically as a
nonspecific sign of ongoing inflammation.
B. Negative (Downregulated):
- Albumin: Reduction conserves amino acids for positive reactants.
- Transferrin: Internalized by macrophages to sequester iron.
Erythrocyte sedimentation rate
▪ RBCs normally remain separated via ⊝ charges.
▪ Products of inflammation (fibrinogen) coat RBCs → ↓ ⊝ charge → ↑ RBC aggregation.
▪ Denser RBC aggregates fall at a faster rate within a pipette tube → ↑ ESR.
▪ Often co-tested with CRP (more specific marker of inflammation).

↑ ESR ↓ ESR
Most anemias Sickle cell anemia (altered shape)
Infections Polycythemia (↑ RBCs “dilute” aggregation
Inflammation (giant cell [temporal] arteritis, factors)
polymyalgia rheumatica) HF
Cancer (metastases, multiple myeloma) Microcytosis
Renal disease (end-stage or nephrotic Hypofibrinogenemia
syndrome)
Pregnancy
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Exudate vs transudate
Exudate Transudate
Cellular (cloudy) Hypocellular (clear)
↑ protein (> 2.9 g/dL) ↓ protein (< 2.5 g/dL)
Due to: Due to:
Lymphatic obstruction (chylous) ↑ hydrostatic pressure (HF, Na retention)
Inflammation/infection ↓ oncotic pressure (cirrhosis, nephrotic
Malignancy syndrome)
▪ Light criteria:
- Pleural fluid is exudative if ≥ 1 of the following criteria is met:
o Pleural fluid protein/serum protein ratio > 0.5.
o Pleural fluid LDH/serum LDH ratio > 0.6.
o Pleural fluid LDH > 2⁄3 of the upper limit of normal for serum LDH.
- Exudate = Excess protein and LDH.
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General Pharmacology
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Chapter 2 General Pharmacology
Pharmacokinetics
▪ Pharmacokinetic characteristics of drug molecules concern the processes of absorption, distribution,

metabolism, and excretion.
Permeation
▪ Drug permeation is dependent on:

A. Solubility:
- Ability to diffuse through lipid bilayers (lipid solubility) is important for most drugs.
B. Concentration gradient:
- Diffusion down a concentration gradient.
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C. Surface area and vascularity:

- Important with regard to absorption of drugs into the systemic circulation.
- The larger the surface area and the greater the vascularity, the better is the absorption of the drug
(stomach VS. small intestine) (IM Vs Subcutaneous).
▪ Ionization:
- Many drugs are weak acids or weak bases and can exist in either nonionized or ionized forms in an
equilibrium, depending on the pH of the environment and the pKa (the pH at which the molecule is
50% ionized and 50% nonionized).
- Only the nonionized (uncharged) form of a drug crosses biomembranes.
- The ionized form is better renally excreted because it is water soluble.
▪ In a nutshell:
- Weak acids: aspirin, penicillin, cephalosporin, loop and thiazide diuretics.
- Weak bases: morphine, local anesthetic, amphetamine and phencyclidine (PCP).
- For Weak Acids and Weak Bases:
o Ionized = Water soluble.
o Nonionized = Lipid soluble.
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▪ Ionization Increases Renal Clearance of Drugs:

- Only free, unbound drug is filtered.
- Both ionized and nonionized forms of a drug are filtered.
- Only nonionized forms undergo active secretion and active or passive reabsorption.
- Ionized forms of drugs are “trapped” in the filtrate.
- Acidification of urine → increases ionization of weak bases (Amphetamine, PCP) → increases renal
elimination.
- Alkalinization of urine → increases ionization of weak acids (Aspirin)→ increases renal elimination.
- To Change Urinary Ph:

o Acidify: NH4Cl, vitamin C, cranberry juice.
o Alkalinize: NaHCO3, acetazolamide.
- If you want to increase the absorption of a drug or to decrease its clearance → put it in the same Ph,
but if you want to increase its clearance → put it in the opposite Ph.
- Gut bacteria metabolize lactulose to lactic acid, acidifying the fecal masses and causing ammonia (NH3)
to become ammonium (NH4). Therefore, lactulose is useful in hepatic encephalopathy.
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▪ Modes of Drug Transport Across a Membrane:

Mechanism Direction Energy required Carrier Saturable
Passive Down gradient No No No
diffusion
Facilitated Down gradient No Yes Yes
Diffusion
Active transport Against gradient Yes Yes Yes
(concentration/
electrical)
Absorption
▪ Concerns the processes of entry of a drug into the systemic circulation from the site of its
administration.
▪ The determinants of absorption are those described for drug permeation.
▪ Intravascular administration (IV) does not involve absorption, and there is no loss of drug
(Bioavailability = 100%).
▪ With extravascular administration (per os [PO; oral], intramuscular [IM], subcutaneous [SC], inhalation),
less than 100% of a dose may reach the systemic circulation because of variations in bioavailability.
▪ Bioavailability (f):
- Measure of the fraction of a dose that reaches the systemic circulation.
- By definition, intravascular doses have 100% bioavailability, f = 1.
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▪ First-Pass Effect:
- With oral administration, drugs are absorbed into the portal circulation and initially distributed to the
liver. For some drugs, their rapid hepatic metabolism decreases bioavailability (the “first-pass” effect).
- Examples:
o Lidocaine (IV vs. PO).
o Nitroglycerin (sublingual).
▪ Oral bioavailability is dependent on the absorptive properties of the drug as well as its first-pass
metabolism.
▪ When a drug is absorbed by the Gl tract after oral administration, it first enters the portal circulation
before gaining access to the systemic circulation.
▪ If the drug is metabolized extensively by the liver (high first-pass metabolism), the amount that reaches
the systemic circulation, and therefore the bioavailability, will be low.
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▪ In order to efficiently use drugs with a high first-pass metabolism, other routes of administration are
typically employed.
▪ For instance, nitroglycerin can be used for preventing or treating anginal pain, but because it has a very
high first-pass metabolism, not enough drug reaches systemic circulation to be effective. To circumvent
this shortcoming, nitroglycerin tablets are given sublingually, where they bypass the first-pass
metabolism by entering the systemic circulation directly via the sublingual capillaries and arterioles.
▪ Long-acting isosorbide dinitrate is absorbed via the gastrointestinal tract and undergoes extensive first-
pass metabolism in the liver prior to release in the systemic circulation. This leads to low bioavailability
and the need for much higher doses of oral formulations as compared to sublingual nitroglycerin.
▪ Propranolol and lidocaine also have a very high first-pass metabolism and thus have better
bioavailability through IV or subcutaneous methods.
❖ N.B:
▪ Rectal drug administration, such as with suppositories, partially bypasses first-pass metabolism. Recall
that the rectum is drained by the superior, middle and inferior rectal veins.
▪ The superior rectal veins drain to the portal circulation via the inferior mesenteric vein.
▪ The middle and inferior rectal veins, however, drain to the systemic circulation via the internal iliac and
internal pudendal veins, respectively.
▪ Thus, two-thirds of the venous drainage of the rectal region goes directly into the systemic circulation,
thereby increasing the bioavailability of drugs that are otherwise highly cleared by the liver after oral
administration.
▪ The amount of drug exposed to the liver within the portal blood flow is the major determinant of
hepatic or first-pass metabolism.
▪ Oral administration subjects a drug to a large amount of first-pass metabolism, whereas IV, sublingual,
and rectal administration bypasses some or all of this process and allows more drug to reach the
systemic circulation.
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Distribution
▪ The processes of distribution of a drug from the systemic circulation to organs and tissue.
▪ Conditions affecting distribution include:

- Many drugs bind to plasma proteins, including albumin, with an equilibrium between bound and free
molecules (recall that only unbound drugs cross biomembranes).
- Competition between drugs for plasma protein-binding sites may increase the “free fraction,” possibly
enhancing the effects of the drug displaced.
- Example: sulfonamides and bilirubin in a neonate.
▪ Apparent Volume of Distribution (Vd):

- A kinetic parameter of a drug that correlates dose with plasma level at zero time.
𝐷𝑜𝑠𝑒
Vd = where C0 = [plasma] at zero time (Initial plasma concentration).
𝐶0
- This relationship can be used for calculating Vd by using the dose only if one knows C0.
- Vd is low when a high percentage of a drug is bound to plasma proteins.
- Vd is high when a high percentage of a drug is being sequestered in tissues.
▪ Approximate Vd Values (weight 70 kg):

- Plasma volume (3 L).
- Blood volume (5 L).
- Extracellular fluid (ECF 12-14 L).
- Total body water (TBW 40-42 L).
▪ Characteristics of a drug such as high molecular weight, high plasma protein binding, high charge, and
hydrophilicity tend to trap the drug in the plasma compartment resulting in a low Vd.
▪ Drugs that are avidly bound in the tissues exhibit the highest volumes of distribution, often much
higher than the total body water volume (41 liters), because these drugs accumulate readily within cells
thereby maintaining low plasma concentrations.
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▪ Redistribution:
- In addition to crossing the blood-brain barrier (BBB), lipid-soluble drugs redistribute into fat tissues
prior to elimination.
- In the case of CNS drugs, the duration of action of an initial dose may depend more on the
redistribution rate than on the half-life.
- With a second dose, the blood/fat ratio is less; therefore, the rate of redistribution is less and the
second dose has a longer duration of action.
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Biotransformation
▪ The general principle of biotransformation is the metabolic conversion of drug molecules to more
water-soluble metabolites that are more readily excreted.
▪ In many cases, metabolism of a drug results in its conversion to compounds that have little or no
pharmacologic activity (Drug → Inactive metabolite).
- In other cases, biotransformation of an active compound may lead to the formation of metabolites that
also have pharmacologic actions (Drug → Active metabolite).
▪ A few compounds (prodrugs) have no activity until they undergo metabolic activation (Prodrug →
drug).
❖ Biotransformation Classification:
▪ There are two broad types of biotransformation, called phase I and phase II.
i. Phase I:
▪ Definition:
- Modification of the drug molecule via oxidation, reduction, or hydrolysis.
1. Microsomal metabolism (Cytochrome P450 isozymes):

- These are major enzyme systems involved in phase I reactions.
- General inducers: anticonvulsants (barbiturates, phenytoin, carbamazepine), antibiotics (rifampin),

chronic alcohol.
- General inhibitors: antiulcer medications (cimetidine, omeprazole), antimicrobials (chloramphenicol,

macrolides, ritonavir, ketoconazole), acute alcohol.
- Grapefruit juice has active components that inhibit metabolism of many drugs including statins.
2. Non-microsomal metabolism:
A. Hydrolysis:
- Phase I reaction involving addition of a water molecule with subsequent bond breakage.
- Includes esterases and amidases.
B. Monoamine oxidases:
- Metabolism of endogenous amine neurotransmitters (dopamine, norepinephrine, and serotonin)
- Metabolism of exogenous compounds (tyramine)
C. Alcohol metabolism:
- Alcohols are metabolized to aldehydes and then to acids by dehydrogenases.
- Genetic polymorphisms exist
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ii. Phase II:

▪ Definition:
- Conjugation with endogenous compounds via the activity of transferases.
▪ May follow phase I or occur directly.
▪ Types of conjugation:
A. Glucuronidation:
- Inducible.
- Reduced activity in neonates.
- Examples: morphine and chloramphenicol.
B. Acetylation:
- Genotypic variations (fast and slow metabolizers).
- Drug-induced SLE by slow acetylators with hydralazine > procainamide > isoniazid (INH)
C. Glutathione (GSH) conjugation:

- Depletion of GSH in the liver is associated with acetaminophen hepatotoxicity.
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Elimination
▪ Concerns the processes involved in the elimination of drugs from the body (and/ or plasma) and their
kinetic characteristics.
▪ The major modes of drug elimination are:

- Biotransformation to inactive metabolites.
- Excretion via the kidney.
- Excretion via other modes, including the bile duct, lungs, and sweat.
▪ t1/2:
- Time to eliminate 50% of a given amount (or to decrease plasma level to 50% of a former level) is called
the elimination half-life.
A. Zero-Order Elimination Rate:

- A constant amount of drug is eliminated per unit time; for example, if 80 mg is administered and 10 mg
is eliminated every 4 h, the time course of drug elimination is:
- Rate of elimination is independent of plasma concentration (or amount in the body).
- Drugs with zero-order elimination have no fixed half-life (t1/2 is a variable).
- Drugs with zero-order elimination include ethanol (except low blood levels), phenytoin (high
therapeutic doses), and salicylates (toxic doses).
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B. First-Order Elimination Rate:

- A constant fraction of the drug is eliminated per unit time. Graphically, first-order elimination follows
an exponential decay versus time.
- For example, if 80 mg of a drug is administered and its elimination half-life = 4 h, the time course of its
elimination is:
- Rate of elimination is directly proportional to plasma level (or the amount present). The higher the
amount, the more rapid the elimination.
- Most drugs follow first-order elimination rates.
▪ t1/2 is a constant.
▪ Elimination Kinetics:
- Most drugs follow first order: rate falls as plasma level falls.
- Zero order is due to saturation of elimination mechanisms; drug metabolizing reactions have reached
Vmax.
Zero order → elimination rate is constant; t1/2 is a variable
First order → elimination rate is variable; t1/2 is a constant
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▪ Graphic Analysis:
- Example of a graphic analysis of t1/2:
- The elimination half-life (t1/2) and the theoretical plasma concentration at zero time (C0) can be
estimated from the graphic relationship between plasma concentrations and time.
▪ Steady state:
- Steady state is reached either when rate in = rate out or when values associated with a dosing interval
are the same as those in the succeeding interval.
▪ Plateau Principle:
- The time to reach steady state is dependent only on the elimination half-life of a drug and is
independent of dose size and frequency of administration, assuming the drug is eliminated by first-
order kinetics.
- The Figure below shows plasma levels (solid lines) achieved following the IV bolus.
- Administration of 100 units of a drug at intervals equivalent to every half-life t1/2 = 4 h. With such
intermittent dosing, plasma levels oscillate through peaks and troughs, with averages shown in the
diagram by the dashed line.
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▪ Time and Steady State:

- 50% = 1 × half-life
- 90% = 3.3 × half-life
- 95% = 4–5 × half-life
- 100% = >7 × half-life
▪ Note: Although it takes > 7 t1/2 to reach mathematical steady state, by convention clinical steady state is
accepted to be reached at 4–5 t1/2.
▪ Rate of Infusion:
- The Figure below shows the increases in plasma levels of the same drug infused at five different rates.
Regardless of the rate of infusion, it takes the same amount of time to reach steady state.
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- Rate of infusion does determine plasma level at steady state. If the rate of infusion is doubled, then the
plasma level of the drug at steady state is doubled.
▪ Effect of Loading Dose:

- It takes 4-5 half-lives to achieve steady state.
- In some situations, it may be necessary to give a higher dose (loading dose) to more rapidly achieve
effective blood levels (Cp).
- Such loading doses are often one time only and are estimated to put into the body the amount of drug
that should be there at a steady state.
- The loading dose equation can be used to calculate the amount of drug in the body at any time by
knowing the Vd and the plasma concentration.
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Michaelis-Menten Equation
▪ The Michaelis-Menten equation describes how the rate of the reaction, V, depends on the
concentration of both the enzyme [E] and the substrate [S], which forms product [P].
▪ Vmax is the maximum rate possible to achieve with a given amount of enzyme.
▪ The only way to increase Vmax is by increasing the [E]. In the cell, this can be accomplished by inducing
the expression of the gene encoding the enzyme.
▪ The other constant in the equation, Km is often used to compare enzymes. Km is the substrate
concentration required to produce half the maximum velocity.
▪ Under certain conditions, Km is a measure of the affinity of the enzyme for its substrate. When
comparing two enzymes, the one with the higher Km has a lower affinity for its substrate.
▪ The Km value is an intrinsic property of the enzyme-substrate system and cannot be altered by changing
[S] or [E].
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Lineweaver-Burk Equation
▪ The Lineweaver-Burk equation is a reciprocal form of the Michaelis-Menten equation. The same data
graphed yield a straight line, as shown below.
▪ The actual data are represented by the portion of the graph to the right of the y-axis, but the line is
extrapolated into the left quadrant to determine its intercept with the x-axis.
▪ The intercept of the line with the x-axis gives the value of -1/Km.
▪ The intercept of the line with the y-axis gives the value of 1/Vmax.
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Pharmacodynamics
▪ Pharmacodynamics relates to drugs binding to receptors and their effects.
▪ Agonist: A drug is called an agonist when binding to the receptor results in a response.
▪ Antagonist: A drug is called an antagonist when binding to the receptor is not associated with a
response. The drug has an effect only by preventing an agonist from binding to the receptor.
▪ Affinity: ability of drug to bind to receptor, shown by the proximity of the curve to the y axis (if the
curves are parallel); the nearer the y axis, the greater the affinity.
▪ Potency: shows relative doses of two or more agonists to produce the same magnitude of effect, again
shown by the proximity of the respective curves to the y axis (if the curves do not cross).
▪ Efficacy: a measure of how well a drug produces a response (effectiveness), shown by the maximal
height reached by the curve.
▪ Graded (quantitative) dose-response (D-R) Curves:

- Plots of dose (or log dose) versus response for drugs (agonists) that activate receptors can reveal
information about affinity, potency, and efficacy of these agonists.
▪ It may be seen from the log dose-response curves that:

1. When two drugs interact with the same receptor (same pharmacologic mechanism), the D-R curves will
have parallel slopes. Drugs A and B have the same mechanism; drugs X and Y do not.
2. Affinity can be compared only when two drugs bind to the same receptor. Drug A has a greater affinity
than drug B.
3. In terms of potency, drug A has greater potency than drug B, and X is more potent than Y.
4. In terms of efficacy, drugs A and B are equivalent. Drug X has greater efficacy than drug Y.
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▪ Full and Partial Agonists:

- Full agonists produce a maximal response (they have maximal efficacy).
- Partial agonists are incapable of eliciting a maximal response and are less effective than full agonists.
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▪ Duality of Partial Agonists:

- In the Figure below, the lower curve represents effects of a partial agonist when used alone: its ceiling
effect = 50% of maximal in this example.
- The upper curve shows the effect of increasing doses of the partial agonist on the maximal response
(100%) achieved in the presence of or by pretreatment with a full agonist.
- As the partial agonist displaces the full agonist from the receptor, the response is reduced (the partial
agonist is acting as an antagonist).
▪ Antagonism and Potentiation:
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A. Pharmacologic antagonism (same receptor):

1. Competitive antagonists:
- Cause a parallel shift to the right in the D-R curve for agonists.
- Can be reversed by ↑ the dose of the agonist drug.
- Appears to ↓ the potency of the agonist.
2. Noncompetitive antagonists:
- Cause a nonparallel shift to the right.
- Can be only partially reversed by ↑ the dose of the agonist.
- Appear to ↓ the efficacy of the agonist.
B. Physiologic antagonism (different receptor):

- Two agonists with opposing action antagonize each other.
- Example: a vasoconstrictor with a vasodilator.
C. Chemical antagonism:
- Formation of a complex between effector drug and another compound.
- Example: protamine binds to heparin to reverse its actions.
D. Potentiation:
- Causes a parallel shift to the left to the D-R curve.
- Appears to ↑ the potency of the agonist.
▪ Toxicity and the Therapeutic Index (TI):

- Comparisons between ED50 (median effective dose) and TD50 (median toxic dose) values permit
evaluation of the relative safety of a drug (the therapeutic index), as would comparison between ED50
and the lethal median dose (LD50) if the latter is known.
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❖ N.B:
▪ Vasoconstriction by α-adrenergic agonists is prominent in the vessels of the nasal mucosa, making
these medications effective decongestants.
▪ Phenylephrine, xylometazoline, and oxymetazoline are used as topical preparations for the treatment
of allergic rhinitis and common cold associated congestion and rhinitis.
▪ These medications, however, are characterized by rapidly declining effect after a few days of use. This
phenomenon is called tachyphylaxis.
▪ It occurs because of decreased production of endogenous norepinephrine from the nerve terminals
due to a negative feedback mechanism, resulting in relative vasodilation (removal of normal
vasoconstrictive tone) and subsequent edema and congestion. This leads to exacerbation of the nasal
congestion symptoms.
▪ Rebound rhinorrhea is associated with the use of topical decongestants for > 3 days. The use of
adrenergic agonists should be stopped to allow the restoration of normal norepinephrine feedback
pathways.
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The Autonomic Nervous System

(ANS)
▪ Anatomy of the ANS:
- The ANS is the major involuntary portion of the nervous system and is responsible for automatic,
unconscious bodily functions, such as control of heart rate and blood pressure and both
gastrointestinal and genitourinary functions.
- The ANS is divided into two major subcategories: the parasympathetic autonomic nervous system
(PANS) and the sympathetic autonomic nervous system (SANS).
▪ Location of ANS Ganglia:

- Both the PANS and SANS have relay stations, or ganglia, between the CNS and the end organ, but the
somatic system does not.
- An important anatomic difference between the SANS and PANS is that the ganglia of the former lie in
two paravertebral chains adjacent to the vertebral column, whereas most of the ganglia of the PANS
system are located in the organs innervated.
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▪ The Figure above highlights the major features of the ANS and the somatic systems and also
shows the location of the major receptor types. These are:
- NN: Nicotinic receptors are located on cell bodies in ganglia of both PANS and SANS and in the adrenal
medulla.
- NM: Nicotinic receptors are located on the skeletal muscle motor end plate innervated by somatic
motor nerves.
- M1–3: Muscarinic receptors are located on all organs and tissues innervated by postganglionic nerves of
the PANS and on thermoregulatory sweat glands innervated by the SANS.
▪ Neurotransmitters:
- Acetylcholine (ACh) is the neurotransmitter at both nicotinic and muscarinic receptors in tissues that
are innervated.
- Note that all direct transmission from the CNS (preganglionic and motor) uses ACh, but postganglionic
transmission in the SANS system may use one of the organ-specific transmitters described below.
- Norepinephrine (NE) is the neurotransmitter at most adrenoceptors in organs, as well as in cardiac and
smooth muscle.
- Dopamine (DA) activates D1 receptors, causing vasodilation in renal and mesenteric vascular beds.
- Epinephrine (E, from adrenal medulla) activates most adrenoceptors and is transported in the blood.
▪ ACh receptors:
- Nicotinic ACh receptors:
o NN (found in autonomic ganglia, adrenal medulla) and NM (found in neuromuscular junction of skeletal
muscle).
- Muscarinic ACh receptors:

o G-protein–coupled receptors that usually act through 2nd messengers.
o 5 subtypes: M1-5 found in heart, smooth muscle, brain, exocrine glands, and on sweat glands
(cholinergic sympathetic).
❖ N.B:
1. Adrenal medulla is directly innervated by preganglionic sympathetic fibers.
2. Sweat glands are part of the sympathetic pathway but are innervated by cholinergic fibers (sympathetic
nervous system results in a “chold” sweat).
55
Drug Receptors Linked Via Coupling Proteins to Intracellular Effectors
▪ Many receptor systems are coupled via GTP-binding proteins (G-proteins) to adenylyl cyclase, the
enzyme that converts ATP to cAMP, a second messenger that promotes protein phosphorylation by
activating protein kinase A.
▪ Protein kinase A serves to phosphorylate a set of tissue-specific substrate enzymes or transcription

factors (CREB), thereby affecting their activity.
A. Gs proteins:
- Binding of agonists to receptors linked to Gs proteins increases cAMP production.
- Such receptors include those for catecholamines (beta), dopamine (D1), glucagon, histamine (H2),
prostacyclin, and some serotonin subtypes.
B. Gi proteins:
- Binding of agonists to receptors linked to Gi proteins decreases cAMP production.
- Such receptors include adrenoreceptors (α2), ACh (M2), dopamine (D2 subtypes), and several opioid and
serotonin subtypes.
C. Gq proteins:
- Other receptor systems are coupled via GTP-binding proteins (Gq), which activate phospholipase C.
- Activation of this enzyme releases the second messengers inositol triphosphate (IP3) and diacylglycerol
(DAG) from the membrane phospholipid phosphatidylinositol bisphosphate (PIP2).
- The IP3 induces release of Ca from the sarcoplasmic reticulum (SR), which, together with DAG, activates
protein kinase C.
- The protein kinase C serves then to phosphorylate a set of tissue-specific substrate enzymes, usually
not phosphorylated by protein kinase A, and thereby affects their activity.
▪ β1, β2, β3, D1: Gs activation of adenylyl cyclase.
▪ M2, α2, D2: Gi inhibition of adenylyl cyclase.
▪ M1, M3, α1: Gq activation of phospholipase C.
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Cholinergic Pharmacology
59
▪ Choline is accumulated in cholinergic presynaptic nerve endings via an active transport mechanism.
▪ Choline uptake is inhibited by hemicholinium.
▪ Ach is synthesized from choline and acetyl-CoA via choline acetyltransferase (ChAT) and accumulates in
synaptic vesicles.
▪ Presynaptic membrane depolarization opens voltage-dependent Ca channels, and the influx of this ion
causes fusion of the synaptic vesicle membranes with the presynaptic membrane, leading to exocytosis
of ACh.
▪ Vesamicol: Inhibits vesicular acetylcholine transporter (VAT) preventing the storage of acetylcholine.
▪ Botulinum toxin interacts with synaptobrevin and other proteins to prevent ACh release and is used in
blepharospasm, strabismus/hyperhydrosis, dystonia, and cosmetics.
▪ Some cholinergic nerve endings have presynaptic autoreceptors for Ach that on activation may elicit a
negative feedback of transmitter release.
▪ Inactivation via acetylcholinesterase (AChE) is the major mechanism of termination of postjunctional

actions of ACh.
▪ AChE is a target for inhibitory drugs (indirect-acting cholinomimetics).
▪ Postjunctional receptors (N and M) activated by ACh are major targets for both activating drugs (direct-
acting cholinomimetics) and blocking agents.
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61
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63
Adrenergic pharmacology
64
▪ Tyrosine is actively transported into nerve endings and is converted to dihydroxyphenylalanine (DOPA)
via tyrosine hydroxylase. This step is rate limiting in the synthesis of NE.
▪ DOPA is converted to dopamine (DA) via DOPA decarboxylase.
▪ DA is taken up into storage vesicles where it is metabolized to NE via DA beta hydroxylase.
▪ Presynaptic membrane depolarization opens voltage-dependent Ca channels. Influx of this ion causes
fusion of the synaptic granular membranes, with the presynaptic membrane leading to NE exocytosis
into the neuroeffector junction.
▪ NE then activates post-junctional receptors, leading to tissue-specific responses depending on the

adrenoceptor subtype activated.
▪ Termination of NE actions is mainly due to removal from the neuroeffector junction back into the
sympathetic nerve ending via NE reuptake transporter system.
▪ Metabolism of NE is by catechol-O-methyltransferase (COMT) in the synapse or MAO-A in the

prejunctional nerve terminal.
▪ At some sympathetic nerve endings, the NE released may activate prejunctional alpha adrenoceptors
involved in feedback regulation, which results in decreased release of the neurotransmitter.
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67
▪ Differentiation of high-dose epinephrine versus norepinephrine:

- Epinephrine reversal: Use of α1 blocker to reverse hypertension to hypotension in a patient receiving
too much epinephrine
- Hypertension was due to predominant α1 tone on the vasculature
- Hypotension results from unmasking β2 receptors
68
▪ Tyramine:
- Normally degraded by monoamine oxidase (MAO) in the gastrointestinal tract.
- Levels ↑ in patients taking MAO inhibitors who ingest tyramine-rich foods (old cheese, red wine).
- Excess tyramine enters presynaptic vesicles and displaces other neurotransmitters (NE) → ↑ active
presynaptic neurotransmitters → ↑ diffusion of neurotransmitters into synaptic cleft → ↑
sympathetic stimulation.
- Classically results in a hypertensive crisis.
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EL Husseiny's Essentials for USMLE step 1 Internal Medicine
Normal Lab Values
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Chapter 16 Normal Lab Values
Retinal Diseases
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What are the different types of cell death?

What are the different types of cell death?

What are the different types of necrosis?

What are the different types of necrosis?

EL Husseiny's Essentials BOOKSTORES

BOOKSTORES EL Husseiny's Essentials

▪ The two mechanisms of cell death are necrosis and apoptosis.

▪ Death of large groups of cells followed by acute inflammation (unlike apoptosis).

▪ Due to some underlying pathologic process; never physiologic.

▪ Divided into several types based on gross features.

▪ Characteristic of ischemic infarction of any organ except the brain.

▪ Combination of coagulative and liquefactive necrosis.

▪ Characteristic of granulomatous inflammation due to tuberculous or fungal infection.

▪ Characteristic of trauma to fat (breast) and pancreatitis-mediated damage of peripancreatic fat.

▪ Saponification is an example of dystrophic calcification in which calcium deposits on dead tissues. In

▪ Characteristic of malignant hypertension and vasculitis.

▪ Characteristic of ischemia of lower limb and GI tract.

▪ ATP-dependent programmed cell death.

▪ DNA laddering (fragments in multiples of 180 bp) is a sensitive indicator of apoptosis.

A. Intrinsic (mitochondrial) pathway:

- Also occurs after exposure to injurious stimuli (radiation, toxins, hypoxia).

B. Extrinsic (death receptor) pathway:

▪ Tends to be localized (calcific aortic stenosis).

▪ Patients are usually not normocalcemic.

A. Reversible cell injury:

▪ Ribosomal/polysomal detachment → ↓ protein synthesis.

▪ Plasma membrane changes (blebbing).

▪ Nuclear changes (chromatin clumping).

B. Irreversible cell injury:

▪ Mitochondrial damage/dysfunction → loss of electron transport chain → ↓ ATP.

▪ Rupture of lysosomes → autolysis.

▪ Nuclear degradation: pyknosis (nuclear condensation) → karyorrhexis (nuclear fragmentation caused

▪ Inadequate blood supply to meet demand.

▪ Mechanisms include ↓ arterial perfusion (atherosclerosis), ↓ venous drainage (testicular torsion,

▪ Regions most vulnerable to hypoxia/ischemia and subsequent infarction:

Brain ACA/MCA/PCA boundary areas

Heart Subendocardium (LV)

Kidney Straight segment of proximal tubule

Thick ascending limb (medulla)

Liver Area around central vein (zone III)

Colon Splenic flexure, rectuma

Infarcts: red vs pale

▪ Reperfusion injury is due to damage by free radicals. Red = reperfusion

Free radical injury

- Drug/chemical toxicity: acetaminophen overdose (hepatotoxicity), carbon tetrachloride (converted

- Metal storage diseases: hemochromatosis (iron) and Wilson disease (copper)

▪ Divided into acute and chronic.

▪ Cardinal signs of inflammation:

Sign Mechanism Mediators

▪ Systemic manifestations (acute-phase reaction):

C. ↑ plasma acute-phase proteins:

▪ Acute phase reactants [More FFiSH in the C (sea):

- Fibrinogen: Coagulation factor; promotes endothelial repair; correlates with ESR.

- Serum amyloid A: Prolonged elevation can lead to amyloidosis.

- Transferrin: Internalized by macrophages to sequester iron.

Erythrocyte sedimentation rate

▪ RBCs normally remain separated via ⊝ charges.

▪ Products of inflammation (fibrinogen) coat RBCs → ↓ ⊝ charge → ↑ RBC aggregation.

▪ Often co-tested with CRP (more specific marker of inflammation).