Adrenergic Agonists PDF

Adrenergic agonists Dr. Romany H Thabet, PhD  List of Adrenomimetic Drugs A. General agonists – Direct (a 1 , a 2 , b 1 , b 2 ) : Epinephrine*, Ephedrine – Indirect, releasers: : Tyramine*, Amphetamine, Ephedrine – Indirect, uptake inhibitors : Cocaine*, Tricyclic antidepre...

Adrenergic agonists Dr. Romany H Thabet, PhD  List of Adrenomimetic Drugs A. General agonists – Direct (a 1 , a 2 , b 1 , b 2 ) : Epinephrine*, Ephedrine – Indirect, releasers: : Tyramine*, Amphetamine, Ephedrine – Indirect, uptake inhibitors : Cocaine*, Tricyclic antidepressants (TCAs)  List of Adrenomimetic Drugs B. Selective agonists na 1 , a 2 , b 1 : Norepinephrine* na 1 > a 2 : Phenylephrine*, methoxamine, metaraminol, midodrine na 2 > a 1 :Clonidine*, methylnorepinephrine, apraclonidine, brimonidine nb 1 = b 2 : Isoproterenol*  List of Adrenomimetic Drugs B. Selective agonists n b 1 > b 2 : Dobutamine* n b 2 > b 1 : Terbutaline*, albuterol, metaproterenol, ritodrine n Dopamine agonist: Dopamine*, bromocriptine  Vascular system effects A. a 1 agonists – eg, phenylephrine (pure alpha agonist) – constrict skin, cutaneous, visceral(splanchnic), pulmonary, renal blood vessels – constrict veins – consequently a rise in BP and an increase in peripheral vascular resistance (PVR or TPR) – Often evoke a compensatory reflex bradycardia  Vascular system effects B. b 2 agonists – eg, terbutaline (pure beta agonist) – dilate arterioles in skeletal muscle, coronary arteries – consequently reduce PVR and BP. – [Voluntary muscle ----> tremor (b 2)] – Low dose of Epi: Beta2 activation is dominant.  Vascular system effects C. a 2 agonists – eg, clonidine (antihypertensive drugs) – when given orally, reduce sympathetic outflow from CNS and consequently decrease BP – cause vasocontriction when given IV or topically (nasal spray)  Vascular system effects D. Dopamine agonists (eg, dopamine) DA1 receptor – locate at smooth muscle of renal, coronary, cerebral, mesenteric arteries relaxation – tubule of kidney inhibit Na+/K+ ATPase pump --> natriuresis, diuresis  Dopamine Low dose (0.5-2 mcg/kg/min): activate Dopamine receptors Intermediate dose(2-10): activate Beta receptors High dose(>10): activate Alpha receptor Very useful in treatment of renal failure associated with shock (low to moderate dose)  Cardiac effects b agonists eg, isoproterenol predominantly b 1 receptor(also b 2 ) activation of which produces an increase in – the rate of cardiac pacemakers (normal and abnormal) – force of contractions – AV node conduction velocity  Net cardiovascular actions a and b 1 agonists – eg, norepinephrine – may cause a reflex increase in vagal outflow (due to BP increase) --> reflex bradycardia – This reflex often dominates any direct beta effects on the heart rate.  Net cardiovascular actions a and b 1 agonists (cont’d) If reflex is blocked (e.g., by ganglion blockers), NE can cause tachycardia (b 1 ) Pure alpha agonists e.g., phenylephrine will routinely slow heart rate via the baroreceptor reflex Pure beta agonists E.g., isoproterenol almost always increases the heart rate  Respiratory System b 2 agonists – eg, terbutaline – produce relaxation of tracheal and bronchial muscle  Eye Radial muscle, iris (pupillary dilator) – contraction (a 1) --> mydriasis – topical phenylephrine and similar alpha agonists – accommodation is not significantly affected – outflow of aqueous humor may be facilitated --> reduce intraocular pressure (IOP) Ciliary muscle: relaxation for far vision (b 2)  Gastrointestinal tract alpha and beta receptors locate on smooth muscle and on neurons of enteric nervous system Stomach and intestine – Motility and tone: (a 2 ,b 2) – Sphincters : contraction (a 1) – Secretion (intestine): inhibition (a 2) : inhibit salt and water secretion  Genitourinary tract Urinary bladder – Detrusor or bladder wall: relax (b 2) – Trigone, sphincter, prostate gland: constrict (a 1 ) Uterus – non-pregnant: relax (b 2) – pregnant: contract(a 1 ), relax (b 2) Metabolic and hormonal effects Kidney – renin release (b 1) Pancreatic b cells – inhibit insulin release (a 2 ) – stimulate insuline release (b 2) Glycogenolysis in liver and skeletal muscle (b 2) Metabolic and hormonal effects Glucose out of liver associated with initially hyperkalemia, then transport into skeletal muscle resulting in a later hyperkalemia. Lipolysis (b 3) : break down of triglycerides (TGs) into free fatty acids(FFAs) --> increase lactate from lipid metabolism  CNS effects Catecholamines do not produce CNS effects eg, Amphetamine have stimulant effects on CNS Beginning with mild alerting or reduction of fatigue Progressing to anorexia, euphoria, and insomnia CNS effects probably represent the release of dopamine in certain dopaminergic tracts Very high doses lead to marked anxiety or aggressiveness, paranoid, and sometimes convulsions  Cardiovascular applications of adrenergic agonists A. Increase blood flow – acute heart failure (b 1), decrease PVR through partial b 2 effect: Dobutamine – cardiogenic shock from MI, CHF or septic shock : Dopamine B. Reduce blood flow and increase BP – Surgery : prolong action of local anesthetics (a 1) – hypotension, during spinal anesthesia (a 1) : NE – congestion (a 2) : oxymetazoline  Cardiovascular applications of adrenergic agonists Shock due to septicemia or myocardial infarction is usually made worse by vasoconstrictors chronic orthostatic hypotension due to inadequate sympathetic tone: midodrine (a 1) C. Cardiac application – paroxysmal atrial tachycardia (a 1) – complete heart block or cardiac arrest (b 1) : Epi or Iso  Respiratory applications of adrenergic agonists Especially selective b 2 agonists are drug of choice in treatment of acute asthmatic bronchoconstriction (Epi and Iso also) Emphysema, bronchitis Anaphylaxis Epinephrine is drug of choice for immediate treatment of anaphylactic shock (a 1 ,b 1, b 2) sometimes supplemented with antihistamines and corticosteroids  Ophthalmic applications of adrenergic agonists Alpha agonists, especially phenylephrine, often used topically to – produce mydriasis, eg, ophthalmologic exam – reduce the conjunctival itching and congestion caused by irritation or allergy – do not cause cycloplegia (paralysis of accommodation) Epi and prodrug, dipivefrin, sometimes used for glaucoma. Phenylephrine also  Genitourinary applications of adrenergic agonists Beta2 agonists (ritodrine, terbutaline) used in premature labor, but cardiac stimulant effect may be hazardous to both mother and fetus.  CNS applications of adrenergic agonists Amphetamine: widely used and abused Legitimate indication: narcolepsy, attention deficit hyperkinetic syndrome, weight reduction Metabolism effect (b 2, b 3 ) and anorexant effect Misuse or abuse for deferring sleep, for mood-elevating, euphoria-producing action  Additional uses Central a 2 agonists – hypertension – menopausal hot flushes – narcotics, alcohol, smoking withdrawal  ADRs of Sympathomimetics Catecholamines – little CNS toxicity – high dose: excessive vasoconstriction, cardiac arrhythmias, MI, pulmonary edema or hemorrhage, tissue necrosis. Other sympathomimetics Amphetamine – mild to severe CNS toxicity depending on dosage – small dose: nervousness, anorexia, insomnia  ADRs of Sympathomimetics amphetamine – higher dose: anxiety, aggressiveness, paranoid, convulsion Peripherally acting agents: predictable toxicity - a 1 agonists: hypertension, bradycardia (reflex) – b 1 agonists: palpitation, sinus tachycardia, serious arrhythmias – b 2 agonists: skeletal muscle tremor  ADRs of Sympathomimetics No drug are perfectly selective; at high dose, selectivity will decrease. Cocaine: - special importance: drug of abuse - cardiac arrhythmias or infarction and convulsions  Drug interactions Tyramine --MAO inhibitors l tyramine not a drug, found in many foods l tyramine is rapidly metabolized by MAO. l MAO inhibitors increase the stores of catecholamines in vesicles. l Tyramine is a releaser of catecholamines l may occur hypertensive crisis due to massive levels of NE Thank you for your attention