1. Drug Therapy of HTN Dr. Shahrzad Shahidi Nephrologist Associate Professor of Isfahan University of Medical Sciences 2.

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Drug Therapy of HTN

Dr. Shahrzad Shahidi

Nephrologist

Associate Professor of Isfahan University of Medical Sciences

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The AlmightyPardons & Grants me heaven

Even if I don't know a single letter about

Crutz Feld Jacob’s Disease

Tsutsugamushi Fever

Crigler-Najjar Syndrome

South American equine encephalitis and

Many and much more rarer topics

BUT …….

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The Almighty

Will drag me to hell and will not pardon

My ignorance of even the minute details of HTN

My indifference to apply the current knowledge

My negligence in screening for HTN, TOD

My despondency about preventing TOD

My inadequacy in maintaining my patients

as normo-tensive as possible –

(This is applicable to all common diseases)

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"The Goal is to Get to Goal!”

HTN-PLUS-

Proteinuria > 1 gr/day

< 140/90 mmHg < 130/80 mmHg

Measurements & goals should be provided to the patient verbally and in writing at each office visit

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HTN

The Truth is

It is only a marker of the bigger problem

HTN is a multi-organ systemic disease

What we record as B.P.

The Problem is

HTN is asymptomatic in 85% of cases

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For adequate control of B.P.

Do you think we can control most of thepatients of hypertension with –

One drugTwo drugsThree drugsCan’t control

In most of the patients of hypertension Two drugs are required for adequate control

More so if the initial BP is 20/10 above the goal

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It is not just ↓B.P.

Paradigm Shift in HTN Therapy

1. Alter the modifiable risk factors

2. Keep the SBP < 140 & DBP < 90

3. Prevent or halt or reduce TOD – • LVH, CHD, CHF, CVA, CKD, PVD & Retino.

4. Prevent or control DM (as HTN + DM is hazardous)

5. Prevent or control Dyslipidemia (Endothelial Dysf.)

6. Reduce morbidity & mortality

7. Improve QUALY – Quality Adjusted Life Years

TODAY we must strive to

The correct Approach to HTN

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Step1

•Are all patients screened for HTN?

•Are all hypertensives correctly identified?

Step 2

•Are they evaluated for co-morbidities/TOD?

•Are they assessed for CHD risk factors?

Step 3

•Are the correct drug combinations prescribed?

•What is the compliance for medicines & f/u?

Step 4

•Is the goal B.P. achieved & maintained?

•Are there any complications/ side effects?

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Lifestyle Modification

1.LSM is the sheet anchor in the management

of HTN.

2.This surely reduces the number of drugs

used & their dosage in controlling HTN.

3.Any drug treatment has value only when

coupled with LSM.

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Treatment Overview

• Pharmacologic treatment• Initial therapy• Combination therapy

• What to do when a patient is still not at goal?

• Follow-up & monitoring

• Cases

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Algorithm for Treatment of Hypertension

Not at Goal BP

Initial Drug Choices

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB)

With Compelling Indications

Lifestyle Modifications

Stage 2 HTN 2-drug combination for most

(usually thiazide-type diuretic &ACEI, or ARB, or BB, or CCB)

Stage 1 HTN Thiazide-type diuretics for most.

May consider ACEI, ARB, BB, CCB, or combination.

Without Compelling Indications

JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314

Not at Goal BP

Optimize dosages or add additional drugs until goal BP is achieved.

Consider consultation with hypertension specialist.

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What to choose first?

• Initial antihypertensive therapy without compelling indications• JNC 6: Diuretic or a beta-blocker• JNC 7: Thiazide-type diuretics

• Most outcome trials base antihypertensive therapy on thiazides

JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314

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Low Dose Combinations

• BP lowering effects from different drug categories were additive

6.7

13.3

0

10

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SBP Reduction (mmHg)

1 Drug 2 Drug 3 Drugs

Law MR et al. BMJ. 2003; 326:1427

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Low Dose Combinations

• Adverse effects in all drug categories, except ACEI, were dose related

• Prevalence of adverse effects in combination was less than additive

Conclusion:

Utilization of low dose combination therapy can effectively reduce blood pressure while limiting the incidence of side effects

Law MR et al. BMJ. 2003; 326:1427

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Compelling Indications for Individual Drug Classes

Compelling Indication Initial Therapy Options

Heart failure THIAZ, BB, ACEI, ARB, ARA

Post MI BB, ACEI

High CAD risk THIAZ, BB, ACEI, CCB

DM ACEI, ARB, CCB,THIAZ, BB

CKD ACEI, ARB

Recurrent stroke prevention THIAZ, ACEI

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When a Patient is Still Not at Goal?

• Optimize dosages or add additional drugs until goal BP is achieved

• What do you do when you are using several effective medications?– Consider causes of resistant HTN– Assure drug therapy is rational– “Tricks of the trade”

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Identifiable Causes of HTN

Sleep apnea Drug-induced or related causes CKD Primary aldosteronism Renovascular disease Chronic steroid therapy & Cushing’s syndrome Pheochromocytoma Coarctation of the aorta Thyroid or parathyroid disease

JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314

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Causes of Resistant HTN

Improper BP measurement Excess sodium intake Inadequate diuretic therapy Medication

• Inadequate doses• Drug actions and interactions:

NSAIDs, illicit drugs, sympathomimetics, OCP• OTC drugs & herbal supplements

Excess alcohol intake Identifiable causes of HTN

JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314

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Drug-Induced HTN: Prescription Medications

• Steroids• Estrogens• NSAIDS• Phenylpropanolamine

s• Cyclosporine/

tacrolimus• Erythropoietin• Sibutramine• Methylphenidate• Ergotamine

• Ketamine• Desflurane• Carbamazepine• Bromocryptine• Metoclopramide• Antidepressants

– Venlafaxine• Buspirone• Clonidine

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COX-2 Inhibitors & NSAIDs• Inhibition of cyclooxygenase, inhibits

prostaglandin synthesis that normally maintains afferent arteriole vasodilatation

• Afferent vasoconstriction decreases renal perfusion → increased BP– Increasing salt & water retention– Increasing renin release

• COX-1 is thought to be primary enzyme responsible for renal vasodilatory prostaglandins

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COX-2 Inhibitors & NSAIDs

• Case reports of severe increases in BP exists in patients after one dose or more typically after 4 weeks for regular usage

• Consider scheduled acetaminophen as an alternative to NSAIDs in patients with difficult to manage HTN

Drugs Aging. 2004; 21:479-84; JAMA. 2001; 286:954-59

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Drug-Induced HTN: Street Drugs & Herbal Products

• Cocaine• Ma huang “herbal ecstasy”• Nicotine• Anabolic steroids• Narcotic withdrawal• Methylphenidate• Phencyclidine• Ketamine• Ergot-containing herbal products• St John’s wort

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Substances Associated with HTN

• Food Substances– Sodium Chloride– Ethanol– Licorice– Tyramine-containing

foods (with MAOI)

• Chemicals– Lead– Mercury– Thallium & other

heavy metals– Lithium salts

Persistence with hypertensive therapy

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26Osterberg, L. et al. N Engl J Med 2005

Adherence to Medication According to Frequency of Doses

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Pharmacologic Sites of Action

ThiazidesLoopsAldosterone Ant.Nitrates

ACEIARB

Beta BlockersDiltiazemVerapamil

Via Central Mechanism:Clonidine

Dihydropyridine CCBsHydralazineMinoxidilAlpha1 Blockers

ACEIARB

HeartArteries

Veins

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Chinese Menu Approach

ThiazidesLoopsAldosterone Ant.Nitrates

ACEIARB

Beta BlockersDiltiazemVerapamil

Via Central Mechanism:Clonidine

DihydropyridinesHydralazineMinoxidilAlpha1 BlockersACEIARB

HeartArteries

Veins

Choose one agent from each category

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OK Now what?

2/3 of patients with HTN will need at least 2 medicines for BP control

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HTN – Why Combinations ?

If goal BP is not achieved by a single drug in full dose

Then adding another agent will help achieve the goal BP

Two agents sometimes nullify each others side effects

Fixed dose combinations will reduce the no. of tablets

Once daily formulations are good for compliance

Sustained release or LA formulations for 24 h BP control

If three drugs can’t achieve goal BP – Resistant HT

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Some Irrational Combinations

B blockers + Beta1 stimulants Rebound HT, Paradoxical BP ↑

Beta blockers + Vepapamil Extreme bradycardia, HB, CHF

Thiazide + Furesemide Potential volume ↓ and K ↓

CCB + Thiazide No RCTs to support the additive

Prazocin + Beta blocker They nullify the effects of each other

Verapa / Dilzem + Nefide No rationale (cardiac actions contridic)

Beta blocker + ACEI Not for HT alone, Good for CHF, MI, IHD

Sub clinical doses of 2 drugs Try one drug in good dosage, then add

2 drugs of same class No rationale (like Enalapril + Ramipril)

(Atenelol + Metoprolol, Nefidepine + Amlo)

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Resistant Hypertension

Resistant HT Usually Stage 2 HTN

May present in young individuals

May have secondary causes Reasons Not taking medication (liers)

Improper BP measurement

Excessive Na intake, Inadequate diuretic Rx

Full doses of drugs not employed

Drug interactions – NSAIDs, SMA, OCP, OTC

Herbal remedies, Excessive alcohol use Rationale Identify the above & correct

Secondary causes to be searched for

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Follow-up and Monitoring

Patients should return for follow-up and adjustment of medications every 1-2 months until the BP goal is reached

After BP at goal and stable, follow-up visits at 3- to 6-month intervals More frequent visits for stage 2 HTN or with

complicating comorbid conditions Continue to encourage self BP monitoring

Serum K & Cr monitored 1–2 times per year

JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314

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Summary• Lifestyle modifications are important for the

prevention of HTN• The goal is to get to goal:

– Initial therapy with a thiazide is indicated for most

– Consider compelling indications– Initiate low dose combination therapy if BP

>20/10 mmHg above goal• Consider the physiologic site of action of

agents when choosing combination therapy

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Pearls

• For resistant HTN – sit down and take a good history – How much water, coffee, milk, juice, tea, ice

– anything liquid do you drink daily.– Food preferences & salt intake– Drugs/Alcohol– Compliance

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Cases

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Case 1: Diagnosis

AB is a 56 yo female with no significant PMH. Her BMI is 26 kg/m2 and she has a family history positive for Type 2 DM. Her BP measured on 2 consecutive clinic visits is 132/84. What is AB’s BP classification?

1. Normal2. Prehypertensive3. Stage 1 Hypertension4. Stage 2 Hypertension

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Case 1: Therapy

What therapy should be initiated for AB?1. Enalapril 5 mg PO daily

2. Hydrochlorothiazide 25 mg PO daily

3. No therapy is indicated

4. Lifestyle modifications including weight loss & DASH eating plan should be encouraged

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Case 1: Goal of Therapy

What is the goal of lifestyle modification in AB?

1. Goal BP < 140/90, the goal is to get to goal

2. Goal BP < 130/80, the goal is to get to goal

3. Improve patients quality of life

4. Prevent onset of hypertension

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Case 1: 5 years later

AB, now 59, returns to clinic with marginal success at lifestyle changes. Her BP has repeatedly measured around 146/92. What is AB’s BP classification?

1. Normal

2. Prehypertensive

3. Stage 1 Hypertension

4. Stage 2 Hypertension

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Case 1: 5 years later

AB, now 59, returns to clinic with marginal success at lifestyle changes. Her BP has repeatedly measured around 146/92. What should be done?

1. Enalapril 5 mg PO daily2. Hydrochlorothiazide 25 mg PO daily3. No therapy is indicated4. Reinforce lifestyle modifications

including weight loss and the DASH eating plan.

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Case 2: Goal of Therapy

CD is a 50 yo black male with diet controlled type 2 diabetes. Consecutive BP measurements during recent clinic visits are 162/98 and 158/96. He is diagnosed with Stage 2 Hypertension. What is the goal of therapy for CD?

1. Goal BP <140/90

2. Goal BP <130/80

3. Slow the progression of diabetic renal disease by reducing BP to <125/80

4. Improve patients quality of life

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Case 2: Therapy

What therapy should be initiated for CD?1. A 6 month trial of lifestyle changes

should be initiated immediately

2. Hydrochlorothiazide 25 mg PO daily

3. Enalapril 10 mg PO daily

4. Enalapril / Hydrochlorothiazide 5/12.5 mg PO daily

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Case 2: 5 years laterCD reaches goal BP of <130/80 after titrating antihypertensive regimen to enalapril/ hydrocholorthiazide 10/25 mg PO QD. At a subsequent follow up visit you learn CD was hospitalized 2 weeks ago for “chest pain”. Reading the discharge summary you note he had ACS for which he was taken to the CATH lab and was found to have 90% occlusion of his LAD which was stented. In clinic his current regimen includes:

– Aspirin 81 mg PO daily– Clopidigrel 75 mg PO daily – Enalapril/ hydrochlorothiazide 10/25 mg PO daily

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Learning is a cyclical process