Adrenergic Drugs drdhriti(updated 2011)

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 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 Receptors

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 2 nd 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 β 3 β 2 β 1 α 2 α 2B α 2C α 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 PK A Phospholamban Increased Interaction with Ca++ Faster relaxation Troponin Cardiac contractility Other Functional proteins PK A alters the functions of many Enzymes, ion channels, transporters and structural proteins. Faster sequestration of Ca++ in SR

Also Recall: Phospholipase C: IP3-DAG pathway PKc

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 β 1 , β 2 and β 3 Beta-1 Beta-2 Beta-3 Location 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 α 1 and α 2 Alpha-1 Alpha-2 Location 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 aggregation Gluconeogenesis

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 inhibition MAO-B inhibition COMT inhibition Moclobemide Selegiline Tolcapone Receptors α 1 α 2 β1 + β2 β1 Prazosin Yohimbine Propranolol Metoprolol

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 β 1 agonist and α 1 antagonist, while the (−) isomer is an α 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
Us es: 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

धन्यवाद /Khublei

Adrenergic Drugs drdhriti(updated 2011)

by Dr. Dhriti Brahma

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Adrenergic Drugs drdhriti(updated 2011) Presentation Transcript