ALPHA BLOCKERS Alpha receptors have been further subdivided into alpha1 and alpha2 receptors. Alpha -1 receptors – Upon stimulation, leads to increased IP3 and DAG through Gq activated PLC. contraction of arterioles and venules. contraction of radial fibers in the eye. contraction of vas deferens (ejaculation). contraction of bladder trigone. Alpha receptors – mediates the actions of epinephrine, norpinephrine and phenyephrine.

ALPHA BLOCKERS Blockade of vasoconstriction - hypotension EFFECTS OF ALPHA-1 BLOCKER: Blockade of vasoconstriction - hypotension Postural reflex is interfered – postural hypotension Reflex tachycardia – due to fall in BP Promote urinary outflow Failure of ejaculation

ALPHA BLOCKERS PROTYPE Phenoxy -benzamine (PBZ) Phentolamine Irreversible Nonselective blockers Reversible Nonselective blockers Reversible Selective α-1 blockers Reversible selective α-1A blockers Selective α-2 blockers PROTYPE Phenoxy -benzamine (PBZ) Phentolamine Prazosin Terazosin Tamsulosin Silodosin Yohimbine INDICATIONS Pheochromo cytoma Pheochromo cytoma Hypertension BPH BPH Erectile dysfunction Since silodosin is a highly selective inhibitor of the α1A adrenergic receptor, it causes practically no orthostatic hypotension (in contrast to other α1 blockers). On the other side, the high selectivity seems to cause more problems with ejaculationYocon (yohimbine hydrochloride) blocks presynaptic alpha-2 adrenergic receptors. Its action on peripheral blood vessels resembles that of reserpine, though it is weaker and of shorter duration. Yohimbine's peripheral autonomic nervous system effect is to increase parasympathetic (cholinergic) and decrease sympathetic (adrenergic) activity. It is to be noted that in male sexual performance, erection is linked to cholinergic activity and to alpha-2 adrenergic blockade which may theoretically result in increased penile inflow, decreased penile outflow or both 10 percent of all Pheochromocytomas are: Malignant (90% are benign) Bilateral (found in both adrenal glands: 90% are arise in just one of the two adrenal glands) Extra-Adrenal (found within nervous tissue outside of the adrenal glands ... see below) In Children (90% are in adults) Familial (10% will have a family member with the same type of tumor) Recur (10% or slightly less, will come back 5 to 10 years later) Associated with MEN syndromes (patients with rare syndromes of endocrine tumors.) Present with a stroke (10% of these tumors are found after the patient has a stroke) Yohimbine has been used as both an over-the-counter dietary supplement in herbal extract form and prescription medicine in pure form for the treatment of sexual dysfunction. Yohimbine has high affinity for the α2A-adrenergic, α2B-adrenergic, and α2C-adrenergic receptors, moderate affinity for the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2B, and D2 receptors, and weak affinity for the D3 receptor. Yohimbine also has unknown but significant affinity for the 5-HT2A receptor. Yohimbine behaves as an antagonist at all receptors except for the 5-HT1A, 5-HT1D, and 5-HT2A receptors, where it acts as a weak partial agonist.

ALPHA -1 BLOCKERS PRAZOSIN (Minipress): Orally active selective alpha-1 blocker. Used in hypertension and treatment of urinary retention due to benign prostrate hypertrophy. Postural hypotension – first dose phenomenon – start with low dose at bed time to reduce it. Sexual dysfunction – retrograde ejaculation. Favorable effects on lipoproteins

BETA BLOCKERS Cornerstone of Coronary Artery Disease therapy – except prinzmetal’s angina Standard therapy for unstable and stable angina. One of the preferred therapies for hypertension with myocardial infarction. One of the major anti-arrhythmic group of drugs.

BETA BLOCKERS Non-selective Selective beta-1 Propranolol Nadolol α- RECEPTOR BLOCKING ACTION Non-selective Selective beta-1 NO INTRINSIC AGONIST ACTIVITY INTRINSIC AGONIST ACTIVITY Propranolol Nadolol Timolol Pindolol Labetolol Carvedilol NO INTRINSIC ACTIVITY Atenolol Metoprolol Esmolol Betaxolol INTRINSIC ACTIVITY Acebutolol

BETA BLOCKERS PROPRANOLOL : It undergoes extensive first pass metabolism and oral bioavailability is low. The proportion of drug reaching systemic circulation increases as the dose is increased suggesting that hepatic extraction mechanism may be saturated.

BETA BLOCKERS PROPRANOLOL : Heart : Negative inotropic action Negative chronotropic action AV conduction is decreased Long term use of beta blockers are associated with unfavorable increase in VLDL and decrease in HDL. Beta blockers have little effects on normal heart at rest but has profound effects when sympathetic control is dominant as during stress or exercise. CO= SV X HR SV= EDV-ESV EF= SV/ EDV

BETA BLOCKERS PROPRANOLOL : Eyes : decrease intraocular tension in chronic simple glaucoma by reducing aqueous humor production CNS : sedation, lethargy, depression, sleep disturbances Skeletal muscle : antagonizes the epinephrine induced tremors (β-2) Respiratory tract : bronchoconstriction and can precipitate bronchial asthma

BETA BLOCKERS PROPRANOLOL: Metabolic effects : blocks the warning signals due to counter regulatory effects of catecholamines during hypoglycemia. delays recovery from hypoglycemia in diabetes mellitus. CAUTION in DM : Beta-1 selective – preferred Benefits outweigh risks in diabetics and myocardial infarction.

BETA BLOCKERS PRECAUTIONS AND ADVERSE EFFECTS : AV block and bradycardia Bronchial asthma and COPD Cold extremities Depression Hyperlipidemia Sexual dysfunction Beta-blockers reduce the amount of blood which the heart pumps out at each stroke. This leads to a fall in blood flow through the body tissues particularly affecting the skin, the muscles and the extremities (fingers, toes, etc). As a result people often complain of feeling listless or tired and experience cold hands and feet, especially for a few weeks after starting treatment. This is entirely predictable and to some extent is an indication that your treatment is working. In most cases the body becomes tolerant to the above effects and they become much less troublesome as treatment continues. It may, however, prove to be an ongoing problem for those who have poor circulation in the first instance. This treatment might not be suitable for those who suffer from conditions affecting the circulation (intermittent claudication or calf pain on walking, Raynaud's phenomenon, systemic sclerosis, etc). Hypoglycemia can occur with beta blockade because β2-adrenoceptors normally stimulate hepatic glycogen breakdown (glycogenolysis) and pancreatic release of glucagon, which work together to increase plasma glucose. Therefore, blocking β2-adrenoceptors lowers plasma glucose. β1-blockers have fewer metabolic side effects in diabetic patients; however, the tachycardia which serves as a warning sign for insulin-induced hypoglycemia may be masked. Therefore, beta blockers are to be used cautiously in diabetics

BETA BLOCKERS USES OF BETA BLOCKERS: Hypertension Coronary artery disease and Arrhythmia CCF – low dose and in mild and moderate cases Hypertrophic obstructive cardiomyopathy Chronic Simple Glaucoma Hyperthyroidism Migraine prophylaxis Prevention of esophageal varices bleeding in portal hypertension / cirrhosis Beta blockers do not reduce BP in normal blood pressure. GG-pp344 Beta blockers are considered first-line therapy for symptomatic HCM. By decreasing contractile force, beta blockers decrease the outflow gradient and decrease oxygen demand. Beta blockers also lengthen diastolic filling by slowing the heart rate. We generally start patients on metoprolol tartrate (Lopressor), 50 mg twice daily, or metoprolol succinate (Toprol-XL), 50 mg daily. If symptoms persist, the dose of metoprolol can be increased by 25-mg increments every few weeks. The peak dose is 400 mg/day. Contraindications to beta blockers include severe bronchospasm, marked bradycardia, and severe conduction system disease. Caution should be exercised with beta blocker use in patients with hepatic impairment. Fatigue is a common side effect of beta blockers. Beta blockers must not be used in the treatment of cocaine, amphetamine, or other alpha-adrenergic stimulant overdose. The blockade of only beta receptors increases hypertension, reduces coronary blood flow, left ventricular function, and cardiac output and tissue perfusion by means of leaving the alpha-adrenergic system stimulation unopposed.[27] The appropriate antihypertensive drugs to administer during hypertensive crisis resulting from stimulant abuse are vasodilators such as nitroglycerin, diuretics such as furosemide and alpha blockers such as phentolamine.[28]

Black Box Warning: SUDDEN DISCONTINUATION IN PATIENTS WITH ISCHEMIC HEART DISEASE Following abrupt cessation of therapy with certain beta-blocking agents, an increased incidence of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered metoprolol-XL (Toprol-XL ®), particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1 - 2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, metoprolol-XL administration should be reinstated promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Warn patients against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue metoprolol-XL therapy abruptly even in patients treated only for hypertension.

Ganglion blockers Ganglion blockers are competitive antagonist at nicotinic N-type receptors in autonomic ganglia. Net effect of the blocker is to reduce the predominant tone. Effects are predictable and depend on the relative dominance in terms of PANS and SANS.

Ganglion blockers EFFECTOR ORGANS DOMINANT SYSTEM EFFECTS OF GANGLIONIC BLOCKADE Arterioles/ veins SANS Vasodilatation, hypotension Sweat glands SANS (cholinergic) Anhydrosis Genitals PANS/SANS Impotence Heart PANS Tachycardia Iris Mydriasis Ciliary muscle Cycloplegia Bladder Urinary retention Salivary Xerostomia GIT Constipation.

Ganglion blockers

Ganglion blockers Ganglionic blocking agents : Mecamylamine, Trimethaphan. It is occasionally used in treatment of hypertensive crisis and dissecting aortic aneurysm. Hexamethonium is not used commonly anymore. Mecamylamine is also used as anti-addictive drug.

Ganglion blocking agents Ganglion blocking agents block the reflex changes in heart rate elicited by increase / decrease in blood pressure. Trimethaphan will block the reflex bradycardia that occurs when phenylephrine causes vasoconstriction, but it will not block a bradycardia that results from direct activation of muscarinic receptors in heart. In normal subjects, skeletal muscle function returns to normal approximately 5 minutes after a single bolus injection of succinylcholine as it passively diffuses away from the neuromuscular junction. Pseudocholinesterase deficiency can result in higher levels of intact succinylcholine molecules reaching receptors in the neuromuscular junction, causing the duration of paralytic effect to continue for as long as 8 hours. This condition is recognized clinically when paralysis of the respiratory and other skeletal muscles fails to spontaneously resolve after succinylcholine is administered as an adjunctive paralytic agent during anesthesia procedures. Frequency International Pseudocholinesterase deficiency is most common in people of European descent; it is rare in Asians.

Role of ganglionic blockers

Ganglion blocking agents The result of the test drug Z are shown in the graph. 100 Control Trimethophan Atropine Heart rate -100

Ganglion blocking agents Drug Z is probably a drug similar to A. Acetylcholine B. Dopamine C. Epinephrine D. Phenylephrine D. Norepinephrine

Glaucoma Glaucoma is divided into Chronic Simple Glaucoma - Common Acute Congestive Glaucoma - Surgery The routes of aqueous humor drainage -- ~ 90% through trabecular route ~ 10% passes through within the ciliary muscle into episceral vessels (uveosceral flow) Objective of glaucoma therapy : --- increase outflow of aqueous humor decrease production of aqueous humor

TREATMENT OF CHRONIC SIMPLE GLAUCOMA Beta blockers Alpha-2 agonist CA inhibitor Pilocarpine PG analog

Bimatoprost, Travoprost DRUG GROUP FOR CHRONIC SIMPLE GLAUCOMA MECHANISM OF ACTION ADDITIONAL COMMENTS PROSTAGLANDINS Latanoprost Bimatoprost, Travoprost Increase uveoscleral outflow and may decrease production of aqueous humor Drugs of 1st Choice BETA BLOCKERS Timolol (β1and β2 ) Betaxolol (β1 selective) Reduce formation of aqueous humor and may increase outflow Can cause severe bronchospasm in asthmatics; probably 2nd choice ALPHA2 AGONISTS Brimonidine Apraclonidine Reduce formation of aqueous humor and may enhance outflow Usually “add on” choice CARBONIC ANHYDRASE INHIBITORS Dorzolamide, Acetazolamide Reduce formation of aqueous humor CHOLINOMIMETICS Pilocarpine Carbachol Increase outflow by its effects on ciliary and sphincter pupillae muscles Much less popular now due to unwanted effects