Lecture 6:

Autonomic Nervous System

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Autonomic Nervous System :
Nervous System
1. Peripheral NS 2. Central NS

*Peripheral Nervous System can be classified according to:

1. Origin : Cranial (12 pairs).
Spinal (31 pairs).
2. Function : Afferent (sensory)
Efferent (motor) which can be divided into:

1. Autonomic NS (Involuntary) 2. Somatic NS (Voluntary)

*Two neurons system. *One neuron system.
*Enteric→ innervates GIT, Pancreas, gall bladder *Affects activities of somatic
*It is divided into: muscles.
a. Sympathetic NS b. Parasympathetic NS
1. Short preganglionic & 1. Long preganglionic & short
long postganglionic. postganglionic.
2. Often discharge as 2. Never discharge as
complete system complete system→ discrete
effects.
3. Arise from thoracic & 3. Arise from cranium III.
lumbar VII. IX,X & sacral 2nd, 3rd &
4th
4. Not essential for life 4. Essential for life
5. Fight or flight response 5. Rest & digest response.

*N.B. All organs receive dual innervations except:

1. Adrenal Medulla.
2. Kidney.
3. Pilomotor muscle.
4. Sweat glands.
*Difference between actions of Sympathetic &

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Parasympathetic systems on different body organs :

A. Drugs affecting Parasympathetic system:

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*Neurotransmission at Cholinergic Neuron:

*Cholinergic receptors:
A. Muscarinic receptors:

M1 M3 M5 M2 M
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Leads to cellular excitation Inhibit cellular excitability
Found on gastric parietal Found on bladder, smooth Found on cardiac cells & smooth
cells muscle & exocrine glands muscles
Activation of M1&M3 receptors→ conformational Activation of M2 receptor→
change of the receptor→ interaction with Gq conformational change→ interaction
protein→ Activation of phospholipase C→ hydrolysis with Gs protein→ inhibition of adenyl
of Phosphatidylinositol 4,5-bisphosphate (PIP2)→ cyclase →↑ K+ conductance→↓ rate &
Diacylglycerol (IP3)→ ↑ intracellular Ca2+ force of contraction of heart muscle.

B. Nicotinic receptors:
*Composed of five subunits.
*Function as ligand- gated channel: binding of 2 ACh molecules→ Conformational
change→ Na+ entry→ depolarization.
*Nicotine or ACh initially stimulates then blocks receptor.
*Nicotinic receptors may be: Nm: nicotinic R located at neuromuscular junction,
inhibited selectively with Tubucurarine.
Nn: other receptors located at the ganglia,
blocked by Hexamethonium

*1. Cholinergic Agonists:

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 Direct Acting: Indirect Acting:
1. Acetyl choline Reversible Irreversible
2. Direct Acting M alkaloids: 1. Neostigmine. 1. Ecothiophate
a. Pilocarpine. 2. Physiostigmine 2. Isoflurophate Organo-
b. Cevimeline. 3. Pyridostigmine 3. Parathion & Malathion phosphates
3. Choline esters: 4. Galantamine 4. Sarine
a. Bethanechol 5. Ambenomium. 5. Metrifonate.
b. Carbachol 6. Edrophonium ttt by ACh Esterase
7. Demecarium
8. Donepzil reactivation
9. Tacrine
10. Ribavamine. By Oximes:
1.Parlidoximes (2 PAM)
2.Diacetyl monoximes (DAM)

A. Direct acting:
1. Acetyl
Choline:

2. Choline esters:
a. Bethanechol:

1. Muscarinic agonist (no action on nicotinic receptors)

2. Used in : a) Urologic ttt→↑ contraction of bladder wall & relaxation of sphincter M.
 ↑ urine flow→ for post operative non obst. urinary retention.
b) Neurogenic atony & Mega colon.
3. Adverse effects: 1. Bronchospasm 2. Sweating
3. Diarrhea 4. ↓ Bp
b. Carbachol:

1. Non selective agonist (acts on both nicotinic & muscarinic receptors)

2. Used in: eye preparation→ Miotic effect→↓ IOP  Used in ttt of Glaucoma
3. No S.E when used topically in ophthalmic preparations.
3. Muscarinic alkaloids or synthetics
a. Pilocarpine: 1. like Bethanechol partial agonist.
2. Causes Miosis & contraction of ciliary muscle.
3. Uses: a) D.O.C in emergency cases of open angle & narrow angle glaucoma.
b) ↑ salivation in patients with Xerostomia
c) Sjogren's Syndrome (dry mouth & lack of tears)
b. Cevimeline: 1. Synthetic M3 selective agonist.
2. Used in Sjogren's syndrome.

B. Indirect Acting: choline esterase inhibitors which inhibit

degradation of Ach by acetyl choline esterase→ prolonging its effect.

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a. Reversible:
1. Physiostigmine: 1. Acts on M & N receptors in ANS & also on N receptors in NMJ.
natural alkaloid 2. Uses: 1) ↑ intestinal motility & bladder motility
3ry amine 2) Topically (↓ IOP)
enters CNS 3) ttt of overdose of drugs having antimuscarinic action (Atropine,
TCAs).
3. S.E : 1) Bradycardia & ↓ C.O.P
2) ↑ Ach at NMJ→ paralysis of skeletal muscle.
3) Convulsions→ crosses CNS
2. Neostigmine: 1 . Uses: 1) ↑ GIT & bladder motility→ post operative, Neurogenic ileus &
Oral & parentral urinary retention.
4ry amine 2) Antidote for Tubucurarine (neuromuscular blocker).
not enter CNS 3) ↓ symptoms of Myasthenia gravis.
N.B. It is not used for ttt of antimuscarinic drug toxicity
( not for Atropine).
2 . S.E: As Physiostigmine but doesn't cross CNS→  No CNS S.E.
3. Pyridostigmine & 1. Used in ttt of Myasthenia gravis with ↑ duration of action (4-6 hrs)>
Ambenomium: Neostigmine.
2 . S.E: Similar to Neostigmine.
4. Demecarium: *Used in: 1) Chronic open angle Glaucoma
2) Diagnosis & ttt of Accommodative esotropia → ‫حول العين‬
5. Edrophonium: * Used in diagnosis of Myasthenia gravis
Alcohol *Atropine is used as antidote.
Short acting
6. Tacrine, Donepzil, *Used in ttt of Alzheimer's disease.
Rivastigmine & *S.E: GIT distress.
Galantamine: *Tacrine→ hepatotoxic
b. Irreversible:
1. Parathion & Malathion Insecticides.
2. Sarine (nerve gas) War gas
3. Metrifonate Anti- bilharzias.
4. Ecothiophate &Isoflurophate Binds irreversibly with Ach esterase causing paralysis & convulsions
*Used topically for ttt of chronic open angle glaucoma.
ttt of toxicity by Oximes → Choline esterase reactivators→ parlidoxime
(2 PAM) & Diacetyl monoxime (DAM).
*Can reactivate Ach esterase before aging (loss of alkyl gp).
*Unable to penetrate CNS.
**Nicotinic Agonists:

1) Nicotine: *Agonist on both Nn & Nm.

*Activates autonomic postganglionic neurons (sympathetic & parasympathetic) &
skeletal muscle neuromuscular end plates.
* Enters CNS & Activates Nn receptors
* Uses : 1) Medicinal use: smoking cessation
2) Non medicinal use: insecticide & smoking
* Interactions: Additive effect with CNS stimulants.
2) Varenicline: *Selective partial agonist at   nicotinic receptors
(Champix®) *Exclusive for smoking cessation
2. Cholinergic Antagonists: (imp)

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a. Neuromuscular b. Antimuscarinics: c. Ganglion
blockers: blockers:
Mivacurium M Atropine A Mecamyl amine
Rocuronium R Cyclopentolate C Nicotine
Ipratropium I Trimethaphane.
Vencuronium V Scopolamine S
Pancuronium P Tropicamide T

Metocurine M Oxybutyrine O
Succinyl Choline S
Tubucurarine T
ACIST +O
Cisatracurium C
Atracurium A
Doxacurium D
CAD ‫ الزم يتعلم‬VP ‫مستر‬

A. Antimuscarinics: ( •) blocks Muscarinic receptors

1. Atropine: * Actions: 1) Eye: Mydriasis & cycloplegia (loss of accommodation for near vision
2)GIT: ↓ motility.
3) Urinary bladder: ↓ hypermotility of the bladder.
4) CVS: low doses→ ↓ HR.
5) Secretions: ↓ Salivation & sweating.

* Uses: 1) Ophthalmic preparations: mydriatic & cycloplegic.

 agonist (phenyl ephrine) for mydriatic effect only.
Tropicamide & Cyclopentolate are also used.
2) Antispasmodic
3) Antidote for Ach esterase toxicity (for ttt of Organophosphorous cpds).

*Adverse effects : 1) blurred vision (sandy eyes). 2) Dry mouth

3) Constipation
4)Atropine cause hemodynamic alteration as it causes initial bradycardia then
Tachycardia
2. Scopolamine: *Used in motion sickness (most effective/ prophylaxis not ttt).
*belladonna alkaloid. *Have amnesic action→  used as adjunct therapy in anesthesia.
*Enters CNS *It blocks short term memory.
*Competitive blocker **May produce Euphoria→  may be abused.
*In low doses→ sedation *In high doses→ excitement.
3. Ipratropium: *Uses: 1) As inhalation for patients with asthma unable to take 2 agonists
2) ttt of chronic obstructive pulmonary disease (COPD).
4. Tropicamide & *As Atropine in ophthalmic preparations.
Cyclopentolate:
5. Oxybutyrine: *For nocturnal enuresis & antispasmodic.

B. Ganglionic blockers
Q) Although Ganglionic agents are very potent antihypertensives, they aren't extensively used as

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 antihypertensive agents→ why?
because they interfere with action of acetyl choline at both: a)Sympathetic→ anti HTN
b) Parasympathetic ganglia→ S.E dry mouth,..
1. Nicotine: *Small doses→ activation, large doses→ blocking
*Used to ↓ nicotine cravings in smoking cessation.
2. *Used to ttt moderate- severe HTN. *May be taken orally
Mecamylamine:
3. Trimethaphane: *IV infusion for emergency lowering of BP
*Na nitroprusside is preferred in emergency ttt of HTN→ WHY?
Due to No tolerance.

C. Neuromuscular blockers
*Difference between neuromuscular B & Central muscle relaxants:
neuromuscular B Central muscle relaxants:
*Used in surgery to maintain muscle Used to: control spastic muscle tone
relaxation &↓ dose of anaesethia.
*They are divided into: *Diazepam & Baclofen→ binds to GABA receptors in CNS
*Dantrolene→ directly acting by ↓ Ca2+ from sarcoplasmic
reticulum.
A. Non Depolarizing (Competitive): B. Depolarizing :
1. Benzylisoquinolone cpds: Atracurium, Succinyl Choline
Cisatracurium, Doxacurium, Mivacurium,
Tubucurarine & Metocurine.
2. Amino-steroid cpds: Rocuronium,
Vencuronium, pipercuronium & Pancuronium.
1. M.O.A: a) Low doses→ blocks N- receptors in NMJ Binds to nicotinic receptors→ transient
*Blocked by Ach esterase inhibitors. depolarization (Phase I) →Repolarizatio
& desensitization of receptors→ Flaccid
b) High doses→ block ion channels of the end plate paralysis (Phase II).
*Ach esterase can't block this action.
2. *All are given IV & don't cross BBB
Pharmaco- *Cisatracurium (Isomer of Atracurium) replaced
kinetics: Atracurium due to release of histamine
3. Uses: 1) Adjunct therapy with Anesthesia to↓ dose. 1) When rapid endotracheal intubation
2) Facilitated intubation. required.
2) Used in electroconvulsive shock ttt.
4. D.I.: 1) Choline esterase inhibitors S.E: 1) Malignant Hyperthermia: whe
Important (Physiostigmine, Neostigmine..)→ ↓ action of NMB taken with halothane
notes: 2) Halogenated anesthetics ttt by cooling patient + Dantrolene.
e.g. Halothane ↑ action of 2) Apnea: in pts who are genetically
3) Aminoglycosides AB NMB deficient in plasma choline esterase.
(Gentamycin or Tobramycin) 3) Hypokalemia: so dangerous with bu
4) Ca2+ ch. blockers pts or with tissue damage.
*Important Notes:

1)Mivacurium: *Short duration of action→ used for short surgical procedures

2)Cisatracurium: *Useful in mechanical ventilation of critically ill patients.
*It is the ONLY NMB that can be used in Renal failure.
3) Rocuronium Rapid onset→ used for tracheal intubation with gastric content
4) ↑ HR
Pancuronium:

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B. Drugs affecting Sympathetic System:
*Neurotransmission at Adrenergic neurons:

*Adrenergic Receptors:
Alpha receptors ( ) Beta receptors ()
   
*Epinephrine- *Nor Epinephrine- * Isoprotrenol *Isoprotrenol- *Epinephrine- *Nor Epinephrine
High affinity Low High affinity Low affinity
affinity
*Activation of Adenyl cyclase→ ↑ cAMP

*V.C (skin & abdominal *(-) NE release. * ↑ Myocardial *V.D (skeletal vascular bed) →↓P
viscera) → ↑ P.R→↑ B.P. *(-) Insulin release. contractility & T.C *Bronchodilation.
*Mydriasis N.B.  present on *↑ Lipolysis *Relaxed uterine smooth muscle.
*↑Closure of internal  cells of the *↑ Renin release *↑ Glucagon release.
sphincter of the bladder. pancrease *↑ liver & muscle glucogenolysis.
n.b.  is divided into (A, B, C, D)
 is divided into (A, B, C, D)
*Tamsulosine Selective  A antagonists.
for ttt of benign prostate hypertrophy.

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  A is found primarily in the urinary tract.
1. Adrenergic Agonists:
*Characteristics of Adrenergic agonists:
A. Catecholamines: Contains 3,4 dihydroxybenzene group.

*Phenylephrine *Ephedrine *Norepinephrine

* Epinephrine *Isoprotrenol *Dopamine.

*Characters: 1) High potency activating ( or )
) Poor CNS penetration
3) Rapid inactivation → why?
Because they are metabolized by:
a) COMT postsynaptically.
b) MAO intraneuronally.
c) COMT in gut wall. Given parenterally
d) MAO in liver & GUT Wall.

B. Non Catecholamines: Amphetamine.

1. Long duration →why?
a) Aren't inactivated by COMT.
b) Poor substrates for MAO.
2. High CNS penetration.

C. Substitution on amine nitrogen:

Isoprotrenol > Epinephrine > Nor epinephrine as B-Agonists why?
affinity to B-receptor by increasing size of group on amine N

**Put (T) or (F):

1) COMT doesn't metabolize isoprenaline (F).
2) Slow IV adrenaline → ↑ diastolic BP (F).
It increases cardiac output with slight decrease in diastolic BP.
3) Stimulation of Sympathetic nerve causes contraction of vascular smooth muscle (T).

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*M.O.A of Adrenergic agonists:
1. Direct Acting agonists:→ drugs directly activates receptor.
2. Indirect Acting agonists: → drugs enhance release of NE from vesicles.
3. Mixed Acting: → direct & indirect.

Direct Acting: Indirect Acting: Mixed

*Epinephrine. *Isoprotrenol. Amphetamine. Ephedrine.
*Nor epinephrine. *Metaprotrenol. Cocaine. Pseudoephedrine.
*Phenylephrine. *Methoxamine. Tyramine.
*Dopamine. *Salmetrol.
*Dobutamine *Formetrol
*Clonidine *Pirbuterol
*Terbutaline. *Albuterol

1. Direct Acting Adrenergic agonists:

Drug: Receptor Action: Uses:
specificity
1. Epinephrine:   a)Cardiovascular: a) ttt of Open angle
*If taken orally→   a)  1: *Strengthen contractility glaucoma → How?
inactive so taken (+ve inotropic) 1-2% solution→ vasoconstriction
parentrally or by *↑ rate of contraction ciliary body blood vessels→
inhalation (+ve chronotropic). a) ↓production of aqueous humor
↑ O2 demand by Myocardium. b) ↑ outflow of Aqueous humor.
b) 1: vasoconstriction *Duration of action of this
(skin, mm, viscera) 1% epinephrine: 1-2 hrs.
c)  vasodilation (sk. muscles).
d) ↓ renal blood flow.
b) Anaphylactic shock:
e)Overall :
(↑ systolic, slight↓ diastolic) D.O.C in ttt of Type I
hypersensitivity Rx.
b)Respiratory:
c) Acute asthma: IV or S.C
*  bronchodilation.
a)Stimulation of   receptor:
relaxation of bronchial muscle.
c)Hyperglycemia:
b) Stimulation of  receptor:
*2: ↓ insulin. constriction of bronchial vessels→
 ↑ glucagon & glucogenolysis. congestion & edema.

d) Lipolysis: d) With local anesthetic:

*  Lipolysis. 1:100,000 solution→ why?
V.C at injection site→ ↑ duration
action.

*D.I: a) Hyperthyroidism→ dose must be reduced→ Why?

Due to ↑ adrenergic receptors on vasculature of hyperthyroid individual.
b) Cocaine→ it inhibits reuptake of catecholamines by adrenergic neuron→ Exaggerated C.V. action

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 c) Narrow angle glaucoma (also Atropine & Homotropine) → why?
due to Mydriasis (produced by epinephrine due to 1 stimulation so if propranolol taken→ no reverse of th
effect of Mydriasis but block other B receptor mediated effects.

2.   Cardiovascular: *ttt of shock (cardiogenic

Norepinephrine:  * V.C→ ↑ Systolic & diastolic → why?
B.P→ baroreceptors→ ↑vagal ↑ B.P.
activity→ reflex bradycardia (but
with no effect on + ve inotropic N.B. Metaraminiol is favored coz
effect). doesn't reduce blood flow to the
kidney as N.E.
N.B. If atropine (which blocks
vagal effect) given before N.E→ *Never used for asthma→ why?
N.E stimulation of heart is weak  effect.
evident as tachycardia.
3. Isoprotrenol   a) Cardiovascular: a) As cardiac stimulant:
= Isoprenaline: *  ↑ force & rate of contraction in ttt of atrioventricular block or
**Stable to MAO but cardiac arrest.
inactivated by COMT. * : V.D→ ↓ P.R
*Overall ↑ systolic & ↓ diastolic b) Acute Asthma: by inhalat
markedly. but now rarely used.
4. Dopamine: *dopa- *Low dose→  1→:+ve inotropic a) ttt of shock→ why?
**D.O.C for ttt of minergic. & chronotropic. as it ↑ B.P.
cardiogenic shock *  *High dose→ → V.C →↑ B.P *Preferred over N.E→ Why?
*D2 & D1→ V.D→ ↑ blood flow to because N.E ↓ blood flow to
kidney. kidney→ renal shut down.
*ttt of C.H.F
5. Dobutamine:  *ttt of C.H.F
*It ↑ C.O with little change on cardiac rate → doesn't
significantly ↑ O2 demand of myocardium.

N.B. It is used with caution in patients with atrial fibrillation

why? → Coz it increases atrioventricular conduction→ lead to
ventricular fibrillation which is fatal
6.  1. Nasal decongestant.
Phenylephrine: (   ) 2. Ophthalmic solution→ mydriasis.
3. ttt of supraventricular tachycardia→ How?
→ V.C→ ↑ B.P→ reflex bradycardia.
7.   *Used locally in nose & eye as vasoconstrictors to ↓ congestion.
Oxymetazoline: *S.E: Rebound congestion with long term use.
8. Methoxamine:  1) ttt of supraventricular tachycardia→ by vagal stimulatio
(   ) 2) Overcome hypotension during surgery involving halothan

*N.B. It is the only adrenergic drug that doesn't trigger cardiac

arrhythmia which is sensitized by these general anesthetics.
9. Clonidine:  1. ttt of HTN
2. Minimize opiate & Benzodiazepine withdrawal symptoms.
10.    *ttt of bronchospasm & asthma.
Metaprotrenol: * not catecholamine→ may be taken orally

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11. Terbutaline,  *ttt of bronchospasm → short duration < 3hrs,
Albuterol & *onset of action: 5 min→ ttt of acute asthmatic attack.
Pirbuterol:
12. Salmetrol &  *ttt of bronchospasm→ long acting → t1/2= 12 hours.
Formetrol: *Used in nocturnal asthma.

N.B. Not recommended for use as monotherapy→ combination with

corticosteroids.

2. Indirect Acting- adrenergic agonists:

a. Amphetamine: *Used as CNS stimulant in ttt of children with attention deficit syndrome,
  CNS narcolepsy & appetite control.
C.I. in pregnancy.
b. Tyramine: *Found in fermented foods such as ripe cheese & wine.
*It is normal byproduct of Tyrosine metabolism.
*Normally it is oxidized by MAO but if patient is taking MAO Inhibitors→
Hypertensive crisis.
c. Cocaine: *Inhibits uptake of N.E

3. Mixed Action adrenergic agonists:

1.Ephedrine: *Long action duration & excellent oral absorption→ why?
  CNS Because it is Non- Catecholamine (not degraded by MAO & COMT).
*uses: 1) Chronic ttt of asthma not acute (for prophylaxis not ttt)→ why?
Due to slow action.
2) With Anticholinestrases→ ttt of Myasthenia gravis.
3) Stimulates CNS→↑ alertness, ↓ fatigue& ↑ athletic performance.
C.I: Ephedrine + Theophylline→ synergistic toxicity.
2. *for ttt of Nasal congestion & eustachian tube congestion.
Pseudoephedrine:

*Adverse effects of Adrenergic agonists:

Hyper-
Arrythmia Insomnia
activity

Tremors
(dose limiting Nausea Headache
toxicity)

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2. Adrenergic Antagonists:
A)  Adrenergic blocking agents:

1) Non selective    blockers:

a) Phenoxybenzamine: b) Phentolamine:
i) Non selective    blockers. i) Non selective    blockers.
*Non competitive irreversible with duration *Competitive blocker with duration = 4 hrs
= 24 hrs → why?
→ Time to synthesize new adreno-receptors.
ii) Action:
1) Blocks  → prevents peripheral V.C by endogenous catecholamines→↓ P.R
→ Orthostatic hypotension Reflex tachycardia
2) Blocks 

3)Sexual dysfunction in males→ why?

Because sexual function is mediated through  adrenergic activation.

4) Nasal stuffiness.
iii) Effect of them on E, N.E & Isoprotrenol :
a) Epinephrine: *Reverse action (↓ B.P.)→ WHY?
1→ V.C→ Interrupted. ↓ B.P
→ V.D→ not blocked
b) Norepinephrine: Not reversed but diminished.
c) Isoprotrenol: No effect→ why? coz it is pure B agonist.
.
iv) Therapeutic uses:
1)Phenoxybenzamine: used in ttt of pheochromocytoma (Catecholamine secreting tumor of cells deriv
from adrenal medulla).
2) Phenoxybenzamine or Phentolamine: ttt of Raynaud's disease.
v) C.I: In patients with decreased coronary perfusion→ why? → Due to tachycardia.

2) Selective Competitive blockers: Prazosin , Terazosin ,

Doxazosin & Tamsulosine .
*Therapeutic Uses:
1) ttt of HTN (All except Tamsulosine) : 1st dose of this drug produce exaggerated
hypotensive response that can result in syncope (fainting)→ How to overcome?
by adjusting 1st dose to 1/3 or 1/4 of the normal dose & by giving drug at bed time.
e.g. Dose of Prazosin: 1mg X 3/d, then can be slowly increased to 10mg X 2/d.
2) ttt of prostate hypertrophy.
*Notes:
1) Metabolites excreted in urine except Doxazosin in feces.

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2) DOXAZOSIN: longest acting of these drugs.
3) PRAZOSIN IS USED WITH DIURETIC due to tendency to retain Na+ & fluids→
risk of CHF if used as monotherapy.
4) Same S.E of non selective blockers but with less degree.

B)  - Adrenergic blocking agents:

**Never produce postural hypotension→ why? Coz  receptors remain functional.

1) Non-Selective  antagonists (blocks  1 &  2):

a) Propranolol : i) Actions:
*blocks → 1) –ve inotropic & chronotropic effects so cardiac work & O2
consumption ↓ → useful in ttt of Angina
2) ↓ B.P.→ ↓ renal perfusion→ Na+ & H2O retention so used with diuretic

*blocks :→1) peripheral vasoconstriction→ why?

-  mediated V.D is blocked.
-  block→ ↓ B.P→ reflex V.C
2) Bronchoconstriction→ C.I. in pts with asthma.
3) Hypoglycemia→ why? → ↓ glycogenolysis & ↓ Glucagon.
 Careful monitoring of blood sugar in insulin dependent patient.

*Sexual impairment: unknown mechanism.

Q) What is effect on E, N.E & Isoprotrenol?

*Isoprotrenol: Blocking of its action
*Epinephrine: No longer lowers diastolic B.P or stimulates the heart but
its Vasoconstrictive action is unimpaired.
*N.E: Unaffected coz its action mediated mainly by  receptors.

ii) Therapeutic uses:

1. Hypertension.
2. Glaucoma→ how?
*↓ secretion of aqueous humor by ciliary body→ ↓ IOP.
*For chronic ttt but acute→ Pilocarpine is D.O.C
3. Migraine (chronic ttt):by blocking of catecholamine induced V.D in brai
4. Hyperthyroidism:
a) protects against cardiac arrhythmia.
b) Prevents conversion of T4 to T3 "Active form".
5. Angina pectoris (chronic ttt): ↑ intolerance to moderate exercise but
not severe exercise as tennis.
6. Myocardial infarction:
a) For prophylaxis against 2nd attack.
b) Immediately following infarction (↓ infarct size & hasten recovery)→↓ morbidi
& mortality.
Q) ttt with  blockers must never be stopped quickly → why?
Due to upregulation of receptors.

iii) Most common S.E of propranolol:

1) Cold extremities 2) Lipophilic→ crosses BBB causing nightmares.

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 Q) Put (T) or (F): Propranolol causes tremors (F).
Only B agonists cause tremors.

iv) Drug interactions:

*inhibit metabolism (Cimetidine, Furosemide & chlorpromazine).
*Stimulate metabolism (barbiturates, phenytoin & Rifampin).
b) Timolol & * More potent than propranolol.
Nadolol : *Nadolol: very long duration of action.
*Timolol: Chronic ttt of open angle glaucoma.

2. Selective 1 Antagonists: Acebutolol , Atenolol ,

Metoprolol & Esmolol..
*ttt of Hypertension especially in:
1) Patients with asthma. 2) Diabetic patients.
*Less effect on vascular → less frequent coldness of extremities which is common with
−blockers therapy.
*Esmolol: very short t1/2 (10 min) → so it is given IV during surgery or for diagnostic
procedures e.g. cystoscopy.

3. Antagonists with Partial Agonist activity: Acebutolol &

Pindolol .
*Have ability to weakly stimulate    receptor→ are said to have
intrinsic sympathomimetic activity (ISA).
*Diminished effect on cardiac rate & Cardiac output compared to - blockers
without ISA.
*Uses: ttt of hypertension especially:
1) Patients with moderate bradycardia.
2) Diabetic patients.

c) Antagonists of both    receptors:

(Labetalol: Carvedilol) :
1. Block → peripheral vasodilation→ orthostatic hypotension.
2. Don't alter serum lipid or blood glucose.
ttt of elderly or block hypertensive ↓ Lipid peroxidation & vascular wall
patients in whom increased peripheral thickening→ ttt of CHF.
vascular resistance is undesirable.

D) Drugs affecting neurotransmitter release or uptake:

1.Reserpine: *Dopamine + preformed N.E Amine transporter vesicles.

Mg+/ ATP
(-)
Reserpine
degraded by MAO in cytoplasm → N.E→ Gradual ↓ in B.P & Heart rate.

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2. *block release of stored N.E→ gradual ↓in B.P & Heart rate.
Guanethidine: *It also displaces N.E from storage vesicles→ transient ↑ in B.P.
*Overall: depletion of N.E except in CNS.
*It may cause Hypertensive crisis in patients with pheochromocytoma→
why? → Due to depletion of N.E→ Supersensitivity to N.E
* S.E: Orthostatic hypotension, inhibition of ejaculation&diarrh
Q) Diarrhea is common during ttt with Guanethidine → why?
because it blocks sympathetic outflow so parasympathetic tone predominates→ diarrh
*D.I of Guanethidine: 1) TCAs→ why? → because they block uptake of Guanethidine in
adrenergic neuron→ so inhibit its antihypertensive effect.
2) MAOIs.
3. Cocaine: *Inhibits Na+/ k+ ATPase→ accumulation of N.E in synaptic gap→ enhancement of
sympathetic activity→ so small dose of Catecholamines produce greater effects in
individual taking cocaine than others who aren't e.g. Epinephrine.

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