Adrenoceptor antagonist drugs Pawitra Pulbutr M.Sc. In Pharm (Pharmacology) Pawitra Pulbutr M.Sc. In Pharm (Pharmacology)

Objectives  นิสิตมีความรู้ความเข้าใจถึงเภสัชวิทยา กลไกการออกฤทธิ์ เภสัชจลนศาสตร์ การ ใช้ประโยชน์ทางคลินิก การเกิดปฏิกิริยา ระหว่างยา ของยาที่ออกฤทธิ์ต้านระบบ ประสาทซิมพาเทติกทั้งชนิด  -receptor antagonist และชนิด  -receptor antagonist

Adrenoceptor blocking agent  Affect many physiological & pathophysiological functions “ Sympatholytics ”  In the past … may be called “ Sympatholytics ” … Not appropriate  Antagonist or Blocker  Antagonist or Blocker >>> More appropriate   blocker   blocker …  Pheochromocytoma, Primary hypertension  blocker   blocker …  Hypertension, Ischemic heart disease, Arrhythmia, Other endocrine disorder

Relative selectivity of antagonist for adrenoceptors

Basic Pharmacology of  -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 blocker Irreversible blocker

Pharmacologic effects  CVS   -receptor control  Arteriolar tone  Venous tone   -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 benign prostatic hyperplasia (BPH)  Use in benign prostatic hyperplasia (BPH)

 -blockers II rreversible blockers PP henoxybenzamine RR eversible blockers NN on-selective blocker PP hentolamine, Tolazoline SS elective  1-blocker PP razosin family DD oxazosin, Terazosin, Alfuzosin, Tamsulosin SS elective  2-blocker YY ohimbine

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  Postural hypotension esp. First dose  Not use non-selective  -blocker   2 blocker … Increase NE release

Urinary obstruction  Benign prostatic hyperplasia (BPH) elderly male  Mostly found in elderly 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 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

Pharmacological effects  CVS  Decrease BP  Heart  Negative chronotropic & inotropic  Slow arterioventricular conduction  Prolong PR interval (AV node suppression)  Renin Angiotensin Aldosterone (RAA) system  Renin Angiotensin Aldosterone (RAA) system … decrease renin release  Vascular resistance  Inhibit  2-mediated vasodilation  Acute effect >>> Vasoconstriction  Prolong action …. Decrease peripheral vascular resistance  Decrease renin (RAA)

Respiratory tract   2-receptor blocking activity  Bronchoconstriction  Danger in asthmatic patients !!  1-selective blocker  Should select  1-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  -blockade  Intrinsic sympathomimetic activity of partial agonist ISA (partial agonist)   -blocker with ISA (partial agonist)  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   1-selective  Partial agonist  May not be replaced with others  Only pure antagonist is used in hyperthyroidism

ADRs  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

ADRs CHF patient  Use with caution in CHF patient  Reversal of life threatening  -blocker effect  Isoproterenol, Glucagon  Drug Interaction  Ca ++ channel blocker  Severe hypotension, Severe bradycardia, Heart failure  Taper dose “ RC upregulation ”  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 with caution in Type 1 DM hypoglycemia recovery   -blocker may interfere hypoglycemia recovery   2 activation >>> Glycogenolysis  Use selective  1-selective blocker  Mask disease/ symptom manifestation  Mask hypoglycemia sign … tachycardia  Mask hyperthyroidism symptom

 -blockers PPPPure antagonists PP ropranolol, Nadolol, Sotalol, Timolol SSSSelective 1-antagonists MM etoprolol, Esmolol, Celiprolol, Acebutolol, Atenolol, Betaxolol, Bisoprolol (MEC 2A 2B) PPPPartial agonist (Blockers with ISA) LL abetalol, Acebutolol, Carteolol, Celiprolol, Penbutolol, Pindolol (LA 2C 2P) MMMMixed antagonist ( and -blockers) LL abetalol, Carvedilol