Adrenergic Agonist Agents

By Dr.SaraSami

Yuzuncu yil university

2015

Adrenergic AgonistsDifferences

Catecholamine

• Cannot use orally

• Cannot cross BBBShort-half live

Examples:

NorepinephrineEpinephrineIsoproteronolDopamineDobutamine

Noncatecholamines

• Can use orally

• Can cross BBB

Longer half life

Examples:

EphedrinePhenylephrineTerbutalineAmphetaminesMethoxamineMephentermine

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

• Catecholamines:

Compounds containing a catechol nucleus (Benzene ring with 2 adjacent OHgroups) and an aminecontaining side chain ( that why its not penterat BBB)

• Non-catecholamines lack

hydroxyl (OH) group (good lipophilic )

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)

ENDOGENOUS CATECHOLAMINES

Naturally occurring in body:

Norepinephrine -Sites: postganglionic sympathetic sites (except sweat glands , erector pillorie, hair follicles, )

• Epinephrine- Secreted by adrenal medulla

• Dopamine- Major transmitter in basal ganglia, CTZ, limbic system, anterior pitutory.

ADRENERGIC DRUGSSymphathomimetics

• DIRECT SYMPHATHOMIMETICS• Adrenaline• Noradrenaline• Isoproterenol/ Isoprenaline• Phenylephrine• Methoxamine• salmeterol• Xylometazoline• Salbutamol / Albutrol

• INDIRECT SYMPHATHOMIMETICS• Tyramine• Amphetamine• Cocaine

• MIXED SYMPHATHOMIMETICS• Ephedrine• Pesudoephedrine• Dopamine• Mephenteramine

Pressor agents

Noradrenaline Phenylephrine

Ephedrine Methoxamine

Dopamine Mephentermine

Cardiac stimulantsAdrenaline DobutamineIsoprenaline

BronchodilatorsAdrenali TerbutalineIsoprenaline SalmeterolSalbutamol Formoterol(Albuterol) Bambuterol

THERAPEUTIC CLASSIFICATION OF ADRENERGIC DRUGS

Nasal decongestantsPhenylephrine NaphazolineXylometazoline PseudoephedrineOxymetazoline Phenyl propanolamine

CNS stimulants

Amphetamine, Dexamphetamine, Methamphetamine

Anorectics

Fenfluramine Dexfenfluramine Sibutramine

Uterine relaxant and vasodilatorsRitodrine Salbutamol

Isoxsuprine Terbutaline

DIRECT SYMPHATHOMIMETICS

• Adrenaline• Noradrenaline• Isoproterenol/

Isoprenaline• Phenylephrine• Methoxamine• salmeterol• Xylometazoline• Salbutamol /

Albutrol

Biosynthesis of Catecholamines

STORAGE, RELEASE, UPTAKEL-Phenylalanine

Hepatic hydroxylase

Stimulation of neuron

Epinephrine as prototype• Potent stimulant of alpha and beta receptors.

• Complex actions on target organs.

• At low concentration vasodilatation.

• At high concentration vasoconstriction.

Epinephrine:• Dose-dependent effects:

α

β

Dose of epinephrine →

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

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 rise (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. Betareceptors 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

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 betaaction) 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

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

• Adverse effects:– Extensions of their effects in the CVS and the CNS– Anxiety, tenseness, headache and paranoia– tachycardia, dysrhythmias– Large dose IV – cerebral hemorrhage, pulmonary

edema

• Route of administration:

– Inhalation

– Injection (IM, SC, IV), not PO

– Topical application

– Rapidly degraded

ADRs

• Restlessness, Throbbing headache, Tremor, Palpitations

• Cerebral hemorrhage, cardiac arrhythmias

• Contraindicated in hypertensives, hyperthyroid and angina poctoris

• Halothane and beta-blockers – not indicated

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

• 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 presynapticadrenergic 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

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

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)

Phenylephrine:

• Acts on α receptors

• Vasoconstriction (↑ BP)

• Longer lasting than epinephrine

• Clinical use:

– Hypotension and shock

– Nasal decongestant

Salbutamol:

• Selective β2 agonist

• Dilates bronchial smooth muscle

• Clinical use:

– Antiasthmatic

phenylephrine(neosynephrine)and methoxamine

• 1.selective α1-R agonists: shock,

hypotension

• 2.paroxysmal atrial tachycardia

• 3.renal vasoconstriction significant

• 4.phenylephrine→mydriasis

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

INDIRECT SYMPHATHOMIMETICS

• Tyramine

• Amphetamine

• Cocaine

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

MIXED SYMPHATHOMIMETICS

• Ephedrine

• Pesudoephedrine

• Dopamine

• Mephenteramine

Mix action 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

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 ciliaryaction

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.