adrenergic agonists sympathomimetic drugs · adrenergic agonists i.direct-acting a. epinephrine (α...
TRANSCRIPT
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Dr. Irfan Ahmad KhanAssistant Professor
Adrenergic agonists
Sympathomimetic drugs
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• Drugs affect receptors that are stimulated by norepinephrine orepinephrine
• Act on adrenergic receptors,located either presynaptically on neuron or postsynaptically on effector organ
Adrenergic agonists
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NEUROTRANSMITTERS
• 3 types→ Collectively called catecholamines
1. Noradrenaline(NA)→ postganglionic sympathetic sites (except sweat glands, hair follicles & some vasodilator fibres) & in certain areas of brain
2. Adrenaline(Adr)→ secreted by adrenal medulla
3. Dopamine(DA)→ transmitter in mammalian extrapyramidal system & of several mesocortical& mesolimbic neuronal pathways
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NEP & EP modulate:
• Rate and force of contraction of heart
• Resistance (constriction and dilation) of blood vessels and bronchioles
• Release of insulin
• Breakdown of fat (lipolysis)
• Therefore, frontline therapies for hypertension, depression, shock, asthma, angina
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Synthesis, Storage & Release of neurotransmitter in
Adrenergic System
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SYNTHESIS OF TRANSMITTER
• Catecholamines are synthesized from amino acid→ Phenylalanine
• In liver, it is 4-hydroxylated to form tyrosine
• Tyrosine is 3-hydroxylated by Tyrosine hydroxylase (TH) to form DOPA
• Tyrosine hydroxylase → rate limiting enzyme & its inhibition by α-methyl-p-tyrosine leads depletion of CAs
• Enzymes are synthesized in nerve cell bodies
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occurs in adrenergic neuronal
cytoplasm
occurs inside granules
occurs in adrenal medulla
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STORAGE
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• Stored in synaptic vesicles or granules
• NA stored in a complex with ATP(4:1)
• In adrenal medulla, Adr so formed is stored in separate granule→ Chromaffin granule
• MAO present on outer surface of mitochondria lowers cytoplasmic pool of CAs
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RELEASE
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Ligandgated
Releasable nucleotidases
peptidases
GPCRs
Vesicle ass. membrane
proteinSynaptosome
ass.protein
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Uptake Vesicular reuptake
VMAT-2 (Vesicular monoamine transporter-2)-70%
• ATP dependent proton translocase
• In exchange of 2H+ →1 amine molecule
• Inhibitor-reserpine
Neuronal uptake
NET(NE transporter)→Uptake-1→87%
• Na+ coupled
• DA>NE>Epi
• Inhibitor-cocaine/desipramine
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Non-neuronal(Uptake-2)
1.OCT-1(organic cation transporters)
• DA>Epi>NE
2.OCT-2
• DA>NE>Epi
3.ENT-extraneuronal transporter(OCT-3)
• Epi>NE>DA
→Not Na+ dependent
→Inhibitor - corticosterone
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MetabolismTwo enzymes involved→
1. Monoamine oxidase (MAO)
outer surface of mitochondria
2. Catechol-O-methyltransferase (COMT)
present largely in cytoplasm except adrenal
medulla where present in membrane bound
• Also metabolized by sulfotransferases
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ALDEHYDE DEHYROGENASE
ALDEHYDE REDUCTASE
ALCOHOL DEHYROGENASE
ALDEHYDE DEHYROGENASE
3,4-DIHYDROXYPHENYL GLYCOL 3,4-DIHYDROXYMANDELIC ACID
VANILLYL MANDELIC ACID
3-METHYL,4-HYDROXYPHENYLGLYCOL
DEAMINATION DEAMINATION
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CLASSIFICATION OF ADRENOCEPTORS
HISTORICAL BACKGROUND
• In 1896, Oliver & Schafer demonstrated inj. of extracts of adrenal gland caused rise in arterial pressure
• Dale in 1913 that adrenaline causes two distinct kinds of effect
– Vasoconstriction
– Vasodilatation
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• 1948 Ahlquist, showed clearly existence of several subclasses of adrenoceptor
• Postulated existence of 2 kinds of receptor, α & β, defined in terms of agonist potencies as follows:
– α: noradrenaline > adrenaline > Isoprenaline
– β: Isoprenaline > adrenaline > noradrenaline
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• There are two main α-adrenoceptor subtypes (α1
and α2) & three β-adrenoceptor subtypes (β1, β2, β3)
• All are G-protein-coupled receptors
• 2nd messengers:
– α1- adrenoceptors activate phospholipase C, thus producing inositol trisphosphate & diacylglycerol
– α2- adrenoceptors inhibit adenylate cyclase & thus decrease cAMP formation
– All β-adrenoceptor stimulate adenylate cyclase
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α- adrenoceptors
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β-adrenoceptors
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Receptor Regulation
• Responses mediated by adr. are not fixed & static
• One of studied examples of receptor regulation is desensitization of adr. that may occur after exposure to catecholamines & other sympathomimetic drugs for long period
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Main effects of receptor activation
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Tissues and effectsα1 α2 β1 β2 β3
Smooth Muscle
Blood vessels Constrict Constrict/dilate
Dilate
Bronchi Constrict Dilate
GI tract Relax Relax (presynaptic effect)
Relax
GI sphincters Contract
Uterus Contract Relax
Bladder detrusor Relax
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α1 α2 β1 β2 β3
Bladder sphincter
Contract
Seminal tract Contract Relax
Iris (radial muscle)
Contract
Ciliary muscle
Relax
Heart:
Rate Increase
Force of contraction
Increase
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α1 α2 β1 β2 β3
Skeletal muscle
TremorIncreased muscle mass and speed of contractionGlycogenolysis
Thermogenesis
Liver Glycogenolysis
Glycogenolysis
Fat LipolysisThermogenesis
Pancreatic islets
Decrease insulin secretion
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α1 α2 β1 β2 β3
Nerve Terminal:
Adrenergic Decrease release
Increase release
Cholinergic Decrease release
Salivary gland
K+ release Amylase secretion
Platelets Aggregation
Mast cells Inhibition of histamine release
Brainstem Inhibits sympathetic outflow
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α1 α2 β1 β2 β3
Second messengers and effectors
PLC activation ↓cAMP ↑cAMP ↑cAMP ↑cAMP
↑ IP3 ↓Calcium channels
↑DAG ↑Potassium channels
↑Ca2+
Agonist potency order
NA ≥A > ISO A > NA >ISO ISO > NA > A ISO > A > NA ISO > NA = A
Selective agonists
Phenylephrinemethoxamine
Clonidine Dobutamine Salbutamol, terbutaline, salmeterol, formoterol
BRL 37344
Selective antagonists
Prazosin, doxazocin
Yohimbine Atenolol, metoprolol
Butoxamine
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ADRENERGIC DRUGS(Sympathomimetics)
• Direct sympathomimetics→ act directly as agonists on α and/or β adrenoceptors—Adr, NA, Isoprenaline (Iso), Phenylephrine, Methoxamine, Xylometazoline, Salbutamol and others
• Indirect sympathomimetics→ act on adrenergic neuron to release NA, which then acts on adrenoceptors—Tyramine, Amphetamine
• Mixed action sympathomimetics→ act directly as well as indirectly—Ephedrine, Dopamine, Mephentermine
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Therapeutic Classification of Adrenergic Drugs• Pressure agents Noradrenaline
➢Ephedrine Dopamine Phenylephrine Methoxamine
• Cardiac stimulants
➢Adrenaline Dobutamine Isoprenaline
• Bronchodilators
➢ Isoprenaline Salbutamol Salmeterol Formoterol
• Nasal Decongestants
➢Phenylephrine Xylometazoline Oxymetazoline Naphazoline
• CNS Stimulants
➢Amphetamine Methamphetamine Dexamphetamine
• Anorectics
➢ Fenfluramine Sibutramine Dexfenfluramine
• Uterine relaxant & vasodilators
➢Ritodrine Isoxsuprine Salbutamol Terbutaline
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Adrenergic Agonists
I.Direct-Acting
A. Epinephrine (α1, α2, β1, β2)At low doses, β effects (vasodilation) on vascular system predominate, whereas at high doses, α effects (vasoconstriction) are strongest
Cardiovascular• β1 action: positive inotropic & chronotropic
• α effects : constricts arterioles in skin, mucous membranes and viscera. Renal blood flow isdecreased.
• β2 effects: dilates vessels going to liver and skeletal muscle
• Therefore, increase in SBP, with a slight decrease in DBP
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A. Epinephrine (α1, α2, β1, β2)
Respiratory
• β2 action: powerful bronchodilation
• Inhibits release of allergy mediators such as histamines from mast cells
• Physiological antagonist of histamine
• In anaphylactic shock, this can be lifesaving→ not only raises BP, but counteracts bronchospasm/laryngeal edema
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A. Epinephrine (α1, α2, β1, β2)Therapeutic uses
• Anaphylactic shock: Epinephrine is DOC
• Glaucoma: Dipivefrine → open-angle glaucoma→reducing production of aqueous humor by vasoconstriction of ciliary body blood vessels
• Cardiac arrest: Epinephrine restore cardiac rhythm
• Anesthetics: Local anesthetic solutions usually contain 1:100,000 parts epinephrine→increase duration of localanesthesia
• Control oozing of capillary blood: epinephrine (1:100,000) used topically to vasoconstrict mucous membranes
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• Transient restlessness, headache, palpitation,
anxiety, tremor and pallor may occur after s.c./ i.m.
injection
• Marked rise in BP leading to cerebral haemorrhage,
ventricular tachycardia/fibrillation, angina, MI →
large doses or inadvertant i.v. injection
• C/I: hypertensive, hyperthyroid and angina
• Not to be given during anaesthesia with halothane
(risk of arrhythmias) and in patients receiving β blockers (marked rise in BP → unopposed α action)
Adverse effects and contraindications of Adr.
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B. Norepinephrine (α1, α2, β1)
• In therapeutic doses, α receptor is mostaffected
Cardiovascular actions:
• Vasoconstriction: α1 effect
• Both SBP and DBP increase
• Note: NE causes greater vasoconstriction than does epinephrine(no vasodilation via β2 receptors)
• Weak β2 activity of norepinephrine also explains why it is not useful in treatment of asthma
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C. Isoprenaline (β1 and β2)
• Direct-acting synthetic catecholamine, stimulates both β1 and β2
• Nonselectivity is one of its drawbacks and reason why it is rarely used therapeutically
• Action on α receptors is insignificant
Therapeutic uses
• Stimulate heart in emergency situations
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C. Isoprenaline (β1 and β2)Cardiovascular
• β1 effect: ↑heart rate and force of contraction→ CO. Useful in AV block or cardiac arrest
• β2 effect: dilates arterioles of skeletal muscle→↓ peripheral resistance
• Because of its cardiac stimulatory action, it increase SBP slightly, but it greatly ↓ mean arterial and DBP
• Other effects on β receptors, such as increased blood sugar and lipolysis
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Effects of intravenous infusion
Slow, β2 Rapid, ⍺
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Effect on BP:
• NA : rise in systolic, diastolic & mean BP; No vasodilatation, peripheral resistance ↑ due to α action
• Isoprenaline : ↑ systolic but marked fall in diastolic BP, mean pressure generally falls
• Adr
• slow i.v. infusion → rise in systolic but fall in diastolic BP, mean BP generally rise
• Rapid i.v. inj. →marked rise in both systolic & diastolic BP, BP returns to normal within a few minutes & secondary fall in BP follows
• When an α blocker has been given, only fall in BP is seen—vasomotor reversal of Dale
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D. Dopamine (D1 and D2, β1,α1)
• High dose→ vasoconstriction → α1
• Moderate dose→ stimulates β1 cardiac receptors
• Low dose→ D1 and D2 occur in mesenteric and renal vascular beds→ dopamine produces vasodilation
• Cardiovascular: β1, α1 receptors
• Renal and visceral: Vasodilator thus increasing blood flow to kidneys and other viscera
• Therefore, useful in shock, in which significant increases in sympathetic activity might compromise renal function
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D. Dopamine (D1 and D2, β1,α1)Therapeutic uses
• Shock: DOC and is given by continuous infusion. It raises BP by stimulating:
• β1 receptors → increase cardiac output,
• α1 receptors → increase total peripheral resistance
• Enhances perfusion to kidney and splanchnic areas→ enhances GFR and causes sodium diuresis
• So, dopamine is far superior to NE, which diminishes blood supply to kidney and may cause renalshutdown
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E. Dobutamine (β1)• Synthetic, deivative of dopamine without D1/D2
effect
• Increases cardiac rate and output with few vascular effects
Therapeutic uses:
• CHF: to increase CO
• Inotropic support after cardiac surgery
• ↑ CO with little change in HR and it does not significantlyelevate oxygen demands of myocardium a majoradvantage over other sympathomimetic drugs
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F. Oxymetazoline (α1 and α2)
• Direct-acting synthetic adrenergic agonist
• Used locally in eye or nose as a vasoconstrictor
• Used
• Nasal decongestant
• Ophthalmic drops for relief of redness of eyesassociated with swimming, colds or contact lens
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G. Phenylephrine (α1)
• Direct-acting, synthetic adrenergic drug
• Vasoconstrictor : raises both systolic and diastolic BP
• No effect on heart but rather induces reflex bradycardia when given parenterally
• Used topically as nasal decongestant and in ophthalmic solutions for mydriasis without cycloplegia
• Reduces IOP by constricting ciliary blood vessels
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H. Methoxamine (α1)
• direct-acting, synthetic adrenergic drug
• Resembles phenylephrine very closely
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I. Clonidine (α2)
• α2 agonist; acts centrally to produce inhibition of sympathetic vasomotor centers, decreasing sympathetic outflow to periphery
• Used in essential hypertension to lower blood pressure
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K. Salbutamol and terbutaline (β2)
• short-acting β2 agonists (3-6 hrs)
• used as bronchodilators
L. Salmeterol and formoterol (β2)
• long-acting bronchodilators (12hours)
• Salmeterol has delayed onset ofaction but not formoterol
• Not recommended as monotherapy and are highly efficacious when combined with acorticorsteroid
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II. Indirect-Acting Adrenergic Agonists• cause norepinephrine release from presynaptic
terminals or inhibit uptake of norepinephrine
A. Amphetamine
• marked central stimulatory action of amphetamine is often mistaken by drug abusers as its only action
• can increase BP significantly by α-agonist action onvasculature as well as β-stimulatory effects on heart
• Exchange diffusion and reverse transport
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• Uses: CNS stimulant
– Narcolepsy
– Appetite control
– Nocturnal enuresis
– Hyperkinetic child
• Drug of abuse
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B. Tyramine
• Not clinically useful drug
• Found in fermented foods, such as ripe cheese
• Normally, oxidized by MAO in GIT, but if patient is taking MAO inhibitors, it can precipitate serious vasopressor episodes
• Like amphetamines, tyramine can enter nerve terminal and displace stored NE
• Released catecholamine then acts on adrenoceptors
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C. Cocaine
• Ability to block Na+/K+-activated ATPase (required for cellular uptake of norepinephrine)
• Consequently, norepinephrine accumulates in synapticspace
• Like amphetamines, it can increase blood pressure by α-agonist actions and β- stimulatory effects
• Cocaine as a CNS stimulant and drug of abuse
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III. Mixed-Action Adrenergic Agonists
1. Induce release of NE from presynaptic terminals
2. Activate adrenergic receptors on postsynaptic membrane
A. Ephedrine
• Plant alkaloids that are now made synthetically
• No effect of MAO→ Orally
• Penetrate into CNS→ Stimulation