Adrenergic Agonists Objectives

ﻋﻠﻰ ﻗدر اﻟﮭدف ﯾﻛون اﻻﻧطﻼق.

Titles Very important Extra information Doctor’s notes

1 Adrenergic transmission

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 ü Neuronal reuptake into neuron ü Monoamine oxidase (MAO) in neuronal mitochondria ü Catechol -O-methyl transferase (COMT) in synaptic space 2 Adrenergic receptors

In general we can say a-adrenoceptors 1 à excitatory b-adrenoceptors 2 à inhibitory b3 a1 a2 b1 b2

postsynaptic Presynaptic postsynaptic postsynaptic Presynaptic postsynaptic

Present in mainly in mainly in smooth heart smooth - - adipose tissue muscles ﻗﻠﺑﻲ ھو ﺑﯾﺗك اﻷول .muscles واﻷﺧﯾر

inhibitory in release excitatory in function Inhibition of of NE function excitatory in present NE (Negative (Posi ive except in GIT function t (feedback ھذا ﺑﯾﺗك اﻟﺛﺎﻧﻲ ا رﺗ ﺎح (feedback inhibitory =relaxation a2 = (a t)wo b2 = (P t)wo

• Vasoconstriction • Relaxation of: of skin & 1- skeletal & peripheral blood coronary blood vessels vessels ®peripheral (vasodilatation). resistance ® hypertension 2-bronchial smooth ↑ heart rate: muscles • Relaxation of GIT + chronotropic muscles effect, Tachycardia 3- GIT muscles • Glycogenolysis (constipation). ↑ force of • Contraction of: contraction : 4-Urinary bladder 1- radial muscle of + inotropic effect eye ® mydriasis 5-Uterus ↑ lipolysis ®↑ free Delay premature fatty acids ﻋﻛس اﻟﻔﺎ١ ھﻧﺎ ﯾﻔﺿل conduction ↑ 2-pregnant uterus. labor اﺳﺗﺧداﻣﮫ ﻟﻠﻣرأة اﻟﻣﺗوﻗﻊ : velocity اﺟﮭﺎﺿﮭ ﺎ ﻻﻧﮫ ﯾﺳوي dromotropic effect+ ﻋﺷﺎن ﻛذا ﻣﺎ ﯾﻧﻔﻊ اﺳﺗﺧدم رﯾﻼﻛﺳﯾﺷن. blood glucos↑ • أي درق ﯾﺷﺗﻐل ﻋﻠﻰ ھذا (pressure level(hyperglycemia blood ↑ اﻟرﯾﺳﺑ ﺗور ﻟﻠﻣرأة اﻟﻣﺗوﻗﻊ is 2nd baby The اﺟﮭﺎﺿﮭ ﺎ . 3- sphincter in GIT + • ↑ glucagon b ↑ renin release coming. = 2 urinary bladder release from pancreas • ↑ liver & muscle glycogenolysis

of Tremor • راح (أ)ﺟﮭض طﻔﻠﻲ skeletal muscles اﻷول ؟ = a1 3 Sympathetic actions

Constipation Relaxation of the uterus. ↑ conversion of glycogen to glucose ( hyperglycemia)

4 Classification of sympathomimetics

•Direct acting: •Direct stimulation of adrenergic receptors -: Adrenaline - Noradrenaline - Isoprenaline - Phenylephrine - Dopamine - Salbutamol - Methoxamine - Naphazoline - Clonidine – dobutamine

•Indirect acting: •Increase noradrenaline release from pre-sympathatic Action adrenergic nerve endings -: Amphetamine – tyramine. NA increase Amphetamine ﻣﺎﻓﯾﮫ زﯾﺎدة ﻣن ﻧورا •Inhibit noradrenaline uptake: Cocaine - Anti depressants

•Mixed “dual acting”: •Direct and indirect stimulation of adrenergic receptors -: Ephedrine - Pseudo-ephedrine

•Catecholamines: •-have catechol rings - Water soluble - Not effective orally - Poor penetration into CNS - Inactinated by COMT and MAO in GIT - Sort half life: Adrenaline - Noradrenaline – Dopamine - ادري ﻧورا از دوﺑﺎ Dopa is Chemistry Isoprenaline Adre Nora •Non-catecholamines: •Lack catechol rings - Lipid soluble - effective orally - cross well BBB - Not inactivated by COMT in GUT wall - Long half life: - Ephedrine – Amphetamine - Phenylephrine

•Non-selective adrenergic agonist: •Adrenaline (a1, a2, B1, B2, B3)

ﻧورا وﻗﻔت ﻋﻧد ﻗﻠﺑ ﻲ B1) b1 a2 (a1, Noradrenaline-• •-Isoprenaline (B1, B2, B3) Isomers of peta receptor Spectrum •-Dopamine (a1, B1, D1) • selective agonist: of action •Phenylephrine (a1) •- a-methyldopa – clonidine (a2)

Amine But be Do it واﻷﻣﺎﻧﺔ واﻟﺿﻣﯾر ﻣﺣﻠﮭﺎ اﻟﻘﻠب(B1) b1 Dobutamine-• •-Salbutamol , terbutaline, ritoderine (B2) 5 Adrenaline • non-selective agonist (a1, a2, B1, B2). • Natural, catecholamine. • Fast onset of action. • Short duration of action. “cause inactivated by COMT and MAO in GIT” • Not effective orally. “inactivated by intestinal enzymes” • Given by inhalation, SC or IV , topically. Pharmacological actions:

Heart b1 Inotropic / Chronotropic / Dromotropic Blood a1 , b1 Increase systolic Pressure b2 Decrease diastolic

Blood vessele a1 Vasoconstriction Of BV in skin and peripheral

b2 Vasodilation of BV of skeletal muscle and coronaries

Eye a1 Mydriasis (not effect on accommodation)

Lung b2 Bronchodilation

GIT a1 Contract sphincter

b2 Decrease motility

a1 Contract sphincter bladder b2 Relaxation of detrusor muscle

Pregnant uterus b2 Relaxation tocolytic Metabolism: a2 B2 B3 CNS ( little ) - insulin - Glucagon - Adipose lipolysis - Headache - liver glycogenolysis - Tremors - skeletal muscle glycolysis - restlessness

uses

Nasal pack in epistaxis Hemostatic “Control bleeding” Such as In dental practice Locally Absorption of local anesthetic Combined with local anesthetic to .. Duration of action Side effect of local anesthetic Bleeding from incision b In acute asthma “given by inhalation, SC “ 2 à bronchodilation a1 à mucosal edema Is the drug of choice given SC Systemically Anaphylactic shock “hypersensitivity reactions” Is the physiological antagonist of histamine BP and bronchodilation Cardiac arrest Given IV 6 Adrenaline

Adverse effects: • Tachycardia / Palpation / Arrhythmias / Angina pains • Headache / Weakness Tremors / Anxiety / Restlessness • Hypertension à Cerebral hemorrhage and pulmonary edema • Coldness of extremities à Tissue necrosis and gangrene if extravasation. • Nasal stuffiness: rebound congestion if used as decongestant

Contraindication

• Hypertyhroidism • Close angle glaucoma “ciliary relaxation , filtration angle” à IOP Cardiovascular disease such as : • Coronary heart disease (CHD) • Ischemic heart disease (angina) • Arrhythmia • Myocardial infarction • Hypertension • Peripheral arterial disease

7 Norepinephrine ( Noradrenaline) Feature : Uses :

- Non selective agonist “mainly in a adrenoreceptors a1, a2, In hypotensive state week action on B2” “ in septic shock if fluid replacement and inotropics fail” - Catecholamine - Sever vasoconstriction (a1) As a local haemostatic with local anesthetic - Increase force of contraction but decrease HR - Reflex bradycardia - Given only by IV - not I.M or S.C à necrosis Isoprenaline Features: Pharmacological actions: Uses Contraindication Non selective B - Inotropic Mainly in cardiac Hyperthyroidism b1 agonist “B1 B2 B3” - Chronotropic arrest - Increase cardiac output “parenteral” Coronary heart Synthetic, Direct - Vasodilation of blood vessels of skeletal muscles and coronaries disease acting b2 - Bronchodilation Rarely in acute - Relaxation of uterus - hyperglycemia attacks of asthma Catecholamine “ inhalation”

Longer effect “no b reuptake, no 3 lipolysis destruction by MAO”

Dopamine - Natural CNS neurotransmitter Features: - Direct acting, catecholamine - Given parenterally via infusion Vasodilation of: - Muscarinic Low: - Coronary “D1” - Renal blood vessel à Improves blood - On heart à “ inotropic, chronotropic effects “ Doses: flow to viscera “has diuretic action” - On Blood pressure à ”according to dose” • First : decrease in BP due D1 effect . Intermediate: + inotropic • Then : increase in BP due to b1 Followed by a1 effect ” b1 ” +chronotropic High: Vasoconstriction “a1 ” - Cardiogenic shock ”IV infusion” : - Can be given in acute heart failure “but better dobutamine” • Septic • Hypovolemia Uses : • Cardiogenic • Increase BP and CO (B1) “without causing renal impairment D1”

8 Dobutamine (selective B1) • Synthetic catecholamine. • Metabolized by COMT Features: • Short duration, given by intravenous infusion • Selective b1–receptor agonist. • Positive inotropic effect, increases cardiac output, with little increase in heart rate.

Uses: short term management of cardiac decompensation after cardiac surgery, in acute myocardial infarction (AMI) & heart failure.

Phenylephrine (selective a1) • A synthetic non catecholamine, direct acting Features: • Not inactivated by COMT, longer duration of action • Vasoconstriction , increased both systolic & diastolic blood pressure, hypertension, reflex bradycardia. Nasal decongestant topically, nasal drops in allergic rhinitis, cold Vasopressor agent: hypotension & terminate atrial tachycardia (reflex bradycardia). Uses: 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 in hypotensive states other

9 Selective b2 agonists

Salbutamol Ritodrine Terbutaline • selective b2 agonists, non catecholamines • Selective b2 agonist, non catecholamines. • Bronchodilator • orally or by inhalation or injection. • orally or by injection • Tocolytic • Produces bronchodilation • Is a tocolytic drug (relaxation of uterus). • Used for acute attack of asthma & COPD. • Used orally and injection to treat premature labor. Ritodrine = Tocolytic = Beta Two

Clonidine (selective a2) • synthetic, imidazoline Features: • Given orally or as patch. • Is a presynaptic a2 agonist. ¤ Pharmacological action Acts centrally (a2 ) at nucleus tractus solitaries to sympathetic outflow to heart & vessels. Inhibit sympathetic vasomotor centers Uses: Used as antihypertensive in essential hypertension to lower BP. Brimonidine

is an imidazoline a2 agonist used in glaucoma

ADRENERGIC STIMULANTS Indirect & DUAL acting sympathomimetics

Synthetic non-catecholamine. o given orally, longer duration o Excreted mostly unchanged ( by acidification of urine) Amphetamine o Acts indirectly, it depletes vesicles from stored NE tachyphylaxsis (a & b) o has CNS stimulant effects; mental alertness, wakefulness, concentration & self-confidence followed by depression & fatigue on continued use o euphoria causes its abuse Indirect acting o¤ Weight ¤ appetite increase energy expenditure o No more used therapeutically induces psychic & physical dependence and psychosis.

Plant alkaloid, synthetic, non-catecholamine, dual acting o direct action on receptors down regulation of receptors o indirect by releasing NE from adrenergic endings depletes stores a b Ephedrine ( & ) o Tachyphylaxsis o Orally, not destroyed by enzymes prolonged action o has CNS stimulant effects (less than amphetamine) o No more therapeutically used but is abused by athletes and prohibited during games. DUAL Acting Dual acting < CNS & pressor effects compared to ephedrine. Pseudoephedrine Used as nasal & ocular decongestant & in flu remedies

10 SUMMARY

§Agents specifically indicated for hypotension Midodrine, Phenylephrine, Norepinephrine, Phenylpropanolamine

§Agents specifically indicated for cardiogenic shockAHF Dobutamine, Dopamine, Epinephrine

§Agents specifically indicated for shock (Dopamine, Norepinephrine)

§Agents specifically indicated for cardiac arrest (Epinephrine, Norepinephrine, Dobutamine)

§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, Naphazoline, Oxymetazoline, Phenylephrine, Xylometazoline

§Agents specifically abused in sports Ephedrine, Amphetamine

11 SAQ

A 47 years old patient with asthma came to the emergency room with difficulties in breathing, after checking his heart beats it turned out he has tachycardia.

Which drugs could be prescribed to him that will slow his heart and reduce the vasoconstriction in his lung? Adrenaline and Noradrenaline

Which receptors do that drugs effect ? Adrenaline (α1, α2 , β1 , β2, β3) Nor adrenaline (α1, α2 , β1)

What's the traits of that drug that you can conclude if you know its a catecholamine? • have catechol ring water soluble (polar) Not effective orally. • Poor penetration into CNS. • inactivated by COMT & MAO in GIT. • short half-life.

What's the best route of administration for his case ? I.V what are 3 adverse effect that is expected to see in this patient after giving him the drug ? • Tachycardia. • Hypertension. • weakness.

12 QUIZ

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