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    adrenergic drugs adrenergic drugs Presentation Transcript

    • 1ADRENERGIC DRUGSADRENERGIC DRUGS
    • 2Basic plan of the mammalian autonomicBasic plan of the mammalian autonomicnervous systemnervous system
    • 3Synthesis, action and fate ofSynthesis, action and fate ofnorepinephrinenorepinephrine TyrosineTyrosine is transported into the axoplasmis transported into the axoplasm(A) and is converted to(A) and is converted to DOPADOPA and then toand then todopaminedopamine (DA). DA is transported into the(DA). DA is transported into thevesicles of the varicosity, where thevesicles of the varicosity, where thesynthesis and the storage ofsynthesis and the storage ofnorepinephrinenorepinephrine (NE) take place (C).(NE) take place (C). An action potential causes an influx of CaAn action potential causes an influx of Ca2+2+into the nerve terminal (not shown) withinto the nerve terminal (not shown) withsubsequent exocytosis of NE (D).subsequent exocytosis of NE (D). The NE activatesThe NE activates αα-- andand ββ-adrenergic-adrenergicreceptorsreceptors in the membrane of thein the membrane of thepostsynaptic cell (E). NE that penetratespostsynaptic cell (E). NE that penetratesinto these cells (into these cells (uptake 2uptake 2 ) probably is) probably israpidly inactivated byrapidly inactivated by catechol-O-catechol-O-methyltransferasemethyltransferase (COMT)(COMT) totonormetanephrine (NMN). The mostnormetanephrine (NMN). The mostimportant mechanism for termination of theimportant mechanism for termination of theaction of NE in the junctional space isaction of NE in the junctional space isactive reuptake (active reuptake (80%80%) into the nerve) into the nerve((uptake 1uptake 1 ) and the storage vesicles (F).) and the storage vesicles (F).
    • 4Byosynthesis of catecholaminesByosynthesis of catecholamines
    • 5Types of adrenergic receptorsTypes of adrenergic receptorsReceptor Typical locationα1Postsynaptic effector cells, especially smoothmusclesα2,Presynaptic adrenergic nerve terminals,platelets, lipocytes, smooth muscleβ1Postsynaptic effector cells, especially heart;lypocytes, brain, juxtaglomerular cells of thekidneyβ2Presynaptic noradrenergic nerve terminals,Postsynaptic effector cells, especially smoothmuscle, cardiac muscleβ3Postsynaptic effector cells, especially lypocytesα-adreoreceptor’s subtypes:α1A, α1B, α1D and α2A, α2B, α2C
    • 6G proteinG protein--coupled receptor – molecularcoupled receptor – molecularmodelmodelNE↓β-AR+↓α2-AR+↓α1-AR+↓Gs-protein+↓Gi- protein-↓Gq- protein+↓Adenylyl cyclase↓Adenylylcyclase↓PhospholypaseC↓↑cAMP ↓ cAMP↓↑ IP3 ↑ DAGProtein kynases
    • Interaction between epinephrine and theβ2-adrenoceptor
    • 8Characteristics ofCharacteristics of adrenoreceptorsadrenoreceptors## Tissue and organ Receptor Effect11 Skin, kidney vessels α1,α2,constrict22 Vessels of skeletal muscles,liver, and coronary vesselsβ2dilation33 Veins α1Аconstriction44 Heart β1increase of rateand force ofcontraction55 Bronchi α1β2constrictiondilation66 Iris (radial musscle) α1contract ⇒midriasis77 GI- smooth musscle- sphinctersα1,α2,β2α1relaxationcontraction
    • 9## Tissue and organ Receptor Effect88 Uterus- myometrium- sphinctersβ2α1relaxationcontraction99 Bladder sphincter α1Аcontraction1010 Juxtaglomerular cells of thekidneyβ1β2increase of renninsecretion1111 Splin capsule α1contract1212 Pancreatic islets α2decrease of insulinsecretion1313 Platelets α2aggregation1414 Liver α1,β2glycogenolysis1515 Fat β3lipolysisCharacteristics ofCharacteristics of adrenoreceptorsadrenoreceptors
    • Effect of adrenoreceptors stimulation The stimulation of certain postsynapticadrenoreceptors is associated with effectsthat are typical for their activation The stimulation of α-adrenorecetrors leadsto an increase of the effectors function(except for the intestine) The stimulation of β-adrenorecetrors usuallyleads to a decrease in the innervated organfunction (except for the heart)
    • 11Classification of adrenergic drugsClassification of adrenergic drugsADRENORECEPTOR STIMULANTSDirect acting(receptor agonists)Indirect acting(sympathomimetics)1. α,β- adrenomimics- epinephrine (α1,α2,β1,β2)- norepinephrine (α1,α2,β1)2. α- adrenomimics- methoxamine (α1,α2)- phenylephrine (α1)- clonidine (α2)- sanorin (α2)3. β- adrenomimics- isoprenaline (β1,β2)- dobutamine (β1)- salbutamol, terbutaline,- tyramine- amphetamine- ephedrine
    • 12Classification of adrenergic drugsClassification of adrenergic drugsADRENORECEPTOR ANTAGONISTSDirect acting(receptor antagonists)Indirect acting(Sympatholytics)1. α-adrenoblockers- phentolamine,phenoxybenzamine (α1,α2)- prazosin (α1)- tamsulosin (α1A)- yohimbine (α2)2. β- adrenoblockers- propranolol (β1,β2)- metoprolol, atenolol, (β1)3. α,β- adrenoblockers- labetalol (α1,β1,β2)- reserpine- guanethidine (octadine)
    • 13Pharmacologic action of epinephrinePharmacologic action of epinephrineβ1β2vesselsα1vagus1. is due to β1 AR activation(cause ventricular contraction)2. is due to vagal discharge3. is due to α1 AR stimulation(cause vasoconstriction)4. is due to β2 (vasodilator)-receptors activationEffects on the heart produced by epinephrine include:Slight initial increase in heart rate (β1-receptors)Increased stroke volumeIncreased cardiac outputA propensity toward arrhythmiasEffects on smooth muscle include:Bronchiolar smooth muscle relaxes (β2).Gastrointestinal smooth muscle relaxes (α2- and β-receptor stimulation)Sphincter contraction (α- stimulation),Metabolic effects of epinephrine include:Hyperglycemia via liver and muscle glycogenolysisInhibition of insulin secretion (α1)An increase in free fatty acids
    • 14Clinical application of epinephrineClinical application of epinephrine It’s used only parenterally (S.C., I.M., rarely I.V.) andIt’s used only parenterally (S.C., I.M., rarely I.V.) andlocal I.V. effect lasts forlocal I.V. effect lasts for ≈≈5` whereas S.C. – up to 30`5` whereas S.C. – up to 30` Clinical usageClinical usage severe bronchospasm, anaphylaxis (primary treatment forsevere bronchospasm, anaphylaxis (primary treatment foranaphylactic shock)anaphylactic shock) severe hypotensionsevere hypotension cardiogenic shockcardiogenic shock AV block and cardiac arrestAV block and cardiac arrest nasal decongestantnasal decongestant ophthalmic vasoconstrictor and mydriaticophthalmic vasoconstrictor and mydriatic chronic open-angle glaucomachronic open-angle glaucoma to prolong the duration of anesthesia in conjunction withto prolong the duration of anesthesia in conjunction withlocal anestheticlocal anesthetic Unwanted effectsUnwanted effects anxiety, headacheanxiety, headache can precipitate angina, myocardial infarction (can precipitate angina, myocardial infarction ( ↑↑ cardiac work)cardiac work) arrhythmiasarrhythmias
    • 15Clinical application ofClinical application ofnorepinephrinenorepinephrine Clinical usageClinical usage severe hypotensionsevere hypotension septic shockseptic shock Unwanted effectsUnwanted effects can precipitate angina, myocardialcan precipitate angina, myocardialinfarction (infarction (↑↑ cardiac work)cardiac work) arrhythmiasarrhythmias If extravasates, can cause tissueIf extravasates, can cause tissuenecrosisnecrosis
    • 16Clinical application ofClinical application ofsympathomimeticssympathomimetics Ephedrine is used:Ephedrine is used: In the treatment of bronchialIn the treatment of bronchialasthmaasthma As a nasal decongestantAs a nasal decongestant As a pressor agent in spinalAs a pressor agent in spinalanesthesiaanesthesia As a mydriaticAs a mydriatic Adverse effectsAdverse effects These are similar to the adverseThese are similar to the adverseeffects seen with epinephrine.effects seen with epinephrine. In addition, CNS effects mayIn addition, CNS effects mayoccur.occur.
    • 17αα11 -stimulating drugs-stimulating drugs Phenylephrine (mesatone)Phenylephrine (mesatone) ((αα11 )) severe hypotensionsevere hypotension nasal decongestantnasal decongestant to prolong the duration of anesthesia in conjunctionto prolong the duration of anesthesia in conjunctionwith local anestheticwith local anesthetic open-angle glaucomaopen-angle glaucoma Naphazoline (naphtizine)Naphazoline (naphtizine) ,, xylometazolinexylometazoline ((αα22 )) nasal decongestantnasal decongestant oral cavity surgeryoral cavity surgery
    • 18ββ11 -stimulating bronchodilators-stimulating bronchodilators Dobutamine is usedDobutamine is used to improve myocardial function in congestive heartto improve myocardial function in congestive heartfailure (it causes minimal changes in heartfailure (it causes minimal changes in heart rate andrate andsystolic pressure).systolic pressure). Adverse effectsAdverse effects Dobutamine increases atrioventricular conduction andDobutamine increases atrioventricular conduction andmust, therefore, be used with caution in atrialmust, therefore, be used with caution in atrialfibrillation.fibrillation. Other adverse effects are similar to those of otherOther adverse effects are similar to those of othercatecholamines.catecholamines.
    • 19ββ22 -stimulating bronchodilators-stimulating bronchodilators such as salbutamol, terbutaline,such as salbutamol, terbutaline,fenoterol, salmeterol, albuterolfenoterol, salmeterol, albuterol are used therapeutically for theare used therapeutically for thetreatment of bronchial asthmatreatment of bronchial asthmaor bronchospasmor bronchospasm they are chiefly used as aerosolthey are chiefly used as aerosolinhalantsinhalants
    • 20Clinical application of antiadrenergicClinical application of antiadrenergicagentsagents αα-ADRENOBLOCKERS-ADRENOBLOCKERS Phentolamine (Phentolamine (αα11 ,, αα22 )) has been used to control acute hypertensive episodeshas been used to control acute hypertensive episodescaused by use of sympathomimetics.caused by use of sympathomimetics. Tolazoline (Tolazoline ( αα11 ,, αα22 )) can be used in the treatment of neonates withcan be used in the treatment of neonates withpersistent pulmonary hypertension, despite use ofpersistent pulmonary hypertension, despite use ofoxygen therapy and mechanical ventilation.oxygen therapy and mechanical ventilation. has been used experimentally to relieve vasospasmhas been used experimentally to relieve vasospasmand in the treatment of Raynauds phenomenon.and in the treatment of Raynauds phenomenon.
    • 21Clinical application of antiadrenergicClinical application of antiadrenergicagentsagents αα-ADRENOBLOCKERS-ADRENOBLOCKERS Prazosin (Minipress) (Prazosin (Minipress) ( αα11 )) HypertensionHypertension PheochromocytomaPheochromocytoma Benign prostatic hyperplasiaBenign prostatic hyperplasia Treatment of Raynoud’s phenomenonTreatment of Raynoud’s phenomenon(vasospasm(vasospasm→→digital ischemia)digital ischemia) Terazosin (Hytrin) and Doxazosin (Cardura) (Terazosin (Hytrin) and Doxazosin (Cardura) ( αα11 )) Benign prostatic hyperplasiaBenign prostatic hyperplasia Tamsulosin (Omnik, Flomax) (Tamsulosin (Omnik, Flomax) ( αα1A1A )) Benign prostatic hyperplasiaBenign prostatic hyperplasia
    • 22Clinical application of antiadrenergicClinical application of antiadrenergicagentsagents ββ-ADRENOBLOCKERS-ADRENOBLOCKERS Propranolol (Inderal, Anaprilin) (Propranolol (Inderal, Anaprilin) ( ββ11 ,, ββ22 )) ischemic heart diseaseischemic heart disease hypertensionhypertension Aortic dissectionAortic dissection arrhythmiasarrhythmias portal hypertensionportal hypertension migrane preventionmigrane prevention Side effectsSide effects sinus bradicardiasinus bradicardia AV blockAV block hypotensionhypotension fatique, depressionfatique, depression impotence,impotence, ↓↓ libidolibido may precipitate bronchospasmmay precipitate bronchospasm
    • 23Clinical application of antiadrenergicClinical application of antiadrenergicagentsagents ββ-ADRENOBLOCKERS-ADRENOBLOCKERS Metoprolol (Lopressor) (Metoprolol (Lopressor) ( ββ11 )) Ischemic heart diseaseIschemic heart disease HypertensionHypertension Aortic dissectionAortic dissection ArrhythmiasArrhythmias Hypertrophic cardiomyopathyHypertrophic cardiomyopathy Side effectsSide effects are similar to those of propranololare similar to those of propranolol
    • Drugs affecting NE synthesis and releaseDrugs affecting NE synthesis and release
    • 25Clinical application of antiadrenergicClinical application of antiadrenergicagentsagents Drugs affecting NE synthesis and releaseDrugs affecting NE synthesis and release Reserpine (a rauwolfia alkaloid)Reserpine (a rauwolfia alkaloid) It acts via catecholamine depletion. It inhibits theIt acts via catecholamine depletion. It inhibits theuptake of norepinephrine into vesicles, anduptake of norepinephrine into vesicles, andintraneuronal degradation of norepinephrine by MAOintraneuronal degradation of norepinephrine by MAOthen occurs. This action takes place both centrally andthen occurs. This action takes place both centrally andperipherally.peripherally. Therapeutic use of reserpine is in:Therapeutic use of reserpine is in: the treatment of hypertensionthe treatment of hypertension Adverse effects include:Adverse effects include: SedationSedation Psychic depression that may result in suicidePsychic depression that may result in suicide Abdominal cramps and diarrheaAbdominal cramps and diarrhea Gastrointestinal ulcerationGastrointestinal ulceration Possible increased incidence of breast carcinomaPossible increased incidence of breast carcinoma
    • 26Clinical application of antiadrenergicClinical application of antiadrenergicagentsagents Guanethidine (Octadine)Guanethidine (Octadine) acts presynaptically. It inhibits the release of NE fromacts presynaptically. It inhibits the release of NE fromperipheral adrenergic neurons.peripheral adrenergic neurons. It displaces norepinephrine from intraneuronal storageIt displaces norepinephrine from intraneuronal storagegranules.granules. Much of the norepinephrine released from theMuch of the norepinephrine released from theadrenergic nerve terminals is deaminated byadrenergic nerve terminals is deaminated byintraneuronal MAO.intraneuronal MAO. Therapeutic useTherapeutic use as a potent, long-acting antihypertensive agentas a potent, long-acting antihypertensive agent Adverse effects include:Adverse effects include: Postural hypotensionPostural hypotension Syncope, especially with strenuous exerciseSyncope, especially with strenuous exercise DiarrheaDiarrhea EdemaEdema Guanethidine is contraindicated in patients takingGuanethidine is contraindicated in patients takingMAO inhibitors.MAO inhibitors.
    • NEXT LECTURENEXT LECTUREThe CNS affecting drugs:The CNS affecting drugs:Introduction, targets for drug’s action.Introduction, targets for drug’s action.Antiepileptics. Drugs for treatment ofAntiepileptics. Drugs for treatment ofParkinson’s disease.Parkinson’s disease.27