Adrenoceptor antagonist drugs

Adrenoceptor antagonist drugs

Pawitra Pulbutr M.Sc. In Pharm (Pharmacology)

Pawitra Pulbutr M.Sc. In Pharm (Pharmacology)

ObjectivesObjectives

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Adrenoceptor blocking agentAdrenoceptor blocking agent

Affect many physiological & pathophysiological functions

In the past… may be called “Sympatholytics”“Sympatholytics” … Not appropriate

Antagonist or BlockerAntagonist or Blocker >>> More appropriate

blockerblocker… Pheochromocytoma, Primary hypertension

blockerblocker… Hypertension, Ischemic heart disease,

Arrhythmia, Other endocrine disorder

Relative selectivity of antagonist for adrenoceptors

Basic PharmacologyBasic Pharmacology of of -blockers-blockersBasic PharmacologyBasic Pharmacology of of -blockers-blockers

Binding with -receptor Reversible

Competitive with catecholamine Phentolamine, Tolazoline,

Prazosin, Labetalol Irreversible

Covalent binding Phenoxybenzamine

Nitrogen mustard like structure Form reactive ethyleneimmonium

compound

Dose-response curve to NE in the presence of two different -blockers.

Reversible blockerReversible blocker Irreversible blockerIrreversible blocker

Pharmacologic effectsPharmacologic effects

CVS -receptor control

Arteriolar tone Venous tone

-receptor antagonist-receptor antagonist Decrease peripheral vascular resistance

(TPR) Decreased BP

May cause postural hypotension or reflex tachycardia (esp. if 2 also blocked … increase NE secretion… more tachycardia)

Body compensation in long term use … Increase blood volume

Other -blocking effects Bladder base & Prostate -blocker …

Decrease resistance Increase urine flow Use in benign prostatic benign prostatic

hyperplasia (BPH)hyperplasia (BPH)

-blockers-blockers

Irreversible blockers Phenoxybenzamine

Reversible blockers Non-selective blocker

Phentolamine, Tolazoline Selective 1-blocker

Prazosin family Doxazosin, Terazosin, Alfuzosin,

Tamsulosin Selective 2-blocker

Yohimbine

Clinical PharmacologyClinical Pharmacology

Pheochromocytoma Hypertensive emergencies Chronic hypertension Peripheral vascular disease Local vasoconstrictor excess Urinary obstruction >> BPH Male sexual dysfunction

Chronic hypertensionChronic hypertension

Prazosin family 1-selective blockers Treatment of mild to moderate

hypertension ADRs

Postural hypotension esp. First dose

Not use non-selective Not use non-selective -blocker-blocker 2 blocker … Increase NE release

Urinary obstructionUrinary obstruction

Benign prostatic hyperplasia (BPH) Mostly found in elderly maleelderly male Treatment

Surgery Drug therapy

1-blocker Partial reversal of smooth muscle

contraction at prostate and bladder base

Prazosin, Doxazosin, Terazosin, Tamsulosin

Good effective esp. in hypertensive patients

Basic Pharmacology of -blockers

Basic Pharmacology of -blockers

Competitive binding to -receptor“Isoproterenol” like structureDifference affinity to 1 or 2 receptorPure antagonist

Pure -blocker

Partial agonist-blocker with intrinsic sympathomimetic activity (ISA)Activate -RC… not to maximal responseInterfere endogenous ligand to bind -RC

-blocker with -blocker activity (Mixed)

Labetalol & Carvedilol

Properties of several Beta-blockersProperties of several Beta-blockers

Pharmacological effectsPharmacological effectsPharmacological effectsPharmacological effects CVS Decrease BP

Heart Heart Negative chronotropic & inotropicNegative chronotropic & inotropic Slow arterioventricular conductionSlow arterioventricular conduction Prolong PR interval (AV node suppression)Prolong PR interval (AV node suppression)

Renin Angiotensin Aldosterone (RAA) Renin Angiotensin Aldosterone (RAA) systemsystem … decrease renin release

Vascular resistance Inhibit 2-mediated vasodilation

Acute effect >>> Vasoconstriction

Prolong action …. Decrease peripheral vascular resistance

Decrease renin (RAA)

Respiratory tractRespiratory tract

2-receptor blocking activity Bronchoconstriction Danger in asthmatic patients !! Should select 1-selective blocker1-selective blocker

… less bronchoconstriction Acebutolol, Atenolol, Betaxolol,

Bisoprolol, Celiprolol, Esmolol, Metoprolol

Use with caution in asthma

Eyes -blocker … decrease aqueous humor

production …decrease intraocular pressure

Use in glaucoma

Metabolic & endocrine effects -blocker … Inhibit lipolysis Inhibit glycogenolysis in liver

May affect hypoglycemia correction ? Should be use with caution in DM esp. Type 1

Increase LDL Decrease HDL

Decrease HDL/ LDL ratio Increase risk of CVS disease Partial agonist … less effects - blockers … No effect

Effects not related to -blockadeEffects not related to -blockade

Intrinsic sympathomimetic activity of partial agonist

-blocker with ISA (partial agonist)ISA (partial agonist) Acebutolol, Carteolol, Celiprolol,

Labetalol, Penbutolol, Pindolol May be useful in asthmatic &

bradycardia patients Less bronchoconstriction Less bradycardia

Clinical PharmacologyClinical PharmacologyClinical PharmacologyClinical Pharmacology

Hypertension Ischemic heart disease Cardiac arrhythmia Other CVS disorder Glaucoma Hyperthyroidism Neurologic disease Miscellaneous

Choice of Choice of -blocker-blockerChoice of Choice of -blocker-blocker

Specific activity of each agent Benefit or Risk of each agent

1-selective Partial agonist

May not be replaced with others Only pure antagonist is used in

hyperthyroidism

ADRsADRs

Propranolol Rash, Fever, Drug allergy Sedation, Sleep disturbance, Depression Less in hydrophillic -blocker…Nadolol,

Atenolol Unwanted -blocking effect

Bronchoconstriction (2) … Asthma Vasospasm (2) … Peripheral vascular dz. Use selective 1-blocker

ADRsADRs Use with caution in CHF patientCHF patient Reversal of life threatening -blocker

effect Isoproterenol, Glucagon

Drug Interaction Ca++ channel blocker

Severe hypotension, Severe bradycardia, Heart failure

Taper dose Prolong use … ““RC upregulation”RC upregulation” Sudden stop … RC over stimulation …

Danger ! Slowly stop using -blocker in ischemic

heart disease Especially in short half-life … propranolol,

metoprolol

Use with caution in Type 1 DM -blocker may interfere

hypoglycemia recoveryhypoglycemia recovery 2 activation >>> Glycogenolysis

Use selective 1-selective blocker

Mask disease/ symptom manifestation

Mask hypoglycemia sign … tachycardia Mask hyperthyroidism symptom

-blockers-blockers

Pure antagonistsPure antagonists Propranolol, Nadolol, Sotalol, Timolol

Selective Selective 1-antagonists1-antagonists Metoprolol, Esmolol, Celiprolol, Acebutolol,

Atenolol, Betaxolol, Bisoprolol (MEC 2A 2B) Partial agonist (Blockers with ISA)Partial agonist (Blockers with ISA)

Labetalol, Acebutolol, Carteolol, Celiprolol, Penbutolol, Pindolol (LA 2C 2P)

Mixed antagonist (Mixed antagonist ( and and -blockers)-blockers) Labetalol, Carvedilol