Adrenergic Agonists - Pharmacology PDF

Sympathomimetic drugs (Adrenergic agonists) Prof. Hanan Hagar Pharmacology Department College of Medicine  Adrenergic transmission 1) Synthesis of norepinephrine 2) Storage of norepinephrine 3) Release of norepinephrine 4) Binding to post synaptic receptors 5) Ending of actio...

Sympathomimetic drugs (Adrenergic agonists) Prof. Hanan Hagar Pharmacology Department College of Medicine  Adrenergic transmission 1) Synthesis of norepinephrine 2) Storage of norepinephrine 3) Release of norepinephrine 4) Binding to post synaptic receptors 5) Ending of action by l Neuronal reuptake into neuron l Monoamine oxidase (MAO) in neuronal mitochondria l Catechol -O-methyl transferase (COMT) in synaptic space  Adrenergic receptors a-adrenoceptors : Subtypes ( a1 & a2 ) b-adrenoceptors : Subtypes ( b1 , b2 & b3 ) a 1 b1 b2 b3 located postsynaptically a2 b2 are located Presynaptically  a-adrenoceptors Subtypes ( a1 & a2 ) α1 are excitatory in function except in GIT (Inhibition) q Present in smooth muscles. q Contraction of radial muscle of eye ® mydriasis q Contraction of pregnant uterus. q Vasoconstriction of skin & peripheral blood vessels ®­peripheral resistance ® hypertension. q Contraction of sphincters in GIT& urinary bladder. l Relaxation of GIT muscles. l ­ Glycogenolysis. Pre-synaptic a2-adrenoceptors Inhibition of norepinephrine (negative feed back mechanism). Pre-synaptic b2 Receptors: ­ Release of norepinephrine (NE) ( Positive feed back mechanism).  b-adrenoceptors Subtypes ( b1 , b2 & b3 ) β1 excitatory in function, mainly in heart Juxtaglomerular cells of the kidney § ↑ heart rate: + chronotropic effect (Tachycardia) § ↑ force of contraction : + inotropic effect § ↑ conduction velocity: + dromotropic effect § ↑ blood pressure § ↑ renin release  b2 is inhibitory in function present mainly in smooth muscles Relaxation of skeletal & coronary blood vessels (vasodilatation). Relaxation of bronchial smooth muscles. Relaxation of GIT muscles (constipation). Relaxation of urinary bladder. Relaxation of the uterus (Delay premature labor) Increase blood glucose level ((hyperglycemia) ↑ glucagon release from pancreas ↑ liver & muscle glycogenolysis Tremor of skeletal muscles b3 In adipose tissue ®­ lipolysis ®­ free fatty acids.  Sympathetic actions l Mydriasis (dilatation of eye pupil) l Increase heart rate. l Bronchodilation l Inhibit peristalsis of GIT and secretion. l Relaxation of GIT muscles (constipation). l Relaxation of urinary bladder. l Relaxation of the uterus (Delay premature labor) l Increase conversion of glycogen to glucose (hyperglycemia) Classification of sympathomimetics (according to action) Direct-acting: direct stimulation of adrenergic receptors e.g. adrenaline, noraderanaline, isoprenaline, dopamine, salbutamol phenylephrine, clonidine, dobutamine, methoxamine. Indirect-acting: — NA release from pre-synaptic adrenergic nerve endings. e.g. amphetamine Or Inhibit NA uptake e.g. Cocaine & antidepressants Mixed (Dual acting): Direct and indirect stimulation of adrenergic receptors e.g. ephedrine, pseudoephedrine. Classification of sympathomimetics Sympathomimetics Indirect acting Direct acting release NA from nerve endings Direct actions on e.g. Amphetamine &Tyramine receptors e.g. Or Inhibit NA uptaker Epinephrine e.g. cocaine Norepinephrine Isoprenaline Phenylephrine Dual acting Dopamine e.g. Ephedrine Dobutamine pseudoephedrine  ADRENERGIC STIMULANTS Indirect; e.g. amphetamine e.g. Cocaine  Classification of sympathomimetics (according to chemistry) Catecholamines Non-catecholamines l have catechol ring l Lack catechol ring l water soluble (polar) l Lipid soluble l Not effective orally. l Effective orally. l Poor penetration into l Cross well BBB CNS l Prominent CNS effects l inactivated by COMT & l Not inactivated by COMT MAO in GIT in gut wall l short half-life. l Long half-life. l e.g. adrenaline, l E.g. noradrenaline, dopamine Ephedrine, amphetamine, isoprenaline, phenylephrine.  Classification of sympathomimetics (according to spectrum of action) Non-selective adrenergic agonists § Adrenaline (a1, a2 , b1 , b2, b3) § Nor adrenaline (a1, a2 , b1) § Isoprenaline (b1, b2, b3) § Dopamine (D1, b1, a1) Selective agonists § Phenylephrine (a1) § a -Methyldopa - clonidine (a2) § Dobutamine (b1) § Salbutamol, terbutaline, ritoderine (b2) Adrenaline (a1, a2 , b1 , b2, b3) Ø Natural, catecholamine Ø Non-selective agonist a1, a2 , b1 , b2 , b3 Ø Fast onset of action & Short duration of action. Ø Not effective orally (inactivated by intestinal enzymes). Ø Given I.V, S.C, inhalation. Pharmacological actions Heart – inotropic, chronotropic, dromotropic (b1) BP –— systolic (b1) (a1) / diastolic ¤ (b2) Blood vessels (Vascular smooth muscle cells): vasoconstriction of b.v. in skin + peripheral (a1) Vasodilatation of b.v.of skeletal muscles and coronaries β2 Eye – mydriasis (a1) / – no effect on accommodation Lung – bronchodilatation (b2) GIT – ¤motility (b2) / contract sphincter (a1) Bladder : relaxation of detrusor muscle (b2) contraction of sphincter (a1) Pregnant uterus – relaxation tocolytic effect (b2) Metabolism ¤insulin (a2) , —glucagon (b2) — liver glycogenolysis + skeletal muscle glycolysis (b2) — adipose lipolysis (b3 ) CNS –little, headache, tremors & restlessness USES Locally: Ø Haemostatic (control bleeding): Nasal pack in epistaxis and in dental practice. Ø combined with local anesthetic to: Ø ↓ absorption of L.A. & ↑duration of action Ø ↓ side effects of local anesthetic. Ø ↓ bleeding from the incision. Systemically: Ø In acute asthma S.C., inhalation, emergency bronchodilatation (b2) + ¤mucosal edema (a1). Ø Anaphylactic shock (Hypersensitivity reactions) is the drug of choice as it is the physiological antagonist of histamine (— BP & bronchodilation). Ø Cardiac arrest (i.v.). ADRENALINE Adverse effects Tachycardia, palpitation, arrhythmias, angina pains Headache, weakness, tremors, anxiety and restlessness. Hypertension – cerebral hemorrhage and pulmonary edema. Coldness of extremities – tissue necrosis Nasal stuffiness: rebound congestion if used as decongestant. Contraindications coronary heart diseases (CHD), Ischemic heart disease Arrhythmia, Myocardial infarction Hypertension, peripheral arterial disease. Hyperthyroidism. Closed-angle glaucoma (ciliary relaxation ¤ filtration angle) – — IOP Norepinephrine: NOREPINEPHRINE = NORADRENALINE - Catecholamine, non-selective agonist - mainly on α adrenoceptors (α1, α2, β1). - Weak action on β2 - Severe vasoconstriction α1 - Increase force of contraction but decrease H.R. - Reflex bradycardia - Only administered IV - Not IM or S.C. –necrosis Uses: In Hypotensive states (in septic shock if fluid replacement and inotropics fail). As a local haemostatic with local anesthetic. Isoprenaline l A synthetic, direct acting catecholamine l Longer effect (no reuptake-no destruction by MAO) l non-selective b agonist (b1, b2 & β3 ) β1 + inotropic effect, + chronotropic effect, increase cardiac output (CO). l β2 Vasodilatation of blood vessels of skeletal muscles and coronaries. l β2 Bronchodilatation. l β2 Relaxation of uterus. l β2 Hyperglycemia l β3 lipolysis Uses: l Used mainly in cardiac arrest (Parenteral). l Rarely in acute attack of asthma (inhalation). Contraindicated in hyperthyroidism & CHD Dopamine (D1 > b1 > a1) Ø Natural CNS neurotransmitter. Ø Direct acting, catecholamine Ø Given parenterally via infusion Low dose: dopaminergic receptors D1 vasodilatation of mesenteric, Kidney D vasodilatation Heart b1 — force 1 coronary, renal blood vessels ® + diuresis improves blood flow to viscera Vessels a1 Has diuretic action Intermediate dose (β1) +ve inotropic +ve chronotropic effects High dose (α1): vasoconstriction On heart : Inotropic, chronotropic effect On BP – According to dose First ¤ D1 then — due to b1 followed by a1 effect Uses Ø Cardiogenic shock: septic, hypovolemia or cardiogenic (I.V infusion) — BP & CO (b1), without causing renal impairment (D1) Ø Can be given in acute heart failure (HF) but better dobutamine Dobutamine l Synthetic catecholamine. l Direct acting, catecholamine l Metabolized by COMT l Short duration, given by intravenous infusion l Selective b1–receptor agonist. Positive inotropic effect increasing heart contractility , increases cardiac output. Uses of Dobutamine short term management of cardiac decompensation after cardiac surgery in acute myocardial infarction (AMI) & heart failure. Phenylephrine (selective a1) Ø A synthetic non catecholamine, direct acting Ø Not inactivated by COMT, longer duration of action Ø Vasoconstriction ,­ increased both systolic & diastolic blood pressure, hypertension, reflex bradycardia. Uses: Nasal decongestant topically, nasal drops in allergic rhinitis, cold Vasopressor agent: hypotension & terminate atrial tachycardia (reflex bradycardia). Local Haemostatic with local anesthesia Mydriatic: In ophthalmic solutions to facilitate eye examination. Adverse effects: Hypertension Midodrine peaks in 20 min, duration 30 min, used mainly in hypotensive states.  ADRENERGIC STIMULANTS Direct Acting Sympathomimetics Nasal & Ocular Decongestants PHENYLETHYLAMINES IMIDAZOLINE Phenylephrine Naphazoline Pseudoephedrine Oxymetazoline HCI (Afrin) Methoxamine Xylometazoline HCI (Otrivine)  Selective b2 agonists Salbutamol Øselective b2 agonists, non catecholamines Øorally or by inhalation or injection. ØProduces bronchodilation ØUsed for acute attack of asthma & COPD. Ritodrine ØSelective b2 agonist, non catecholamines. Øorally or by injection ØIs a tocolytic drug (relaxation of uterus). ØUsed orally and injection to treat premature labor. Ø Terbutaline Bronchodilator & Tocolytic Clonidine selective a2 l Synthetic l Given orally or as patch. l Is a presynaptic a2 agonist. l Acts centrally (a2) at nucleus tractus solitaries to ¤ sympathetic outflow to heart & vessels. l Inhibit sympathetic vasomotor centers. l Used as antihypertensive in essential hypertension to lower BP. Brimonidine a2 agonist used in glaucoma (reduce aqueous humor production by the ciliary body)  ADRENERGIC STIMULANTS Indirect acting sympathomimetics Amphetamine a& b o Synthetic non-catecholamine. o given orally, longer duration o Excreted mostly unchanged (— by acidification of urine) o Acts indirectly, it depletes vesicles from stored NE – tachyphylaxsis o has CNS stimulant effects; mental alertness, wakefulness, concentration & self-confidence followed by depression & fatigue on continued use o— euphoria – causes its abuse o¤ Weight – ¤ appetite — increase energy expenditure o No more used therapeutically – induces psychic & physical dependence and psychosis.  ADRENERGIC STIMULANTS DUAL Acting Sympathomimetics Ephedrine a & b § Plant alkaloid, synthetic, non-catecholamine, dual acting § direct action on receptors § indirect by releasing NE from adrenergic endings – depletes stores § Tachyphylaxsis § Orally, not destroyed by enzymes – prolonged action § has CNS stimulant effects (less than amphetamine) § No more therapeutically used – but is abused by athletes and prohibited during games. Pseudoephedrine § Produce vasoconstriction of blood vessels, mainly those located in the nasal passages, pseudoephedrine causes a decrease in the symptoms of nasal congestion. § Used as nasal & ocular decongestant & in flu remedies.  SUMMARY FOR USES OF Sympathomimetics §Agents specifically indicated for hypotension Midodrine, Phenylephrine, Norepinephrine, Phenylpropanolamine §Agents specifically indicated for cardiogenic shock– Acute Hear Failure Dobutamine, Dopamine, Epinephrine §Agents specifically indicated for shock Dopamine, Norepinephrine §Agents specifically indicated for cardiac arrest (Dobutamine, Epinephrine, Norepinephrine) §Agents specifically indicated for bronchial asthma Salbutamol, Salmeterol, Formoterol, Terbutaline, Isoprenaline §Agents specifically indicated for premature labour Ritodrine, Terbutaline §Agents specifically indicated for nasal decongestion Pseudoephedrine, Phenylephrine Agents specifically abused in sports – Ephedrine, Amphetamine