Adrenergic Agonists (Sympathomimetics)

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Adrenergic Agonists (Sympathomimetics). Characteristics of Adrenergic Agonists. Most of adrenergic agonists are -phenylethylamine derivatives. Substitution on either the benzene ring or on the ethylamine side chain give a great variety of compounds which can be divided into: Catecholamines - PowerPoint PPT Presentation

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  • Adrenergic Agonists(Sympathomimetics)

  • Characteristics of Adrenergic AgonistsMost of adrenergic agonists are -phenylethylamine derivatives.Substitution on either the benzene ring or on the ethylamine side chain give a great variety of compounds which can be divided into:Catecholamines non-catecholamines

  • CatecholaminesContain 3,4 dihydroxybenzene groupExamples: Epinepheine, Norepinephrine, Isoproterenol & DopamineSubstitiution on the amine nitrogenThey have common characters:Highest potency in activating or -receptorsRapid inactivation by MAO & COMT when given parenterally and inactive orallyPoor penetration of CNS (anxiety, tremor & headache)

  • NoncatecholaminesExample: Phenylepheine, Ephedrine & AmphetamineCharacters:They are poor substrate for COMT & MAO i.e. longer duration of actionIncreased lipid solubility i.e. enter CNS

  • PharmacokineticsCatecholaminesNon-CatecholaminesRapid onsetShorter durationLonger duration & higher bioavailabilityOrally ineffectiveOnly metabolites areExcreted in urine (VMA)Orally effectiveExcreted unchanged in urine by urine acidificationCross BBBMetabolized byMAO & COMTNot metabolizedby MAO & COMTSubstrate for uptake 1

  • Mechanism of action of the Adrenergic agonistsDirect-acting agonists:Epinephrine, Norepinephrine, Isoproterenol, Dopamine, Dobutamine & Phenylephrine -produce their effect by directly stimulating the receptor site.Indirect-acting agonists:Amphetamine & Tyramine- release endogenous norepinephrine which then stimulates the receptor.Mixed-action agonists:Ephedrine & Metaraminoleither directly stimulate the receptor or release endogenous NA.

  • Direct-Acting Agonist: e.g. Phenylephrine (1)Clonidine (2) (sympathomimetic ?)Isoprenaline & Dobutamine (1)Salbutamol & Terbutaline (2)

  • Effects of Adrenergic AgonistsCardiovascular:Heart: HR, contractility CO + O2 consumptionConductivity (atria, AV node & ventricles)Excitability arrhythmia

    BV: VD or VC depending on the selective activity of drug and the anatomic site of vessels e.g. Skin, Splanchnic, Sk.M., renal BV

    BP: Depends on effect on heart, PR & venous return

    The effect of -agonist is different from -agonist

  • CVS Effect of -agonistVasoconstriction leading to rise in PR & BP

    Systolic & diastolic BP (abolished by -blocker)

    Baroreceptor reflex causing vagal supply to the heart leading to bradycardia (blocked by atropine)

    CO is not decreased in proportion to the decrease in HR because the venous return increase the stroke volume

  • CVS Effect of -agonist1 : +ve chronotropic effect ( HR)

    +ve inotropic effect ( force of contraction)

    CO and so systolic BP

    2: Dilation of arterioles of Sk.M. (PR) and so both of systolic & diastolic BPNo vasoconstriction

    Slightly of systolic BP & diastolic BP

  • SummaryAdrenalin ( & ): systolic BP & slight diastolic BP

    NA: ( & 1) systolic & diastolic BP + Reflex bradycardia

    Isoproterenol (-agonist): slight systolic BP & diastolic BP

    Indirect acting sympathomimetics: BP (hypertensive crisis)

    Dopamine: D receptors (renal vasculature VD) + 1 (heart) + 1 at high doses (VC)

  • Effects of I.V. infusion of Norepinephrine and Isoprenaline in Humans isoprenaline decrease DBP because they act on 2Reflex bradycardia Isoprenaline decrease resistance because it acts on only without Blood pressurePeripheral resistance

  • Effects of Adrenergic Agonists

    Smooth Muscles:Bronchi: bronchodilation (2) & bronchial secretion (1)GIT: relax wall & contract sphincter (constipation)Urinary Bladder: relax wall & contract sphincter (urinary retention)Eye: Ciliary muscle (2)Vasoconstriction of conjunctival BV (decongestion) Active mydriasis (1)

  • Effects of adrenergic agonists (cont.)METABOLISMHyperglycemia:Increase liver glycogenolysis (2)Increase glucagon release (2)Decrease insulin release (2)

    Lipolysis:Increase hydrolysis of TG into free fatty acids & glycerol (3)cAMP

  • Central Nervous System (CNS)These drugs produce CNS excitation or alertnessHigher doses produce anxiety, apprehension, restlessness, and tremors.

  • DopamineImmediate precursor of NEOccurs inCNS (act as neurotransmitter)Adrenergic nerve ending Adrenal medulla

    Activates: 1(at high doses)1 (at small doses)D1(occurs in renal vascular bed) D2 (occurs in presynaptic adrenergic neurons)

  • Pharmacological Effects of DopamineCVS:+ve chronotropic & inotropic effectsAt high doses: VC of BV

    Renal & visceral:VD of renal and splanchnic arteriolesEffective in treatment of shock (the drug of choice taken by continuous infusion)

  • Indirect-Acting Adrenergic AgonistsThey are structurally related to NA but lack one or two OH gp of catechol ring (Not metabolized by COMT)

    They are taken by uptake-1 and displace NA from vesicles without exocytosis, so their action do not require calcium ions

    They have CNS effect particularly amphetamine which depends on their ability to release, not only NA, but also 5-HT and dopamine from nerve terminals in the brain

    Tachyphylaxis

  • Indirect-Acting Adrenergic Agonists (cont.)Drug InteractionsReserpine: Abolishing their effectDepleting the stored vesicles

    MAOI: PotentiationThey inhibit the metabolism of released NA & also tyramine

    TCA: Interfere with their effectUptake-1 inhibitor

  • Inhibit storage

  • EphedrinePlant origin, synthetic compoundMixed-action acting drugIt is not a catechol and is a poor substrate for COMT and MAO

    Pharmacological effects: systolic & diastolic BP by VC and cardiac stimulationBronchodilation (slowly and less than EP & isoproterenol), so used as prophylactic in chronic asthma (not acute)Mild CNS stimulation ( alertness, fatigue & prevent sleep)Improve athletic performanceNasal decongestant

  • Clinical Uses of Adrenergic AgonistsCardiovascular: Cardiogenic Shock, Cardiac arrest: agonist: Adrenaline, dobutamine or dopamine Dopamine is clinically more useful in the treatment of shock, in which significant increase in sympathetic activity might compromise renal function and worsens the peripheral circulation Malignant hypertension: 2 agonist: ClonidineHYPOTENSION: 1 agonist phenylephrineHeart block : agonist: isoprenaline Its only used now to reverse the block which is produced by overdoses of blockers

  • N.B. cardiac arrest means : complete cessation of hearts activity.While heart block means : partial or complete inhibition of the spread of conduction of the electrical impulse from the atria to the ventricles Anaphylactic reactions:Ad is the first line of treatment for bronchoconstriction & CV collapse Both and agonist required. We use EP with steroid and antihistamine to cause Bronchodilation, Increase BP

  • Clinical Uses of Adrenergic Agonists (cont.)Respiratory:Asthma and premature labor contractions: For treatment Isoprenaline ( agonist), Salbutamol, Terbutalin & Salmeterol (selective 2 is preferred) For prophylaxis Salmeterol & FormoterolNorepinephrine is NOT used in treatment of asthmaNasal Decongestion: EphedrineHaemostatic in epistaxis: Adrenaline & Ephedrine

    Miscellaneous:Mydriatic: EphedrineGlaucoma: Adrenaline decrease IOP in open angel glaucoma, decrease aqueous humor production by VC of ciliary body BV.Depression: Amphetamineritordine

  • With local anesthetics: Adrenaline & NAThese drugs are used in dentistry because of their vasoconstrictive actions on blood vessels. They are added to local anesthetics because they prolong the action of the local anesthetic, reduce the risk for systemic toxicity, and help to create a dry field.

  • Central Nervous System StimulationThese medications are used for the treatment of attention deficit hyperactivity disorder, narcolepsy, and as diet aids.

  • Adverse EffectsCNS disturbance: anxiety, fear, tension, headache & tremors

    Cerebral hemorrhage

    Tachycardia & Cardiac arrhythmias

    Tachyphylaxis occurs with indirectly acting drugs

  • Contraindications to use of adrenergicsCardiac dysrhythmias, angina pectorisHypertensionHyperthyroidismCerebrovascular diseaseDistal areas with a single blood supply such as fingers, toes, nose and earsRenal impairment use caution

  • Toxicity of adrenergics in critically ill patientsAffects renal perfusionCan induce cardiac dysrhythmiasIncreases myocardial oxygen consumptionMay decrease perfusion of liverTissue necrosis with extravasation

  • PhenylephrineClinical uses:As a mydriatic agent to examine the fundus of the eyeIt acts on 1 receptors in the radial dilator pupillary muscle As a decongestant Used as nasal drops to cause VC in the nasal blood vessels & relief congestion As a vasopressor agent in case of hypotension 1 stimulation causes VC leading to increase BP

  • Clinical use of Amphetamine-like drugsTo suppress appetite In very obese persons Amphetamine can act centrally on the hunger center in the hypothalamus to suppress appetite In narcolepsyNarcolepsy is irresistible attacks of sleep during the day in spite of enough sleep at night Amphetamine stimulates the CNS & makes the patient awake In ADHD Attention Deficit Hyperactivity Disease

  • EphedrineClinical uses:Pressor agent (used to increase BP) Decongestant It is no longer used to treated bronchial asthma. (because its less potent + slow onset of action)

  • Pseudoephedrine:Has similar pharmacological activities to ephedrineIt is not controlled : OTC (over the counter) It is commonly used a