Adrenergic Drugs - drdhriti

Adrenergic System

Dr. D. K. Brahma

Department of Pharmacology

NEIGRIHMS, Shillong, Meghalaya

Neurotransmission in ANS

Noradrenergic transmission Nor-adrenaline is the major

neurotransmitter of the Sympathetic system

Noradrenergic neurons are postganglionic sympathetic neurons with cell bodies in the sympathetic ganglia

They have long axons which end in varicosities where NA is synthesized and stored

Adrenergic transmission

Catecholamines: Natural: Adrenaline, Noradrenaline, Dopamine Synthetic: Isoprenaline, Dobutamine

Non-Catecholamines: Ephedrine, Amphetamines, Phenylepherine, Methoxamine,

Mephentermine

Also called sympathomimetic amines as most of them contain an intact or partially substituted amino (NH2) group

• Catecholamines: Compounds containing a catechol nucleus (Benzene ring with 2 adjacent OH groups) and an amine containing side chain• Non-catecholamines lack hydroxyl (OH) group

Biosynthesis of Catecholamines

Phenylalanine

PH

Rate limiting Enzyme

5-HT, alpha Methyldopa

Alpha-methyl-p-tyrosine

Storage of Noradrenaline

Release of NA – Feedback Control

Regulators of NA release

Uptake of Catecholamines

Reuptake

Sympathetic nerves take up amines and release them as neurotransmitters

Uptake I is a high efficiency system more specific for NA Located in neuronal membrane Inhibited by Cocaine, TCAD, Amphetamines

Uptake 2 is less specific for NA Located in smooth muscle/ cardiac muscle Inhibited by steroids/ phenoxybenzamine No Physiological or Pharmacological importance

Metabolism of CAs

Mono Amine Oxidase (MAO) Intracellular bound to mitochondrial membrane Present in NA terminals and liver/ intestine MAO inhibitors are used as antidepressants

Catechol-o-methyl-transferase (COMT) Neuronal and non-neuronal tissue Acts on catecholamines and byproducts VMA levels are diagnostic for tumours

Metabolism of CAs

(Homovanillic acid) (Vanillylmandelic acid)

Adrenergic neurotransmission

Adrenergic Rece

ptors

Adrenergic Receptors

Adrenergic receptors (or adrenoceptors) are a class of G-protein coupled receptors that are the target of catecholamines

Adrenergic receptors specifically bind their endogenous ligands – catecholamines (adrenaline and noradrenline) Increase or decrease of 2nd messengers cAMP or IP3/DAG

Many cells possess these receptors, and the binding of an agonist will generally cause the cell to respond in a flight-fight manner. For instance, the heart will start beating quicker and the pupils

will dilate

How Many of them ????

Alpha (α) Beta (β)

Adenoreceptors

α 1 β3β 2β1α 2

α 2B α 2Cα 2A

α 1A α 1B α 1D

Differences - Adrenergic Receptors (α and β) !

Alpha (α) and Beta (β) Agonist affinity of alpha (α):

adrenaline > noradrenaline > isoprenaline Antagonist: Phenoxybenzamine IP3/DAG, cAMP and K+ channel opening

Agonist affinity of beta (β):

isoprenaline > adrenaline > noradrenaline Propranolol cAMP and Ca+ channel opening

Potency of catecholamines on Adrenergic Receptors

Adr NA

Iso

Iso Adr

NA

Log Concentration

Aortic strip contraction Bronchial relaxation

α β

Molecular Effector Differences - α Vs β

α Receptors: IP3/DAG cAMP K+ channel opening

β Receptors: cAMP Ca+ channel opening

Recall: Adenylyl cyclase: cAMP pathway

PKA Phospholamban

Increased Interaction with Ca++

Faster relaxation

Troponin

Cardiac contractility

OtherFunctionalproteins

PKA alters the functions of manyEnzymes, ion channels, transportersand structural proteins.

Faster sequestration of Ca++ in SR

PKc

Also Recall: Phospholipase C: IP3-DAG pathway

Beta receptors All β receptors activate adenylate cyclase, raising the intracellular cAMP

concentration Type β1:

These are present in heart tissue, and cause an increased heart rate by acting on the cardiac pacemaker cells

Type β2: These are in the vessels of skeletal muscle, and cause vasodilatation, which

allows more blood to flow to the muscles, and reduce total peripheral resistance

Beta-2 receptors are also present in bronchial smooth muscle, and cause bronchodilatation when activated

Stimulated by adrenaline, but not noradrenaline Bronchodilator salbutamol work by binding to and stimulating the β2

receptors Type β3:

Beta-3 receptors are present in adipose tissue and are thought to have a role in the regulation of lipid metabolism

Differences between β1, β2 and β3

Beta-1 Beta-2 Beta-3Location Heart and JG cells Bronchi, uterus,

Blood vessels, liver, urinary tract, eye

Adipose tissue

Agonist Dobutamine Salbutamol -

Antagonist Metoprolol, Atenolol Alpha-methyl propranolol

-

Action on NA

Moderate Weak Strong

Clinical Effects of β-receptor stimulation β1: Adrenaline, NA and Isoprenaline:

Tachycardia Increased myocardial contractility Increased Lipolysis Increased Renin Release

β2: Adrenaline and Isoprenaline (not NA) Bronchi – Relaxation SM of Arterioles (skeletal Muscle) – Dilatation Uterus – Relaxation Skeletal Muscle – Tremor Hypokalaemia Hepatic Glycogenolysis and hyperlactiacidemia

β3: Increased Plasma free fatty acid – increased O2 consumption - increased heat production

Adrenergic receptors - alpha Type α1

Blood vessels with alpha-1 receptors are present in the skin and the genitourinary system, and during the fight-or-flight response there is decreased blood flow to these organs

Acts by phospholipase C activation, which forms IP3 and DAG

In blood vessels these cause vasoconstriction Type α2

These are found on pre-synaptic nerve terminals Acts by inactivation of adenylate cyclase, cyclic AMP levels

within the cell decrease (cAMP)

Differences between α1 and α2

Alpha-1 Alpha-2Location Post junctional – blood vessels

of skin and mucous membrane, Pilomotor muscle & sweat gland, radial muscles of Iris

Prejunctional

Function Stimulatory – GU, Vasoconstriction, gland secretion, Gut relaxation, Glycogenolysis

Inhibition of transmitter release, vasoconstriction, decreased central symp. Outflow, platelet aggregation

Agonist Phenylephrine, Methoxamine Clonidine

Antagonist Prazosin Yohimbine

α1 adrenoceptors Clinical effects

Eye -- Mydriasis Arterioles – Constriction (rise in BP) Uterus -- Contraction Skin -- Sweat Platelet - Aggregation Male ejaculation Hyperkalaemia Bladder Contraction α2 adrenoceptors on nerve endings mediate negative

feedback which inhibits noradrenaline release

Molecular Basis of Adrenergic Receptors

Also glycogenolysis in liver

Inhibition of Insulin release and Platelet aggregationGluconeogenesis

Dopamine receptors

D1-receptors are post synaptic receptors located in blood vessels and CNS

D2-receptors are presynaptic present in CNS, ganglia, renal cortex

Summary of agents modifying adrenergic transmission

Step Actions Drug

Synthesis of NA Inhibition α - methyl-p-tyrosine

Axonal uptake Block Cocaine, guanethidine, ephedrine

Vesicular uptake Block Reserpine

Vesicular NA Displacement Guanethidine

Membrane NA pool Exchange diffusion Tyramine, Ephedrine

Metabolism MAO-A inhibitionMAO-B inhibitionCOMT inhibition

MoclobemideSelegilineTolcapone

Receptors α 1α 2β1 + β2β1

PrazosinYohimbinePropranololMetoprolol

Adrenaline as prototype

Potent stimulant of alpha and beta receptors Complex actions on target organs

Heart Beta-1 mediated action - Powerful Cardiac stimulant - +ve

chronotropic, +ve inotropic Acts on beta-1 receptors in myocardium, pacemaker cells and

conducting tissue Heart rate increases by increasing slow diastolic depolarization of cells

in SAN High doses cause marked rise in heart rate and BP causing reflex

depression of SAN – unmasking of latent pacemaker cells in AVN and PF – arrhythmia (sensitization of arrhythmogenic effects by Halothane)

Cardiac systole is shorter and more powerful Cardiac output is enhanced and Oxygen consumption is increased Cardiac efficiency is markedly decreased

Conduction velocity in AVN, atrial muscle fibre, ventricular fibre and Bundle of His increased – benefit in partial AV block Reduced refractory period in all cardiac cells

Blood Vessels

Seen mainly in the smaller vessels – arterioles – Vasoconstriction (alpha) and vasodilatation (beta) – depends on the drug

Decreased blood flow to skin and mucus membranes and renal beds – alpha effect (1 and 2) -

Increased blood flow to skeletal muscles, coronary and liver vessels - (Beta-2 effect) counterbalanced by a vasoconstrictor effect of alpha receptors

Blood Pressure

Depends on the Catecholamine involved NA causes rise in Systolic, diastolic and mean

BP (no beta-2 action) – unopposed alpha action Isoprenaline causes rise in systolic but fall in

diastolic BP – mean BP falls (beta-1 and beta-2) Adr causes rise in systolic BP, but fall in diastolic

BP – mean BP generally rises (slow injection) Decreased peripheral resistance at low conc. Beta

receptors are more sensitive to Adr than alpha receptors

Blood Pressure – contd.

Rapid IV injection of Adrenaline marked rise in Systolic and diastolic BP Large concentration alpha action predominates –

vasoconstriction even in skeletal muscle But BP returns to normal in few minutes A secondary fall in mean BP occurs Mechanism – rapid uptake and dissipation of Adr

– at low conc. Alpha action lost but beta action predominates – Dale`s Vasomotor reversal phenomenon

Dale`s Vasomotor Reversal Phenomenon

Actions of Adrenaline Respiratory:

Powerful bronchodilator Relaxes bronchial smooth muscle (not NA)

Beta-2 mediated effect Physiological antagonist to mediators of

bronchoconstriction e.g. Histamine GIT : Relaxation of gut muscles (alpha and beta) and constricted

sphincters – reduced peristalsis – not clinical importance

Bladder: relaxed detrusor muscle (beta) muscle but constriction of Trigone – both are anti-voiding effect

Uterus: Adr contracts and relaxes Uterus (alpha and beta action) but net effect depends on status of uterus and species – pregnant relaxes but non-pregnant - contracts

Actions of Adrenaline – contd.

Skeletal Muscle: Facilitation of Ach release in NM junction (alpha -1) Beta-2 acts directly on Muscle fibres Abbreviated active state and less tension in slow

conducting fibres and enhanced muscle spindle firing – tremor

CNS: No visible clinical effect in normal doses – as low penetration except restlessness, apprehension and tremor Activation of alpha-2 in CNS decreases sympathetic outflow and

reduction in BP and bradycardia - clonidine

Metabolic effects

Increases concentration of glucose and lactic acid

Calorigenesis (β-2 and β-3) Inhibits insulin secretion (α-2) Decreases uptake of glucose by peripheral

tissue Simulates glycogenolysis - Beta effect Increases free fatty acid concentration in blood Hypokalaemia – initial hyperkalaemia

ADME

All Catecholamines are ineffective orally Absorbed slowly from subcutaneous tissue Faster from IM site Inhalation is locally effective Not usually given IV Rapidly inactivated in Liver by MAO and

COMT

Clinical Question!

Question: A Nurse was injecting a dose of penicillin to a patient in Medicine ward without prior skin test and patient suddenly developed immediate hypersensitivity reactions. What would you do?

Answer: As the patient has developed Anaphylactic reaction, the only way to resuscitate the patient is injection of Adrenaline 0.5 mg (0.5 ml of 1:10000) IM and repeat after 5-10

minutes Antihistaminics: Chlorpheniramine 10 – 20 mg IM or IV Hydrocortisone 100 – 200 mg

Adrenaline – Clinical uses

Injectable preparations are available in dilutions 1:1000, 1:10000 and 1:100000

Usual dose is 0.3-0.5 mg sc of 1: 10000 solution Used in:

Anaphylactic shock… Prolong action of local anaesthetics Cardiac arrest Topically, to stop bleeding Hyperkinetic children – ADHD, minimal brain dysfunction Anorectic

CPR - Image

ADRs

Restlessness, Throbbing headache, Tremor, Palpitations

Cerebral hemorrhage, cardiac arrhythmias Contraindicated in hypertensives,

hyperthyroid and angina poctoris Halothane and beta-blockers – not indicated

Other Adrenergic Drugs

Noradrenaline

Neurotransmitter released from postganglionic adrenergic nerve endings (80%)

Orally ineffective and poor SC absorption IV administered Metabolized by MAO, COMT Short duration of action

Actions and uses Agonist at α1(predominant), α2 and β1 Adrenergic receptors

Equipotent with Adr on β1, but No effect on β2 Increases systolic, diastolic B.P, mean pressure, pulse pressure

and stroke volume Total peripheral resistance (TPR) increases due to vasoconstriction -

Pressor agent Increases coronary blood flow Decreases blood flow to kidney, liver and skeletal muscles Uses: Injection Noradrenal bitartrate slow IV infusion at the rate

of 2-4mg/ minute used as a vasopressor agent in treatment of hypovolemic shock and other hypotensive states in order to raise B.P Problems: Down regulation of receptors, Renal Vasoconstriction Septic and neurogenic shock (?)

Noradrenaline - ADRs

Anxiety, palpitation, respiratory difficulty Acute Rise of BP, headache Extravasations causes necrosis, gangrene Contracts gravid uterus Severe hypertension, violent headache,

photophobia, anginal pain, pallor and sweating in hyperthyroid and hypertensive patients

Isoprenaline

Catecholamine acting on beta-1 and beta-2 receptors – negligible action on alpha receptor

Therefore main action on Heart and muscle vasculature

Main Actions: Fall in Diastolic pressure, Bronchodilatation and relaxation of Gut

ADME: Not effective orally, sublingual and inhalation (10mg tab. SL) Overall effect is Cardiac stimulant (beta-1)

Increase in SBP but decrease in DBP (beta-2) Decrease in mean BP

Used as Bronchodilator and for treatment of AV block, Stokes-Adam Syndrome etc. – but not preferred anymore

Adrenaline, NA and Isoprenaline - Summary

Dopamine

Immediate metabolic precursor of Noradrenalin

High concentration in CNS - basal ganglia, limbic system and hypothalamus and also in Adrenal medulla

Central neurotransmitter, regulates body movements ineffective orally, IV use only,

Short T 1/2 (3-5minutes)

Dopamine

MECHANISM:

Agonists at dopaminergic D1, D2 receptors Agonist at adrenergic α1 and β1

Dopamine

In small doses 2-5 μg/kg/minute, it stimulates D1-receptors in renal, mesenteric and coronary vessels leading to vasodilatation (Increase in cAMP) Recall: Renal vasoconstriction occurs in CVS shock due to

sympathetic over activity

Increases renal blood flow, GFR an causes natriuresis Interaction with D2 receptors (present in presynaptic adrenergic

neurones) – suppression of NA release (no alpha effect)

Dopamine – cond.

Moderate dose (5-10 μg/kg/minute), stimulates β1-receptors in heart producing positive inotropic and chronotropic actions actions

Releases Noradrenaline from nerves by β1-stimulation

Does not change TPR and HR Great Clinical benefit in CVS shock and CCF High dose (10-30 μg/kg/minute), stimulates vascular

adrenergic α1-receptors (NA release) – vasoconstriction and decreased renal blood flow

Why renal and mesenteric vasodilatation is useful in Shock?

Increases renal blood flow, GFR an causes natriuresis

In CVS shock – excessive sympathetic activity leading to ischemia of gut, sloughening and entry of Bacteria to systemic circulation - septicemia

Dobutamine - Derivative of Dopamine MOA:

Acts on both alpha and beta receptors but more prominently in beta-1 receptor – increase in contractility and CO

Does not act on D1 or D2 receptors – No release of NA and thereby hypertension

Predominantly a beta-1 agonist with weak beta-2 and selective alpha-1 activity

Racemic mixture consisting of both (+) and (−) isomers - the (+) isomer is a potent β1 agonist and α1 antagonist, while the (−) isomer is an α1 agonist

Overall beta-1 activity and weak beta-2 activity Increase in force of contraction and cardiac output but no change in

heart rate Uses: Clinically give in dose of 2-8 mcg/kg/min IV infusion in Heart

failure in cardiac surgery, Septic and cardiogenic shock, Congestive Heart failure

ADRs: Tachycardia, hyperension, angina and fatal arrhythmia

Adrenergic agonists

Selective Alpha-1 Agonists: Phenylepherine, Ephederine, Methoxamine,

Metaraminol, Mephentermine Selective Alpha-2 Agonists:

Clonidine, α-methyldopa, Guanfacine and Guanabenz

Β-2 Adrenergic agonists: Salbutamol, Terbutaline, Salmeterol,

Reproterol, Oxiprenaline, Fenoterol, Isoxsuprine, Rimiterol, Ritodrine, Bitolterol and Isoetharine

Adrenergic Drugs – Therapeutic Classification Pressor agents:

NA, Phenylephrine, ephedrine, Methoxamine, Dopamine Cardiac Stimulants:

Adr, Dobutamine and Isoprenaline, Dopexamine Nasal Decongestants:

Phenylepherine, Xylometazoline, Oxymetazoline, Naphazoline and Tetrahydrazoline and Phenylpropanolamine and Pseudoephidrine

Bronchodilators: Isoprenaline, Salbutamol, Salmeterol, Terbutaline, Formeterol

Uterine Relaxants: Ritodrine, Salbutamol, Isoxsuprine

Anorectics Fenfluramine, Dexfenfluramine and Sibutramine

CNS Stimulants: Amphetamine, Methamphetamine

Ephedrine Plant alkaloid obtained from Ephedra vulgaris – Mixed acting drug

(also metaraminol) – effective orally Crosses BBB and Centrally – Increased alertness, anxiety,

insomnia, tremor and nausea in adults. Sleepiness in children Effects appear slowly but lasts longer (t1/2-4h) – 100 times less

potent Tachyphylaxis on repeated dosing (low neuronal pool) Used as bronchodilator, mydriatic, in heart block, mucosal

vasoconstriction & in myasthenia gravis Not used commonly due to non-specific action Uses: Mild Bronchial asthma, hypotension due to spinal anaesthesia Available as tablets, nasal drop and injection

Phenylepherine - Selective, synthetic and direct α1 agonist

Actions qualitatively similar to noradrenaline Long duration of action Resistant to MAO and COMT Does not cross BBB, so no CNS effects Peripheral vasoconstriction leads to rise in BP but Reflex

bradycardia Produces mydriasis and nasal decongestion Use:

hypovolaemic shock as pressor agent Sinusitis & Rhinitis as nasal decongestant (common in oral preparations) Mydriatic in the form of eye drops and lowers intraocular pressure

ADRs: Photosensitivity, conjunctival hyperemia and hypersensitivity Administered parenteraly & topically (eye, nose)

What are Mucosal Decongestants?

Nasal and bronchial decongestants are the drugs used in allergic rhinitis, colds, coughs and sinusitis as nasal drops - Sympathomimetic vasoconstrictors with α- effects are used

Drugs: Phenylepherine, xylometazoline, Oxymetazoline, PPA, Pseudoephidrine etc.

Drawbacks: Rebound congestion due to overuse However, mucosal ischaemic damage occurs if used excessively

(more often than 3 hrly) or for prolonged periods (>3weeks) CNS Toxicity Failure of antihypertensive therapy Fatal hypertensive crisis in patients on MAOIs

Use only a few days since longer application reduces ciliary action

Nasal Decongestants Pseudoephedrine to Ephedrine but less CNS and Cardiac

effects Poor Bronchodilator Given in combination with antihistaminics, antitussives and NSAIDs

in common cold and, allergic rhinitis, blocked Eustachian tube etc. Rise in BP inhypertensives

Phenylpropanolamine (PPA) is similar to ephedrine and used as decongestants in many cold and cough preparations Also as weight loosing agent

Xylometazoline, Oxymetazoline etc.

Amphetamine Synthetic compound similar to Ephedrine Pharmacologically Known because of its CNS stimulant action – psychoactive drug and

also performance enhancing drug Actions:

alertness, euphoria, talkativeness and increased work capacity – fatigue is allayed (acts on DA and NA neurotransmitters etc. –reward pathway)

increased physical performance without fatigue – short lasting (Banned drug and included in the list of drugs of “Dope Test)” – deterioration occurs

RAS Stimulation – wakefulness, sleep deprivation (then physical disability) However, anxiety, restlessness, tremor and dysphoria occurs

Other actions: Stimulation of respiratory centre, Hunger suppression, also anticonvulsant, analgesic and antiemetic actions

Amphetamine – contd.

Drug of abuse – marked psychological effect but little physical dependence

Generally, Teenage abusers - thrill or kick High Dose – Euphoria, excitement and may progress to

delirium, hallucination and acute psychotic state Also peripheral effects like arrhythmia, palpitation, vascular

collapse etc.

Repeated Dose – Long term behavioural abnormalities Starvation – acidic urine Uses: Hyperkinetic Children (ADHD), Narcolepsy,

Epilepsy and Parkinsonism

Anorectics

Drugs used for suppression of appetite MOA: Inhibition of NA/DA or 5-HT uptake –

enhancement of monoaminergic transmission NA agents affect the appetite centre and

Serotonergics act on satiety centre Fenfluramine, dexfenfluramine and

sibutramine – ALL ARE BANNED NOW Reasons: Heart valve defects, fibrosis and

pulmonary hypertension etc.

Clonidine

Centrally acting: Agonist to postsynaptic α2A adrenoceptors in brain – vasomotor centre in brainstem (presynaptic Ca++ level – increased NA release) Decrease in BP and cardiac output

Peripherally action: High dose activates peripheral presynaptic autoreceptors on adrenergic nerve ending mediating negative feedback suppression of noradrenaline release

Overdose stimulates peripheral postsynaptic α1 adrenoceptors & cause hypertension by vasoconstriction

Clonidine – contd. Uses: ADHD in children, opioid withdrawal (restless legs, jitters and

hypertension), alcohol withdrawal (0.3 to 0.6 mg) Abrupt or gradual withdrawal causes rebound hypertension

Onset may be rapid (a few hours) or delayed for as long as 2 days and subsides over 2-3 days

Never use beta-blockers to treat Available as tablets, injections and patches Sedation, dry mouth, dizziness and constipation etc. TCAs antagonize antihypertensive action & increase rebound

hypertension of abrupt withdrawal Low dose Clonidine (50-100μg/dl) is used in migraine prophylaxis,

menopausal flushing and chorea Moxonidine, Rilmenidine – Newer Imidazolines

β2 Adrenergic Agonists – discussed elsewhere! Short acting : Salbutamol, Metaproterenol, Terbutaline,

pirbuterol Selective for β2 receptor subtype Used for acute inhalational treatment of bronchospasm. Onset of action within 1 to 5 minutes Bronchodilatation lasts for 2 to 6 hours Duration of action longer on oral administration Directly relax airway smooth muscle Relieve dyspnoea of asthmatic bronchoconstriction Long acting: Salmeterol, Bitolterol, colterol

Uterine Relaxants - discussed elsewhere! Antioxytocics or tocolytic agents β2 agonists relax uterus Used by i.v. infusion to inhibit premature labour Isoxsuprine, Terbutaline, Ritodrine, Salbutamol Tachycardia & hypotension occur Use minimum fluid volume using 5% dextrose as

diluents Ritodrine: 50 μg/min, increase by 50 μg/min every

10 minutes until contractions stop or maternal heart rate is 140 beats/minute. Continue for 12-48 hours after contractions stop

Remember ?

Steps of Biosynthesis of Catecholamine Distribution of adrenergic receptors Individual Functions of Adrenergic receptors All aspects of adrenaline – Dale`s

Phenomenon Dopamine/Dobutamine actions Nasal decongestants - Phenylephrine Amphetamine and Clonidine - Desirable

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