Download and -blockers - e

Adrenoceptor
antagonist drugs
Pawitra Pulbutr
M.Sc. In Pharm (Pharmacology)
Objectives
 นิ สติ มีความรูค้ วามเข้าใจถึงเภสัชวิทยา กลไกการออกฤทธิ์ เภสัชจลนศาสตร์
การใช้ประโยชน์ทางคลินิก การเกิดปฏิกริ ยิ าระหว่างยา ของยาที่ออกฤทธิ์ตา้ น
ระบบประสาทซิมพาเทติกทัง้ ชนิ ด -receptor
antagonist และชนิ ด -receptor antagonist
Adrenoceptor blocking agent
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Affect many physiological &
pathophysiological functions
In the past… may be called “Sympatholytics”
… Not appropriate
Antagonist or Blocker >>> More appropriate
 blocker…
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Pheochromocytoma, Primary hypertension
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Hypertension, Ischemic heart disease,
Arrhythmia, Other endocrine disorder
 blocker…
Relative selectivity of antagonist for
adrenoceptors
Basic Pharmacology of -blockers
 Binding with -receptor
 Reversible
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Competitive with catecholamine
Phentolamine, Tolazoline, Prazosin,
Labetalol
 Irreversible
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Covalent binding
Phenoxybenzamine
 Nitrogen mustard like structure
 Form reactive ethyleneimmonium compound
Reversible blocker
Irreversible blocker
Dose-response curve to NE in the presence of two
different -blockers.
Pharmacologic effects
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CVS
-receptor control
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Arteriolar tone
Venous tone
-receptor antagonist
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Decrease peripheral vascular resistance (TPR)
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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 …
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Decrease resistance
Increase urine flow
Use in benign prostatic hyperplasia
(BPH)
-blockers
 Irreversible
blockers
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Phenoxybenzamine
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Non-selective blocker
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Selective 1-blocker
 Reversible
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blockers
 Phentolamine,
Tolazoline
 Prazosin family
 Doxazosin, Terazosin,
Tamsulosin
Selective 2-blocker
 Yohimbine
Alfuzosin,
Clinical Pharmacology
Pheochromocytoma
Hypertensive emergencies
Chronic hypertension
Peripheral vascular disease
Local vasoconstrictor excess
Urinary obstruction >> BPH
Male sexual dysfunction
Chronic hypertension
 Prazosin family
 1-selective blockers
 Treatment of mild to moderate
hypertension
 ADRs
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Postural hypotension esp. First dose
 Not
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use non-selective -blocker
2 blocker … Increase NE release
Urinary obstruction
 Benign
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Mostly found in elderly male
Treatment
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prostatic hyperplasia (BPH)
Surgery
Drug therapy
1-blocker
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Partial reversal of smooth muscle contraction
at prostate and bladder base
Prazosin, Doxazosin, Terazosin, Tamsulosin
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Good effective esp. in hypertensive patients
Basic Pharmacology of -blockers
Competitive binding to -receptor
“Isoproterenol” like structure
Difference affinity to 1 or 2 receptor
Pure antagonist
Pure -blocker
Partial agonist
-blocker with intrinsic sympathomimetic
activity (ISA)
Activate -RC… not to maximal response
Interfere endogenous ligand to bind -RC
-blocker with -blocker activity (Mixed)
Labetalol & Carvedilol
Properties of several Beta-blockers
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Pharmacological effects
CVS
Decrease BP
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Heart
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Negative chronotropic & inotropic
Slow arterioventricular conduction
Prolong PR interval (AV node suppression)
Renin Angiotensin Aldosterone (RAA) system …
decrease renin release
Vascular resistance
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Inhibit 2-mediated vasodilation
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Acute effect >>> Vasoconstriction
Prolong action …. Decrease peripheral vascular
resistance
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Decrease renin (RAA)
Respiratory tract
 2-receptor blocking activity
 Bronchoconstriction
 Danger in asthmatic patients !!
 Should select 1-selective blocker …
less bronchoconstriction
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Acebutolol, Atenolol, Betaxolol,
Bisoprolol, Celiprolol, Esmolol,
Metoprolol
Use with caution in asthma
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Eyes
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-blocker … decrease aqueous humor
production …decrease intraocular pressure
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Use in glaucoma
Metabolic & endocrine effects
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-blocker … Inhibit lipolysis
Inhibit glycogenolysis in liver
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May affect hypoglycemia correction ?
Should be use with caution in DM esp. Type 1
Increase LDL
Decrease HDL
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Decrease HDL/ LDL ratio
Increase risk of CVS disease
Partial agonist … less effects
- blockers … No effect
Effects not related to -blockade
 Intrinsic
sympathomimetic activity of
partial agonist
 -blocker with ISA (partial agonist)
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Acebutolol, Carteolol, Celiprolol,
Labetalol, Penbutolol, Pindolol
May be useful in asthmatic & bradycardia
patients
Less bronchoconstriction
Less bradycardia
Clinical Pharmacology
Hypertension
Ischemic heart disease
Cardiac arrhythmia
Other CVS disorder
Glaucoma
Hyperthyroidism
Neurologic disease
Miscellaneous
Choice of -blocker
 Specific activity of each agent
 Benefit or Risk of each agent
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1-selective
Partial agonist
 May not be replaced with others
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Only pure antagonist is used in
hyperthyroidism
ADRs
 Propranolol
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Rash, Fever, Drug allergy
Sedation, Sleep disturbance, Depression
Less in hydrophillic -blocker…Nadolol,
Atenolol
 Unwanted
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-blocking effect
Bronchoconstriction (2) … Asthma
Vasospasm (2) … Peripheral vascular dz.
Use selective 1-blocker
ADRs
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Use with caution in CHF patient
Reversal of life threatening -blocker
effect
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Isoproterenol, Glucagon
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Ca++ channel blocker
Drug Interaction
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Severe hypotension, Severe bradycardia, Heart
failure
Taper dose
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Prolong use … “RC upregulation”
Sudden stop … RC over stimulation … Danger !
Slowly stop using -blocker in ischemic heart
disease
Especially in short half-life … propranolol,
metoprolol
 Use
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with caution in Type 1 DM
-blocker may interfere hypoglycemia
recovery
 2
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Use selective 1-selective blocker
 Mask
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activation >>> Glycogenolysis
disease/ symptom manifestation
Mask hypoglycemia sign … tachycardia
Mask hyperthyroidism symptom
-blockers
 Pure
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antagonists
Propranolol, Nadolol, Sotalol, Timolol
 Selective
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1-antagonists
Metoprolol, Esmolol, Celiprolol,
Acebutolol, Atenolol, Betaxolol, Bisoprolol
(MEC 2A 2B)
 Partial
agonist (Blockers with ISA)
 Mixed
antagonist ( and -blockers)
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Labetalol, Acebutolol, Carteolol,
Celiprolol, Penbutolol, Pindolol (LA 2C 2P)
Labetalol, Carvedilol