Adrenergic System Department of Pharmacology NEIGRIHMS, Shillong
May 07, 2015
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 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
धन्यवा�द/Khublei