Pharmacology of Sympathetic Nervous System Adrenergic Agonists Dr

Pharmacology of Sympathetic Nervous System Adrenergic Agonists Dr: Saed. M. Aldalaen 2019 -2020 ﻡ 05: 24 11/01/2022 1

Adrenergic Agonists: (Sympathomimetics) v Mimic actions of sympathetic system and stimulate adrenergic receptors (adrenoceptors) v Derivatives of phenylethylamine v Chemical modification of the molecule results in various agents ﻡ 05: 24 11/01/2022 2

Adrenergic Agonists: classification v Direct-acting: ØSelective (Salbutamol, Dobutamine) ØNon-selective (Noradrenaline, Adrenaline) v Indirect-acting: ØReleasing agents (Amphetamines, Tyramine) ØUptake inhibitors (Cocaine) ØMAO Inhibitors v Mixed sympathomimetics (Ephedrine) ﻡ 05: 24 11/01/2022 3

Adrenergic Agonists: classification v Catecholamines: ØAdrenaline, NA, Dopamine (natural) ØIsoprenaline, Dobutamine (synthetics) v Non-catecholamines: (synthetics) ØAlpha & beta-stimulants ﻡ 05: 24 11/01/2022 4

Adrenergic Agonists: classification v Alpha-stimulants v Beta-stimulants v Mixed alpha & beta stimulants ﻡ 05: 24 11/01/2022 5

Actions of symapothomimetics v Mediated through stimulation of Alpha, Beta & Dopaminergic adrenoceptors v These receptors are metabotropic Ø(G protein-coupled) ﻡ 05: 24 11/01/2022 6

Molecular mechanism of action v Beta stimulation: Adenylate cyclase Protein kinases Cyclic AMP Actions v Alpha 1 stimulation: IP 3 & DAG v Alpha 2 stimulation: Cyclic AMP ﻡ 05: 24 11/01/2022 7

Pathway of catecholamines q Synthesis: v In adrenergic nerves & adrenal medulla v Adrenal medulla synthesizes adrenaline v Secrets about: Ø 80% adrenaline Ø 20 % NA ﻡ 05: 24 11/01/2022 8

Pathway of catecholamines q Synthesis: v Tyrosine is transported actively into nerve terminals & hydroxylated into DOPA v DOPA is decarboxylated into dopamine ﻡ 05: 24 11/01/2022 9

Pathway of catecholamines v Dopamine is transported actively into vesicles & converted enzymatically into NA & stored in the vesicles v In the adrenal medulla noradrenaline is methylated into adrenaline ﻡ 05: 24 11/01/2022 10

Pathway of catecholamines q Release of NA: v Action potential v Opening of Ca channels v Increase intra-neuronal calcium v Fusion of vesicles with nerve membrane v Exocytosis ﻡ 05: 24 11/01/2022 11

Pathway of catecholamines q Binding: v NA binds with adrenoceptors present both post-synaptically & pre-synaptically ﻡ 05: 24 11/01/2022 12

Termination of actions of NA v Reuptake 1 into nerve terminals (main) ØStored or metabolized v Reuptake 2 into post-synaptic membranes v Diffusion of NA into the circulation v Enzymatic transformation: MAO & COMT ﻡ 05: 24 11/01/2022 13

Inhibitors of noradrenaline pathway in the body v Synthesis: metyrosine ØUseful in treatment phaeochromocytoma v Release: bretylium & guanethidine v Binding: alpha & beta-blockers v Reuptake: Cocaine & tricyclic AD ﻡ 05: 24 11/01/2022 14

Pharmacokinetics v Catecholamines: ØParenteral (not oral) Øshort t ½, short duration of action ØEnzymatic metabolism by MAO & COMT ØPoor crossing of BBB v Non-catecholamines: ØOral, parenteral; slower onset, longer duration ØLess enzymatic degradation ØMore central effects ﻡ 05: 24 11/01/2022 15

Adrenoceptors v -adrenoceptors: 1 & 2 v -adrenoceptors: 3 subtypes of -receptors v Dopamine receptors: 4 subtypes ﻡ 05: 24 11/01/2022 16

1 -Adrenoceptors: v Vascular SM Vasoconstriction v Radial M. of iris Mydriasis v Bladder sphincter Contraction v Intestine sphincter Contraction v Male sex organs Ejaculation v Inhibits entry of K into cells ﻡ 05: 24 11/01/2022 17

2 -adrenoceptors v Presynaptic v Platelets v Islet cells ﻡ 05: 24 11/01/2022 Inhibits NA release Enhances aggregation Inhibits insulin release 18

q. Alpha-stimulants 1. Pressor agents v Non-catecholamines v Increase PVR & ABP (SBP & DBP) v HR may decrease v Reduce RBF and splanchnic BF v Used in shock with low sympathetic tone v Not in shock with high sympathetic tone ﻡ 05: 24 11/01/2022 19

q. Phenylephrine q Useful as: v Pressor agent v Nasal decongestant v Mydriatic agent ØNo impairment of near vision accommodation v Vasoconstrictor with local anaesthetics ﻡ 05: 24 11/01/2022 20

Methoxamine v Has direct 1 -agonist with no 1 -effect v Used as a pressor agent to increase ABP in shock v Useful in shock during halothane anaesthesia ØIt lacks beta stimulant effect ØDoes not produce arrhythmias ﻡ 05: 24 11/01/2022 21

2. Mucosal decongestants: Pseudoephedrine, Oxymetazoline v Useful in allergic rhinitis, colds, sinusitis v Oxymetazoline is used topically v Should be avoided in: ØProlonged use ØHypertension ØChildren below 2 years ØPatients using tricyclic AD or MAO inhibitors ﻡ 05: 24 11/01/2022 22

3. Alpha 2 -agonists: Clonidine, Alpha-methyldopa v Central hypotensive agents ØStimulate central 2 -adrenoceptor in vasomotor centre in medulla v Reduce NA release v Reduce sympathetic outflow v Risk of rebound hypertension on withdrawal v Clonidine v Alpha-methyldopa (Aldomet) ﻡ 05: 24 11/01/2022 23

Beta-adrenoceptors ( -receptors) q 3 subgroups 1, 2 & 3 v 1 & 2 in the heart: ØIncrease HR, contractility ØIncrease automaticity, conductivity v 1 Kidneys: ØIncrease renin release ﻡ 05: 24 11/01/2022 24

2 -adrenoceptors v Bronchi Bronchodilatation v Skeletal M. arterioles Vasodilatation ( BF) v Liver Blood glucose ( glycogenolysis & gluconeogenesis) v Uterus v Skeletal muscles ﻡ 05: 24 11/01/2022 Relaxation Tremor 25

-adrenoceptors 2: v Mast cells v Cells Inhibits release of autacoids Enhances entry of K into cells 3: v Post-synaptic in lipocytes; ﻡ 05: 24 11/01/2022 Lipolysis 26

Dopamine receptors q Four subgroups, D 1, D 2, D 3, D 4 v D 1 v D 2 Basal ganglia Renal BV (vasodilatation) Presynaptic (inhibitory) q All are present in the brain ﻡ 05: 24 11/01/2022 27

-Stimulants: 1. Selective 2 -agonists v Salbutamol (ventolin, albuterol) v Terbutaline v Pirbuterol v Salmeterol ﻡ 05: 24 11/01/2022 28

Selective 2 -agonists q Salbutamol (Ventolin) v Non-catecholamine v Given by inhalation, orally, by injection v Rapid onset v Up to 20 % may be absorbed v t ½ is about 4 hours ﻡ 05: 24 11/01/2022 29

Salbutamol q Therapeutic uses: ØBronchial asthma ØPremature labour or threatened abortion ØHeart failure ( 1 & 2 effects) q Adverse effects: ØTremor ØTachycardia ØHyokalemia (with IV) ﻡ 05: 24 11/01/2022 30

Salmeterol q Salmeterol v Long acting; t ½ (12 h) v Similar to salbutamol v Useful in prophylaxis of nocturnal asthma v Not for acute attacks v Given by inhalation v Useful with inhalation steroids ﻡ 05: 24 11/01/2022 31

2. Selective 1 -agonist: Dobutamine v Synthetic catecholamine v +ve inotropic agent v Improve myocardial function v Useful in: ØAcute myocardial infarction with heart failure (AMI) ØChronic heart failure (CHF) ﻡ 05: 24 11/01/2022 32

3. Non-selective - stimulants q Isoprenaline v Synthetic catecholamine 1 & 2 agonist v Increases SBP & HR v Decreases DBP v Useful during CPR in cardiac arrest v Used previously in heart block v Non-selective ﻡ 05: 24 11/01/2022 33

Mixed alpha & Beta agonists q Adrenaline (Epinephrine) v Endogenous catecholamine v Pharmacodynamics: ØBlood vessels: ØSkin, mucous membrane, splanchnic vessels: 1ØVasoconstriction; decrease flow ØSkeletal BV: Ø 2 -receptors; vasodilatation; increase flow ØCoronary vessels: 1 & mainly 2 ﻡ 05: 24 11/01/2022 34

Pharmacodymanics of adrenaline On the Heart: v +ve inotropic ( contractility) v +ve chronotropic ( heart rate) v +ve dromotropic effects ( conductivity) ﻡ 05: 24 11/01/2022 35

Pharmacodymanics of adrenaline On blood pressure: v Small doses of adrenaline (SC, IM): ØIncreases SBP ( 1 & 1) ØDecreases DBP ( 2) v Large doses or IV ØIncreases both SBP & DBP ( 1) v Large doses: stimulate alpha receptors v Small doses: stimulate beta receptors ﻡ 05: 24 11/01/2022 36

Pharmacodymanics of adrenaline On smooth muscles: v Iris (mydriasis) v Bronchi (bronchodilatation) v Sphincters of gut & bladder: contraction v Walls of gut & bladder: relaxation ﻡ 05: 24 11/01/2022 37

Pharmacodymanics of adrenaline Metabolic effects: v Increases blood glucose: ØIncreases glycogenolysis ( 2 -effect) ØDecreases release of insulin ( 2 -effect) v Increases blood lipids ﻡ 05: 24 11/01/2022 38

Therapeutic uses of adrenaline v Anaphylaxis & angioedema: ØPhysiological antagonist to histamine ØStabilizer of mast cells Vasoconstrictor with LA v Cardiac arrest v Local haemostasis (as epistaxis) v ﻡ 05: 24 11/01/2022 39

Other uses of adrenaline v Chronic open angle glaucoma: (topical) v Bronchial asthma ØVasoconstriction ØReduces aqueous humour production ØReduces IOP ØNot in closed angle glaucoma ﻡ 05: 24 11/01/2022 40

Adverse effects of adrenaline q Small doses: ØAnxiety, headache, tremor q High doses: ØIncrease ABP ØArrhythmias ﻡ 05: 24 11/01/2022 41

Contraindications of adrenaline v CV diseases v Hyperthyroidism v Halothane general anaesthesia v Tricyclic antidepressants therapy ﻡ 05: 24 11/01/2022 42

Noradrenaline (norepinephrine): v Catecholamine ( 1, weak 2 agonist) v Increase both SBP & DBP v With reflex decrease in HR v 1 -effect is less potent than adrenaline v Central & metabolic effects less than adrenaline v Mainly used as a vasoconstrictor ﻡ 05: 24 11/01/2022 43

Dopamine v Catecholamine v Alpha, beta & dopaminergic agonist & releases NA v Increases RBF (D 1 vasodilatation) v Increases CO, HR and ABP v Used in shock (cardiogenic and septic) ØTo improve RBF v Also in chronic CHF ﻡ 05: 24 11/01/2022 44

Indirectly-acting sympathomimetics Amphetamines: v Central psychostimulants v Release endogenous dopamine & NA v Increase alertness, improve mood & activity v Have s central anorectic effects v Sedation in children v Peripheral effects: ØIncrease ABP, arrhythmias v Produce dependence (mainly psychological) ﻡ 05: 24 11/01/2022 45

Amphetamines q Therapeutic uses ØNarcolepsy (uncontrollable sleep) ØAttention deficit hyperactivity disorder (ADHD; Hyperkinetic children) q Adverse effects ØWeight loss, insomnia ØEmotional dependence, psychosis ØArrhythmias, increase ABP ﻡ 05: 24 11/01/2022 46

Other indirect-acting symaptho v Cocaine ØInhibits NA reuptake ØDrug of addiction v Tyramine ØPresent in cheese, yogurts, pickles ØIncreases ABP if given IV ØResponsible for food-MAO inhibitors interaction ﻡ 05: 24 11/01/2022 47

Mixed direct & indirect q Ephedrine, Phenylephrine q Ephedrine v Alkaloid with predominantly indirect actions & has direct actions v Non-selective agonist similar to adrenaline v Has central & peripheral actions v Tachyphylaxis may occur ﻡ 05: 24 11/01/2022 48

Therapeutic uses of ephedrine v Bronchial asthma v Mydriatic agent v Nasal mucosal decongestant v Pressor in chronic orthostatic hypotension v Heart block v Myasthenia gravis to improve NM transmission ﻡ 05: 24 11/01/2022 49

Adverse effects of ephedrine v Insomnia v Tremor v Anxiety l ﻡ 05: 24 11/01/2022 50