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Drugs Affecting
The Autonomic Nervous System(ANS)
Alpha-Adrenergic Blockers
ANS Pharmacology
Lecture 6
Dr. Hiwa K. Saaed
College of Pharmacy/University of Sulaimani
2017-2018
Review of Agonist Effects of α1 Adrenergic Receptors
Receptor
Tissues Response
α1
Eye-radial (dilatory) muscle Contracts (mydriasis)
Most vascular smooth muscle
-Arterioles (skin, viscera)
-veins
Contraction
↑TPR→↑ diastolic pressure
↑afterload
↑ venous return→↑ preload
Bladder trigone and sphincter Contraction→urinary retention
Male sex organs Vas deferens→ ejaculation
Liver (in some species, rat ) Stimulate glycogenolysis
Kidney ↓ rennin release
Pilomotor smooth muscle Contraction (erect hair)
Review of Agonist Effects of α2 Adrenergic Receptors
Receptor tissue Response
α 2
Adrenergic & cholinergic
Prejunctional nerve terminals
↓ transmitter release and NE
synthesis
Platelets Stimulate Aggregation
Pancreas (β cells) Inhibit insulin release
Some vascular smooth muscle Contracts
Fat cells Inhibits lipolysis
Medullary vasomotor center ↓sympathetic outflow → CO
& vasodilation→↓ BP
Localization of 1-Adrenergic Receptors
Alpha-Adrenergic Blockers Classification
I. Type of blockade
1. Irreversible (non-competitive) : Phenoxybenzamine; slow onset and long duration.
2. Reversible (competitive): All the rest
II. Selectivity: Like the agonists, the adrenergic antagonists are classified according to
their relative affinities for α1 or α2 receptors.
-Nonselective: Phenoxybenzamine and phentolamine
-Selective: α1 or α2 receptors
1. α1 selective: Prazosin, terazosin, others
2. α2 selective: Yohimbine
3. α/ℬ blockers: Labetalol
-Others: phenothiazines, haloperidol, tricyclic antidepressants, trazodone
α Antagonists Receptor Affinity
Prazosin, terazosin, doxazosin α1>>>>α2
Phenoxybenzamine α1>α2
Phentolamine α1=α2
Rauwolscine, yohimbine, tolazoline α2>α1
Mixed antagonists
Labetalol, carvedilol β1=β2≥α1>α2
Alpha-Adrenergic Blockers Classification/ Receptor Selectivity
Nonselective
• Phenoxybenzamine (3-4 days)
Selective
• Short-acting selective 1-blocker
• Prazosin t1/2 3 hrs, Alfuzosin t1/2 5 hrs
• Long-acting selective 1-blockers
• Terazosin t1/2 9-12 hrs
• Doxazosin t1/2 22 hrs
• Long-acting selective 1A-subtype
• Tamsulosin t1/2 9-15 hrs
Alpha-Adrenergic Blockers Classification/ Duration of action
Pharmacological Effects-Phenoxybenzamine
1. Cardiovascular system
• ↓PR: ↓ Blood pressure: reflex tachycardia:
• ↑Increase CO: Furthermore, the ability to block presynaptic
inhibitory α2-receptors in the heart will result in more
norepinephrine release, which stimulates β- receptors on the
heart to increase cardiac output.
• It reduces BP when sympathetic tone is high such as in upright
posture, reduced blood volume
Adrenergic System - Antagonists
Epinephrine reversal:
• All α-adrenergic blockers reverse the α-agonist actions
of epinephrine. the vasoconstrictive action of
epinephrine is interrupted, but vasodilation of other
vascular beds caused by stimulation of β2 receptors is
not blocked.
• Therefore, the systemic blood pressure decreases in
response to epinephrine given in the presence of
phenoxybenzamine. ….Why?
• The actions of norepinephrine are not reversed but are
diminished, …why?
Pharmacological Effects – Phenoxybenzamine
2. Eye – miosis
3. Nasal stuffiness
4. GI tract – Increased motility
5. Urinary bladder – decreased tone in sphincter
6. Metabolic effects – increased insulin secretion
7. It also blocks histamine, serotonin and cholinergic receptors
Clinical uses -Phenoxybenzamine
1. Pheochromocytoma: a catecholamine-secreting tumor of cells derived
from the adrenal medulla
2. Raynaud; peripheral vascular disease
3. Autonomic hyperreflexia which predisposes paraplegics to strokes
4. BPH
Adverse effects Phenoxybenzamine
• Postural hypotension
• Tachycardia it is contraindicated in patients with decreased
coronary perfusion.
• Sedation, fatigue
• Nasal stuffiness
• Miosis
• Impotence (inhibits ejaculation)
• Exercise care in hypovolemic patients.
Imidazoline derivatives – phentolamine (5-7hr)
produces a competitive block of α1 and α2-receptors.
1. Block serotonin receptors
2. Stimulate H1 & H2
3. Stimulate M1; Parasympathomimetic
• Increased gastric motility & acid secretion
• Increased secretion from exocrine glands, such as salivary, sweat, lacrimal,
pancreatic
• Cardiac stimulation reflex and direct!!
• it can be injected intracavernosally to produce vasodilation of penile arteries
(rarely used)
Alpha-1 selective blockers
Prazosin, terazosin, doxazosin, alfuzosin, and tamsulosin
• The first three drugs are useful in the treatment of hypertension.
• Alfuzosin & Tamsulosin are indicated for the treatment of benign prostatic
hypertrophy (BPH)
• Prazosin (t1/2 3hrs): No significant tachycardia
Used in CHF and in hypertension but tolerance develops with time, may be due to
fluid retention.
• Adverse effects: First dose phenomenon.
• Favorable effect on plasma lipids: increase HDL/LDL ratio
• Terazosin (t1/2 9-12 hrs)
Other α -adrenoceptor antagonists
• Indoramin: antihypertensive.
• Urapidil is an α1 antagonist (its primary effect) that also has weak α2-agonist
and 5-HT1A-agonist actions and weak antagonist action at β1 receptors. It is
used in Europe as an antihypertensive agent and for BPH.
• Labetalol has both α1-selective and β-antagonistic effects.
• Neuroleptic drugs such as chlorpromazine and haloperidol are potent
dopamine receptor antagonists but are also antagonists at α-receptors.
• Antidepressant: trazodone block α1 receptors.
2 - selective antagonists Yohimbine
Chief active compound in Pausinystalia yohimbine (bark),
Effects opposite of Clonidine
Enters CNS => increased sympathetic output => increased HR, BP, can cause
severe tremors
Ingredient in many weight loss products
Enhances sexual activity – aphrodisiac
Blocks other receptors: serotonin, dopamine, Increases ADH release
Experimental uses in Treatment of :
1. Raynaud's phenomenon to inhibit smooth muscle contraction,
2. type 2 diabetes (α2 receptors inhibit insulin secretion),
3. depression.
Therapeutic Uses of Alpha-Adrenergic Blockers
• Hypertension - α1selective
• Pheochromocytoma
• Peripheral vascular disease – Raynaud’s
• Local Vasoconstrictor Excess
• Benign prostatic hyperplasia
• Erectile Dysfunction: Yohimbine or intracavernous phentolamine + papaverine
L6 ans pharmacology 17 18

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L6 ans pharmacology 17 18

  • 1. Drugs Affecting The Autonomic Nervous System(ANS) Alpha-Adrenergic Blockers ANS Pharmacology Lecture 6 Dr. Hiwa K. Saaed College of Pharmacy/University of Sulaimani 2017-2018
  • 2. Review of Agonist Effects of α1 Adrenergic Receptors Receptor Tissues Response α1 Eye-radial (dilatory) muscle Contracts (mydriasis) Most vascular smooth muscle -Arterioles (skin, viscera) -veins Contraction ↑TPR→↑ diastolic pressure ↑afterload ↑ venous return→↑ preload Bladder trigone and sphincter Contraction→urinary retention Male sex organs Vas deferens→ ejaculation Liver (in some species, rat ) Stimulate glycogenolysis Kidney ↓ rennin release Pilomotor smooth muscle Contraction (erect hair)
  • 3. Review of Agonist Effects of α2 Adrenergic Receptors Receptor tissue Response α 2 Adrenergic & cholinergic Prejunctional nerve terminals ↓ transmitter release and NE synthesis Platelets Stimulate Aggregation Pancreas (β cells) Inhibit insulin release Some vascular smooth muscle Contracts Fat cells Inhibits lipolysis Medullary vasomotor center ↓sympathetic outflow → CO & vasodilation→↓ BP
  • 5. Alpha-Adrenergic Blockers Classification I. Type of blockade 1. Irreversible (non-competitive) : Phenoxybenzamine; slow onset and long duration. 2. Reversible (competitive): All the rest II. Selectivity: Like the agonists, the adrenergic antagonists are classified according to their relative affinities for α1 or α2 receptors. -Nonselective: Phenoxybenzamine and phentolamine -Selective: α1 or α2 receptors 1. α1 selective: Prazosin, terazosin, others 2. α2 selective: Yohimbine 3. α/ℬ blockers: Labetalol -Others: phenothiazines, haloperidol, tricyclic antidepressants, trazodone
  • 6. α Antagonists Receptor Affinity Prazosin, terazosin, doxazosin α1>>>>α2 Phenoxybenzamine α1>α2 Phentolamine α1=α2 Rauwolscine, yohimbine, tolazoline α2>α1 Mixed antagonists Labetalol, carvedilol β1=β2≥α1>α2 Alpha-Adrenergic Blockers Classification/ Receptor Selectivity
  • 7. Nonselective • Phenoxybenzamine (3-4 days) Selective • Short-acting selective 1-blocker • Prazosin t1/2 3 hrs, Alfuzosin t1/2 5 hrs • Long-acting selective 1-blockers • Terazosin t1/2 9-12 hrs • Doxazosin t1/2 22 hrs • Long-acting selective 1A-subtype • Tamsulosin t1/2 9-15 hrs Alpha-Adrenergic Blockers Classification/ Duration of action
  • 8. Pharmacological Effects-Phenoxybenzamine 1. Cardiovascular system • ↓PR: ↓ Blood pressure: reflex tachycardia: • ↑Increase CO: Furthermore, the ability to block presynaptic inhibitory α2-receptors in the heart will result in more norepinephrine release, which stimulates β- receptors on the heart to increase cardiac output. • It reduces BP when sympathetic tone is high such as in upright posture, reduced blood volume
  • 9. Adrenergic System - Antagonists
  • 10. Epinephrine reversal: • All α-adrenergic blockers reverse the α-agonist actions of epinephrine. the vasoconstrictive action of epinephrine is interrupted, but vasodilation of other vascular beds caused by stimulation of β2 receptors is not blocked. • Therefore, the systemic blood pressure decreases in response to epinephrine given in the presence of phenoxybenzamine. ….Why? • The actions of norepinephrine are not reversed but are diminished, …why?
  • 11. Pharmacological Effects – Phenoxybenzamine 2. Eye – miosis 3. Nasal stuffiness 4. GI tract – Increased motility 5. Urinary bladder – decreased tone in sphincter 6. Metabolic effects – increased insulin secretion 7. It also blocks histamine, serotonin and cholinergic receptors
  • 12. Clinical uses -Phenoxybenzamine 1. Pheochromocytoma: a catecholamine-secreting tumor of cells derived from the adrenal medulla 2. Raynaud; peripheral vascular disease 3. Autonomic hyperreflexia which predisposes paraplegics to strokes 4. BPH
  • 13. Adverse effects Phenoxybenzamine • Postural hypotension • Tachycardia it is contraindicated in patients with decreased coronary perfusion. • Sedation, fatigue • Nasal stuffiness • Miosis • Impotence (inhibits ejaculation) • Exercise care in hypovolemic patients.
  • 14. Imidazoline derivatives – phentolamine (5-7hr) produces a competitive block of α1 and α2-receptors. 1. Block serotonin receptors 2. Stimulate H1 & H2 3. Stimulate M1; Parasympathomimetic • Increased gastric motility & acid secretion • Increased secretion from exocrine glands, such as salivary, sweat, lacrimal, pancreatic • Cardiac stimulation reflex and direct!! • it can be injected intracavernosally to produce vasodilation of penile arteries (rarely used)
  • 15. Alpha-1 selective blockers Prazosin, terazosin, doxazosin, alfuzosin, and tamsulosin • The first three drugs are useful in the treatment of hypertension. • Alfuzosin & Tamsulosin are indicated for the treatment of benign prostatic hypertrophy (BPH) • Prazosin (t1/2 3hrs): No significant tachycardia Used in CHF and in hypertension but tolerance develops with time, may be due to fluid retention. • Adverse effects: First dose phenomenon. • Favorable effect on plasma lipids: increase HDL/LDL ratio • Terazosin (t1/2 9-12 hrs)
  • 16. Other α -adrenoceptor antagonists • Indoramin: antihypertensive. • Urapidil is an α1 antagonist (its primary effect) that also has weak α2-agonist and 5-HT1A-agonist actions and weak antagonist action at β1 receptors. It is used in Europe as an antihypertensive agent and for BPH. • Labetalol has both α1-selective and β-antagonistic effects. • Neuroleptic drugs such as chlorpromazine and haloperidol are potent dopamine receptor antagonists but are also antagonists at α-receptors. • Antidepressant: trazodone block α1 receptors.
  • 17. 2 - selective antagonists Yohimbine Chief active compound in Pausinystalia yohimbine (bark), Effects opposite of Clonidine Enters CNS => increased sympathetic output => increased HR, BP, can cause severe tremors Ingredient in many weight loss products Enhances sexual activity – aphrodisiac Blocks other receptors: serotonin, dopamine, Increases ADH release Experimental uses in Treatment of : 1. Raynaud's phenomenon to inhibit smooth muscle contraction, 2. type 2 diabetes (α2 receptors inhibit insulin secretion), 3. depression.
  • 18. Therapeutic Uses of Alpha-Adrenergic Blockers • Hypertension - α1selective • Pheochromocytoma • Peripheral vascular disease – Raynaud’s • Local Vasoconstrictor Excess • Benign prostatic hyperplasia • Erectile Dysfunction: Yohimbine or intracavernous phentolamine + papaverine