adrenergic agonists
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| Sympathomimetics | 1. Direct-acting = directly stimulates receptors (epinephrine or norepinephrine)
2. Indirect-acting = stimulates release of norep. from terminal nerve endings (amphetamine)
3. Mixed-acting (indirect & direct)
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| α-Adrenoceptors | -itsaffinity is epinephrine ≥ norepinephrine >> isoproterenol
-two subgroups, α1 and α2 "/affinity to agoinst@antagonist"
ex-.α1 have a higher affinity for phenylephrine than α2.
the drug clonidine selectively binds to α2
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| α1 Receptors | -on postsynaptic membrane of the effector organs
-act via G protein activation of phospholipase C,which produce 2nd messenger IP3 & DAG.
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| α2 Receptors: | -on sympathetic presynaptic nerve endings and control the release of norepinephrine.
-Stimulation of α2 receptors causes feedback inhibition
inhibits further release of norepinephrine
-local mechanism for modulating norepinephrine output
-acting as in
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| α2 Receptors: | -found on presynaptic parasympathetic neurons.
-inhibiting acetylcholine release
-activation α2 receptors cause inhibition of adenylyl cyclase and decrease cAMP
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| tamsulosin | is a selective α1A antagonist that is used to treat benign prostatic hyperplasia.
- has fewer cardiovascular side effects
-α1A receptors found primarily in the urinarytract and prostate gland
-does not affect the α1B in the blood vessels
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| β-Adrenoceptors | -potency is isoproterenol > epinephrine > norepinephrine
-three major subgroups, β1, β2, and β3
β1 have equal affinities for epinephrine and NE
β2 have a higher affinity for epinephrine than for NE
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| β3 receptors | involved in lipolysis and also have effects on the detrusor muscleof the bladder.
-Binding of a NT at any of the three types of β receptors results in activation of adenylyl cyclase and increased concentrations of cAMP within the cell.
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| ... | the vasculature of skeletal muscle have both α1
and β2 receptors, but the β2 receptors predominate.
- Other tissues may have one type of receptor almost exclusively. ex, the heart contains predominantly β1 receptors.
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| Major effects mediated by α- and β-adrenoceptors | photo
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| Desensitization of receptors: | 1) sequestration of the receptors so unavailable for interaction with the ligand;
2) down-regulation, by destruction or by decreased synthesis;
3) inability to couple to G protein, because the receptor has been
phosphorylated on the cytoplasmic side.
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| Two important structural features of ADRENERGIC AGONISTS | 1) the number and location of OH substitutions on the benzene ring
2) the nature of the substituent on the amino nitrogen
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| Catecholamines | -contain the 3,4-dihydroxybenzene group
-epinephrine, norepinephrine, isoproterenol, and dopamine
-1. High potency.. in directly activating α or β receptors
-2. Rapid inactivation:metabolized by COMT postsynaptically and by MAO intraneuronally.
-given
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| Noncatecholamines | lacking the catechol hydroxyl groups
have longer halflives,they are not inactivated by COMT
-include phenylephrine,ephedrine, and amphetamine
-are poor substrates for MAO (an important route of metabolism
-greater access to the CNS
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| Substitutions on the amine nitrogen | -important indetermining β selectivity
-epinephrine,with a –CH3 substituent
-isoproterenol, which has an isopropyl substituent
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| Direct-acting adrenergic agonists | -act directly on α or β receptors, producing effects similar to those of epinephrine
-ex.epinephrine,norepinephrine, isoproterenol, and phenylephrine
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| Indirect-acting agonists: | -may block the reuptake of norepinephrine or cause the release of norepinephrine from the cytoplasmic pools or vesicles of the adrenergic neuron
-ex-cocaine and amphetamines
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| Mixed-action agonists: | Ephedrine and its stereoisomer, pseudoephedrine,
both stimulate adrenoceptors directly and release norepinephrine
from the adrenergic neuron
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| Epinephrine | administered : subcutaneous, inhalation,eye, drops ,intracardiac
-In the adrenal medulla, norepinephrine is methylated to yield epinephrine, which is stored in chromaffin cells along with norepinephrine
-80% epinephrine and 20% norepinephrine directly i
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| Actions of Epinephrine similar to sympathetic stimulation | Cardiovascular system
Heart : ↑all cardiac properties (↑contractility, heart rate , AV conduction, excitability, automaticity
Blood vessels: • Vasoconstriction (skin, mucous membrane, renal) • Vasodilatation (skeletal muscle, coronary blood vessel
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| Actions of Epinephrine similar to sympathetic stimulation | Respiratory system: Bronchodilatation (β2) Decongestion of bronchial mucosa (α1)
urinary bladder and Gastrointestinal tract : Spasm of spincters (α1) Relaxation of the wall (β2) urinary retention and inhibits defecation
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| Actions of Epinephrine similar to sympathetic stimulation | - Skeletal muscle Facilitate NM transmission Vasodilatation (β2)
-Eye Vasoconstriction of conjunctival blood vessels (decongestion) ↓intraocular pressure Mydriasis
-Antiallergic Adrenaline is Physiological antagonist of histamine --Metabolism
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| Adrenaline Uses | With local anesthetic (delay absorption and prolong duration of drugs) Open angle glaucoma (eye drops) Epistaxis (haemostatic nasal pack) Anaphylactic shock Cardiac resuscitation in cardiac arrest Acute bronchial asthma
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| Pharmacokinetics of Epinephrine | -rapid onset but a brief duration of action
-The preferred route is intramuscular (anterior thigh)
-rapidly metabolized by MAO and COMT,
-the metabolites metanephrine and vanillylmandelic acid are excreted in urine.
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| -Adverse effects of Epinephrine | -CNS effectsthat" anxiety, fear, tension, headache, and tremor"
-Tachycardia, palpitation, angina and arrhythmia
-induce pulmonary edema.
-In diabetic patients, dosages of insulin may have to
be increased.
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| Contraindications of Epinephrine | Injection Around finger or toe
Hypertension coronary heart disease Arrhythmia
Hemorrhagic shock Thyrotoxicosis
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| Norepinephrine | -α-adrenergic receptor is most affected.
-Neurotransmitter released from postganglionic adrenergic nerve endings (80%)
-Orally ineffective and poor SC absorption
-IV administered
-Metabolized by MAO, COMT ..Short duration of action
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| Actions | -Agonist at α1(predominant), α2 and β1 Adrenergic receptors
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
Incre
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| uses Norepinephrine | used as a vasopressor agent in treatment of hypovolemic shock and other hypotensive states in order to raise B.P
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| -Adverse effects of norEpinephrine | -Anxiety, palpitation, respiratory difficulty
-Acute Rise of BP, headache
-Extravasations causes necrosis, gangrene
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| Isoprenaline ....isoproterenol | -Catecholamine acting on beta-1 and beta-2 receptors
Overall effect is Cardiac stimulant (beta-1)
-Increase in SBP but decrease in DBP (beta-2)
-Decrease in mean BP
-potent Bronchodilatation
-Used as Bronchodilator and for treatment of AV block
-daw
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| 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 (3-5min
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| MECHANISM OF Dopamine | -Agonists at dopaminergic D1, D2 receptors
-Agonist at adrenergic α1 and β1
stimulates-- D1-receptors in renal, mesenteric and coronary vessels leading to vasodilatation .
-D2 receptors (present in presynaptic adrenergic neurones) suppression of NA re
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| actions | -Cardiovascular: stimulatory effect on heart, positive inotropic and chronotropic <β1>. At very high doses, dopamine activates α1 resulting in vasoconstriction.
-Renal and visceral: Dopamine dilates renal and splanchnic
arterioles by D1&D2
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| therapeutic use | -drug of choice for cardiogenic and septic shock and is given by continuous infusion.
-It raises blood pressure
-enhances perfusion to the kidney and splanchnic areas
-used to treat hypotension and severe heart failure,
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| Adverse effects: | - as sympathetic stimulation.
Dopamine is rapidly metabolized by MAO or COMT,
(nausea, hypertension,and arrhythmias)
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| Fenoldopam [fen-OL-de-pam] | is an agonist of peripheral D1 receptors.
-used as a rapid-acting vasodilator to treat severe
hypertension in hospitalized patients
-act coronary arteries,kidney arterioles, and mesenteric arteries. -undergoes extensive first-pass metabolism and has
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| Dobutamine [doe-BYOO-ta-meen] is a synthetic, direct-acting catecholamine that is a β1 receptor agonist. | It increases cardiac rate and output with few vascular effects.
- used to increase cardiac output in acute heart failure &inotropic support after cardiac surgery
. The drug increases cardiac output and does not significantly elevate oxygen demands of
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| Oxymetazoline | -stimulates both α1- and α2.
- found in many over-the-counter short-term nasal spray decongestants,& ophthalmic drops for the relief of redness
-It is absorbedin the systemic circulation regardless of the route of administration and may produce nervous
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| Phenylephrine [fen-ill-EF-reen] | -binds primarily to α1 receptors.
Phenylephrine is a vasoconstrictor that raises both systolic and diastolic blood pressures.
- It has no effect on the heart but induces reflex bradycardia
The drug is used to treat hypotension in hospitalized or surgi
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