SYMPATHOMIMETIC AGENTS Department of Pharmacology

Sympathomimetic amines – Classification based on use 1. Pressor agents 2. Cardiac stimulants Dopamine Adrenaline Phenylephrine Dobutamine Methoxamine Isoprenaline Noradrenaline 3. Bronchodilators 4. Nasal decongestants Adrenaline Ephedrine Salbutamol (Albuterol) Pseudoephedrine Terbutaline Oxymetazoline

Classification… 5. Anorectics 6. CNS stimulants Fenfluramine Ephedrine Amphetamine 7. Uterine relaxants & vasodilators Salbutamol Isoxsuprine Nylidrin

Must Read Other methods of Classification of sympathomimmetics with their examples

Review Major effects mediated by  &  -adrenoceptors 1 2 1 2 Vasoconstriction Inhibition of NE release +ve chronotropic Vasodilation  PR Inhibition of insulin release +ve inotropic Slight  in PR  BP Increased lipolysis Bronchodilation Mydriasis Uterine relaxation Contraction of prostatic capsule  Muscle & liver glycogenolysis

Epinephrine (Adrenaline) Source: adrenal medulla & synthetic Agonist at  & ß-receptors CVS: Heart – ß1 stimulation – +ve chronotropic +ve inotropic  COP   BP  Oxygen consumption  Automaticity

BP: Biphasic response – a rise followed by a slight fall before returning to basal level. receptors are predominant in number. ß receptors are more sensitive & action is persistent. Initial rise in BP – predominant  action Fall - due to persistent ß2 receptor action. Dale’s vasomotor reversal Following  blocker (phenoxybenzamine) – only ß2 stimulation  BP – Dale’s reversal

Dale’s vasomotor reversal α β Epinephrine α blocker Epinephrine

Lungs – ß2 Receptors Bronchodilatation  release of inflammatory mediators used in Bronchial asthma, Anaphylactic shock Skeletal muscle - ß2 – Blood vessels dilated Uterus – ß2 receptor stimulation – relaxation Hence, used in Premature labor Metabolic – Hyperglycemia - α & ß Lipolysis – ß3 receptors

Eye – Mydriasis – on systemic administration Secretions:  renin secretion (ß1) ADME: Oral - Bioavailability is poor due to metabolism by MAO & COMT in the intestine & liver. Routes: SC, IM, topical Intracardiac – in emergencies like cardiac arrest due to drowning, anaesthesia, electrocution. IV - very, very rarely used as IV adrenaline may cause death due to ventricular arrhythmias.

Always check concentrations of adrenaline before injecting as low concentrations (1 in 100,000) are used for epistaxis & high concentrations for bronchial asthma (1 in 1000) ADR: Tachycardia, palpitation, anxiety, tremor BP- cerebral hemorrhage, ventricular arrhythmia after iv injection Norepinephrine: , ß1 agonist sympathetic neurotransmitter

Isoproterenol: Nonselective ß agonist Direct & reflex myocardial stimulation No more used in bronchial asthma. Why???? Phenylephrine, Oxymetazoline: 1 agonists Less potent & longer acting than NE Uses: Shock (hypotension) - Vasopressors Nasal decongestion Mydriatic (dilates pupil) topically

Clonidine: 2 agonist -  sym. activity Uses: Hypertension, addiction, Menopausal flushes Dobutamine: 1 >>> 2 +ve inotropic,  COP No change in PR, hence, no reflex tachycardia No  in O2 consumption Uses: as inotropic in pump failure due to myocardial infarction, cardiac surgery etc.

Dopamine Catecholamine - Receptor action: DA >>  >>  Neurotransmitter in basal ganglia Metabolized by MAO & COMT In low doses – increases urine output by increasing renal blood flow (RBF) to kidney by DA - R stimulation which causes dilatation of renal artery. RBF  GFR   urine output & Na+ excretion  splanchnic blood flow also. Given in higher doses – myocardial stimulation ß1 agonist -  in HR & FOC   COP  BP  O2 consumption of heart

In still higher doses – dopamine produces Vasoconstriction by acting as 1 agonist & this results in  in blood flow to various organs. Uses Cardiogenic shock & septic shock – DOC CCF with oliguria, renal failure ADR: Angina, cardiac arrhythmias

Selective ß2 agonists Orciprenaline, salbutamol, terbutaline, ritodrine Bronchodilatation &  release of mediators of inflammation Vasodilatation Uterine relaxation Cardiac stimulation – negligible at therapeutic doses. At high doses may produce cardiac stimulation. Resistant to metabolism by MAO & COMT – hence, duration of action is longer

Premature labour-iv infusion – Ritodrine Side effects Uses of ß2 agonists Bronchial asthma - aerosol, nebulizer, rotahaler – 10% of the inhaled drug only enters lung. Oral Tablets Premature labour-iv infusion – Ritodrine Side effects Fine finger tremors Palpitations

Its use by athletes is banned. Clenbuterol: ß2 agonist. used to ↑ the rate & force of contraction of skeletal muscle by athletes. Its use by athletes is banned. Tyramine Source - Cheese, beer (fermented food). Metabolised by MAO Indirect acting - releases NE at synapses. Tachyphylaxis seen. Clenbuterol: ß2 agonist. used to ↑ the rate & force of contraction of skeletal muscle by athletes. It acts by causing long term changes in the expression of the sarcoplasmic reticular proteins that control contraction kinetics and thereby increase the rate and force of contraction of skeletal muscle.

Sympathomimetic agents – indirect acting Tyramine, Amphetamine, Ephedrine

Ephedrine Alkaloid from Ephedra vulgaris Has direct & indirect actions - Tachyphylaxis Resistant to MAO - Longer acting (4-6 hrs) & Orally effective Stimulates CNS & CVS Uses- Nasal decongestant Pseudoephedrine Ephedrine isomer Less CNS & cardiac effects Use - Nasal decongestant

Amphetamine Synthetic, direct & indirect action d- amphetamine – more CNS effects & less CVS actions methamphetamine – more CVS actions Orally active & long acting CNS actions - alertness, sed conc., euphoria, talkativeness,  sed work capacity, sed fatigue High doses - mental confusion, delirium, hallucinations & acute psychosis

Appetite suppressant – inhibits feeding centre Improve physical performance in athletes temporarily - followed by deterioration Drug of abuse & misused by athletes in sports Chronic use leads to psychosis & long lasting behavioral abnormalities ADR: CVS – arrhythmias, ↑ in BP Uses: Narcolepsy Obesity - temporary Attention deficit hyperactivity disorder in children.

Clinical uses of sympathomimetic agents Adrenaline: Cardiac arrest – IV, intracardiac Anaphylactic shock – IV Bronchial asthma – safer drugs are available To prolong duration of action of local anaesthetics – 1 in lakh concentration Topically - Glaucoma Epistaxis Salbutamol, Terbutaline: Asthma Inhibition of premature labor Adrenaline is used as a topical hemostatic agent on bleeding surfaces such as in the mouth

Clinical uses of sympathomimetic agents Oxymetazoline, Ephedrine, Pseudephedrine : Nasal decongestants Phenylephrine: decongestant Clonidine: Hypertension Glaucoma Postmenopausal flushes Prophylaxis of migraine

Clinical uses of sympathomimetic agents Dopamine: Cardiogenic shock & septicaemic shock – DOC CCF with oliguria, renal failure Dobutamine: Cardiogenic shock Amphetamine: Narcolepsy Obesity Attention deficit hyperkinetic disease Cardiogenic shock, usually due to massive myocardial infarction, has a poor prognosis. Mechanically assisted perfusion and emergency cardiac surgery have been utilized in some settings. Optimal fluid replacement requires monitoring of pulmonary capillary wedge pressure and other parameters of cardiac function. Positive inotropic agents such as dopamine or dobutamine may have a role in this situation. In low to moderate doses, these drugs may increase cardiac output and, compared with norepinephrine, cause relatively little peripheral vasoconstriction.

Objectives for self study – Sympathomimetics 2 Pharmacology of: Epinephrine - Dale’s vasomotor reversal Norepineprhine Isoprenaline Phenylephrine, Oxymetazoline Clonidine Dobutamine Dopamine Salbutamol, Terbutaline, Salmeterol Ephedrine, Pseudoephedrine, Amphetamine, phenylephrine Uses of sympathomimetic amines