Adrenergic System

Department of Pharmacology NEIGRIHMS, Shillong

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

Alpha-methyl-ptyrosine

Rate limiting Enzyme

5-HT, alpha Methyldopa

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 Located in smooth muscle/ cardiac muscle Inhibited by steroids/ phenoxybenzamine No Physiological or Pharmacological importance

Uptake 2 is less specific for NA

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 Receptors

Adrenergic receptors (or adrenoceptors) are a class of Gprotein 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 ????

Adenoreceptors

Alpha ()

Beta ()

2A 2B 2C
1A 1B 1D

Differences - Adrenergic Receptors ( and ) !

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

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

Agonist affinity of beta ():

Potency of catecholamines on Adrenergic Receptors

Aortic strip contraction Bronchial relaxation NA Adr

Iso

Adr

NA

Iso

Log Concentration

Molecular Effector Differences - Vs

Receptors:

IP3/DAG cAMP K+ channel opening

Receptors:

cAMP Ca+ channel opening

Recall: Adenylyl cyclase: cAMP pathway

PKA alters the functions of many Enzymes, ion channels, transporters and structural proteins.

Other Functional proteins

PKA
Troponin Increased Interaction with Ca++

Phospholamban

Faster sequestration of Ca++ in SR

Cardiac contractility

Faster relaxation

Also Recall: Phospholipase C: IP3-DAG pathway

PKc

Beta receptors

All receptors activate adenylate cyclase, raising the intracellular cAMP concentration Type 1:

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

Type 2:

Type 3:

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

Differences between 1, 2 and 3

Beta-1
Location Heart and JG cells

Beta-2
Bronchi, uterus, Blood vessels, liver, urinary tract, eye Salbutamol

Beta-3
Adipose tissue

Agonist Antagonist

Dobutamine

Metoprolol, Atenolol Alpha-methyl propranolol

Action on NA

Moderate

Weak

Strong

Clinical Effects of -receptor stimulation

1: Adrenaline, NA and Isoprenaline:

Tachycardia Increased myocardial contractility Increased Lipolysis Increased Renin Release

2: Adrenaline and Isoprenaline (not NA)

Bronchi Relaxation SM of Arterioles (skeletal Muscle) Dilatation Uterus Relaxation Skeletal Muscle Tremor Hypokalaemia Hepatic Glycogenolysis and hyperlactiacidemia 3: Increased Plasma free fatty acid increased O2 consumption increased heat production

Adrenergic receptors - alpha

Type 1

Blood vessels with alpha-1 receptors are present in the skin and the genitourinary system, and during the fight-orflight 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 These are found on pre-synaptic nerve terminals Acts by inactivation of adenylate cyclase, cyclic AMP levels within the cell decrease (cAMP)

Type 2

Differences between 1 and 2

Alpha-1
Location

Alpha-2

Post junctional blood vessels Prejunctional of skin and mucous membrane, Pilomotor muscle & sweat gland, radial muscles of Iris Stimulatory GU, Vasoconstriction, gland secretion, Gut relaxation, Glycogenolysis Phenylephrine, Methoxamine Prazosin Inhibition of transmitter release, vasoconstriction, decreased central symp. Outflow, platelet aggregation Clonidine Yohimbine

Function

Agonist Antagonist

1 adrenoceptors Clinical effects

Eye -- Mydriasis Arterioles Constriction (rise in BP) Uterus -- Contraction Skin -- Sweat Platelet - Aggregation Male ejaculation Hyperkalaemia Bladder Contraction 2 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 aggregation Gluconeogen esis

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 Synthesis of NA Axonal uptake Vesicular uptake Vesicular NA Membrane NA pool Actions Inhibition Block Block Displacement Exchange diffusion Drug - methyl-p-tyrosine Cocaine, guanethidine, ephedrine Reserpine Guanethidine Tyramine, Ephedrine

Metabolism

MAO-A inhibition MAO-B inhibition COMT inhibition 1 2 1 + 2 1

Moclobemide Selegiline Tolcapone Prazosin Yohimbine Propranolol Metoprolol

Receptors

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 (-2 and -3) Inhibits insulin secretion (-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 1(predominant), 2 and 1 Adrenergic receptors

Equipotent with Adr on 1, but No effect on 2

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 1 and 1

Dopamine

In small doses 2-5 g/kg/minute, it stimulates D1receptors 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 g/kg/minute), stimulates 1receptors in heart producing positive inotropic and chronotropic actions actions Releases Noradrenaline from nerves by 1stimulation Does not change TPR and HR Great Clinical benefit in CVS shock and CCF High dose (10-30 g/kg/minute), stimulates vascular adrenergic 1-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 1 agonist and 1 antagonist, while the () isomer is an 1 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 Clonidine, -methyldopa, Guanfacine and Guanabenz Salbutamol, Terbutaline, Salmeterol, Reproterol, Oxiprenaline, Fenoterol, Isoxsuprine, Rimiterol, Ritodrine, Bitolterol and Isoetharine

Selective Alpha-2 Agonists:

-2 Adrenergic agonists:

Adrenergic Drugs Therapeutic Classification

Pressor agents:

NA, Phenylephrine, ephedrine, Methoxamine, Dopamine

Cardiac Stimulants:

Adr, Dobutamine and Isoprenaline, Dopexamine

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

Nasal Decongestants:

Bronchodilators:

Isoprenaline, Salbutamol, Salmeterol, Terbutaline, Formeterol

Ritodrine, Salbutamol, Isoxsuprine Fenfluramine, Dexfenfluramine and Sibutramine Amphetamine, Methamphetamine

Uterine Relaxants:

Anorectics

CNS Stimulants:

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 1 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 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 2A 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 1 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 (50-100g/dl) is used in migraine prophylaxis, menopausal flushing and chorea Moxonidine, Rilmenidine Newer Imidazolines

2 Adrenergic Agonists discussed elsewhere!

Short acting : Salbutamol, Metaproterenol, Terbutaline, pirbuterol Selective for 2 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 2 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 g/min, increase by 50 g/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