adrenoceptor antagonist drugs pawitra pulbutr m.sc. in pharm (pharmacology) pawitra pulbutr m.sc. in...
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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