Pharmacology of hypertension
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Pharmacology of Hypertension. Vicki Groo , Pharm.d . Clinical Associate Professor Clinical pharmacist, heart center. [email protected] objectives. Classify hypertension and define treatment goals

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Pharmacology of Hypertension

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Pharmacology of hypertension

Pharmacology of Hypertension

Vicki Groo, Pharm.d.

Clinical Associate Professor

Clinical pharmacist, heart center

[email protected]


Objectives

objectives

  • Classify hypertension and define treatment goals

  • Be able to describe the pharmacology of oral antihypertensives with considerations in drug choice and compelling indications

  • Be able to describe the pharmacology of intravenous antihypertensives used in the treatment of hypertensive emergency


Classification

CLASSIFICATION

**Adults (18 yo)

**Avg of 2 readings, 2 mins apart, on 2 occasions

Secondary HTN only accounts for 5-10% of population

JAMA 2003;289:2560-2572


Epidemiology

epidemiology

  • 31% of US population with HTN

  • 30% of US population with pre-HTN

  • Present in:

    • 69% of patients who present with 1st MI

    • 77% of patients who present with 1st stroke

    • 74% of patients with heart failure

  • Only 47% have BP under control

  • http://www.cdc.gov/bloodpressure/facts.htm


National health nutrition examination survey

National Health & Nutrition Examination Survey

2007-2008

81%

73%

50%


Treatment goals jnc 7

TREATMENT GOALS JNC-7

  • REDUCE MORBIDITY AND MORTALITY

  • Measurable goal:

    • Prehypertension: <120/80

    • HTN w/ diabetes or renal disease: <130/80

    • Others: <140/90

  • Minimize/ control other CV risk factors

  • Reduce/ minimize adverse drug effects

JAMA 2003;289:2560-2572


Aha bp targets 2007

AHA BP targets 2007:

  • For prevention and management of ischemic heart disease:

*Don’t worry about learning these for now. They may change

Circulation 2007:115:2761-88


Algorithm for treatment of hypertension

Without Compelling Indications

With Compelling Indications

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.

Stage 1 Hypertension(SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.

Stage 2 Hypertension(SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB)

Not at Goal Blood Pressure

Optimize dosages or add additional drugs until goal blood pressure is achieved.Consider consultation with hypertension specialist.

Algorithm for Treatment of Hypertension

Lifestyle Modifications

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

JNC VII JAMA 2003;289:2560-2572


Drug therapy considerations

Drug Therapy Considerations

  • Clinical trial data

  • Over 2/3 of patients will require ≥2 drugs

  • Cost/ adverse effects

  • JAMA 2003;289:2560-2572


Pharmacology of hypertension

Limit salt intake

Physical activity

Lifestyle

Modifications

DASH eating

Plan

Lose weight

Limit alcohol intake


Pharmacology of antihypertensives

Pharmacology of Antihypertensives

  • Diuretics:

    • Deplete sodium thereby decreasing blood volume

  • Agents that block production or action of angiotensin

    • Reduce peripheral vascular resistance

    • Potentially ↓ blood volume

  • Sympathoplegic agents:

    • ↓ peripheral vascular resistance

    • Inhibit cardiac function

    • ↑ venous pooling in capacitance vessels

  • Direct vasodilators:

    • Relax vascular smooth muscle, thus dilating resistance vessels


Diuretic moa

Diuretic moa


Diuretic comparison

Diuretic Comparison

P = 0.054 and 0.009 for 24 hr and pm BP respectively

Indapamide

Hypertension 2004;43:4-9,


Diuretic considerations

Diuretic Considerations

Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com


Diuretics

diuretics

  • Compelling Indications:

    • Heart Failure

    • High CAD risk

    • Diabetes

    • Recurrent Stroke Prevention

  • Monitoring

    • Electrolytes after initiation or dose increases

    • Every 6-12 months

    • K sparing, every 3 months if also on RAAS inhibitor

  • Side Effects

    • Increase glucose

    • Increase uric acid— precipitate gout

    • dehydration— orthostatic hypotension

    • Spironolactone— gynecomastia


Mechanism of action

Mechanism of Action


Pharmacology of hypertension

ACE Inhibitors

ARBs

* generic

Combining with thiazide usually more effective than dose increase

  • Direct Renin Inhibitors

  • Aliskiren(Tekturna)

  • 150-300 mg/day

  • As effective as ACE or ARB in HTN

* Dual elimination: liver & kidney

Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com


Ace inhibitors and arb

ACE Inhibitors and ARB

  • Compelling Indications

    • Systolic Heart Failure

    • DM

    • CKD with Proteinuria

    • CAD

  • Monitoring

    • 1-2 weeks after initiation or dose change for K & Cr

    • Every 6 months on stable doses

  • Side Effects

    • Dry Cough  Switch to ARB

    • Angioedema: ARB likely okay, consider severity

    • Hyperkalemia: supplements, diet, worsening renal fxn

  • Combining RAAS inhibitors is generally not recommended

    • No added benefit CV or renal outcomes / Increased toxicity

    • ACE or ARB + aldosterone antagonist is the exception

  • Avoid in Pregnancy


Beta blockers

Beta Blockers

  • MOA: Sympatholytic  ↓ HR and CO / ↓ release of renin

Avoid sudden discontinuation Rebound HTN d/t up regulation of ᵦ receptors

Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com


Beta blockers1

Beta Blockers

  • Compelling Indications

    • CAD

    • Systolic Heart Failure

  • Monitoring

    • ECG if bradycardic- AV block

    • Avoid combining with other AV nodal blocking agents

  • Side Effects

    • Bronchoconstriction—Reactive Airway Disease

      • Choose B1 selective agent and keep at lower doses

    • Metabolic—↓HDL, ↑ LDL and triglycerides

    • Diabetes—↓ insulin sensitivity

      • Mask symptoms of hypoglycemia, delay recovery

      • Carvedilol may have advantage as it ↑’s insulin sensitivity

    • Peripheral Vascular Disease—↑ symptoms, use B1 selective

    • Depression—Choose agent with low lipid solubility

    • Fatigue


Calcium channel blockers

Calcium channel blockers

  • http://www.accesspharmacy.com/content.aspx?aID=6543820

  • http://www.drugdevelopment-technology.com/projects/istaroxime/istaroxime4.html


Ccb considerations

CCB Considerations

^ Do not use short acting agents in treatment of HTN

# Do not combine with beta-blockers: increased risk of bradycardia

Doses provided in DrDiDomenico’s lecture on angina

Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com


Calcium channel blockers1

Calcium channel blockers

  • Compelling Indications

    • High CAD risk

    • Diabetes

  • Monitoring / Side Effects

    • Dihydropyridine (DHP)

      • peripheral edema

      • reflex tachycardia

      • dizziness

    • Non DHP

      • Bradycardia

      • Contra-indicated in heart failure

      • Constipation (especially verapamil)


Vasodilators alpha 1 blockers

Vasodilators: alpha-1 blockers

Doxazosin: start 1 mg daily: max 8 mg daily

Prazosin: start 1 mg bid-tid: max 15 mg/day

Terazosin: start 1 mg qhs: max 20 mg/day

http://cvpharmacology.com/vasodilator/alpha.htm


Vasodilators alpha 1 blockers1

Vasodilators: alpha-1 blockers

  • Compelling Indications: None

  • Second line therapy

    • Also used to treat BPH (benign prostatic hypertrophy)

  • Monitoring:

    • Na and H20 retention with high doses

  • Side Effects:

    • Dizziness —Orthostatic hypotension, first dose syncope

    • Headaches

    • Reflex tachycardia

    • Fatigue


Vasodilators direct

Vasodilators: direct

  • MOA: vascular smooth muscle relaxation

  • Compelling Indications: None

  • Second line therapy: Resistant HTN

  • Hydralazine

    • 10 – 50 mg qid; max 300 mg /day

    • Often dosed bid or tid to improve adherence

    • Rare but serious SE: Lupus erythematosus, blood dyscrasias, peripheral neuritis

    • Headaches, tachycardia, angina, nausea, diarrhea, rash

  • Minoxidil

    • Start 5 mg daily; usual 10-40 mg daily; max 100 mg daily

    • Rare but serious SE: Stevens-Johnson syndrome

    • Hypertrichosis— used topically to promote hair growth

    • Headache, edema, tachycardia, paresthesia


Vasodilators direct1

Vasodilators: direct

Caution: Increased myocardial work

Use in combination with B-blocker / diuretic to combat these effects


Central alpha 2 agonists

Central alpha 2 agonists

  • Bind to and activate α2 receptors in the brain

  • ↓ sympathetic outflow to the heart → CO and HR

  • ↓ sympathetic outflow to vasculature → ↓ vascular tone

http://www.cvpharmacology.com/vasodilator/Central-acting.htm


Central alpha 2 agonists1

Central alpha 2 agonists

  • Compelling Indications: None

  • Second line therapy: Resistant HTN

  • Clonidine

    • Start 0.1 mg bid, titrate up weekly: max 2.4 mg/day

    • Available as a transdermal patch changed weekly

    • Severe rebound HTN if stopped abruptly

    • Side Effects: sedation, depression, bradycardia + many more

  • Methyldopa

    • Start 250-500 mg bid-tid, adjust every 2-3 days, max 3gm/day

    • Can be used in pregnancy

    • Serious but uncommon SE: blood dyscrasias, myocarditis, pancreatitis

    • Side effects: sedation, orthostatic hypotension + many more


Antihypertensives

Antihypertensives:

  • α 1 blocker:

  • Prazosin, Doxazosin, Terazosin

  • Dizziness, edema

  • Centrally Acting:

  • Methlydopa

  • Clonidine

  • Sedation, dry mouth

  • Vascular Smooth Muscle:

  • Hydralazine, Minoxidil

  • CCBs

  • Headache, Dizziness, edema,

  • B-blockers:

  • Atenolol

  • Carvedilol

  • Metoprolol

  • Propranolol

  • Bradycardia

  • Diuretics:

  • Thiazide

  • Loop

  • Other

  • hypokalemia

Renin

ACE

Angiotensinogen

Angiotensin I

Angiotensin II

ARBs

Aliskiren

ACE Inhibitors

Hyperkalemia, dry cough


Algorithm for treatment of hypertension1

Without Compelling Indications

With Compelling Indications

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.

Stage 1 Hypertension(SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.

Stage 2 Hypertension(SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB)

Not at Goal Blood Pressure

Optimize dosages or add additional drugs until goal blood pressure is achieved.Consider consultation with hypertension specialist.

Algorithm for Treatment of Hypertension

Lifestyle Modifications

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

JNC VII JAMA 2003;289:2560-2572


Inadequate bp response with initial agent

Inadequate BP Response with Initial Agent

  • Increase dose

  • Substitute new drug from different class

    • Little to no response to initial drug

    • No compelling indication for the drug

    • Troublesome SE

  • Add a new drug from a different class

    • Initial drug produces some response and is well tolerated

    • Compelling indication for the initial drug

    • Add thiazide if not used initially


Htn special populations

HTN: Special Populations

  • Elderly

    • Isolated systolic HTN common

      • SBP rises and DPB declines with aging

    • Generally salt sensitive

    • Use lower initial drug doses and slower dose titration

    • Avoid 1-blockers, labetalol, central 2 agonists

    • JNC-8 – higher BP goal?

  • AHA Consensus Statement on the Elderly 2011

    • Goal SBP < 140 mm Hg

    • Age > 80, goal SBP < 150 mmHg

    • No evidence for lower BP goals for elderly patients at high risk, eg DM, CAD, CKD.

    • Maintain DBP > 65 mmHg --- coronary perfusion

Circulation 2011;123:2434-2506


Htn elderly guidelines

HTN Elderly Guidelines

  • Canada 2013

    • In the very elderly (age ≥ 80), the target for SBP should be < 150 (grade C)

    • No changes for those age 65-79; ie goal remains at < 140/90

  • Europe 2013

    • In elderly < 80 years old with SBP ≥160 mmHg there is solid evidence to reducing SBP to 150 and 140 mmHg (IA)

    • In fit elderly patients < 80 years old SBP values <140 mmHg may be considered, whereas in the fragile elderly population SBP goals should be adapted to individual tolerability (IIb C)

    • If > 80 years and with initial SBP ≥160 mmHg, it is recommended to reduce SBP to between 150 and 140 mmHg provided they are in good physical and mental conditions (IB)

  • Benefit in treating elderly, ↓ stroke, CV events, heart failure

Canadian Journal of Cardiology 2013;29:528-542


Htn special populations1

HTN: Special Populations

  • African Americans

    • Prevalence, severity and impact increased compared to other populations

    • Onset at younger age

    • More Na+ sensitive, lower plasma renin activity

    • Good response to Na restriction and diuretic therapy

    •  response to ACE inhibitors, ARBs, and -blockers as monotherapy

      • HOWEVER, can be overcome by adding a diuretic

      • Still indicated if compelling indication exists!

    • ACE inhibitor angioedema 2-4 x more frequent


Hypertensive crisis

Hypertensive crisis


Hypertension crises

EMERGENCY

BP >180/120

Acute Target Organ Damage

Life threatening

GOAL:  BP now

IV therapy

URGENCY

BP >180/120

No Target Organ Damage

Not life-threatening

GOAL:  BP over days

Oral therapy

HYPERTENSION CRISES


Hypertensive emergencies

HYPERTENSIVE EMERGENCIES

  • Heart

    • Acute coronary syndrome

    • Acute heart failure with pulmonary edema

    • Dissecting aortic aneurysm

  • CNS

    • Intra-cerebral hemorrhage / CVA

    • Encephalopathy

  • Eclampsia

  • Acute Renal Failure

  • Eyes:

    • Papilledema, hemorrhage


Treatment for hypertensive emergencies

IV Vasodilators

Sodium Nitroprusside

Nicardipine

Nitroglycerin

Enalaprilat

Fenoldopam

Hydralazine

IV Adrenergic Inhibitors

Labetalol

Esmolol

Phentolamine

Treatment for Hypertensive Emergencies

  • Goal:

    • Lower MAP no greater than 20-25% in a few hours

    • Maintain DBP 100-110 mmHg

    • Too rapid or too much  cerebral hypoperfusion

  • Continuous BP monitoring


Iv vasodilators

IV vasodilators

* See next slide


Iv vasodilators moa

IV vasodilators: MOA

Fenoldopam

D1 receptor agonist

moderate affinity α2

vasodilation

Release

Pro drug

  • Nitroprusside:

  • arteriole and venous

  • No tolerance

  • Less effect on HR

  • Nitroglycerin

  • 1° venodilator

  • Arteriole dilator at high doses

  • + tolerance

http://cvpharmacology.com/vasodilator/nitrodilator%20mech.gif http://www.drugabuse.gov/sites/default/files/imagecache/content_image_landscape/images/colorbox/dopamine.gif


Iv vasodilators1

IV vasodilators

Duration of action varies from 1-2 min to 6 hours


Nitroprusside toxicity

Nitroprusside Toxicity

Metabolism releases Cyanide

  • Increased Risk if:

  • Rate at ≥ 5 ug/kg/min

  • 2 ug/kg/min for prolonged use (24-48 hours)

  • Renal insufficiency

  • Can administer Na Thiosulfate to enhance metabolism of cyanide

  • Cyanide Toxicity

  • Weakness

  • Headaches

  • Vertigo

  • Confusion / giddiness

  • Perceived difficulty breathing

  • Thiocyanate Toxicity

  • Anorexia / nausea

  • Fatigue

  • Toxic psychosis

http://www.biomedcentral.com/content/figures/1471-2253-13-9-1-l.jpg


Iv adrenergic blockers

IV adrenergic blockers

Duration of action varies from 3-10 min to 6 hours


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