Post on 08-Feb-2017
Pharmacotherapy: A Pathophysiologic Approach The McGraw-Hill Companies
Presented byDr.Muhammad Umair
Pharm.DMPhil. (Clinical)
LecturerLahore Pharmacy College of
Lahore Medical & Dental College
AbbreviationsACE: angiotensin-converting enzymeARB: angiotensin II receptor blockerAHA: American Heart AssociationBP: blood pressureCCB: calcium channel blockerCV: cardiovascularDBP: diastolic blood pressureGFR: glomerular filtration rateHF: heart failure ISA: intrinsic sympathomimetic activityJNC 7: Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood PressureMI: myocardial infarctionRAAS: renin-angiotensin aldosterone systemSBP: systolic blood pressure 2
OverviewDefinition, classification of hypertension (HTN)Goals of therapy Compelling indicationsLifestyle modifications Hypertension in pregnancyTreatment Orthostatic hypotensionHypertensive crisisMonitoring antihypertensive drug therapy
3
HypertensionPersistent elevation of arterial blood pressure (BP)National Guideline
7th Report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC7)
~72 million Americans (31%) have BP > 140/90 mmHg
Most patients asymptomatic Cardiovascular morbidity & mortality risk directly
correlated with BP; antihypertensive drug therapy reduces cardiovascular & mortality risk
4Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.
Target-Organ DamageBrain: stroke, transient ischemic attack,
dementiaEyes: retinopathy Heart: left ventricular hypertrophy, anginaKidney: chronic kidney disease Peripheral Vasculature: peripheral arterial
disease
5
6
EtiologyEssential hypertension:
> 90% of caseshereditary component
Secondary hypertension:< 10% of casescommon causes: chronic kidney disease,
renovascular diseaseother causes: Rx drugs, street drugs, natural
products, food, industrial chemicals
7
Causes of 2˚ HypertensionDiseases
chronic kidney diseaseCushing's syndrome (abnormal secretion of ACTH
i.e. adreno corticotropic hormone)coarctation of the aortaobstructive sleep apneaparathyroid diseasepheochromocytomaprimary aldosteronismrenovascular diseasethyroid disease
8
Causes of 2˚ HypertensionPrescription drugs:
prednisone, fludrocortisone, triamcinoloneamphetamines/anorexiants: phendimetrazine,
phentermine, sibutramineantivascular endothelin growth factor agentsestrogens: usually oral contraceptivescalcineurin inhibitors: cyclosporine, tacrolimusdecongestants: phenylpropanolamine & analogserythropoiesis stimulating agents: erythropoietin,
darbepoietin9
Causes of 2˚ HypertensionPrescription drugs:
NSAIDs, COX-2 inhibitorsvenlafaxine bupropionbromocriptinebuspironecarbamazepineclozapineketaminemetoclopramide
10
Causes of 2˚ HypertensionSituations:
β-blocker or centrally acting α-agonists when abruptly discontinued
β-blocker without α-blocker first when treating pheochromocytoma
Food substances: sodiumethanol licorice
11
cocainecocaine withdrawalephedra alkaloids
(e.g., ma-huang)“herbal ecstasy” phenylpropanolamin
e analogsnicotine withdrawal
anabolic steroidsnarcotic withdrawalmethylphenidatephencyclidineketamineergot-containing
herbal productsSt. John's wort
12
Street drugs, other natural products: Causes of 2˚ Hypertension
Mechanisms of PathogenesisIncreased cardiac output (CO):
increased preload: increased fluid volume excess sodium intake renal sodium retention
venous constriction: excess RAAS stimulation sympathetic nervous system overactivity
13
Mechanisms of PathogenesisIncreased peripheral resistance (PR):
functional vascular constriction: excess RAAS stimulation sympathetic nervous system overactivity genetic alterations of cell membranes endothelial-derived factors
structural vascular hypertrophy: excess RAAS stimulation sympathetic nervous system overactivity genetic alterations of cell membranes endothelial-derived factors hyperinsulinemia due to obesity, metabolic syndrome
14
Arterial Blood PressureSphygmomanometry: indirect BP measurement MAP = 1/3 (SBP) + 2/3 (DBP)BP = CO x TPR
MAP: Mean Arterial Pressure SBP: Systolic Blood Pressure DBP: Diastolic Blood Pressure BP: Blood Pressure CO: Cardiac Output TPR: Total Peripheral Resistance
15
Arterial Pressure Determinants
16
Adult Classification Classification
Systolic Blood Pressure (mmHg)
Diastolic Blood Pressure (mmHg)
Normal Less than 120 and Less than 80
Prehypertension 120-139 or 80-89
Stage 1 hypertension 140-159 or 90-99
Stage 2 hypertension > 160 or > 100
17Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.
Clinical ControversyWhite coat hypertension: elevated BP in
clinic followed by normal BP reading at homeAggressive treatment of white coat
hypertension is controversialPatients with white coat hypertension may
have increased CV risk compared to those without such BP changes
18
Classification for AdultsClassification based on average of > 2
properly measured seated BP measurements from > 2 clinical encounters
If systolic & diastolic blood pressure values give different classifications, classify by highest category
> 130/80 mmHg: above goal for patients with diabetes mellitus or chronic kidney disease
Prehypertension: patients likely to develop hypertension
19
Clinical ControversyAmbulatory BP measurements may be more
accurate & better predict target-organ damage than manual BP measurements using a sphygmomanometer in a clinic setting (gold standard)
many patients may be misdiagnosed, misclassified
poor technique, daily BP variability, white coat HTN
Validated ambulatory BP monitoring: role in the routine HTN management unclear
20
Treatment GoalsReduce morbidity & mortality Select drug therapy based on evidence
demonstrating risk reduction
21
Patient Population Target Blood PressureMost patients < 140/90 mmHgDiabetes mellitus < 130/80 mmHgChronic kidney disease
<130/80 mmHg
Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.
2007 AHA RecommendationsMore aggressive BP lowering for high risk
patients
22Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic heart disease: A scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation 2007;115(21):2761–2788.
Most patients for general prevention <140/90 mmHgPatients with diabetes (CAD risk equivalent), significant CKD, known CAD (MI, stable angina, unstable angina), noncoronary atherosclerotic vascular disease (ischemic stroke, TIA, PAD, abdominal aortic aneurism [CAD risk equivalents]), Framingham risk score > 10%
<130/80 mmHg
Patients with left ventricular dysfunction (HF) <120/80 mmHg
ALLHATAntihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT)
Primary endpointsfatal CHD nonfatal MI
Secondary endpointsother hypertension-related complications
HF stroke
23ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981–2997.
ALLHATProspective, double-blind trial
randomized patients to: chlorthalidone amlodipine doxazosin lisinopril-based therapy
42,418 patients: age > 55 yr with HTN + 1 additional CV risk factor (mean subject participation 4.9 years)
Thiazide-type diuretics remain unsurpassed for reducing CV morbidity & mortality in most patients
24ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288(23):2981–2997.
JNC7 RecommendationsThiazide-like diuretics preferred 1st line therapy
based on clinical trials showing morbidity & mortality reductionsALLHAT confirms 1st line role of thiazide
diureticsCompelling indications: comorbid conditions
where specific drug therapies provide unique long-term benefits based on clinical trialsdrug therapy recommendations are in
combination with or in place of a thiazide diuretic
25Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206–1252.
Clinical ControversyAvoiding Cardiovascular Events through
COMbination Therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH)
Endpoint: composite of death from CV causes, hospitalization for angina, nonfatal MI or stroke, coronary revascularization, & resuscitation after cardiac arrest
Prospective, double-blind, industry sponsored trialrandomized patients to benazepril + amodipdine or
benazepril + HCTZ11,506 patients with HTN & high CV risk
Combination benazepril + amlodipine superior to benazepril + HCTZ for reducing CV events in high risk patients
26Jamerson KA, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension. N Engl J Med. 2009;359(23):2417-2428.
Compelling IndicationsHeart FailurePost Myocardial InfarctionHigh Coronary Disease Risk Diabetes MellitusChronic Kidney DiseaseRecurrent Stroke Prevention
27
Recommendations & EvidenceStrength of recommendations
A: good, B: moderate, C: poor Quality of evidence
1: more than 1 properly randomized, controlled trial2: at least 1 well-designed clinical trial with
randomization; cohort or case-controlled analytic studies; dramatic results from uncontrolled experiments or subgroup analyses
3: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert communities
28
29
ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; CCB: calcium channel blocker; DBP: diastolic blood pressure; SBP: systolic blood pressure
3030
Lifestyle ModificationsModification Recommendation
Approximate Systolic Blood Pressure Reduction (mm Hg)a
Weight loss Maintain normal body weight (body mass index 18.5–24.9 kg/m2)
5–20 per 10-kg weight loss
DASH-type dietary patterns
Consume a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat
8–14
Reduced salt intake
Reduce daily dietary sodium intake as much as possible, ideally to 65 mmol/day (1.5 g/day sodium, or 3.8 g/day sodium chloride)
2–8
Physical activity
Regular aerobic physical activity (at least 30 min/day, most days of the week)
4–9
Moderation of alcohol intake
Limit consumption to 2 drinks/day in men and 1 drink/day in women and lighter-weight persons
2–4
31
DASH, Dietary Approaches to Stop Hypertension.a Effects of implementing these modifications are time and dose dependent and could be greater for some patients.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/
Clinical ControversyPrehypertension: patients do not have HTN
but at risk for developing itTrial of Preventing Hypertension (TROPHY)
showed treating prehypertension with candesartan decreased progression to stage 1 hypertension
Unknown whether managing prehypertension with drug therapy and lifestyle modifications decreases CV events or if this approach is cost-effective
32Julius S, Nesbitt SD, Egan BM, et al. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med 2006;354(16):1685–1697.
Hypertension in PregnancyImportant to differentiate preeclampsia from
chronic, transient, & gestational hypertensionPreeclampsia: >140/90 mmHg after 20
weeks’ gestation with proteinuriarestricted activity, bed rest, close monitoring
beneficialdefinitive treatment: delivery
Methyldopa: drug of choice
33
Chronic HTN in PregnancyDrug/Class CommentsMethyldopa Preferred based on long-term follow-up data
supporting safetyβ-Blockers Generally safe, but intrauterine growth retardation
reportedLabetolol Increasingly preferred over methyldopa because of
fewer side effectsClonidine Limited data
Calcium channel blockers
Limited data; no increase in major teratogenicity with exposure
Diuretics Not first-line, probably safe in low doses
ACE inhibitors, ARBs
Pregnancy category C in 1st trimester, category D in 2nd & 3rd trimester. Major teratogenicity has been reported with exposure (fetal toxicity, death)
34DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/
DiureticsExact hypotensive mechanism unknownInitial BP drop caused by diuresis
reduced plasma & stroke volume decreases CO and BP
causes compensatory increase in peripheral vascular resistance
Extracellular & plasma volume return to near pretreatment levels with chronic useperipheral vascular resistance becomes lower than
pretreatment values results in chronic antihypertensive effects
35
DiureticsThiazide
chlorthalidone, hydrochlorothiazide (HCTZ), indapamide, metolazone
Loopbumetanide, furosemide, torsemide
Potassium-sparingamiloride, triamterene
Aldosterone antagonistseplerenone, spironolactone
36
Thiazide DiureticsDose in morning to avoid nocturnal diuresisAdverse effects:
hypokalemia, hypomagnesemia, hypercalcemia, hyperuricemia, hyperuricemia, hyperglycemia, hyperlipidemia, sexual dysfunction
lithium toxicity with concurrent administrationMore effective antihypertensives than loop
diuretics unless CrCl < 30 mL/minChlorthalidone 1.5 to 2 times as potent as
HCTZ3737
Loop Diuretics Dose in AM or afternoon to avoid nocturnal
diuresisHigher doses may be needed for patients
with severely decreased glomerular filtration rate or heart failure
Adverse effects:hypokalemia, hypomagnesemia, hypocalcemia,
hyperuricemia, hyperuricemia
38
Potassium-sparing DiureticsDose in AM or afternoon to avoid nocturnal
diuresisGenerally reserved for diuretic-induced
hypokalemia patientsWeak diuretics, generally used in combination
with thiazide diuretics to minimize hypokalemiaAdverse effects:
may cause hyperkalemia especially in combination with an ACE inhibitor, angiotensin-receptor blocker or potassium supplements
avoid in patients with CKD or diabetes39
Aldosterone antagonistsDose in AM or afternoon to avoid nocturnal diuresisDue to increased risk of hyperkalemia, eplerenone
contraindicated in CrCl < 50 mL/min & patients with type 2 diabetes & proteinuria
Adverse effects:may cause hyperkalemia especially in combination
with ACE inhibitor, angiotensin-receptor blocker or potassium supplements
avoid in CKD or DM patients Gynecomastia: up to 10% of patients taking
spironolactone
40
ACE Inhibitors2nd line to diuretics for most patients Block angiotensin I to angiotensin II conversion ACE (Angiotensin Converting Enzyme)
distributed in many tissuesprimarily endothelial cellsblood vessels: major site for angiotensin II
productionBlock bradykinin degradation; stimulate synthesis
of other vasodilating substances such as prostaglandin E2 & prostacyclin
Prevent or regress left ventricular hypertrophy by reducing angiotensin II myocardial stimulation
41
4242
ACE InhibitorsMonitor serum K+ & SCr within 4 weeks of
initiation or dose increaseAdverse effects:
cough up to 20% of patients due to increased bradykinin
angioedema hyperkalemia: particularly in patients with CKD or
DMneutropenia, agranulocytosis, proteinuria,
glomerulonephritis, acute renal failure 43
ARBs Angiotensin II Receptor BlockersAngiotensin II generation
renin-angiotensin-aldosterone pathwayalternative pathway using other enzymes such
as chymasesInhibit angiotensin II from all pathways
directly block angiotensin II type 1 (AT1) receptor
ACE inhibitors partially block effects of angiotensin II
44
ARBs Do not block bradykinin breakdown
less cough than ACE InhibitorsAdverse effects:
orthostatic hypotensionrenal insufficiencyhyperkalemia
45
4646
ACE Inhibitor/ARB WarningsReduce starting dose 50% in some patients
due to hypotension riskpatients also taking diureticvolume depletion elderly patients
May cause hyperkalemia in: CKD patients patients on other K+ sparing medications
K+ sparing diuretics aldosterone antagonists
47
ACE Inhibitor/ARB WarningsCan cause acute kidney failure in certain
patients severe bilateral renal artery stenosis severe stenosis in artery to solitary kidney
Pregnancy category C in 1st trimesterPregnancy category D in 2nd & 3rd trimester
48
Clinical ControversyCV events risk further reduced when ARB
combined with an ACE inhibitor for patients with left ventricular dysfunction
Data supports ACE/ARB combination therapy for patients with severe forms of nephrotic syndrome
Combination ACE/ARB therapy not well studied as standard treatment for HTN
Significantly higher risk of adverse effects such as hyperkalemia
49
Clinical ControversyONgoing Telmisartan Alone and in combination with
Ramipril Global Endpoint Trial (ONTARGET)Endpoint: composite of death, dialysis, SCr doubling Prospective, randomized, multicenter, double-blind
trial; patients randomized patients to ramipril, telmisartan, combination of both25,620 patients > age 55 yr with diabetes & end-organ
damage or established atherosclerotic vascular diseaseCombination therapy reduces proteinuria more than
monotherapy but worsens major renal outcomes
50Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-543.
Renin Inhibitor1st agent FDA approved in 2007: aliskirenInhibits angiotensinogen to angiotensin I conversionFDA approved as monotherapy & combination
therapy with other antihypertensives Efficacy demonstrated with other antihypertensives
including amlodipine, HCTZ, ACEIs/ARBsDoes not block bradykinin breakdown
less cough than ACE InhibitorsAdverse effects: orthostatic hypotension,
hyperkalemia
51
5252
β-BlockersInhibit renin release
weak association with antihypertensive effectNegative chronotropic & inotropic cardiac
effects reduce CO β-blockers with intrinsic sympathomimetic activity
(ISA) do not reduce CO lower BP decrease peripheral resistance
Membrane-stabilizing action on cardiac cells at high enough doses
53
β-BlockersAdverse effects:
bradycardiaatrioventricular conduction abnormalitiesacute heart failureabrupt discontinuation may cause rebound
hypertension or unstable angina, myocardial infarction, & death in patients with high coronary disease risk
bronchospastic pulmonary disease exacerbationmay aggravate intermittent claudication,
Raynaud’s phenomenon
54
β-ReceptorsDistributed throughout the body
concentrate differently in certain organs & tissuesβ1 receptors:
heart, kidneystimulation increases HR, contractility, renin release
β2 receptors: lungs, liver, pancreas, arteriolar smooth musclestimulation causes bronchodilation & vasodilation mediate insulin secretion & glycogenolysis
55
Cardioselective β-BlockersGreater affinity for β1 than β2 receptors
inhibit β1 receptors at low to moderate dosehigher doses block β2 receptors
Safer in patients with bronchospastic disease, peripheral arterial disease, diabetesmay exacerbate bronchospastic disease when
selectivity lost at high doses dose where selectivity lost varies from patient
to patientGenerally preferred β-blockers for HTN
56
β-BlockersCardioselective
atenolol, betaxolol, bisoprolol, metoprolol, nebivolol
Nonselectivenadolol, propranolol, timolol
Intrinsic sympathomimetic activityacebutolol, carteolol, penbutolol, pindolol
Mixed α- and β-blockerscarvedilol, labetolol
57
Nonselective β-Blockers Inhibit β1 & β2 receptors at all dosesCan exacerbate bronchospastic diseaseAdditional benefits in:
essential tremormigraine headachethyrotoxicosis
58
Intrinsic sympathomimetic activityPartial β-receptor agonists
do not reduce resting HR, CO, peripheral blood flow
No clear advantage except patients with bradycardia who must receive a β-blocker
Contraindicated post-myocardial infarction & for patients at high risk for coronary disease
May not be as cardioprotective as other β-blockers
Rarely used 59
Clinical ControversyMeta-analyses suggest β-blocker based therapy
may not reduce CV events as well as other agents
Atenolol t½: 6 to 7 hrs yet it is often dosed once dailyIR forms of carvedilol & metoprolol tartrate have
6- to 10- & 3- to 7-hour half-lives respectively: always dosed at least BID
Findings may only apply to atenolol may be a result of using atenolol daily instead of
BID60
Mixed α- & β-blockersCarvedilol reduces mortality in patients with
systolic HF treated with diuretic & ACE inhibitor
Adverse effects:additional blockade produces more orthostatic
hypotension
61
CCBsCalcium Channel BlockersInhibit influx of Ca2+ across cardiac & smooth
muscle cell membranesmuscle contraction requires increased free
intracellular Ca2+ concentrationCCBs block high-voltage (L-type) Ca2+ channels
resulting in coronary & peripheral vasodilationdihydropyridines vs non-dihydropyridines
different pharmacologically similar antihypertensive efficacy
62
CCBsDihydropyridines:
amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, clevidipine
Non-dihydropyridines: diltiazem, verapamil
Adverse effects of non-dihydropyridines:bradycardiaatrioventricular blocksystolic HF
63
CCBsDihydropyridines:
baroreceptor-mediated reflex tachycardia due to potent vasodilating effects
do not alter conduction through atrioventricular node not effective in supraventricular tachyarrhythmias
Non-dihydropyridines:decrease HR, slow atrioventricular nodal
conductionmay treat supraventricular tachyarrhythmias
64
Non-dihydropyridine CCBsER products preferred for HTNBlock cardiac SA & AV nodes: reduce HRMay produce heart blockNot AB rated as interchangeable/equipotent
due to different release mechanisms & bioavailability
Additional benefits in patients with atrial tachyarrhythmia
65
Dihydropyridine CCBsAvoid short-acting dihydropyridines
particularly IR nifedipine, nicardipineDihydropyridines more potent peripheral
vasodilators than nondihydropyridines may cause more reflex sympathetic discharge:
tachycardia, dizziness, headaches, flushing, peripheral edema
Additional benefits in Raynaud’s syndromeEffective in older patients with isolated
systolic HTN66
α1-BlockersNot appropriate monotherapy for HTNInhibit smooth muscle catecholamine uptake in
peripheral vasculature: vasodilation & BP lowering Adverse effects:
orthostatic hypotension1st dose phenomenon: transient dizziness, faintness,
palpitations, syncope within 1 to 3 hours of 1st doselassitude, vivid dreams, depressionpriapismNa+/H2O retention
67
α1-Blockers1st dose at bedtimeUsed with diuretics to minimize edemaCaution in elderly patients Reduce benign prostatic hypertrophy
symptomsblock postsynaptic α1-adrenergic receptors on
the prostate relaxation decreased urinary outflow resistance
68
Central α2-AgonistsStimulate α2-adrenergic receptors in the
brain reduces sympathetic outflow from the brains
vasomotor center increases vagal tone
peripheral stimulation of presynaptic α2-receptors may further reduce sympathetic tone
decrease HR, CO, TPR, plasma renin activity, baroreceptor activity
69
Central α2-AgonistsAdverse effects:
sodium/water retentionabrupt discontinuation may cause rebound
HTNdepressionorthostatic hypotension dizziness
Clonidine: anticholinergic side effectsMethyldopa: can cause hepatitis, hemolytic
anemia (rare)70
Central α2-AgonistsMost effective if used with a diuretic
minimizes fluid retentionUse caution in elderly patients Clonidine transdermal patch: placed weekly
may result in fewer adverse effects avoids high peak serum drug concentrations
delayed onset: 2 to 3 days overlap with PO formulation at
initiation/discontinuation
71
Direct Arterial Vasodilators Direct arterial smooth muscle relaxation
causes antihypertensive effect (little or no venous vasodilation)reduce impedence to myocardial contractilitypotent reductions in perfusion pressure activate
baroreceptor reflexesbaroreceptor activation: compensatory increase
in sympathetic outflow; tachyphylaxis can cause loss of antihypertensive effect counteract with concurrent β-blocker clonidine if β-blocker contraindicated
72
Direct Arterial Vasodilators Adverse effects:
sodium/water retentionangina
Hydralazine can cause lupus-like syndromeMinoxidil can cause hypertrichosis
73
ReserpinePeripheral adrenergic antagonist
depletes norephinephrine from sympathetic nerve endings; blocks norephinephrine transport into storage granules
reduces norephinephrine release into synapse following nerve stimulation reduced sympathetic tone peripheral vascular resistance reduction decreased BP
depletes catecholamines from brain & myocardium Maximum antihypertensive effect: 2 to 6 weeks
74
ReserpineAdverse effects:
sedationdepressiondecreased COsodium/water retentionincreased gastric acid secretiondiarrheabradycardia
Use with diuretic (preferably thiazide) to avoid fluid retention
75
Direct Arterial Vasodilators Use with diuretic (preferably thiazide) & β-
blocker to reduce fluid retention & reflex tachycardiaminoxidil
more potent vasodilatorhydralazine
76
Orthostatic HypotensionDecrease in SBP > 20 mmHg or DBP > 10
mmHg when changing from supine to standing position
Older patients with isolated systolic hypertension at risk at initiation of drug therapy
Prevalent with diuretics, ACE inhibitors, ARBs
Treatment should remain the same with low initial doses & gradual dose titrations
77
Hypertensive CrisisBP > 180/120 mmHg
reduce gradually Hypertensive urgency
elevated BPno acute or progressing target-organ injury
Hypertensive emergencyacute or progressing target-organ damage
encephalopathy, intracranial hemorrhage, acute left ventricular failure with pulmonary edema, dissecting aortic aneurysm, unstable angina, eclampsia
78
Hypertensive EmergencyDrug Dose Onset
(min)Duration
(min)Adverse Effects Special Indications
Sodium nitroprusside
0.25–10 mcg/kg/min intravenous infusion (requires special delivery system)
Immediate 1–2 Nausea, vomiting, muscle twitching, sweating, thiocyanate and cyanide intoxication
Most hypertensive emergencies; caution with high intracranial pressure, azotemia, or in chronic kidney disease
Nicardipine hydrochloride
5–15 mg/h intravenous
5–10 15–30; may exceed 240
Tachycardia, headache, flushing, local phlebitis
Most hypertensive emergencies except acute heart failure; caution with coronary ischemia
Clevidipine butyrate
1-2 mg/h intravenous infusion; may double dose every 90 sec initially; maximum: 32 mg/h; typical maintenance dose: 4 to 6 mg/h
2-4 5-15 Headache, syncope, dyspnea, nausea, vomiting
Most hypertensive emergencies except severe aortic stenosis; caution with heart failure
Fenoldopam mesylate
0.1–0.3 mcg/kg/min intravenous infusion
< 5 30 Tachycardia, headache, nausea, flushing
Most hypertensive emergencies; caution with glaucoma
79DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/
Hypertensive EmergencyDrug Dose Onset
(min)Duration
(min)Adverse Effects Special
IndicationsNitroglycerin 5–100 mcg/min
intravenous infusion2–5 5–10 Headache, vomiting,
methemoglobinemia, tolerance with prolonged use
Coronary ischemia
Hydralazine hydrochloride
12–20 mg intravenous10–50 mg intramuscular
10–2020–30
60–240240–360
Tachycardia, flushing, headache vomiting, aggravation of angina
Eclampsia
Labetalol hydrochloride
20–80 mg intravenous bolus every 10 min; 0.5–2.0 mg/min intravenous infusion
5–10 180–360 Vomiting, scalp tingling, bronchoconstriction, dizziness, nausea, heart block, orthostatic hypotension
Most hypertensive emergencies except acute heart failure
Esmolol hydrochloride
250–500 mcg/kg/min intravenous bolus, then 50–100 mcg/kg/min intravenous infusion; may repeat bolus after 5 min or increase infusion to 300 mcg/min
1–2 10–20 Hypotension, nausea, asthma, first-degree heart block, heart failure
Aortic dissection; perioperative
80DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/
Monitoring Antihypertensives Class ParametersDiuretics blood pressure
BUN/serum creatinineserum electrolytes (K+, Mg2+, Na+)uric acid (for thiazides)
β-Blockers blood pressureheart rate
Aldosterone antagonistsACE inhibitorsAngiotensin II receptor blockers Direct Renin inhibitors
blood pressureBUN/serum creatinineserum potassium
Calcium channel blockers blood pressureheart rate
81DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/
Combination TherapyMost patients require > 2 agents to control
BPA thiazide-type diuretic should be one of
these agents unless contraindicatedCombination regimens should include a
diuretic (preferably a thiazide)Resistant hypertension: failure to achieve BP
goal on full doses of 3 drug regimen including a diuretic
82
AcknowledgementsPrepared By/Series Editor: April Casselman, Pharm.D.
Editor-in-Chief: Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA
Chapter Authors: Joseph J. Saseen, Pharm.D., FCCP, BCPSEric J. Maclaughlin, Pharm.D., BS Pharm
Section Editor: Robert L. Talbert, Pharm.D., FCCP, BCPS, FAHA
83