1. Adrenergic antagonists I (alpha blockers)
Dr. Asmaa Fady PhD., MSC., M.B, B.Ch
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8/20/2019

2. Learning objectives: At the end of this lecture the student should:
Identify the location & action of adrenergic receptors
Classify the adrenergic antagonists based on the mechanism of action
Describe the mechanism of action of each class
List the therapeutic uses of each class
Identify & explain the adverse effects of each class
اسم ورقم المقرر – Course Name and No.
8/20/2019

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4. Sympathetic versus parasympathetic nervous system
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6. Location & action of adrenergic receptors
Presynaptic Alpha (α 2 mainly, α 1) & Beta (β) receptors
The pre-synaptic receptors are found in CNS and on the surface of adrenergic nerves & mediate the negative feed back which control release of NA (auto-receptors)
Stimulation of presynaptic α2 : Decreased release of NA
Stimulation of presynaptic β: Increased release of NA
اسم ورقم المقرر – Course Name and No.
8/20/2019

7. Location & action of adrenergic receptors
Postsynaptic alpha (α 1, α 2) – Beta (β 1, β 2, β 3).
α1 (Gq) α2 (Gi)
Β (Gs)
CVS: (Heart)
Increased all cardiac properties β1
*Increased Contractility (Positive inotropic) *Increased rate (Positive chronotropic)
*Increased conductivity (Positive dromotropic)
*Increased excitability
CVS (blood vessels)
Vasoconstriction “VC” skin & mucus membranes blood vessels α1
VasodilatationVD of coronary & Skeletal BV β2
Smooth muscle fibers
1- Relaxation of wall of GIT α1
2- Contraction of All sphincter (GIT, urinary). α1
3- Male sex organs: contraction of corporal muscles (ejaculation) α1
Relaxation of
▪ Bronchi β2
▪ Wall of GIT β2
▪ Wall of urinary bladder β2
▪ Wall of uterus β2
اسم ورقم المقرر – Course Name and No.
8/20/2019

8. Location & action of adrenergic receptors Postsynaptic alpha (α 1, α 2) – Beta (β 1, β 2, β 3).
Liver, pancreas , kidneys & adipose tissues
- Decreased Insulin secretion α 2
- Decreased Lipolysis α2
-Decreased Renin α2
▪ Increased glycogenolysis β2
▪ Increased insulin secretion β2
▪ Increased lipolysis in fat cells β1* -β3
▪ Increased renin production β1
Eye:
Dilator pupillae active mydriasis α1
decreased aqueous humor formation α2
Increased aqueous humor formation β1* -β2
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8/20/2019

9. SYMPATHETIC DEPRESSANTS [Sympatholytics]
1- Adrenergic receptor blockers
A- Alpha adrenergic blockers e.g. Phentolamine.
B- Beta adrenergic blockers (BB) e.g. propranolol.
C- Combined Alpha & Beta adrenergic blockers e.g. labetalol.
2- Adrenergic neuron blockers or Antiadrenergic drugs
A- Drugs inhibiting release of noradrenaline from sympathetic nerve endings e.g. Guanethidine.
B- Drugs depleting noradrenalin from sympathetic nerve endings e e.g. Reserpine.
3- Centrally acting symp.depressant drugs (--VMC in brain stem -- sympathetic outflow NA release
• Alpha 2 agonists: e.g. alpha-methyldopa, clonidine, guanfacine and guanabenz.
• Imidazoline Receptor agonists (I1): – Rilmenidine – Moxonidine.
4- Ganglion blockers: Blocking transmission in sympathetic ganglia.
SYMPATHETIC DEPRESSANTS [Sympatholytics]
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10. Non selective α blocker (α1 & α2)
Alpha blockers
α blockers: block α receptors mostly in blood vessels so produce VD (except ergot).
Alpha blockers
Non selective α blocker (α1 & α2)
A- Ergot alkaloids Ergotamine: Partial agonist on α-1 & 5-HT receptors
B- Phentolamine.
C-Phenoxybenzamine
Selective α1 blocker
Prazosin,
Trimazosin
Tamsulosin
terazosin, doxazosin.
Selective α2 blocker
Yohimbine.
MAP= COP * SVR
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8/20/2019

11. Pharmacological action of alpha blockersα1
site
agonist
Blocker
Side effect BV VC
*Veins: VR (Preload).
*Arteries: TPR systolic & diastolic BP
* reflex bradycardia VD
* veins: VR (preload).
* Arteries (congestion)& BP.
*Reflex tachycardia
*postural hypotension
* nasal stuffiness
Eye (dilator puipllae ms)
Active mydriasis
miosis
Sphincters (UB, GIT)
Contract sphincters
Relax sphincter
Male sex organ
ejaculation
Delayed or failed ejaculation α2
presynaptic
Noradrenaline release
tachycardia
8/20/2019
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13. A) Non-selective α blockers: 1- phentolamine & Phenoxybenzamine:
Mechanism:
Phentolamine:
competitive antagonist of α1&2 receptors (its action last only for 4 hours )
Phenoxybenzamine: prodrug: the most potent alpha blocker
irreversible non competitive antagonists of α1&2 receptors (delayed onset & its action lasts for 2-3 days)
Actions:
α1 blockade vasodilation ↓ peripheral resistance (may ↓ BP, BUT cause PROFOUND reflex tachycardia)
Block presynaptic α2 in heart more NE release & bind to β1 ↑ C.O & tachycardia .
8/20/2019
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14. A) Non-selective α blockers: 1- phentolamine & Phenoxybenzamine
Additional actions:
Phentolamine:
additional histamine like action (vasodilation, bronchospasm & increased HCL secretion & motility)
Phenoxybenzamine:
Anti histaminic.
Anti Ach (anti muscarinic (atropine like).
Anti-shock effect: prevent irreversible stage of shock
a- α blocking action VD (improve tissue perfusion).
b- excess release of ADH (vasopressin) by hypothalamus VD
[ADH causes VC of coronary, mesenteric, renal Bl.V irreversible shock].
8/20/2019
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15. A) Non-selective α blockers: 1- phentolamine & Phenoxybenzamine
Therapeutic uses:
Phentolamine
Diagnosis of pheochromocytoma
Peripheral Vascular diseases.
Phenoxybezamine
Treatment of pheochromocytoma (It may be used prior to surgical removal of the tumor to prevent a hypertensive crisis) + Beta blocker
Shock (hemorrhagic): pretreatment with plasma & blood first, then give phenoxybenzamine [fill up, then, open up].
Remember:
Non-selective α blockers are NOT USED for routine management of primary hypertension
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8/20/2019

16. Adverse effects of Phenoxybenzamine & Phentolamine:
α blocking ( VD produces nasal stuffiness, dizziness and postural hypotension).
Reflex tachycardia
Failure of ejaculation
sedation & fatigue with Phenoxybenzamine
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17. B) Selective α1 blockers: Prazosin, Terazosin, Doxazosin, Alfuzosin, Tamsulosin
Mechanism of action:
Prazosin, Terazosin, Doxazosin, Alfuzosin
Competitive selective antagonists of α vasodilation ↓ peripheral resistance ↓ BP.
+ Direct smooth muscles relaxation (phosphodiesters enzymes inhibitors cAMP free Ca VD)
This VD action is less accompanied by reflex tachycardia
Tachycardia
Brady cardia
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18. B) Selective α1 blockers: Prazosin, Terazosin, Doxazosin, Alfuzosin, Tamsulosin
less selective for α1B receptors found in the blood vessels and more selective for α1A receptors in the prostate and bladder
Blockade of the α1A receptors ↓ tone in the smooth muscle of the bladder neck and prostate and improves urine flow with less pronounced hypotension
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8/20/2019

19. B) Selective α1 blockers: Prazosin, Terazosin, Doxazosin, Alfuzosin, Tamsulosin
Therapeutic uses:
Hypertension (essential & secondary hypertension)
(Prazosin, Terazosin, Doxazosin, Alfuzosin)
The 1stdose may produce an exaggerated orthostatic hypotensive response that can result in syncope (fainting). This action called “first-dose” effect. may minimized by starting with small dose & taking drug at bedtime.
Peripheral vascular disease
Benign Prostatic hyperplasia (BPH): (All α1-selective blockers): Tamsulosin (preferred) due to its selectivity.
Heart failure: VD on both arteries & veins, decreased both Peripheral Resistance & Venous return so decreasing both preload and after load
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8/20/2019

20. adverse effects of selective α1 blockers:
This VD action is less accompanied by reflex tachycardia since:
a- It is selective alpha 1-blocker (non selective blockers block alpha 2-receptors with 2ry increase in NA).
b- balance between cAMP & cGMP productions.
VD of cerebral BVs
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22. C) Selective competitive α2-blocker: Yohimbine
NO CLINICAL USES
Dilates skin and m.m. blood vessels more in sex organs by unexplained mechanism: used as sexual stimulant & for erectile dysfunction (aphrodisiac).
Adverse effects:
cardiovascular disease, psychiatric conditions, and renal dysfunction
اسم ورقم المقرر – Course Name and No.
8/20/2019

23. Therapeutic uses of alpha-blockers
1- Essential hypertension (Selective α1 blockers). 2- Secondary Hypertension (non selective α blockers): due to pheochromocytoma. should be combined with BB. 3- Peripheral vascular diseases. 4- Benign prostatic hyperplasia (BPH): antagonize smooth muscle contraction in enlarged prostate. 5- Heart failure: prazosin.(decreases both pre & afterload)
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