Presentation on theme: "Treatment of Hypertension: 7 classification"— Presentation transcript:
1Treatment of Hypertension: 7 classification CategoriesRisk factorsBPSystolicDiastolicNormal>120<80Prehypertension80-89Stage190-99Stage2>160>100Age above 55 and 65 in Men and Woman respectivelyFamily HistorySmokingDM and DyslipidemiaHypertensionObesityMicroalbuminuria
4Treatment of Hypertension – General principles Stage I:Start with a single most appropriate drug with a low dose. Preferably start with Thiazides. Others like beta-blockers, CCBs, ARBs and ACE inhibitors may also be considered. CCB – in case of elderly and stroke prevention. If required increase the dose moderatelyPartial response or no response – add from another group of drug, but remember it should be a low dose combinationIf not controlled – change to another low dose combinationIn case of side effects lower the dose or substitute with other groupStage 2: Start with 2 drug combination – one should be diuretic
5Treatment of Hypertension – combination therapy In clinical practice a large number of patients require combination therapy – the combination should be rational and from different patterns of haemodynamic effectsSympathetic inhibitors (not beta-blockers) and vasodilators + diureticsDiuretics, CCBs, ACE inhibitors and vasodilators + beta blockers (blocks renin release)Hydralazine and CCBs + beta-blockers (tachycardia countered)ACE inhibitors + diuretics3 (three) Drug combinations: CCB+ACE/ARB+diuretic; CCB+Beta blocker+ diuretic; ACEI/ARB+ beta blocker+diuretic
6Treatment of Hypertension. Never combine:Alpha or beta blocker and clonidine - antagonismNifedepine and diuretic synergismHydralazine with DHP or prazosin – same type of actionDiltiazem and verapamil with beta blocker – bradycardiaMethyldopa and clonidineHypertension and pregnancy:No drug is safe in pregnancyAvoid diuretics, propranolol, ACE inhibitors, Sodium nitroprusside etcSafer drugs: Hydralazine, Methyldopa, cardioselective beta blockers and prazosin
8Complications of Hypertension: End-Organ Damage Hemorrhage,StrokeLVH, CHD, CHFComplications of Hypertension: End-Organ DamageHypertension is an important contributing risk factor for end-organ damage and for the development of cardiovascular and other diseases, including retinopathy, peripheral vascular disease, stroke, coronary heart disease, heart failure, cardiac disease, renal failure, and proteinuria.Blood pressure reduction has been shown to decrease the rate of stroke, myocardial infarction, end-stage renal disease, and proteinuria.Reference:Chobanian AV, Bakris GL, Black HR, et al, for the National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:PeripheralVascularDiseaseRenal Failure,ProteinuriaRetinopathyCHD = coronary heart diseaseCHF = congestive heart failureLVH = left ventricular hypertrophyChobanian AV, et al. JAMA. 2003;289:8
9Conditions favouring the use of some antihypertensive drugs versus other Subclinical organ damage:LVH ACEI, CA, ARBAsymptomatic Atherosclerosis CA, ACEIMicroalbuminuria ACEI, ARBRenal dysfunction ACEI, ARB
10Conditions favouring the use of some antihypertensive drugs versus other Clinical event:Previous stroke any BP lowering agentPrevious MI BB, ACEI, ARBHeart failure diuretics, BB, ACEI,ARB, anti-aldosterone agentsTachyarrhythmias BBPeriph.art.disease CALV dysfunction ACEI
11Conditions favouring the use of some antihypertensive drugs versus other ISH (elderly) diuretics,CAMetabolic syndrome ACEI,ARB,CADiabetes mellitus ACEI, ARBPregnancy CA,methyldopa,BBGlaucoma BB
12Monotherapy versus combination therapy Monotherapy allows to achieve BP target only in a limited number of patientsUse of more than one agent is necessary to achieve target BPInitial therapy: monotherapy or combination of two drugs in low doses with subsequent increase in drug doses or number
13Monotherapy versus combination therapy Monotherapy in mild BP elevation with low or moderate total CV riskTwo drugs at low doses should be preferred as the first step when BP is in grade 2 or 3 or total CV risk is high or very high with mild hypertensionFixed combination of two drugs simplify the treatmentIf BP control is not achieved by two drugs, combination of three or more drugs is required
14Possible combinations of different classes of antihypertensive agents DiureticsAT1-receptor blockersβ-blockersα-blockersCCBsPossible combinations of difference classes of antihypertensive agentsContent pointsACE inhibitor–CCB combinations are among those two-drug combinations that have been found to be effective and well tolerated.1Therefore, ACE inhibitors and CCBs have a clear role in combination antihypertensive therapy.1. European Society of Hypertension – European Society of Cardiology Guidelines Committee European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003; 21: 1011–1053ACE, angiotensin-converting enzymeAT, angiotensinCCB, calcium-channel blockerACE inhibitorsThe preferred combinations in general hypertensive population are represented as thick lines. The frames indicate classes of agents proven to be beneficial in controlled interventional trialsESH – ESC Guidelines Committee. J Hypertens 2007; 25: 1105–1187
15Antihypertensive therapy in special groups Elderly patientsDiabetic patientsPatients with renal dysfunctionPatients with cerebrovascular diseasePatients with coronary heart disease and heart failurePatients with atrial fibrillation
16Beta-adrenergic blockers Non selective: Propranolol (others: nadolol, timolol, pindolol, labetolol)Cardioselective: Metoprolol (others: atenolol, esmolol, betaxolol)All beta-blockers similar antihypertensive effects – irrespective of additional propertiesReduction in CO but no change in BP initially but slowlyAdaptation by resistance vessels to chronically reduced CO – antihypertensive actionOther mechanisms – decreased renin release from kidney (beta-1 mediated)Reduced NA release and central sympathetic outflow reductionNon-selective ones – reduction in g.f.r but not with selective onesDrugs with intrinsic sympathomimetic activity may cause less reduction in HR and CO
17Beta-adrenergic blockers Advantages:No postural hypotensionNo salt and water retentionLow incidence of side effectsLow costOnce a day regimePreferred in young non-obese patients, prevention of sudden cardiac death in post infarction patients and progression of CHFDrawbacks (side effects):Fatigue, lethargy (low CO?) – decreased work capacityLoss of libido – impotenceCognitive defects – forgetfulnessDifficult to stop suddenlyTherefore cardio-selective drugs are preferred now
18Beta-adrenergic blockers Advantages of cardio-selective over non-selective:In asthmaIn diabetes mellitusIn peripheral vascular diseaseCurrent status:JNC 7 recommends - 1st line of antihypertensive along with diuretics and ACEIsPreferred in young non-obese hypertensiveAngina pectoris and post angina patientsPost MI patients – useful in preventing mortalityIn old persons, carvedilol – vasodilatory action can be given
283- K+ sparing diuretics Not effective alone, so used in combination Eg: Spironolactone, Amiloride ,Uniretic ( HCT + Amiloride)SE: ↑ K+, gynecomastia
29Beta Blockers MOA: Block beta receptors ↓ sympathetic drive 1- ↓ H.R. & contractility, ↑ P.R ↓ C.O.2- ↓ Renin release & activity ↓ Ang II↓BPAct as anti HTN within 3-7 days
30Beta Blockers Metabolism: Hydroxylated in liver to water soluble compounds excreted in kidneysPreferred in HTN with angina, SVT, HOCM, Thyrotoxicosis, Pheochromocytoma, Migraine and L.cirrhosis.
31Beta BlockersSE: bradycardia, bronchospasm, cold extremeties, hypoglycemia, insomnia, bad dreamsOverdose: hypotension, bradycardia, bronchospasm, coma ( treated with Atropine, Isoprenaline, glucagon )C.I: HF, Asthma, DM, H.Block, Periph.vascular diseases , Hyperlipidemia
32Beta Blockers Atenolol: less lipid soluble less CNS SE Timolol: lipid soluble more CNS SE.
33Thiazides Mechanism of action: = lower blood pressure by reduction of blood volume and by directvascular effectinhibition of sodium chloride transport in the early segment of the distalconvoluted tubule natriuresis, decrease in preload and cardiacoutput - renal effectslow decrease of total peripheral resistance (raised initially) duringchronic treatment, suggesting an action on resistance vessels -extrarenal effectscompensatory responses to pressor agents including angiotensin II andnoradrenaline are reduced during chronic treatment with thiazidesused with loop diuretic - synergistic effect occurs
34Thiazides Adverse effects: - Idiosyncratic reactions (rashes - may be photosensitiv, purpura)- Increased plasma renin (which limits the magnitude of their effect on BP)- Metabolic and electrolyte changesHyponatremiaHypokalemia(combine with potassium-sparing diuretics)HypomagnesemiaHyperuricemia (most diuretics reduce urate clearance)HyperglycemiaHypercalcemia(thiazides reduce urinary calcium ion clearance precipitate clinically significant hypercalcemia in hypertensive patients withhyperparathyroidism)Hypercholesterolemia (a small in plasma cholesterol concentration)
35LOOP DIURETICS furosemid - useful in hypertensive patients with moderate or severe renalimpairment, or in patients with hypertensive heart failure.- relatively short-acting (diuresis occurs over the 4 hours following adose) used in hypertension if response to thiazides is inadequateMechanism of action:- they inhibit the co-transport of Na+, K+ and Cl-- of Ca2+ and Mg2+ excretion- they have useful pulmonary vasodilating effects (unknown mechanism)
36LOOP DIURETICSToxicity:- hypokalemic metabolic alkalosis (increased excretion of K+)- ototoxicity (dose dependent, reversible)- decrease of Mg2+ plasma concentration (hypomagnesemia)- hyperuricemia (competition with uric acid about tubular secretion)- sulfonamide allergy- risk of dehydration (> 4 L urine/ 24 h)Imporatant drug interaction may occurs if loop diuretic is given with Li+ (thymoprofylactic drug). Decrease of Na+ reabsorption can lead to increase of Li+ reabsorption toxicity.
37b -adrenoreceptor antagonists Mechanism of action:the fall in cardiac output BP- they reduce renin secretionCNS-effects ???additional mechanisms involve baroreceptors or other homeostaticadaptationsPossible mechanisms include:b-adrenoceptors located on sympathetic nerve terminals can promotenoradrenaline release, and this is prevented by b-receptorantagonistslocal generation of angiotensin II within vascular tissues is stimulatedby b2-agonists.
38b-adrenoreceptor antagonists cardio-selective:b1 blockers atenolol, metoprololb1 blockers with ISA acebutolb1 + a1 blockers labetalol, carvedilolcardio non-selective:b1 + b2 blockers metiprolol, propranolol, nadololb1 + b2 blockers with ISA pindolol, bopindololNote: Partial agonist activity (intrinsic sympathomimetic activity – ISA) - may be an advantage in treating patients with asthma because these drugs will cause bronchodilation; they have moderate (lower) effect on lipid metabolism, cause lesservasospasms and negative inotropic effect
39b-adrenoreceptor antagonists Adverse effectsCardiovascular adverse effects, which are extension of the betablockade, include:bradycardiaantrioventricular blockadecongestive heart failure (unstable)asthmatic attacks (in patients with airway disease)premonitory symptoms of hypoglycemia from insulin overdosage(eg, tachycardia, tremor and anxiety, may be marked)CNS adverse effects - sedation, fatigue, and sleep alterations.
40Hypertension & regulation of blood pressure Baroreflexes (mediated by autonomic nerves)Humoral mechanisms(include: RAAS system and local release of hormones from vascular endothelium, such as, NO, endothelin 1)Anatomic sites of blood pressure control
41Hypertension & regulation of blood pressure A. Postural baroreflex: responsible for rapid , moment to moment adjustments in blood pressure.Sense the stretch of the vessel wallsfrom a reclining to an upright posture;reduction of peripheral vacular resistance;Reduction in intravascular volume;-
42Hypertension & regulation of blood pressure B. Renin-Angiotensin-Adolsteron (RAAS)Angiotensin IIRedistribution of renal blood flowThis is responsible for long-term blood pressure control.
44I. Basic pharmacology of antihypertension agents 1. Diuretics: depleting the sodium and reducing blood volume and perhaps by other mechanisms.2. Sympathoplegic agents: reducing peripheral vascular resistance, inhibiting cardic output, increasing venous pooling.3. Direct vasodilators: relaxing vacular smooth muscle, dilaing resistance vessels and/or increasing capacitance.4. Agents that block RAAS: reduce peripheral vacular resistance and blood volume.
451. Diuretics 1) Pharmacological roles (1) Diurectic action: Sodium restriction is very preventive in the control of blood pressure. It is a nontoxic and therapeutic measure.1) Pharmacological roles(1) Diurectic action:In the early stage: reducing blood volume and cardiac output;In the late stage: reduce peripheral vascular resistance (by reducing the Na+; reduce Na+-Ca2+ exchange in vascular smooth muscle cells (Ca2+i , peripheral resistance )(2) Non diurectic action: direct vasodilating, e.g. Indapamide, a non-thiazide sullfonamide diuretic with both diuretic and vasodilator activity; Amiloride inhibits smooth muscle responses to contractile stimuli.
48Diuretics Drugs causing net loss of Na+ and water in urine Mechanism of antihypertensive action:Initially: diuresis – depletion of Na+ and body fluid volume – decrease in cardiac outputSubsequently after weeks, Na+ balance and CO is regained by 95%, but BP remains low!Q: Why? Answer: reduction in total peripheral resistance (TPR) due to deficit of little amount of Na+ and water (Na+ causes vascular stiffness)Similar effect is seen with sodium restriction (low sodium diet)
49Thiazide diuretics – adverse effects Hypokalaemia – muscle pain and fatigueHyperglycemia: Inhibition of insulin release due to K+ depletion (proinsulin to insulin) – precipitation of diabetesHyperlipidemia: rise in total LDL level – risk of strokeHyperurecaemia: inhibition of urate excretionSudden cardiac death – tosades de pointes (hypokalaemia)All the above metabolic side effects – higher doses (50 – 100 mg per day)But, its observed that these adverse effects are minimal with low doses (12.5 to 25 mg) - Average fall in BP is 10 mm of HgInhibition of insulin release due to K+ depletion – ppt of diabetesa type of ventricular tachycardia with a spiral-like appearance ("twisting of the points") and complexes that at first look positive and then negative on an electrocardiogram. It is precipitated by a long Q-T interval, which often is induced by drugs (quinidine, procainamide, or disopyramide) but which may be the result of hypokalemia, hypomagnesemia, or profound bradycardia. The first line of treatment is IV magnesium sulfate, as well as defibrillation if the patient is unstable
50Thiazide diuretics – current status Effects of low dose:No significant hypokalaemiaLow incidence of arrhythmiaLower incidence of hyperglycaemia, hyperlipidemia and hyperuricaemiaReduction in MI incidenceReduction in mortality and morbidityJNC recommendation:JNC recommends low dose of thiazide therapy (12.5 – 25 mg per day) in essential hypertensionPreferably should be used with a potassium sparing diuretic as first choice in elderlyIf therapy fails – another antihypertensive but do not increase the thiazide doseLoop diuretics are to be given when there is severe hypertension with retention of body fluids
51Diuretics K+ sparing diuretics: Modified thiazide: indapamide Thiazide and K sparing diuretics are combined therapeutically – DITIDE (triamterene + benzthiazide) is popular oneModified thiazide: indapamideIndole derivative and long duration of action (18 Hrs) – orally 2.5 mg doseIt is a lipid neutral i.e. does not alter blood lipid concentration, but other adverse effects may remainLoop diuretics:Na+ deficient state is temporary, not maintained round –the-clock and t.p.r not reducedUsed only in complicated cases – CRF, CHF marked fluid retention cases
521. Diuretics Selection of diuretcs Normally used in severe hypertension, in renal insufficiency and in cardiac failure or cirrhosis.Normally used in mild or moderate hypertension with normal renal and cardiac function.Useful to avoid excessive potassium depletion.Nephron, a functional unit of kidneyBe careful increase blood pressure
531. Diuretics2) Clinical application: diuretics alone for mild or moderate essential hypertension. Combine with sympathoplegic and vasodilator drugs to control the tendency toward sodium retention caused by these agents.Dosing considerations (thiazide vs. Furosemide)mg thiazide diuretics are more natriurectic but the same effect of anti-hypertension is the same as 25 – 50 mg thiazide diuretcs.A threshold amount of body sodium depletion may be sufficient for anti-hypertensive efficacy.The blood pressure response to loop diuretics continues to increase at doses many times greater than the usual therapeutic dose.
541. Diuretics Adverse effects of diuretcs Hypokalemia: K+ depletion (except for potassium – sparing diuretcs); hypokalemia may be hazardous in persons taking digitalis, who have chronic arrhythmias, acute myocardial infarction or left ventricular dysfunction.Restriction of dietary Na+ intake will minimize K+ loss.Mg2+ depletion;Impair glucose tolerance, induce hyperglycemia;Increase serum lipid concentrations, induce hyperlipidemia;Hyperuricemia, precipitate gout;
552. Sympathoplegic agents Sedation, mental depression, sleep disturbance, dry mouth, analgesiaMore selective actionInhibition of parasympathetic regulation, profound sympathetic blockadeSimilar like surgical sympathectomyThe antihypertensive effect of these agents used alone may be limited by retention of Na+ by the kidney and expansion of blood volume. So sympathoplegic antihypertensive drugs are most effective when used concomitantly with a diuretc.
57Sympathoplegic agents Adrenoceptor antagonists Receptor blockers: Propranolol(1) Mechanism & Sites of Action: nonselective –block in brain, kidney and heart etc.
58Sympathoplegic agents Adrenooceptor antagonists Receptor blockers: Propranolol(2) Clinical usesA. Hypertension: all kinds of hypertensionmore effective in young patients than elderlyuseful in treating coexisting conditions such as supraventricular tachycardia, previous myocardial infarction, angina pectoris, glaucoma and migraine headacheB. Other uses: angina pectoris; arrhythmias
59 Receptor blockers: Propranolol Sympathoplegic agentsAdrenooceptor antagonists Receptor blockers: Propranolol(3) Side effectsA. Bradycardia or cardiac conduction disease (over inhibition);B. Asthma (Why);C. Peripheral vascular insufficiencyD. DiabetesE. Withdrawal syndrome after prolonged regular use: nervousness, tachycardia, increased intensity of angina (even myocardial infarction), or increase of blood pressure;
60 and 1 Receptor blockers Drugs that alter sympathetic nervous system functionAdrenooceptor antagonists and 1 Receptor blockersBlocker effect:>1>>2Labetalol 拉贝洛尔Carvedilol 卡维地洛Amosulalol 氨磺洛尔
61 and 1 Receptor blockers Sympathoplegic agentsAdrenooceptor antagonists and 1 Receptor blockersLabetalol is formulated as a racemic mixture of four isomers(S,S)- and (R,S)-isomers—are inactive(S,R)- is a potent - blocker (1)(R,R)- is a potent - blocker (3)Blood pressure is lowered by reduction of systemic vascular resistance without significant alteration in heart rate or cardiac output.Treating the hypertension of pheochromocytoma and hypertensive emergencies.
62Sympathoplegic agents Adrenooceptor antagonistsOther Receptor blockers:CarvedilolS(–) isomer is a nonselective -receptor blockerBoth S(–) and R(+) isomers have approximately equal -receptor blocking potency.NebivololD –Nebivolol 1 blockerL-Nevivolol causes vasoliating not mediated by blocked.Has active metabolites
63 and 1 Receptor blockers Drugs that alter sympathetic nervous system functionAdrenooceptor antagonists and 1 Receptor blockersMild decrease of blood pressureMinimal changes in cardiac output and heart rateUsed for all kinds of hypertension, including hypertensive emergencyLess adverse effects
64Drugs that alter sympathetic nervous system function Adrenooceptor antagonists