RATIONAL COMBINATION THERAPIESFOR MANAGING HYPERTENSION

A MOHAMED KASIM

DEFINITION: Hypertension may be defined as that level blood pressure at which then institution of therapy reduces blood pressure related morbidity and mortality.Current clinical criteria for defining generally based on the average of two or more seated blood pressure readings during each of tow or more outpatient visits.In children and adolescents it is defined as systolic/ diastolic pressure consistently more than 95th percentile for age, sex and height.

• JNC 7 (reclassified) classification of blood pressure:Classification SBP DBPNormal less than 120 less than 80Prehypertension 120-139 80-89Stage-1 HTN 140-159 90-99Stage-2 HTN more than 160 more than 100

CAUSES :1- Primary or idiopathic cause2- Secondary cause: Renal- Parenchymal disesase, Renal cysts, Renal tumors, obstructive uropathy Renovascular- Arteriosclerotic Fibromuscular dysplasia Adrenal- Primary aldosteronism, Cushings, Pheochromocytoma, Aortic coarctation Obstructive sleep apnea Pre-eclampsia/Eclampsia

Neurogenic – Psychogenis, diencephalic syndrome, polyneuritis, Acute increased ICT, spinal cord sectionEndocrine causes- Hypothyroidism, Hyperthyroidism, Hypercalcemia, AcromegalyDrug Induced- High dose oestrogens, Adrenal Steroids, cyclosporine, decongestants, Tricyclic antidepressants, NSAIDS, cocaine

Classifications of Anti- Hypertensives:1- ACE inhibitors2- Angiotensin(AT1 receptor) Blockers3- Calcium channel blockers4- Diuretics5- Beta blockers6- Alpha blockers7- Beta + alpha blockers8- Central sympatholytics9- Vasdodilators

INTODUCTION:

1- The goal of antihypertensive therapy is to abolish the risk associated with blood pressure elevation without affecting their quality of life.

2-Drug selection is based on the efficacy of lowering the blood pressure and also in reducing the cardiovascular end points.

•COMBINATION THERAPY A PRACTICAL NECESSITY:BP is primarily determined by 3 factors renal sodium excretion and resultant plasma and total body volume, cardiac performance and vascular tone.Both sympathetic nervous system and RAAS are intimately involved in adjusting these parameters.In addition genetic makeup, diet and environmental factors influence BP in individual patients.In recent meta analysis of law and colleagues of 354 randomized double blind trials the mean reduction is 9.1/5.5 mmhg. But there was a little difference between a diuretic, beta blocker, ACE inhibitor and ARB or CCBIn ALLHAT only 26% achieved BP control with single drug and in HOT trial 33% achieved control with monotherapy, 45% required 2 drugs 22% needed three or more drugs.

In LIFE study trial in which goal was to reduce BP less than 140/90 was pursued in LVH patients and in patients with BP more than 175/80.More than 90 % required combination therapies.The aggregate available data from all these studies suggests that 75% of patients required combination therapies to achieve contemporary BP targets.

• COMBINATION THERAPY: THEORETIC CONSIDERATIONS.

1- Efficacy 2- Tolerability3- Adherence4- Cost

PATIENT SELECTION: INITIAL THERAPY:1) Should treatment be started with monotherapy or a combination?2) If two drugs are initiated, should they be administered as single

entities or an single pill combinations.By beginning with combination therapy, counter regulatory responses will be reduced, thus there will be a increase in percentage of responders.In VALUE trial , post analysis indicated that subjects who reached target BP within 6months of entering the protocol demonstrated substantially better outcomes throughout the 5yr duration of the study.

Current guidelines suggest that two be used for initial therapy if there is a 20/10mmhg elevation in BP above goal.In meta-analysis of weir the magnitude of in terms of time-specific achievement of BP was greater in Stage-1 compared to Stage-2 subgroup.Among patients in Stage 1 72% achieved JNC-7 target with valsartan monotherapy , whereas 92% were achieved in those who received initial combination therapy – Valsartan with HCTZ.

•PREFERRED COMBINATIONS:

1- ACE inhibitor/Diuretics2- ARB/Diuretics3- ACE inhibitor/CCB4- ARB/CCB

•ACCEPTED COMBINATIONS:1- Beta-Blockers/Diuretics2- CCB(DHP)/Beta- Blockers3- CCB/Diuretics4- Renin inhibitor/Diuretics5- Renin inhibitor/ARB6- Thiazide diuretics/K sparing diuretics

•LESS EFFECTIVE1- ACE inhibitor/ARB2- ACE inhibitor/Beta- blockers3- ARB/Beta- blockers4- CCB(DHP)/Beta- blockers5- Centrally acting agents/Beta- Blockers

•SUMMARY:1- Use combination therapy to routine achieve BP targets.2- Use only preferred or acceptable two- drug combinations.3- Initiate combination therapy routinely in patients who require 20/10mmhg BP reduction to achieve target BP.4- Initiate combination therapy in Stage-1 patients especially when the second agent will improve the side- effect profile of initial therapy.

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