Antiadrenergic system and drugs

sympatholytics

1. Anti-adrenergic Drugs/ Sympatholytics These are the drugs that antagonize the action of adrenaline & related drugs. They are competitive antagonist of α or β or both receptors. Classification: Alpha ( α ) blocker α 1 selective α 2 selective Nonselective Beta ( β ) blocker Nonselective Cardioselective ( β 1)

2. α 1 selective Prazosin , Terazosin , Doxazosin , Tamsulosin α 2 selective Yohimbine , Idazoxan , Atipamezole Non- selective α blocker Phenoxybenzamine , Phentolamine , tolazoline , ergotamine, ergotoxine , chlorpromazine Alpha (α) blockers

3. Actions : Vasodilation (venous):- Fall in BP Reflex tachycardia Nasal congestion Miosis Increase intestinal motility Trigone , sphincter& prostate tone is reduced:-Improve urine flow Inhibit ejaculation:- Impotence

4. Prazosin , T erzosin , Doxazosin & Tamsulosin These are selective competitive blockers of the α 1 receptor. Prazosin , Terzosin & Doxazosin are useful in the treatment of hypertension as they cause dilation of artery. It can cause first dose effect so started at low dose at bedtime. They are orally effective with high plasma protein bound, metabolised in liver & excreted from bile. Tamsulosin is uroselective ( α 1 A & α 1 D ) indicated for the treatment of benign prostatic hypertrophy (BPH). Uses : HTN, BPH, CHF, Raynaud’s disease

5. Yohimbine is a selective competitive α 2 blocker. It is found as a component of the bark of the yohimbe tree. It directly blocks α 2 receptors and has been used to relieve vasoconstriction associated with Raynaud disease. Yohimbine is contraindicated in CNS and cardiovascular conditions because it is a CNS and cardiovascular stimulant.

6. Phenoxybenzamine is nonselective , linking covalently to both α 1 and α 2 receptors. The actions of phenoxybenzamine last about 24 hours after a single administration. Dose: 20-60mg/day oral P hentolamine produces a competitive block of α 1 and α 2 receptors. This drug’s action lasts for approximately 4 hours after a single administration. Dose: 5mg i.v . repeated as required Uses : Pheochromocytoma Hypertension Secondary shock B enign prostatic hypertrophy Peripheral vascular disease

7. Non-selective β- blocker Propanolol , sotalol , timolol , pindolol , labetalol , carvedilol Cardioselective ( β 1) Atenolol , Metoprolol , Acebutol , Esmolol Beta (β)- blockers

8. Propanolol Propanolol is the β-adrenergic antagonist and blocks both β 1 and β 2 receptors with equal affinity. Pharmacological Actions: 1. Cardio Vascular System (CVS) Heart: HR, FOC, A-V conduction 2. Respiratory Tract Increased bronchial resistance ( β 2 blockade) 3. CNS Subtle behaviour changes, forgetfulness, increased dreaming and nightmares Anti-anxiety effect (peripheral action of propranolol ) 4. Metabolic Blocks adrenergically mediated lipolysis Inhibits glygenolysis in heart, skeletal muscles, liver May reduce carbohydrate tolerance (decreased insulin release)

9. 5. Skeletal muscle Inhibits adrenergically provoked tremor (β2 blockade) Attenuate exercise capacity 6. Eye Reduced secretion of aqueous humour and intra ocular tension 7. Uterus Relaxant activity of β agonists blocked Dose : 10mg BD to 160mg QID oral, 2-5mg i.v . parenteral

10. Timolol Timolol blocks β 1 and β 2 adrenoceptors and is more potent than propranolol . Timolol reduces the production of aqueous humor in the eye. It is used topically in the treatment of chronic open-angle glaucoma and occasionally for systemic treatment of hypertension. (0.25-5% eyedrops ) Labetalol and carvedilol Labetalol and carvedilol are β blockers with additional α 1 blocking actions that produce peripheral vasodilation , thereby reducing blood pressure. It is useful in treating hypertensive patients with increased peripheral vascular resistance.

11. Acebutolol , Atenolol , Metoprolol & Esmolol Cardioselective β blockers, such as acebutolol , atenolol , and metoprolol antagonize β 1 receptors. This cardio selectivity is pronounced at low doses. These drugs lower blood pressure in hypertension and increase exercise tolerance in angina. Esmolol has a very short lifetime due to metabolism of an ester linkage. It is only given intravenously if required during surgery or diagnostic procedures. The cardiospecific blockers have relatively little effect on pulmonary function, peripheral resistance, and carbohydrate metabolism. Dose : Acebutolol 200-400mg OD, Atenolol 12.5-50mg OD

12. Uses: Hypertension Stable Angina Cardiac arrhythmias Myocardial infarction Congestive heart failure Hypertrophic obstructive cardiomyopathy Dissecting aortic aneurysm Pheochromocytoma Thyrotoxicosis Migraine Anxiety Essential tremor Glaucoma

13. Adverse Effects: Can accentuate myocardial insufficiency and precipitate CHF/edema Bradycardia Exacerbates variant angina Impaired Carbohydrate tolerance Altered plasma lipid profile Tiredness and reduced exercise capacity Cold hands and feet Others: G.I. upset, lack of drive, nightmares, forgetfulness, hallucinations, sexual distress in male Contraindications: Sudden withdrawal : rebound hypertension, worsening of angina, sudden death Worsens COPD; can produce acute Bronchial asthma Partial or complete heart block

14. Glaucoma Glaucoma is an eye disease that is associated with increased intraocular pressure, in which damage to the eye (optic) nerve can lead to loss of vision and even blindness. It can be open angle glaucoma & angle closure glaucoma. Drugs for Glaucoma: Beta blockers : Timolol , Betaxolol , Levobunolol Alpha agonists : Dipivefrine , Apraclonidine , Brimonidine Prostaglandin analogues : Latanoprost , Travoprost Carbonic anhydrase inhibitors : Acetazolamide , Dorzolamide Anticholinesterase / Miotics : Pilocarpine

15. Timolol , Acetazolamide Latanoprost

16. 1. Beta ( β) blockers : Timolol , Betaxolol , Levobunolol Topical β blockers have been the first line drugs in treatment of glaucoma. They lower i.o.t . by reducing aqueous formation. Ocular β blockers are lipophilic with high ocular penetration. 2. Alpha ( α) agonists : Dipivefrine , Apraclonidine Dipivefrine is a prodrug of Adrenaline that penetrates cornea. The released Adr (from dipivefrine ) lowers i.o.t . by augmenting uveoscleral outflow, β 2 receptor mediated increase in hydraulic conductivity of trabecular filtering cells, as well as by reducing aqueous formation (α 1 + α 2 receptor mediated). Apraclonidine is a polar clonidine congener which does not cross blood-brain barrier, but applied topically (0.5–1%) that lowers i.o.t . by ~25%.

17. 3. Prostaglandin analogues : Latanoprost , Travoprost Prostaglandins at low concentration lowers i.o.t without inducing ocular inflammation. It acts by increasing uveoscleral outflow, increasing permeability of tissues in ciliary muscle or by an action on episcleral vessels. Ciliary body COX-2 has been found to be down regulated in wide angle glaucoma indicating a physiological role of PGs in aqueous humor dynamics. 4. Carbonic anhydrase inhibitors : Acetazolamide , Dorzolamide Oral treatment with acetazolamide (0.25 g 6–12 hourly) reduces aqueous formation by limiting generation of bicarbonate ion in the ciliary epithelium. It is used to supplement ocular hypotensive drugs for short term indications like angle closure, before and after ocular surgery/laser therapy.

18. 5. Anticholinesterase / Miotics : Pilocarpine Pilocarpine is used to treat glaucoma and is the drug of choice in the emergency lowering of intraocular pressure of both narrow-angle (or closed-angle) and wide-angle (also called open-angle) glaucoma. It is extremely effective in opening the trabecular meshwork around Schlemm’s canal, causing an immediate drop in intraocular pressure as a result of the increased drainage of aqueous humour. (action within few minutes, lasts 4-8 hours) Mechanism of action : Pilocarpine produces rapid miosis , contraction of the ciliary muscle & fall in intraocular pressure. It acts through direct stimulation of muscarinic receptors and smooth muscle such as the iris and secretory glands. It is used as 0.5-4% eye drop. Adverse effects : Pilocarpine can enter the brain and cause CNS disturbances, sweating & salivation. Nursing Management : Parenteral atropine 2mg (until atropinization ) is administered to counteract the toxicity of pilocarpine