Adrenergic Receptor Antagonists These are drugs which antagonize α or β or both α and β adrenergic receptors Adrenergic neurone blocking agents (Sympatholytic) act by interfering with the release of adrenergic transmitter on nerve stimulation. Differences between antiadrenergic and adrenergic neurone blocking drugs Antiadrenergic drugs Adrenergic neurone blocking drugs Locus of actionAdrenergic receptors on neuronal membrane or neurones contents Effects of adrenergic nerve stimulation Blocked (less completely) Blocked (more completely) Effect of injected AdrBlocked Not blocked (may be potentiated) Examplesα—Phentolamine β—Propranolol Reserpine, Guanethidine, Bretylium

α ADRENERGIC BLOCKING DRUGS A. Nonselective Hydrogenated ergot alkaloids—Dihydroergotamine (DHE), Dihydroergotoxine, Nicergoline Phentolamine Phenoxybenzamine B. α1 selective— Prazosin, Terazosin, Doxazosin, Alfuzosin — Tamsulosin (α 1 A) C. α2 selective —Yohimbine

EFFECTS OF α1α2-BLOCKERS 1. Blockade of vasoconstrictor α1 (also α2) receptors → vasodilation → fall in BP → marked postural hypotension → dizziness and syncope. 2. Reflex tachycardia 3. Nasal stuffiness (blockade of α receptors in nasal blood vessels) 4. Miosis (blockade of α receptors in radial muscles of iris) 5. Intestinal motility is increased 6. Tone of smooth muscle in bladder trigone, sphincter and prostate is reduced by blockade of α1 receptors (mostly of the α1A subtype) → urine flow in patients with benign hypertrophy of prostate (BHP) is improved. 7. Contractions of vas deferens and related organs which result in ejaculation are coordinated through α receptors—α blockers can inhibit ejaculation; this may manifest as impotence.

Hydrogenated ergot alkaloids Ergot alkaloids are partial agonists and antagonists at α adrenergic receptors. The natural ergot alkaloids produce long lasting vasoconstriction → peripheral vascular insufficiency and gangrene of toes and fingers occurs in ergotism. Hydrogenation reduces vasoconstrictor and increases α blocking activity. Treatment of- acute migraine headache! -dementia or problems with memory

Phenoxybenzamine is a non-selective, irreversible α -blocker → blockade lasts for 3–4 days till fresh receptors are synthesized. It is used in the treatment of:  Hypertension  Pheochromocytoma (to control blood pressure and reduce sweating) ADR:  Postural hypotension  Tachycardia  Inhibition of ejaculation  Nasal congestion  Miosis  Drowsiness and fatigue  Dizziness

Pheochromocytoma A pheochromocytoma is a tumor of the medulla of the adrenal glands (originating in the chromaffin cells) that secretes high amounts of norepinephrine and epinephrine. Symptoms : Malignant hypertension / Hypertensive emergency Tachycardia Headaches Profuse sweating

Phentolamine a reversible nonselective α-adrenergic antagonist It is used as:  a quick and short acting α blocker for diagnosis and intraoperative management of pheochromocytoma  for control hypertensive emergencies ADR:  Postural hypotension  Tachycardia  Inhibition of ejaculation  Nasal congestion  Miosis  Drowsiness and fatigue  Dizziness

Prazosin It is first of the highly selective α1-blockers. ‘First dose effect’-Postural hypotension occurs especially in the beginning. This can be minimized by starting with a low dose and taking it at bedtime. The treatment of : Hypertension Raynaud’s disease benign hypertrophy of prostate (BHP).

Tamsulosin (Omnic) Selective α1A-blocker α1A subtype predominate in the bladder base and prostate Indication:  Benign prostatic hyperplasia/ difficult urination ADR: Dizziness Retrograde ejaculation (the fluid is redirected to the urinary bladder) Postural hypotension (rare)

Yohimbine An alkaloid from the West African plant Yohimbehe. It is a selective α2 -blocker. Effects : Heart rate and BP are elevated Excitation Tremor Nausea and vomiting. It may cause congestion in genitals and has been considered to be an aphrodisiac. This effect is only psychological, but can overcome psychogenic impotence in some patients. Potential treatment for erectile dysfunction but there is insufficient evidence to rate its effectiveness

β ADRENERGIC BLOCKERS Nonselective (β1 and β2) a. Without intrinsic sympathomimetic activity:  Propranolol  Sotalol  Timolol b. With intrinsic sympathomimetic activity:  Pindolol Cardioselective (β1):  Metoprolol  Atenolol  Acebutolol  Bisoprolol  Esmolol  Betaxolol  Nebivolol α and β blockers (with additional vasodilator property):  Labetalol  Carvedilol

Cardioselective drugs are more potent in blocking cardiac (β1) than bronchial (β2) receptors. However, selectivity is only relative and is lost at high doses( Lower ability to cause ADR) Intrinsic sympathomimetic activity (in pindolol, celiprolol, acebutolol)- ability to activate β1 and/or β2 receptors submaximally. The benefits of this property are controversial. 1. Bradycardia and depression of contractility at rest are not prominent, but exercise tachycardia is blocked; may be preferred in those prone to severe bradycardia (elderly patients; sick sinus) or with low cardiac reserve. 2. Not suitable for secondary prophylaxis of MI.

PHARMACOLOGICAL ACTIONS Heart:  Decreasing of heart rate  Retarding of force of contraction  A-V conduction is delayed. Blood vessels Blockade of β2-mediated vasodilatation → peripheral vasospasms BP Both systolic and diastolic BP fall (on prolonged administration) Respiratory tract Bronchospasm (increasing of bronchial resistance by blocking dilator β2 receptors)

PHARMACOLOGICAL ACTIONS CNS Sleep disturbances (increased dreaming and nightmares) Sexual and erectile dysfunctions Depression Eye β blockers reduces secretion of aqueous humor. Uterus Constriction of uterus

Indications Hypertension They are one of the first choice drugs because of good patient acceptability and cardioprotective potential Angina pectoris (stenocardia) All β blockers benefit angina of effort. β blockers are not suitable for variant (vasospastic) angina. Cardiac arrhythmias β blockers suppress extrasystoles and supraventricular tachycardias. Myocardial infarction (MI) CHF Thyrotoxicosis Glaucoma (Timolol(β1 + β2), Betaxolol (β1))

Metoprolol It is the prototype of cardioselective (β1) blockers. Metoprolol was first made in It is on the WHO Essential Medicines(the most important medications needed in a basic health system). Use:  Hypertension  Angina Pectoris  Myocardial Infarction t½ is 3-4 hours.

Atenolol A selective β1 blocker. It is one of the most commonly used β blockers for hypertension and angina. Atenolol does not pass through the blood–brain barrier thus decreasing the side effects related to CNS. Antihypertensive effects persist for at least 24 hours. Uses:  Hypertension  Angina  Long QT syndrome  Acute myocardial infarction  Supraventricular tachycardia  Ventricular tachycardia.

Nebivolol a β1 receptor blocker with nitric oxide → potentiating vasodilatory effect. Along with labetalol and carvedilol, it is one of  blockers to cause dilation of blood vessels in addition to effects on the heart Uses:  in treatment of hypertension  for left ventricular failure (in Europe)

Labetalol A nonselective  blocker/  -1 blocker To treat: chronic and acute hypertension pheochromocytoma Side effects : Orthostatic hypotension (due to  receptor blockade) Drowsiness Fatigue Weakness Difficulty sleeping Diminished sexual function

Carvedilol It is a β1 + β2 + α1 adrenoceptor blocker. Producing vasodilatation due to α1 blockade and has antioxidant property. Use:  Angina Pectoris  Congestive Heart Failure  Hypertension  Left Ventricular Dysfunction. t½ - 6–8 hrs.

Side effects Dizziness Drowsiness (sleepiness) Depression Sexual dysfunction (impotence) Peripheral vasospasms → bluish discoloration of the fingers and toes, numbness/tingling/swelling of the hands or feet Bradycardia ↓ BP Symptoms of Congestive Heart Failure (CHF) Bronchospasm Allergic reaction