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Treatment of Hypertension: 7 classification

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1 Treatment of Hypertension: 7 classification
Categories Risk factors BP Systolic Diastolic Normal >120 <80 Prehypertension 80-89 Stage1 90-99 Stage2 >160 >100 Age above 55 and 65 in Men and Woman respectively Family History Smoking DM and Dyslipidemia Hypertension Obesity Microalbuminuria

2 Treatment of Hypertension –
7 compelling Indications: Heart failure Coronary artery disease H/o MI H/o stroke Diabetes Chronic Renal failure

3 Treatment of Hypertension

4 Treatment 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 moderately Partial response or no response – add from another group of drug, but remember it should be a low dose combination If not controlled – change to another low dose combination In case of side effects lower the dose or substitute with other group Stage 2: Start with 2 drug combination – one should be diuretic

5 Treatment 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 effects Sympathetic inhibitors (not beta-blockers) and vasodilators + diuretics Diuretics, CCBs, ACE inhibitors and vasodilators + beta blockers (blocks renin release) Hydralazine and CCBs + beta-blockers (tachycardia countered) ACE inhibitors + diuretics 3 (three) Drug combinations: CCB+ACE/ARB+diuretic; CCB+Beta blocker+ diuretic; ACEI/ARB+ beta blocker+diuretic

6 Treatment of Hypertension.
Never combine: Alpha or beta blocker and clonidine - antagonism Nifedepine and diuretic synergism Hydralazine with DHP or prazosin – same type of action Diltiazem and verapamil with beta blocker – bradycardia Methyldopa and clonidine Hypertension and pregnancy: No drug is safe in pregnancy Avoid diuretics, propranolol, ACE inhibitors, Sodium nitroprusside etc Safer drugs: Hydralazine, Methyldopa, cardioselective beta blockers and prazosin

7 Treatment guidelines (ESH/ESC 2007)
Average risk Low added risk Moderate added risk High added risk Very high added risk ESH – ESC Guidelines Committee. J Hypertens 2007; 25: 1105–1187

8 Complications of Hypertension: End-Organ Damage
Hemorrhage, Stroke LVH, CHD, CHF Complications of Hypertension: End-Organ Damage Hypertension 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: Peripheral Vascular Disease Renal Failure, Proteinuria Retinopathy CHD = coronary heart disease CHF = congestive heart failure LVH = left ventricular hypertrophy Chobanian AV, et al. JAMA. 2003;289: 8

9 Conditions favouring the use of some antihypertensive drugs versus other
Subclinical organ damage: LVH ACEI, CA, ARB Asymptomatic Atherosclerosis CA, ACEI Microalbuminuria ACEI, ARB Renal dysfunction ACEI, ARB

10 Conditions favouring the use of some antihypertensive drugs versus other
Clinical event: Previous stroke any BP lowering agent Previous MI BB, ACEI, ARB Heart failure diuretics, BB, ACEI, ARB, anti-aldosterone agents Tachyarrhythmias BB CA LV dysfunction ACEI

11 Conditions favouring the use of some antihypertensive drugs versus other
ISH (elderly) diuretics,CA Metabolic syndrome ACEI,ARB,CA Diabetes mellitus ACEI, ARB Pregnancy CA,methyldopa,BB Glaucoma BB

12 Monotherapy versus combination therapy
Monotherapy allows to achieve BP target only in a limited number of patients Use of more than one agent is necessary to achieve target BP Initial therapy: monotherapy or combination of two drugs in low doses with subsequent increase in drug doses or number

13 Monotherapy versus combination therapy
Monotherapy in mild BP elevation with low or moderate total CV risk Two 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 hypertension Fixed combination of two drugs simplify the treatment If BP control is not achieved by two drugs, combination of three or more drugs is required

14 Possible combinations of different classes of antihypertensive agents
Diuretics AT1-receptor blockers β-blockers α-blockers CCBs Possible combinations of difference classes of antihypertensive agents Content points ACE inhibitor–CCB combinations are among those two-drug combinations that have been found to be effective and well tolerated.1 Therefore, 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: 1011–1053 ACE, angiotensin-converting enzyme AT, angiotensin CCB, calcium-channel blocker ACE inhibitors The preferred combinations in general hypertensive population are represented as thick lines. The frames indicate classes of agents proven to be beneficial in controlled interventional trials ESH – ESC Guidelines Committee. J Hypertens 2007; 25: 1105–1187

15 Antihypertensive therapy in special groups
Elderly patients Diabetic patients Patients with renal dysfunction Patients with cerebrovascular disease Patients with coronary heart disease and heart failure Patients with atrial fibrillation

16 Beta-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 properties Reduction in CO but no change in BP initially but slowly Adaptation by resistance vessels to chronically reduced CO – antihypertensive action Other mechanisms – decreased renin release from kidney (beta-1 mediated) Reduced NA release and central sympathetic outflow reduction Non-selective ones – reduction in g.f.r but not with selective ones Drugs with intrinsic sympathomimetic activity may cause less reduction in HR and CO  

17 Beta-adrenergic blockers
Advantages: No postural hypotension No salt and water retention Low incidence of side effects Low cost Once a day regime Preferred in young non-obese patients, prevention of sudden cardiac death in post infarction patients and progression of CHF Drawbacks (side effects): Fatigue, lethargy (low CO?) – decreased work capacity Loss of libido – impotence Cognitive defects – forgetfulness Difficult to stop suddenly Therefore cardio-selective drugs are preferred now

18 Beta-adrenergic blockers
Advantages of cardio-selective over non-selective: In asthma In diabetes mellitus In peripheral vascular disease Current status: JNC 7 recommends - 1st line of antihypertensive along with diuretics and ACEIs Preferred in young non-obese hypertensive Angina pectoris and post angina patients Post MI patients – useful in preventing mortality In old persons, carvedilol – vasodilatory action can be given

19 The End

20 Adrenergic Receptors Review of ANS
Sympathetic Nervous System Alpha 1 = vasoconstriction Alpha 2 = feedback/vasodilation Beta 1 = increases heart rate Beta 2 = bronchodilation

21 Beta Adrenergic Blocking Agents
Known as Beta-blockers Axn: Inhibit cardiac response to sympathetic nerve stimulation by blocking Beta receptors Decreases heart rate and C.O. Decreases blood pressure

22 Beta Adrenergic Blocking Agents
Examples – “olol” names Beta 1: Atenolol Beta 1 and 2: Propranolol

23 Nursing Implications Can not be abruptly discontinued
Check baseline b.p. Check hx. of resp. condition-aggravates bronchoconstriction

24 Side effects Bradycardia Bronchospasm, wheezing Diabetic: hypoglycemia
Heart failure: edema,dyspnea,rhales

25 DIURETICS MOA: 1- ↑ renal excretion of Na & water
↓ plasma volume ↓ C.O. 2- ↓ peripheral resistance ( desensitize smooth muscles to action of catecholamines )

26 1-Thiazide Sulfonamide molecule Prolonged action Flat curve response
Potentiates action of other anti HTN Eg: Hydrochlorothiazide ( Ezidrex ) , Bendrofluazide SE: hypo K+ , hypo Na+, hyperuricemia, hyperglycemia, lipid profile disturb.

27 2- Loop Diuretics Steep curve response Restricted to CCF & CRF
Eg: Frusemide SE: ↓ K+ , ↓ Na+ , hypotension, ototoxic in v.high doses

28 3- K+ sparing diuretics Not effective alone, so used in combination
Eg: Spironolactone, Amiloride , Uniretic ( HCT + Amiloride) SE: ↑ K+, gynecomastia

29 Beta Blockers MOA: Block beta receptors ↓ sympathetic drive
1- ↓ H.R. & contractility, ↑ P.R ↓ C.O. 2- ↓ Renin release & activity ↓ Ang II ↓BP Act as anti HTN within 3-7 days

30 Beta Blockers Metabolism:
Hydroxylated in liver to water soluble compounds excreted in kidneys Preferred in HTN with angina, SVT, HOCM, Thyrotoxicosis, Pheochromocytoma, Migraine and L.cirrhosis.

31 Beta Blockers SE: bradycardia, bronchospasm, cold extremeties, hypoglycemia, insomnia, bad dreams Overdose: hypotension, bradycardia, bronchospasm, coma ( treated with Atropine, Isoprenaline, glucagon ) C.I: HF, Asthma, DM, H.Block, Periph.vascular diseases , Hyperlipidemia

32 Beta Blockers Atenolol: less lipid soluble less CNS SE
Timolol: lipid soluble more CNS SE.

33 Thiazides Mechanism of action:
= lower blood pressure by reduction of blood volume and by direct vascular effect inhibition of sodium chloride transport in the early segment of the distal convoluted tubule  natriuresis, decrease in preload and cardiac output - renal effect slow decrease of total peripheral resistance (raised initially) during chronic treatment, suggesting an action on resistance vessels - extrarenal effects compensatory responses to pressor agents including angiotensin II and noradrenaline are reduced during chronic treatment with thiazides used with loop diuretic - synergistic effect occurs

34 Thiazides Adverse effects:
- Idiosyncratic reactions (rashes - may be photosensitiv, purpura) - Increased plasma renin (which limits the magnitude of their effect on BP) - Metabolic and electrolyte changes Hyponatremia Hypokalemia (combine with potassium-sparing diuretics) Hypomagnesemia Hyperuricemia (most diuretics reduce urate clearance) Hyperglycemia Hypercalcemia (thiazides reduce urinary calcium ion clearance  precipitate clinically significant hypercalcemia in hypertensive patients with hyperparathyroidism) Hypercholesterolemia (a small  in plasma cholesterol concentration)

35 LOOP DIURETICS furosemid
- useful in hypertensive patients with moderate or severe renal impairment, or in patients with hypertensive heart failure. - relatively short-acting (diuresis occurs over the 4 hours following a dose)  used in hypertension if response to thiazides is inadequate Mechanism 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)

36 LOOP DIURETICS Toxicity: - 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.

37 b -adrenoreceptor antagonists
Mechanism of action: the fall in cardiac output   BP - they reduce renin secretion CNS-effects ??? additional mechanisms involve baroreceptors or other homeostatic adaptations Possible mechanisms include: b-adrenoceptors located on sympathetic nerve terminals can promote noradrenaline release, and this is prevented by b-receptor antagonists local generation of angiotensin II within vascular tissues is stimulated by b2-agonists.

38 b-adrenoreceptor antagonists
cardio-selective: b1 blockers atenolol, metoprolol b1 blockers with ISA acebutol b1 + a1 blockers labetalol, carvedilol cardio non-selective: b1 + b2 blockers metiprolol, propranolol, nadolol b1 + b2 blockers with ISA pindolol, bopindolol Note: 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 lesser vasospasms and negative inotropic effect

39 b-adrenoreceptor antagonists
Adverse effects Cardiovascular adverse effects, which are extension of the beta blockade, include: bradycardia antrioventricular blockade congestive 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.

40 Hypertension & 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

41 Hypertension & regulation of blood pressure
A. Postural baroreflex: responsible for rapid , moment to moment adjustments in blood pressure. Sense the stretch of the vessel walls from a reclining to an upright posture; reduction of peripheral vacular resistance; Reduction in intravascular volume; -

42 Hypertension & regulation of blood pressure
B. Renin-Angiotensin-Adolsteron (RAAS) Angiotensin II Redistribution of renal blood flow This is responsible for long-term blood pressure control.

43 Basic pharmacology of antihypertension drugs

44 I. 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.

45 1. 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.


47 Diuretics commonly used

48 Diuretics 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 output Subsequently 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)

49 Thiazide diuretics – adverse effects
Hypokalaemia – muscle pain and fatigue Hyperglycemia: Inhibition of insulin release due to K+ depletion (proinsulin to insulin) – precipitation of diabetes Hyperlipidemia: rise in total LDL level – risk of stroke Hyperurecaemia: inhibition of urate excretion Sudden 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 Hg Inhibition of insulin release due to K+ depletion – ppt of diabetes a 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

50 Thiazide diuretics – current status
Effects of low dose: No significant hypokalaemia Low incidence of arrhythmia Lower incidence of hyperglycaemia, hyperlipidemia and hyperuricaemia Reduction in MI incidence Reduction in mortality and morbidity JNC recommendation: JNC recommends low dose of thiazide therapy (12.5 – 25 mg per day) in essential hypertension Preferably should be used with a potassium sparing diuretic as first choice in elderly If therapy fails – another antihypertensive but do not increase the thiazide dose Loop diuretics are to be given when there is severe hypertension with retention of body fluids

51 Diuretics K+ sparing diuretics: Modified thiazide: indapamide
Thiazide and K sparing diuretics are combined therapeutically – DITIDE (triamterene + benzthiazide) is popular one Modified thiazide: indapamide Indole derivative and long duration of action (18 Hrs) – orally 2.5 mg dose It is a lipid neutral i.e. does not alter blood lipid concentration, but other adverse effects may remain Loop diuretics: Na+ deficient state is temporary, not maintained round –the-clock and t.p.r not reduced Used only in complicated cases – CRF, CHF marked fluid retention cases

52 1. 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 kidney Be careful increase blood pressure

53 1. Diuretics 2) 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.

54 1. 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;

55 2. Sympathoplegic agents
Sedation, mental depression, sleep disturbance, dry mouth, analgesia More selective action Inhibition of parasympathetic regulation, profound sympathetic blockade Similar like surgical sympathectomy The 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.

56 2. Sympathoplegic agents
Centrally acting sympathoplegic drugs Ganglion blocking agents Adrenergic neuron-blocking agents Adrenoceptor antagonists

57 Sympathoplegic agents
Adrenoceptor antagonists  Receptor blockers: Propranolol (1) Mechanism & Sites of Action: nonselective –block in brain, kidney and heart etc.

58 Sympathoplegic agents
Adrenooceptor antagonists  Receptor blockers: Propranolol (2) Clinical uses A. Hypertension: all kinds of hypertension more effective in young patients than elderly useful in treating coexisting conditions such as supraventricular tachycardia, previous myocardial infarction, angina pectoris, glaucoma and migraine headache B. Other uses: angina pectoris; arrhythmias

59  Receptor blockers: Propranolol
Sympathoplegic agents Adrenooceptor antagonists  Receptor blockers: Propranolol (3) Side effects A. Bradycardia or cardiac conduction disease (over inhibition); B. Asthma (Why); C. Peripheral vascular insufficiency D. Diabetes E. 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 function Adrenooceptor antagonists  and 1 Receptor blockers Blocker effect: >1>>2 Labetalol 拉贝洛尔 Carvedilol 卡维地洛 Amosulalol 氨磺洛尔

61  and 1 Receptor blockers
Sympathoplegic agents Adrenooceptor antagonists  and 1 Receptor blockers Labetalol 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.

62 Sympathoplegic agents
Adrenooceptor antagonists Other  Receptor blockers: Carvedilol S(–) isomer is a nonselective -receptor blocker Both S(–) and R(+) isomers have approximately equal -receptor blocking potency. Nebivolol D –Nebivolol 1 blocker L-Nevivolol causes vasoliating not mediated by  blocked. Has active metabolites

63  and 1 Receptor blockers
Drugs that alter sympathetic nervous system function Adrenooceptor antagonists  and 1 Receptor blockers Mild decrease of blood pressure Minimal changes in cardiac output and heart rate Used for all kinds of hypertension, including hypertensive emergency Less adverse effects

64 Drugs that alter sympathetic nervous system function
Adrenooceptor antagonists

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