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Sympathomimmetics

This document summarizes adrenergic agonists and antagonists. It describes the synthesis and metabolism of catecholamines like dopamine, norepinephrine, and epinephrine. It also discusses the different adrenergic receptor types (alpha and beta), their locations and functions. Various adrenergic drugs are classified and their mechanisms, effects, uses, and adverse effects outlined, including epinephrine, norepinephrine, dopamine, dobutamine, dopexamine, fenoldopam, phenylephrine, clonidine and others.

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Adrenergic Agonists and Antagonists (for MD Pharmacology) Dr. Advaitha
CATECHOLAMINES • These are compounds containing a catechol moiety (a benzene ring with two adjacent hydroxyl groups and an amine side chain.)
Dopamine : • It is the metabolic precursor of noradrenaline and adrenaline. • Main neurotransmitter in the Brain.
• Noradrenaline (norepinephrine) : a transmitter released by sympathetic nerve terminals. • Adrenaline (epinephrine): a hormone secreted by the adrenal medulla
Synthesis, Storage, Release, and Removal of Norepinephrine In Noradrenergic Neuron • It starts with the amino acid tyrosine (from diet) • It enters the Noradrenergic neuron by active transport. In the neuronal cytosol…. • Tyrosine is converted by the enzyme tyrosine hydroxylase to dihydroxyphenylalanine (dopa).
------------------------------- Drug : • Tyrosine hydroxylase enzyme inhibitor : “α-Methyl-p-tyrosine” • Can be Used to control the discharge of NE and E in surgical removal of adrenal tumor. ------------------------------------
• DOPA is converted to dopamine by the enzyme L–amino acid decarboxylase or DOPA decarboxylase • The dopamine is actively transported into storage vesicles. In storage vesicles….. • It is in here, Dopamine, is converted to Norepinephrine by dopamine –beta-hydroxylase (exclusively present in synaptic vesicles)
In the adrenal medulla.. • The synthesis is carried one step further. • The enzyme phenyl-ethanolamine N-methyltransferase converts norepinephrine to epinephrine. • The human adrenal medulla contains approximately 80% epinephrine and 20% norepinephrine.
• NE is stored in the synaptic vesicles. • Noradrenergic transmitter is released during action potentials through exocytosis. Action Potential causes : Na+, Ca2+ and Cl- enter while K+ efflux… Ca2+ entry causes disruption of Vesicles to release NE
Drugs : • Release of NE is inhibited by bretylium and guanethidene. • Can be used in HTN (now obsolete)
• So.. after Action Potential and effect….. • There is removal of norepinephrine from Synapse. Three processes contribute : 1. Transport back into the noradrenergic neuron (uptake1) • For vesicular storage or enzymatic inactivation by mitochondrial MAO.
------------------------------------------------ About , Monoamine Oxidase (MAO) and Catecholamine-O-Methyltransferase (COMT) : • Both enzymes inactivates NE and E. • Both are widely distributed (Liver, Intestine, Kidney, Brain) • However, COMT is absent In ADRENERGIC Neuron. • So it is only MAO which metabolises NE, intraneuronally… --------------------------------------------
2.Diffusion from the synapse into the circulation For ultimate enzymatic destruction in the liver ( by COMT and MAO ) and renal excretion 3. Active transport of the released transmitter into effector cells (extraneuronal uptake or uptake2) followed by enzymatic Inactivation by COMT
Drugs : • Neuronal reuptake (uptake1) inhibitors : Cocaine and Tricyclic antidepressants. -potentiates effect of NE and E • Vesicular reuptake inhibitors : Reserpine (used in HTN, obsolete)
• Inhibitors of MAO-A (present in Adrenergic neuron, intestine, liver, Kidney and Placenta) : Clorgyline and Meclobemide ( rarely used in depression) • Inhibitors of MAO-B (present in Dopaminergic neuron, brain, Platelets and Iiver) : Selegeline ( used in parkinson’s disease)
Termination of NE, E
Termination of Dopamine
Adrenergic Receptors • The liberated NE at Synaptic junction stimulates postsynaptic adrenoreceptors--- Alpha1, Alpha2. Beta1, Beta2, Beta3 to elicit end organ response. So what are the end organ responses of each receptor ????
• All belong to the superfamily of G-protein-coupled receptors • α1 receptors activate phospholipase C, producing inositol trisphosphate and diacylglycerol as second messengers • α2 receptors inhibit adenylyl cyclase, decreasing cAMP formation • All types of β receptor stimulate adenylyl cyclase
• All receptors Are mostly present Postsynaptically except α2 which is in Presynaptic region.
α1 Receptors • When activated produces Excitatory effects on in most organs. • E.g, Vascular smooth muscle, Salivary glands, Bronchi, Uterus, Radial muscle of iris etc. • Except in intestine where they produce Relaxation.
α2 Receptors • Present Presynaptically in Post ganglionic Adrenergic and Cholinergic (gut) Neuron. • When activated by NE in synaptic cleft- it inhibits further release of NE from presynaptic Adrenergic neuron.
They also inhibit Ach in cholinergic neuron (in gut) • They are also present Postsynaptically in blood vessels etc. where it behaves like α 1 (vasoconstriction) In Brain, whether Pre or Post synaptically present it decreases sympathetic outflow.
β1 receptors • located Postsynaptically. • found in heart. - Produce Positive ionotropic and Chronotropic effects. • found in Kidney - Promotes Renin release.
β2 Receptors • Their action causes smooth muscle relaxation (Except in Myocardium) • It is present in Bronchi, Blood vessels supplying Skeletal Muscles, coronary artery, uterus , GIT, Heart smooth muscle. • There are also some presynaptic β2. these facilitates NE release unlike α2.
• Uterus Non pregnant Contraction α1 Pregnant Relaxation β2
Classification of Sympathomimetic Drugs Classified as : • Direct-acting, • Indirect-acting, • Mixed-acting sympathomimetics.
• Direct-acting sympathomimetic drugs act directly on one or more of the adrenergic receptors.
• Indirect-acting drugs are those increase the availability of norepinephrine (NE) or epinephrine to stimulate adrenergic receptors. By releasing or displacing NE from vesicles of sympathetic nerve varicosities
 or by blocking the transport of NE into sympathetic neurons  or by blocking the metabolizing enzymes, (MAO ,COMT)
Epinehrine or Adrenaline • Acts on β2 > β1= α1= α2, and weak β3 action • Cardiac Effects : β1, β2 effects • Final effect : increase in SBP
Vascular Effects : • Constricton of arterioles in skin,mucous membrane, viscera and renal beds-- α1 effect • Dilation predominates in skeletal muscle, liver and coronaries– β2 effect. Decrease in peripheral vascular resistance • So the cumulative effect decease in DBP
• What happens when adrenaline is given after pretreatment of α Blocker ? ANS : Hypotension ( Dale’s vasomotor reversal phenomenon ) predominant β2 effect. • What happens when adrenaline is given after pretreatment of β Blocker ? ANS : Accentuated Hypertensive effect.
• Effects on smooth muscle : • Bronchial :  bronchodilation- β2 effect. Decrease in bronchial secretion α1 effect • GIT : • Constriction on sphincters α1 effect • Gut relaxation α2 and β effect
Uses of Adrenaline Anaphylactic Shock : • Relieves Bronchospasm and Angioneurotic edema of larynx • Prevents release of histamine from mast cell. • Dose : 0.3 – 0.5 ml IM. 1: 1000 solution IM or SC
• Bronchial Asthama : Rarely used. • Cardiac resusitation : Intracardiac route to reverse sudden cardiac arrest in drowning and electrocution (Absolute Containdication in Ventricular Fibrillation) • To prolong duration of loacal Anaesthetic agents. • To control Epistaxis : Rarely
Adverse effects • Cerebral Haemorrage • Angina • Palpitation • Arrhythmias • CNS side effects : Anxiety, tremors and headache.
Contraindications/ interactions • Angina and Hypertension • Hyperthyroidism ( upregulation of receptors) • Concomitant use of MAO
Noradrenaline • Acts on α1=α2>β1, β3. • Poor β2 action. Cardiovascular effects : • Raises both SBP and DBP. (because β1-SBP, α1-DBP )
Uses • Cardiogenic Shock • Hypotensive states in Surgical shock and MI ( it increases peripheral vascular resistance) • Dose : 0.5 to 1 ml per minute. IV infusion.
Facts : • Should be careful of renal shut down. So Dopamine is preferred. • As it is a powerful vasoconstrictor, if given undiluted via SC or IM causes, Necrosis.
Dopamine • Acts on D1, D2, β1, little α action • No β2 and β3 action. • Does not enter the BBB when given Parentrally. • Effects : It is dose dependent.
Uses • Cardiogenic Shock • CCF, liver and renal failure • Hypotensive states (after correcting hypovolemia) • Dose is 5mcg-10mcg/kg/min IV
Adverse effects • Nausea vomitting • Tachycardia • Hypertension • Ectopic beats • Arrhythmias
Dobutamine • Synthetic Catecholamie. • Racemic Mixture of - L-form (α1 agonist ) D- form (α1 antagonist and β1 agonist) • So it is relatively selective β1 agonist.
Effects : • More selective ionotropic and chronotropic effects. Uses : • Heart failure : it increases CO and stroke Volume without increasing Heart rate. Adverse effects : • Sharp rise in BP in HTN patients • Angina can be aggravated
Dopexamine • Synthetic Catecholamie. • Acts on D1, D2, and β2 receptors • Effects : Peripheral Vasodilation, increase Cardiac output and increased renal blood flow. • Uses : To provide Haemodynamic suppport in CCF and Shock Adverse Effects : • Tachycardia and Hypotension
Fenoldapam • Synthetic. Selective D1 agonist Effects : • vasodilation in peripheral arteriole, coronary, Renal and Mesentric vessels Uses : • Short term management of Severe Hypertension in Patients with severe Renal impairement. • Adverse Effects : Reflex Tachycardia, Headache.
“ α1 Selective agonists ” Phenylephrine • Non Catecholamine • So not metabolized by MAO or COMT • Effects : α1 stimulation increases Peripheral vascular resistance and BP ( associated with reflex Bradycardia) Uses : • Nasal decongestant • Mydriatic • Hypotension (rarely)
Other similar drugs are : • Oxymetaxoline • Xylometazoline • Midodrine • Naphazoline
α 2 Selective Agonist Clonidine Uses with MOA : 1) Moderate Hypertension Mechanism : Not properly elucidated. • stimulates central α 2 receptors to decrease sympathetic outflow.
• Stimulates presynaptic α2 on postganglionic sympathetic neuron to supress NE release. ---------------------------------- • When given I.V there is transient rise in BP ( post syaptic α2 effect which causes vasoconstriction) and then Decrease. • However when given oral, there is only hypotensive effects • 100 % bioavailability.
• Dose :100-300 mcg BD. • Also available as Transdermal Patch. • Major limitation is Rebound Hypertension. 2) In the Prophylaxis of migraine • It reduces cerebral blood flow 3) Management of opiate, alcohol and Nicotine Withdrawl • It reduces sympathetic effects associated with withdrawl
4) Preanaesthetic Medication: • For its slightly sedative, anxiolytic and analgesic effect 5)Menopausal Hot flushes : • For counteracting symptoms
6) To control diarrhoea in diabetic patients with autonomic neuropathy α2 in GIT decreases sodium,water retention and reduces motility by inhibiting Ach
Adverse Effects : • Dry mouth • Sedation • Nasal stuffiness • Constipation • Impotence • Contact dermatitis (in patch usage)
Newer congeners of clonidine • Moxonidine • Rilmenidine In these rebound hypertension is less frequent  longer acting than Clonidine ----------------------------------
• Apraclonidine • Brimonidine Used in Glaucoma (reduces Aqueous Humor by α2 action in cilliary muscles)
β2 selective Agonists Salbutamol Effect : Produce relaxant effect on bronchi, uterus. • Has minimal cardiac stimulant property. • Half life : 4hr Uses : • Immediate relief of Asthama
• Dose : 100mcg in Metered dose inhaler • or 2-4 mg PO TDS • To arrest uncomplicated premature labour (inbetween 24 to 34 weks of gestation) by slow IV injection Adverse effects : • Tremors in hands, Palpitations, hypokalemia
• Terbutaline • Salmetrol and Formetrol ( longer acting 12hr) • Pirbuterol • Clenbuterol ( anabolic strength on skeletal muscle, illicit use in sports)
Indirectly acting drugs Tyramine • Not used clinically • It is found in cheese, beef, wine, beer, yoghurt yeast. • Metabolized by MAO. • Significance : If patient on MAO inhibitor, it can trigger hypertensive crisis
Amphetamine • Powerful CNS stimulant . CNS effects : Stimulation of • cortical region • Reticular activating system. • Medullary respiratory centre. Causes • Wakefullness • Alertness
• Decreased sense of fatigue • The performance of simple task increases but errors increase • Physical performance improves
CVS effects : • Increases SBP and DBP • Tachycardia followed by bradycardia Other effects • Suppression of appetite by depressing lateral hypothalamic centre
Uses : • Narcolepsy : prevents attacks of daytime time sleep • ADHD (excitability, impulsiveness, difficulty in sustaining attention) : Paradoxically improves with low dose • Weight reduction
Other Analogues… • Methylphenidate : more prominent action on mental function. • Methamphetamine : High potential of abuse • Pemoline : minimal CVS effects and longer plasma half life. Used in ADHD
Mixed Action drugs Ephedrine • Non catecholamine alkaloid • Has direct action on α and β. Also enhance NE release. • CNS : powerful stimulant • CVS: increase in BP, CO, HR. • RS : Bronchodilation.
Uses : Very restricted. • Hypotension following Spinal Anaesthesia • Chronic asthma. Adverse effects : • HTN, • Insomnia, • Tachyphylaxis.
Pseudoephedrine : • Stereoisomer of ephedrine used as nasal decongestant.
Adrenergic Antagonists
Phenoxybenzamine • Irreversible, nonselective, Non competitive Antagonist at α1,α2 • Also inhibits reuptake of NE by adrenergic nerve terminal. • Crosses BBB. Effects : • Vasodilation • Decrease Peripheral vascular Resistance
• Hypotension ( this triggers baroreceptors causing sympathetic discharge) • Tachycardia (sympathetic discharge action on β 1 )
Uses : Treatment Phaeochromocytoma : • Controls episodes of severe hypertension during surgical manipulation . • Dose : 1mg /kg , slow IV infusion In Raynaud’s syndrome and Frostbite. Dose 10mg TDS PO
Adverse effects : • Marked Postural Hypotension with initial doses. • Tolerance develops later. • Inhibition of ejaculation • Salt and water retention • Sedation • Fatigue • Nausea
Phentolamine and Tolazoline • Competitive, Reversible antagonist of α1, α2. Effects : • Vasodilation • Decrease Peripheral vascular Resistance
• Hypotension ( this triggers baroreceptors causing sympathetic discharge) • Tachycardia (sympathetic discharge action on β 1 )
Other effects • Nasal stufiness • Miosis (loss of tone of radial muscles) • Failure of ejaculation • Nausea vomitting diarrhoea ( inhibition of inhibitory sympathetic influence of GIT and agonist action on H2 receptors, Tolazoline)
Uses • Treatment Phaeochromocytoma. • In peripheral vascular disease • To prevent dermal necrosis ( after incidental extravasation of NE after IV infusion) • To treat hypertensive crisis
α1 selective blockers Prazosin Effects : • Peripheral vasodilation • Fall in arterial pressure • Lesser tachycardia  Because of lack α 2 blocking no promotion of NE release, so no β1 stimulation.
Also partly because it decreases sympathetic outflow from CNS It decreases cardiac preload • It is also potent phosphodiesterase inhibitor  this leads to rise in cAMP in smooth muscle So vasodilating effect. • It relaxes smooth muscle - in bladder neck Prostate capsule Prostatic urethra
• So improves urine outflow in BPH • Uses : • In Hypertension : oral dose is 1mg bed time to avoid postural hypotension • In BPH : 1-5 mg BD PO, however newer ones are preferred. • In raynaud’s disease : rarely, because CCB are preferred.
Adverse effects : • Postural hypotension • Impotence • Nasal congestion