-ADRENOCEPTOR ANTAGONISTS ( -BLOCKERS )

CLASSIFICATION I. ACCORDING TO SELECTIVITY A) NON-SELECTIVE (1, 2) BLOCKERS 1. PURE BLOCKES v SOTALOL v TIMOLOL v NADOLOL 2. WITH MEMBRANE STABILIZING ACTIVITY (MSA) v PROPANOLOL 3. WITH INTRINSIC SYMPATHETIC ACTIVITY (ISA) v PENBUTOLOL v CARTEOLOL 4. WITH ISA & MSA v OXPRENOLOL v ALPRENOLOL v PINDOLOL (MSA )

B) CARDIOSELECTIVE (1) BLOCKERES 1. PURE BLOCKERS v ATENOLOL v BISOPROLOL 2. WITH MSA v METOPROLOL v TOLAMOLOL v BETAXOLOL 3. WITH ISA v PRACTALOL 4. WITH ISA & MSA v ACEBUTALOL C) BOTH  &  BLOCKERS v LABETALOL v CARVEDILOL D) 1 BLOCKER WITH PARTIAL 2 AGONIST ACTIVITY v CELIPROLOL E) 2 selective blocker Butoxamine, used only in research.

CLASSIFICATION II. ACCORDING TO SOLUBILITY LIPID SOLUBLE PROPRANOLOL TIMOLOL METOPROLOL WATER SOLUBLE NADOLOL ATENOLOL

CLASSIFICATION III. ACCORDING TO DURATION OF ACTION ULTRA SHORT ACTING ESMOLOL t ½ 9min INTERMEDIATE ACTING PROPRANOLOL 3-5 hours PINDOLOL 3-4 hours METOPROLOL 3-4 hours LONG ACTING NADOLOL 10-20 hours ATENOLOL 05-08 hours BISOPROLOL

PHARMACOKINETICS

Absorption: well absorbed orally, peak concentration 1-3 hrs Sustained release preparations are available Bioavailability: Propranolol extensive hepatic (first pass metabolism) Rapidly distributed and have large volume of distribution. Can cross blood brain barrier

Nadolol is excreted unchanged in urine and has longest half life of 24 hrs.

EFFECT OF BINDING OF ADRENALINE TO  RECEPTORS. -Receptor are G Protein Mediated Binding Adrenaline to  Receptors (Extracellular) Stimulation of Adenyl cyclase (intracellular) Increase Conversion of ATP to cAMP Stimulation of Protein Kinase C. Phosphorylation of Enzymes (Enzyme-PO4) Response

PHARMACOLOGICAL ACTIONS 1.      CVS

Suppression of renin release and effects in the central nervous system. Prominent effect on heart Negative inotropic and chronotropic effects. In vascular system, β2 mediated vasodilatation

3. Eye (reduce aqueous humor production) 2.  Respiratory System (increase in airway resistance) 3.  Eye (reduce aqueous humor production) 4.   Metabolism (increase VLDL and decrease HDL 5.   Intrinsic Sympathomimetic Activity (ISA) Precipitation of asthma, excessive bradycardia is prevented 6. Membrane stabilizing Activity (MSA) Local anesthetic action (Na+ channel blockade)

THERAPEUTIC USES ANTI-HYPERTENSIVE ANTI-ANGINAL (reduce the frequency of anginal episode) ANTI-ARRHYTHMIC Prophylaxis after myocardial infarction, Treatment of other Cardiac Arrhythmias, Supraventricular and ventricular arrhythmias. Sotalol Metoprolol Timolol Propranolol Esmolol Acebutolol

Slowing of ventricular ejection and decrease outflow resistance. MYOCARDIAL INFARACTION (MI) (prolong survival) HYPERTROPHIC SUBAORTIC STENOSIS HYPERTROPHIC CARDIOMYOPATHY: Propranolol Slowing of ventricular ejection and decrease outflow resistance.

THYRO TOXICOSIS, Thyroid storm: Inhibition of peripheral conversion of thyroxine to triiodothyronine GLAUCOMA: TIMOLOL BETAXOLOL Reduce production of aqueous humor by ciliary body

MIGRAINE (frequency and intensity of migraine attacks) PHEOCHROMOCYTOMA: LABETALOL TREATMENT OF CHRONIC (NOT ACUTE) CCF: LABETALOL CARVEDILOL

FAMILAL TREMORS, OTHER TYPES OF TREMORS (sympathetic activity may enhance skeletal muscle tremor)

ANXIETY Alcohol WITHDRAWAL SYNDROME (symptomatic treatment) PORTAL HYPERTENSION ACUTE PANIC SYMPTOMS – stage fright, viva-voce examination, public appearance etc. (PROPAYLACTIC USE)

ADVERSE EFFECTS 1. CNS (bad dreams, lassitude, depression). 2. CVS (Congestive Cardiac failure, Bradycardia, Atrioventricular blockade). 3. METABOLIC EFFECTS HYPOGLYCEMIA – exercise induced, insulin induced. Slow recovery from hypoglycemia and masking the manifestations of sympathetic activity due to exercise / insulin induced hypoglycemia in diabetic patients, resulting in loss of warning signal and the patient may land into hypoglycemic coma.

4. RESPIRATORY EFFECTS Bronchoconstriction Worsening of preexisting asthma

5. COLDNESS OF EXTREMITIES 6. FATIGUE 7. Aggravation of diabetes mellitus, hyperlipidemic states, peripheral vascular spastic diseases by the use of Non selective beta blockers. 8. ADVERSE EFFECTS ON SUDDEN WITHDRAWAL (up regulation of receptors)

ANTIDOTE OVER DOSAGE a. PRENALTEROL: SELECTIVE 1 AGONIST, MAY BE USED IN -BLOCKERS’ TOXICITY CAUSED BY HIGH DOSES. b. Pressor agents c. Atropine d. Glucagon

CONTRA-INDICATIONS 1. ASTHMA 2. DIABETESE MELLITUS 3. HYPER LIPIDAEMIC STATES 4. DEPRESSION 5. PERIPHERAL VASCULAR DISEASES 6. 2ND OR 3RD DEGREE HEART BLOCK 7. HEART FAILURE INTERMITTENT CLAUDICATIONS

DRUG INTERACTIONS Enzyme inducers & Inhibitors Lignocaine & GAs Oral anti-diabetic drugs

Esmolol ultra short acting ester linkage Esterases in RBC rapidly metabolize esmolol. Useful supraventricular arrhythmias, arrhythmias associated with thyrotoxicosis, perioperative hypertension and myocardial ischemia.

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