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  • *Cardiovascular-Renal Drugs11Antihypertensive Agents

  • *11 Antihypertensive Agentsblood pressureBP=CO PVRCardiac output.COPeripheral vascular resistance.PVR200028

  • *3083~126 mmHg6093~150 mmHg7595~170 mmHg

  • *prevalence/incidence/

  • *2005500,0001000100=100/500000=0.0002=1000/500000=0.002mortality0/00/ 1000

  • *Hypertension and regulation of B.Pdiagnosis2004 Joint National Committee

    2004Classification of blood pressureJNC VIISystolic BP, mm HgDiastolic BP, mm HgNormal100Adapted form JNC Vll

  • *

  • *B.P.=C.O.P.R.

  • *

    ACETONEKETONEKETONE BODY2000 mg/l

  • *Etiology of hypertensionPrimaryessential hypertension90baroreceptor reflex-renin-angiotensin-aldosterone systen

  • *Secondary hypertension10Renal hypertension renal parenchymal2-3% polycystic kidneychronic pyelonephritisacute,chronic glomerulonephritisRenal vascular 1-2%stenosis of renal arteryrenal infarctionrenal arteriosclerosisdiabetic nephropathy

  • *Endocrine hypertensionPrimary aldosteronism 0.3%mineralocorticoid aldosteroneCushing disease
  • *Decapetide 10Octopetide 8Heptapetide 71. 2. CA3. Na+ retention4. PR5.

  • *Agents that inhibit the rennin-angiotensin system and points at which they act. CE=converting enzymes: Aase = aspartylaminopeptidase

  • *

  • * 3th mechanism

  • *

  • *

  • *Therapy(1)90%(..)(2),25%(3),50%(1),(2)(3),(4)..

  • *,

  • *Antihypertensive agents.Diureticsblood volume.Sympathoplegic agentsPVR, (C.O. ).Direct vasodilators capacitance.Agents that block production or action of angiotensin angiotensionPVRblood volumeV.MAO Inh.tyrosine hydroxylase

  • *

  • *.DiureticsNadepletionextracellular fluid volume C.O.High salt intakeLow rate of glomerular filtration(anephric pt)

  • *(1) Thiazide DiureticsChlorothiazide (Diuril)250mg p.o2Hydrochlorothiazide(Esidrex)25mg p.o2Trichlormethiazide(Naqua)2-8mgp.o210-15mmHg, (distal convoluted tubule DCT)NaClCa++()

  • *potassium depletion (hypokalemia)CNS symptons: (drowsiness, irritability, confusion, dizziness, coma)Muscle weakness, cardia arrhythmia, respiratory arrest, () G-I disturbance, paralytic ileus ()digitalis glycosides thiazidesthiaziderenin, aldosterone, hypokalemiachronic arrhythmia, acute myocardial infarction, left ventricular dysfunction

  • *magnesium depletion (Hypomagnesemia:, seizure) impair glucose tolerance, serum lipiduric acid goutAzotemia () BUN

  • *Azotemia.prerenal azotemiapostrenal azotemiaAzotemia:

  • *Mineralocorticoid antagonist spironolactone (Aldactone) potassium-sparing diureticsandrogen antagonist hirsutism () hyperkalemiaCardiac arrhythmiaMenstrual abnormalities ()Gynecomastia ()gyne: womanmastos: breast

  • *(2) Loop diureticsFurosemide(Lasix)A.primary action(+++)B. nephron(proximal tubules)Na/H exchange, block Na reabsorption (+)natriuresis (High-ceiling diuretics)Na, KCl Loop diureticsreninAB

  • *:(Na, K, Cl loss), hypochloremic alkalosis, ototoxicity (loss of hearing)aminoglycoside(streptomycim,kanamycin)Liver dysfunction, Orthostatic hypotension, Lithium excretion

  • *Drugs that alter sympathetic nervous system function

  • * depress,4(1)impulse(2)neurotransmittersrelease(3)depleting the store of neurotransmitters(4)neurotransmitterseffector cell

  • *(1)carotids sinus()aortic arch()Baroreceptorchemoreceptorsensory(afferent fiber)Brain stemmedulla oblongataadrenergic impulse (impulse vasomator center VMC)(2)Adrenergic impulsebulbospinal tract cordgrey matter (2intermediolateral cell columns)

  • *(3)Efferent fiber spinal cord synapse(paravertebral ganglia)ganglionic synapse neurotransmittersAchAchnicotinic receptor,postganglionic neurcons(4)postganglionic fiberheart(.)neurotransmitternorepinephrineNEnerve varicosity release. receptor: Heart rate(chronotropic) Contractive force(inotropic) Conduction velocity: Blood vessels: constriction()constriction

  • *Cardiac rateforce of contractioncardiac outputAdrenergic fiber implus relaxation(vasodilation) B.P

  • *Centrally acting sympathoplegic drugsbrain stemvasomotor center outflow1.Methyldopa (L-a-methyl-3.4-dihydroxyphenylalanine)196019631977potentguanethidine(more potent)reserpine(milder)Levodopa (dihydroxyphenyphenylalanine)-methyldopaside chain carbonmethylgroup

  • *

  • *P.V.RC.O. () C.OPVRIn the supine position()P.V.R,C.OIn the upright position ()C.O.renal blood flow glomerular filtration rate renal insufficiency pt B.Psympathetic depressantvasodilatorfluid retention, edema formation, plasma volume expansion

  • *Mechanism and site of action(1)L-amino acid decarboxylase(dopa decarboxylase)dopa dopaminesympathetic neuon(2):-methyldopadopa decarboxylase -methyldopaminedopamine -hydroxtlase(DBH) -methylnorepinephrine -methylnorepinephrinesympathetic nerve storage visiclesNEvesicle act as an false transmitter.stimulation-methyl NE NErelease-methyl NEpotentNEnerve stieffect

  • *(3)-methyldopaadrenergic nerveconvert to -methyl NE release-methyl NE release activate CNS - adrenoceptor, outflow, B.P 22-blockerCNS -adrenoceptorsympathetic outflow -methyldopa(4)methyldopa

  • *(5)brainmedulla oblongataNTS (Nucleus of the tractus solitarius)NTSnoradrenergic nerve ending,baroreceptor(receives afferent nerve input from the carotid body and aortic arch baroreceptors)NTSinhibitory neuronvasomotor center-methyldopanoradrenergic nerve,-methyl NE-methyl NENTS, NTSinhibitory impulsevasomotor center decrease sympathetic outflow B.Pcentral sympathetic nervous activity

  • *4-6 hrClinical uses:mild to moderate primary hypertensionplasma volumediureticsrenal blood flowGFR, renal failure

  • *Toxicity:sedation , drowsinesssedationdrowsiness(CA level)dopaminergic depressiondry mouth,nasal congestion,orthoststic hypotension, impotence (orthostasis impotenceguanethidine.guanethidine 35-40%)lactation:prolaction()(dopaminergic mechanism)-methyldopa-induced hepatitis

  • *Preparation:Aldomet250,500mg tabmethyldopate HCl50mg/ml inj

  • *2.Clonidine(2-agonist) clonidine-antagonist(phentolamine)imidazoline

  • *:(1)Heart ratecapacitance vessel relaxationC.O.P.V.R.(2)renal vascular resistancerenal blood flowclonidine2 receptor

  • *mechanism(1)sympathetic activity from brain (2)clonidineelectrical discharge (3)-methyldopasend inhibitory impulse vasomotor center sympathetic outflowdepression of cardiovascular control center(4)clonidine -receptor-methyldopaadrenergic synthetic enzyme convert to -methyl NE ,CNS-adrenoceptor(5)clonidine-receptor stimulation,yohimbine(yohimbine antagonist)

  • *Pharmacokinetics8-12hr, bioavailability 95% (lipid-soluble,brain)Clinical uses:(1)mild to moderate hypertension(2) clondine Na ,water retention, diuretics(3)pt,clonidine (catapres), vasodilator , diuretic(4)clonidineb-blockerexcessive sedation

  • *Toxicity:(1)7% pt(2)50% ptdrowsiness,impotence . Gastric upset()(3)rebound hypertension(excessive sympathetic acticity)(4)Insomnia, restlessness, tremorPreparation:Catapres :Oral: 0.1,0.2,0.3mg tabTransdermal(catapres TTS): patches that release 0.1, 0.2, 0.3mg/24h

  • *.Ganglionic Blocking Agentsautonomic gangliatransmission ganglionblockimpulse postganglionic sympathetic(parasympathetic) nervenumbervascular tone , C.O, B.P

  • *Trimethaphan (Arfonad)1.mechanismAch (the transmitter of the preganglionic autonomic nerves) Achnicotinic receptorspostsynaptic number

  • *2.Clinical uses: severe hypertension3.Toxicity:block:excessive orthostatic hypotension, sexual dysfunction:constipation, urinary retention, glaucoma, blurred vision, drymouthtrimethaphan

  • *4.preparations:Trimethaphan(arfonad) parenteral 50mg/mlneurosurgeryhemorrhagept BPMecamylamine HCl (Inversine)Oral 2.5mg tablet

  • *.Adrenergic neuron-blocking agentsNEstimulation,vascular smooth muscle relax, BP

    1.Guanethidine (Ismelin)(1)vascular tone()()impulseNECO venous return B.P.

  • *(2)Mechanism1.guanethidine uptake adrenergic varicosity(active transport) nerve terminal NE storereleaseblockade NE releaseimpulseBP2.guanethidine accumulationadrenergic varicosityNEstorage vesiclesNE releaseguanethidine i.v.BP, NEguanethidineNEBPreleaseslow, prolong, amphetaminerapid. Brief

  • *guanethidine prevent release of NE from nerve ending when the nerves are stimulatedNEdepletion BP

  • *3. guanethidineadrenal medullaCAmedulla deplete CA, (pheochromocytoma) release CAptcontraindication(3)pharmacokinetics:Half-life 5 (4)usesmoderateseverethiazide85%

  • *(5) Toxicity:15 pt 35-40% orthostatic hypotension, impotence. difficulty in ejaculation () G.I (6) Drug interaction: tricyclic antidepressant (amitriptyline), cocaine block the sympathetic neuronal amine-uptake system block guanethidine uptake (7) :Guanethidine selectively blocking NE release in response to activation of postganglionic adrenergic neurou (bretylium-like) guanethidine B.B.B, reserpine B.B.B(8) Preparation:Guanethidine (Ismelin) oral 10.25mg tablets. 10 mg

  • *2. Reserpine (Drug interfering with NE storage) snake-root, Rauwolfia serpentia Raudixin, Semisynthetic alkaloidsRescinnamide, syrosingopine, reserpine.(1) guanethidine adrenergic function. vascular smooth muscle tonec.o. postural hypotension, guanethidine (2) Mechanism adrenergic nerve terminal NE releace NE neuronal membrane cytosol: recaptured amine( energy-dependent) recaptured amine cytosol adrenergic storage vesicles ,Reserpine uptake process, NE intraneuron cytosolic amine MAO reserpine NE storage catabolism

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