ADRENERGIC DRUGSPharmacological DepartmentMedical School UNPADIke Husen

ADRENERGIC DRUGS Affect receptors which are stimulated by NE (noradrenalin) & E (adrenalin)Adrenergic drugs

Agonist Antagonists (sympathomimetic agents) (sympatholytic agents)

SYNTHESIS OF NE Tyr

DOPA

Dopamine VESICLES: Dopamine

NE uptakereleaseBINDING TO RECEPTORIntracellular responseREMOVAL OF NEMETABOLISMInactive metaboliteInhibitor: cocaine & imipramine Tyr12 Inhibitor:1= reserpine2= guanethidine bretylium Tirosin hidroksilasedopamine--hydroxylase

Adrenoreceptor 1 2 1 2Vasoconst. Periph. resist. BPMydriasis Closure internal sphincter bladderInhibition of NE releaseInhibition of insulin release(+) Inotropic (+) Chronotropic lipolysisVasodilatationSlightly periph. Resist.BronchodilatationGlycogenolysis release of glucagonRelaxed uterine smooth musc.

DIRECT- ACTING ADRENERGIC AGONISTS* : Cathecolamine

DrugReceptorSpecificityDrugReceptorSpecificityEpinephrine*1, 21, 2Phenylephrine1Norepinephrine*1, 21 Methoxamine1Isoproterenol*1, 2Clonidine2Dopamine*Dopaminergic1, 2Metaproterenol 2> 1

Dobutamine*1 TurbetalineRitodrinAlbuterol2

EPINEPHRINE and Low doses : - predominant on vasc. syst. High doses : - predominant on vasc. syst.

EPINEPHRINE ACTION; cvs:1 : (+) inotropic & chronotropic CO

O2 consumption

: constrict arteriole (skin, mucous memb. viscera)

2 : vasodilator (skeletal m.) Syst. BP - Diast. BP slightly

EPINEPHRINE ACTIONRespiratory (2 ) : bronchodilator; dyspnea (-) and tidal vol.

Hyperglycemia: glycogenolysis and release glucagon (2 ), release insulin ()

Lipolysis: 1 (3 ?)

BiotransformationsCOMT (catechol-O-methyl transferase) MAO

Metabolites in urine : metanephrine and vanillylmandelic acid

THERAPEUTIC USESBronchospasm: Acute asthma attack and anaphylactic shock

Glaucoma : topical IO pressure in open angle glaucoma

In anesthetics : local DOA

PHARMACOKINETICSRapid OOABrief DOAAdministration : Sc.InhalationTopical

ADVERSE EFFECTSCNS disturbances: anxiety, fear, tension, headache, tremor

Hemorrhage:cerebral hemorrhages

Cardiac arrhytmias

Pulmonary edema

NOREPINEPHRINE and 1 ; is the most affected in therapeutic doses

CVS: syst. (1)- diast. BP: (1)Bradycardia (baroreflex: )

Therapeutic uses: (levarterenol)Shock (RBF: )

ISOPROTERENOL (1 and 2 )CVS: CO: - syst. BP: slightly (1)Diast. BP: (2 ) Mean arterial BP: Pulmo: Bronchodilator (2 )Th/ uses: AV block / cardiac arrestAsthmaAdverse reactions = epinephrine

DOPAMINE1 and dopamine receptor ; high doses :

Cardiac stimulant (1 ) Th/ uses: CHF

RBF: (dopaminergic rec. dilates renal & visceral arterioles ) DOC : shock

AR: Overdose: sympathetic stimulationNausea, hypertension, arrhythmias: short-lived (=DOA) rapidly metabolized to homovanillic acid

ADRENERGIC ANTAGONISTS (SYMPATHOLYTICS)

Antagonists = blockers bind to adrenoceptors BUT do not trigger the usual receptor- mediated intracellular effects. preventing their activation by endogenous catecholamines

Classification-BLOCKERSPhenoxybenzamine PhentolaminePrazosinTerazosinDoxazosin-BLOCKERSPropanololTimololAcebutololMetoprololPindololLabetalolCarvedilolDRUGS AFFECTING NEUROTRANSMITTER UPTAKE/RELEASE

-ADRENERGIC BLOCKING AGENTS

Main effects: BP (normally main effect of -adrenoceptor :control of the vasculature)

Reduces sympathetic tone of blood vessels: decreases peripheral vasc. resistance BP reflex

Adverse effect: Orthostatic hypotension Tachycardia Fatigue Sexual disturbances

PHENTOLAMINECompetitive -blockers (4hrs)

Th/ uses: FrostbiteSex. Dysfunction (male)

AR: TachycardiaPostural hypotensionGI stimulation

PRAZOSIN, TERAZOSIN and DOXAZOSIN (1 blockers)

Action: CVS: peripheral resist. and BP Th/ uses: hypertensionAR: Syncope (first pass effect), may be minimized by adjusting the first dose to 1/3 or of normal doseNasal congestion, GI hypermotility, fluid retention, orthostatic hypotension

- ADRENERGIC BLOCKING AGENTSCompetitive antagonists:Non cardioselectiveCardioselective (1)ISA (intrinsic sympathomimetic activity)ISA (+) or ISA (-)Orthostatic hypotension : does not occur (the - adrenoceptor is not blocked)

Adverse effect of - ADRENERGIC BLOCKING AGENTS Hypotension Bradycardia FatigueDrowsiness

PROPRANOLOL (Non cardiosel. -blocker)Actions:CVS: (>< 2, but hypotension triggers a reflex vasoconst. blood flow to the fingers and toeBronchoconstrictionIncreased Na+ retentionDisturbance in glucose metabolism

Therapeutic usesHypertension ( CO)Glaucoma: IOP ( the secretion of aqueous H.)Migraine: reducing migraine episodesHyperthyroidsm (protecting cardiac arrhythmias)Angina pectorisMyocardial infarction

Adverse effect

BronchoconstrictionArrhythmias (rapid withdrawal)Sexual impairment (pathogen. ???)Disturbances in glucose metabolismOther : TAG level

TimololNonselective -blocker the secretion of aqueous HumorTherapeutics uses:Topical: glaucomaSystemic: Hypertension

Acebutolol, atenolol,and metoprolol (Cardioselective in low drugs doses)

Action:Decrease BPIncrease exercise tolerance in anginaTherapeutic use in hypertension, espec.:Diabetic hypertensive patients who are receiving insulin or oral hypoglycemic agents

Agonist, antagonist and partial agonist of adrenoceptor Agonist Receptor Cell. effect Antagonist

blockedPartial Agonist Cell. effect Epin./NE/agonists agents antagonists agents partial agonists agents

Pindolol and acebutolol (Positive ISA (intrinsic sympathomimetic activity/partial agonists)

Actions:CVS: Diminish effect on cardiac rate and CO (the effect < epinephrine)

Decreased metabolic effects: the disturbances of lipid and carbohydrate metabolism < -blockers effects

Therapeutic uses in hypertension:Hypertension with moderate bradycardiaHypertension patients whom taking hypoglycemic agentsHypertensive athletes

Labetalol and Carvedilol (-blocker with concurrent 1 blockers)Actions:Periph. Vasodilator (!!) and BPNot alter serum lipid or blood glucose levelsTherapeutic uses:Elderly hypertensive patient in whom increased peripheral vasc. Resistance is undesirable Adverse effects:Orthostatic hypotension and Dizziness

Drugs Affecting Neurotransmitter Release or UptakeI. Reserpine Inhibits transport NE into vesicle: Impair sympathetic functionActions: Decrease BP Increase parasympathetic activity, esp. :GIT

Therapeutic Uses:Hypertension Adverse reactions:Insomnia, nighttime hallucinations, depression