Drugs Acting on the

Autonomic Nervous System

(Sympathetic Agents)
Part 1
Divisions of the Nervous System
CONVENTIONAL DIVISION
Central Nervous System (CNS)
Brain to spinal cord

Peripheral Nervous System (PNS)

Neuronal tissues outside the CNS
Divisions of the Nervous System
DIVISION OF THE MOTOR (EFFERENT)
PORTION
SOMATIC AUTONOMIC
Movements Controlled Voluntary Involuntary
No. of Neurons 1 neuron 2 neurons
Type of Neurons Cholinergic Cholinergic, Adrenergic
Ganglia No ganglia With ganglia
Cell Body Found in the CNS 1 in each (CNS, PNS)
Action Produced Excitatory Inhibitory
Divisions of the ANS
Sympathetic
Parasympathetic
Enteric
Located at the walls of the GIT from the esophagus to
the distal colon
 Includes 2 Plexuses:
 Myenteric Plexus (Auerbach)
 Submucous Plexus (Meissner)
Functions in a semiautonomous manner
Neurotransmitters: ATP, VIP, Substance P, Neuropeptide
Y
Divisions of the ANS
Sympathetic vs. Parasympathetic
(Anatomy & Physiology)
Sympathetic Parasympathetic
Other name Adrenergic NS Cholinergic
Origin of roots in the CNS Thoraco – Lumbar Cranio – Sacral
(T1 – T12; L1 – L2) (CN III, VII, IX, X; S1 – S4)
Location of Ganglia Near the spinal cord Near the end organ
Length of Neurons Pregang – Short Pregang – Long
Postgang – Long Postgang – Short
Degree of Branching 1:20 1:1
Receptors
Ganglionic Nicotinic (N1) Nicotinic (N1)
End Organ Alpha , Beta N2, Muscarinic (M)
Neurotransmitters Dopamine (D),
Preganglionic Acetylcholine (ACh) ACh
Postganglionic NE, Epi, Dopamine ACh
Divisions of the ANS
Sympathetic vs. Parasympathetic
(Anatomy & Physiology)
Divisions of the ANS
Sympathetic vs. Parasympathetic
(Organ Effect)
Sympathetic Parasympathetic
Unifying Concept Fight, Flight, Fright Rest & Digest
Heart Inc. HR Dec. HR
Inc. Contraction Dec. Contraction
Eye (Pupils) Mydriasis Miosis
Lungs (Bronchial S.M.) Bronchodilation Bronchoconstriction
Dec. secretions Inc. Secretions
GIT
Intestinal sm Relaxation Contraction
Sphincter sm Contraction Relaxation
GUT
Bladder sm Relaxation Contraction
Trigone Sphincters Contraction Relaxation
Divisions of the ANS
Sympathetic vs. Parasympathetic
(Unique Features)
Sympathetic Parasympathetic
Sym & Parasym Tone Vascular system HR, digestive system,
Urinary Tract
Organs/tissues supplied only  Adrenal Medulla
with Sym. Fibers  Sweat Glands (Apocrine) Sweat Glands (Eccrine)
 Arrector Pili muscles
 Kidneys
 Most BV

Thermoregulatory Response to  Dilation of the skin vasculature

Heat (high temp); Constriction (cold
temp)
 Sweat glands

Metabolic Effects  Inc. Metabolic rate

 inc. Blood glucose
 Inc. Lipolysis

Cooperative Effects Ejaculation Erection

 The Sympathetic NS
Biosynthesis of NE

Tyrosine  DOPA  Dopamine  NE

Note (Enzymes):
 Tyrosine  DOPA: Tyrosine
Hydroxylase
 This is the rate-limiting step
 DOPA  Dopamine: Dopa
Decarboxylase
 Dopamine  NE: Dopamine B-
hydroxylase

 NE can be converted to Epi by the

enzyme Phenylethanolamine N-methyl
Transferase (PNMT)
 The Sympathetic NS
Adrenergic Transmission
Fate of the Catecholamines at
the Synaptic Cleft:
 Binding to post-synaptic
receptors

 Metabolism by COMT & MAO

 Reuptake of NE via Uptake 1

Transporters
 The Adrenoceptors
Receptors Location Response
Alpha 1 Smooth Muscles
• Vascular SM / BV Vasoconstriction
• Prostatic SM & Bladder Contraction (esp. in enlarged
Trigone & Sphincters prostate) – urinary retention
• Radial Muscles of the Iris Contraction (shortens) – mydriasis
• Pilomotor SM Contraction – gooseflesh
Alpha 2 Presynaptic
• CNS – inh release of NE Sedation / Depression, peripheral
vasodilation; (-) feedback
Post-synaptic
• Vascular SM Vasoconstriction

Ciliary Muscles Dec aqueous humor

Beta 1 •Heart (+) Inotropic, Chronotropic &
Dromotropic Effect
•JGA (Juxtaglomerular Renin Release
Apparatus)
 The Adrenoceptors

Receptors Location Response

Beta 2 Smooth Muscles
• Bronchial SM Bronchodilation
• Uterine SM Uterine Relaxation – Tocolytics
• Vascular SM Vasodilation
•Intestinal SM Relaxation
• Heart Tachycardia
• Muscle End plate Tremors
• Endothelial Cells Potassium influx
Beta 3 Adipose Tissues Lipolysis
Dopamine Renal and Splanchnic Renal Vasodilation – Increased GFR
(D1) (abdominal) BV Loss of Peristalsis – vomiting
D2 – D4 • CNS Behavior & Perception regulation
Modulation of motor activity
 Adrenergic Drugs

Sympathomimetics

Direct Acting Indirect Acting Mixed Acting

Non-selective

Selective α1
α -blockers
blockers

Selective α2
blockers
Sympatholytics

Non-selective

Β-blockers

β1-selective
 Adrenergic Drugs
Cocaine
Re-Uptake 1
Inhibitors
Norepinephrine TCAs

Indirect Acting
Non-selective Epinephrine Agents Amphetamine

Dopamine Ephedrine

Releasers

Direct Acting Angiotensin II

Agents β-non-selective

Tyramine
B1 selective

Selective B2 - selective
Mixed Acting Agents:
Phenylpropanolamine
a1-selective
Ephedrine
Amphetamine
a2 - selective Hydroxyamphetamine
Propylhexedryl
Pseudoephedrine
Non-selective Sympathetic Agonists
Stimulates alpha, beta and dopamine receptors
Natural Catecholamines (NE, Epi, Dopamine)
Clinical Uses
Epinephrine
 1st
line cardiac stimulant
 Anaphylaxis
o Additional benefit: stabilize cell membrane preventing release of histamine
 Givenwith local anesthetics
 Management of Glaucoma

Norepinephrine
 1st line inotropic in the management of septic shock
Non-selective Sympathetic Agonists
Dopamine
1 – 3 mcg/kg/min  stim. D1 – increased GFR – diuretic
 2-5 mcg/kg/min  additional B1 stimulation – inotropic effect
 > 5 mcg/kg/min  additional A1 stimulation –
vasoconstriction
o Used in the management of septic shock, cardiogenic shock, acute
HF complicated by oliguria or anuria

Common ADRs
Tachyarrythmias (B1 overstimulation)
Peripheral vasoconstriction (AI overstimulation)
Selective Sympathetic Agonists
 Methyldopa (Alpha-methyl-DOPA)
 Prodrug
 False neurotransmitter
 Management of hypertension in pregnancy
 ADRs: sedation, depression, hepatotoxicity (>2g / day);
positive Coomb’s test (Ab that causes hemolytic anemia)

Dopamine1 Selective Agonist

Fenoldopam
 Vasodilator
 Adjunct in the management of Hypertensive crisis
Indirect Acting Sympathomimetics
Increases concentration of NE at the synaptic cleft
Re-uptake Inhibitors
 Inhibit the mechanism of loss of NE at the cleft (TCAs, Cocaine)
Releasers
 Stimulate exocytotic release of NE (amphetamines, ephedrine)

 Ephedrine
 “ma huang”
 Direct receptor agonism at A1, B1, and B2
 Releaser of NE
 Used as nasal decongestant
 Used in the management of Hypotension
 ADR: exacerbate HTN (risk of HTN on px taking MAOIs); risk of
tachyarrythmia
Centrally Acting
Sympathomimetic
Amphetamines, Methamphetamines, Methylphenidate,
Phentermine, PPA
Used in the management of ADHD
 DOC: methylphenidate; alt. Amphetamines
Anorexiants
 Phentermine, PPA
Management of narcolepsy
 Amphetamines, Phentermine
ADRs
 Risk of addiction
 Hemorrhagic stroke (PPA)
 Risk of primary pulmonary HTN (phentermine)
 Adrenergic Drugs
Phenoxybenzamine

Non-selective Phentolamine

Tolazoline

Prazosin
Alpha
Blockers
Doxazosin
Alpha 1 -
Selective
Terazosin

Selective
Tamsulosin

Alpha 2 -
Yohimbine
Selective
 Adrenergic Drugs
Propranolol

Non-selective Nadolol

Timolol

Metoprolol
Beta Blockers

Acebutolol

Atenolol
Beta 1 -
Selective
Bisoprolol

Betaxolol

Esmolol
Sympatholytics (Adrenergic Antagonists)
Alpha Blockers
Effects: Vasodilation, relieves urinary retention
Non-Selective Alpha Blockers
 Irreversible: Phenoxybenzamine
 Reversible: Phenolamine
Selective Alpha Blockers
 A1 Blockers: (-zosin) Prazosin, Doxazosin, Alfuzosin, Tamsulosin
 A2 Blocker: Yohimbine, Rauwolfscine
Clinical Uses:
 HTN in px with Pheochromocytoma
 Sx of Raynaud’s Syndrome
 HTN in BPH
 Urinary retention in BPH
 Phenoxybenzamine – sx of Carcinoid Syndrome
 Phentolamine – erectile dysfunction
Pheochromocytoma
Hypersecretory tumor or hyperplasia of the adrenal
medulla
Excessive release of NE and Epi (NE > Epi)
CM (Hypersympathetic)
 Paroxysmal HTN
 Tachycardia
 Palpitations
 Nervousness
Diagnosis
 Radiographic : CT Scan or MRI
 Biochemical : urine or serum VMA (metanephrine) Assay
Raynaud’s Syndrome
Vasospasm in response to cold environment

Carcinoid Syndrome
CA involving enterochromaffin cells of the intestines
 Storage site of 90% of serotonin
CM
 Serotonin Syndrome (Flushing, Watery Diarrhea, Severe
Headache)
Sympatholytics (Adrenergic Antagonists)
Alpha Blockers
ADR
 First Dose Phenomenon
 Orthostatic or Postural HTN
 Syncope

Remedy
 Give doses at bedtime
 Start Low, Go Slow
Sympatholytics (Adrenergic Antagonists)
Beta Blockers
Classifications
 Based on Selectivity
 Based on Intrinsic Sympathomimetic Activity
 Based on Membrane Stabilizing Activity
 Based on the Presence of Alpha Blocking Activity
Sympatholytics (Adrenergic Antagonists)
Beta Blockers (Based on Selectivity)
B1 Selective aka Cardioselective
 BEAM (bisoprolol, betaxolol, Esmolol, Acebutolol, Atenolol,
Metoprolol)
 Nevibolol – the most highly selective B1 blocker

Non-Selective
 Propranolol, Pindolol, Carteolol, Labetalol
 Bucindolol

Note:
 ALL are contraindicated in Bronchial Asthma and COPD
Sympatholytics (Adrenergic Antagonists)
Beta Blockers (Based on Intrinsic
Sympathomimetic Activity)
Act as partial agonists / mixed agonist – antagonist
 Carteolol, Labetalol, Acebutolol, Pindolol

Note:
 Less associated with rebound tachycardia or HTN when
withdrawn
Sympatholytics (Adrenergic Antagonists)
Beta Blockers (Based on Membrane Stabilizing
Activity)
Local Anesthetic / Quinidine Like Effect
 Pindolol, Acebutolol, Labetalol, Propranolol, Metoprolol

Note:
 Cannot be given as topical ophthalmic drugs
 Can cause ulceration and infection of the cornea
Sympatholytics (Adrenergic Antagonists)
Beta Blockers (Based on Alpha-Blocking Activity)
Mixed Alpha – Beta Blockers
 Labetalol, Carvedilol
Sympatholytics (Adrenergic Antagonists)
 Clinical Uses of Beta Blockers
 1st line for HTN with Hx of MI
 Due to the blockade of B1 receptor at the JGA – dec. Renin
release
 Blocks B1 in the heart – dec inotropic effect

 DOC for long-term tx of CSAP (Chronic Stable Angina Pectoris)

 Reduction of oxygen demand

 Management of Arrythmias
 Propranolol, Esmolol, Acebutolol

 Adjunct in the Tx of Stable CHF at very low doses

 Metoprolol (2.5-10mg/day); Bisoprolol; Carvedilol
Sympatholytics (Adrenergic Antagonists)
Clinical Uses of Beta Blockers
Management of Glaucoma
 Decreases intraocular pressure

 Management of Sympathetic Sx of Hyperthyroidism

 Propranolol

Prophylaxis for Migraine

 Reduces skeletal muscle tremors

Familial Tremors / Stage Freight / Performance Anxiety

To be continued...