Download PPT

PHARMACOLOGY
OF
HYPERTENSION
VICKI GROO, PHARM.D.
CLINICAL ASSOCIATE PROFESSOR
CLINICAL PHARMACIST, HEART CENTER
[email protected]
413-0928
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
Normal
Prehypertension
Hypertension
Stage 1
Stage 2
SBP
< 120
120-139
and
or
DBP
< 80
80-89
140-159
≥ 160
or
or
90-99
≥ 100
**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
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
2007-2008
81%
73%
50%
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:
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
Lifestyle Modifications
Not at Goal Blood Pressure (<140/90 mmHg)
(<130/80 mmHg for those with diabetes or chronic kidney disease)
Initial Drug Choices
Without Compelling
Indications
With Compelling
Indications
Stage 1 Hypertension
Stage 2 Hypertension
(SBP 140–159 or DBP 90–99 mmHg)
Thiazide-type diuretics for most.
May consider ACEI, ARB, BB, CCB,
or combination.
(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.
JNC VII JAMA 2003;289:2560-2572
Drug(s) for the compelling
indications
Other antihypertensive drugs
(diuretics, ACEI, ARB, BB, CCB)
as needed.
DRUG THERAPY CONSIDERATIONS
Clinical trial data
Over 2/3 of patients will require ≥2 drugs
Cost/ adverse effects
JAMA 2003;289:2560-2572
Limit salt intake
Physical activity
Lifestyle
Modifications
DASH eating
Plan
Lose weight
Limit alcohol intake
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 COMPARISON
HCTZ
CTD
Indapamide
benzothiadiazine
thiazide-like
Non-thiazide
sulfonamide
VD
2.5 L
3-13 L
25 L
T½
8-15 hours
45-60 hours
14 hours
duration
16-24 hours
48-72 hours
24 hr SBP
(-) 7.4 ± 1.7
(-) 12.4 ± 1.8
PM BP
(-)6.4 ± 1.8
(-) 13.5 ± 1.9
P = 0.054 and 0.009 for 24 hr and pm BP respectively
Hypertension 2004;43:4-9,
Indapamide
DIURETIC CONSIDERATIONS
K
Dose
Other
1st line choice
Thiazides:
Hydrochlorothiazide
↓
12.5-50 mg/d
Chlorthalidone
↓↓
12.5-25 mg/d
Metolazone
↓↓↓
2.5-10 mg/d
Reserve for resistant edema
---
1.25-2.5 mg/d
1st line choice elderly
Indapamide
Aldosterone Antag
Reserve for resistant HTN or HF
Spironolactone
↑
12.5-50 mg/d
avoid K > 5.0 or CrCl < 30
Eplerenone
↑
25-100 mg/d
avoid K > 5.0 or CrCl < 30
K sparing
Caution, ACE/ARB, renal failure
Amiloride
↑
5- 20 mg/d
Use in combo to counteract K loss
Triamterene
↑
37.5-50 mg/d
Combo product with HCTZ available
Loop
Reserve for HF or resistant edema
Furosemide
↓↓
20-80 mg/d
Bioavailability 60% or less
Bumetanide
↓↓
0.5-4 mg/d
Bioavailability 80%
Torsemide
↓↓
5-10 mg/d
Bioavailability 80%
Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com
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
ACE INHIBITORS
ARBS
Drug
Dose
Drug
Captopril
12.5-50 mg tid
Candesartan (Atacand)* 4-32 mg/d
Enalapril
2.5-40 mg/day
Eprosartan (Tevetan)*
400-800 mg/d
Lisinopril
5-40 mg/day
Irbesartan (Avapro)*
75-300 mg/d
Benazepril
5-80 mg/day
Losartan (Cozaar)*
25-100 mg/d
Fosinopril*
10-80 mg/day
Omelsartan (Benicar)
20-40 mg/d
Moexipril
7.5-30 mg/day
Telmisartan (Micardis)
40-80 mg/d
Quinapril
5-80 mg/day
Valsartan (Diovan)
80-320 mg/d
Ramipril
1.25-20 mg/day
* generic
Perindopril
2-16 mg/day
Trandolapril
1-8 mg/day
Combining with thiazide usually more
effective than dose increase
* Dual elimination: liver & kidney
Dose
Direct Renin Inhibitors
• Aliskiren (Tekturna)
• 150-300 mg/day
• As effective as ACE or ARB in HTN
Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com
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
MOA: Sympatholytic  ↓ HR and CO / ↓ release of renin
Receptor
Affinity
Lipid
Solubility
Renal
Elimination
Dose
Atenolol
β1
Low
Yes
25-100 mg/d
Bisoprolol
β1
Low
No
2.5-10 mg/d
Carvedilol
β1, β2, α
Mod
No
3.125-25 mg bid
Labetalol
β1, β2, α
Low
No
100-400 mg bid
Metoprolol tartrate
Metoprolol succinate
β1
Mod
No
50-200 mg bid
25-200 mg/d
Nebivolol
β1
Low
No
5-40 mg/d
β1, β2
High
No
40-120 mg bid
Propranolol
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 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
http://www.accesspharmacy.com/content.aspx?aID=6543820
http://www.drugdevelopment-technology.com/projects/istaroxime/istaroxime4.html
CCB CONSIDERATIONS
AV
Node
SA
Node
Contractility
Vasodilation
Nifedipine^
0
1
1
5
Amlodipine
0
1
1
5
Felodipine
0
1
1
5
Nicardipine
0
1
0
5
Diltiazem^
4
2
2
3
Verapamil^
5
4
4
3
DHP
Non-DHP#
^ Do not use short acting agents in treatment of HTN
# Do not combine with beta-blockers: increased risk of bradycardia
Doses provided in Dr DiDomenico’s lecture on angina
Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition: http://www.accesspharmacy.com
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
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 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
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:
DIRECT
Caution: Increased myocardial work
Use in combination with B-blocker / diuretic to combat these effects
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
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:
Centrally Acting:
• Methlydopa
• Clonidine
Sedation, dry
mouth
B-blockers:
• Atenolol
• Carvedilol
• Metoprolol
• Propranolol
Bradycardia
Angiotensinogen
Renin
Aliskiren
α 1 blocker:
• Prazosin, Doxazosin,
Terazosin
Dizziness, edema
Vascular Smooth Muscle:
• Hydralazine, Minoxidil
• CCBs
Headache, Dizziness, edema,
Diuretics:
• Thiazide
• Loop
• Other
hypokalemia
ACE
Angiotensin
ACE
I
Inhibitors
Hyperkalemia, dry cough
Angiotensin II
ARBs
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
Without Compelling
Indications
With Compelling
Indications
Stage 1 Hypertension
Stage 2 Hypertension
(SBP 140–159 or DBP 90–99 mmHg)
Thiazide-type diuretics for most.
May consider ACEI, ARB, BB, CCB,
or combination.
(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.
JNC VII JAMA 2003;289:2560-2572
Drug(s) for the compelling
indications
Other antihypertensive drugs
(diuretics, ACEI, ARB, BB, CCB)
as needed.
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
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
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 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
HYPERTENSION CRISES
EMERGENCY
URGENCY
BP >180/120
BP >180/120
Acute Target Organ
Damage
No Target Organ
Damage
Life threatening
Not life-threatening
GOAL:  BP now
GOAL:  BP over days
IV therapy
Oral therapy
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
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 Adrenergic Inhibitors
Sodium Nitroprusside
Labetalol
Nicardipine
Esmolol
Nitroglycerin
Phentolamine
Enalaprilat
Fenoldopam
Hydralazine
IV VASODILATORS
MOA
Indication
Nitroprusside
Vasodilator*
Most HTN emergencies
• Caution high ICP or azotemia
Nicardipine
CCB
Most HTN emergencies
• Except acute heart failure
• Caution coronary ischemia
Nitroglycerin
Vasodilator*
Coronary Ischemia
Enalaprilat
ACE inhibitor
Acute heart failure
• Avoid in acute MI
Fenoldopam
Dopamine 1 agonist*
Most HTN emergencies
• Caution glaucoma
Hydralazine
Direct vasodilator
Eclampsia
* See next slide
IV VASODILATORS: MOA
Fenoldopam
Release
Pro drug
D1 receptor agonist
moderate affinity α2
vasodilation
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 VASODILATORS
Dose
Onset
Adverse Effects
Nitroprusside
0.25-10 ug/min
immediate
Thiocyanate
Cyanide toxicity
Nicardipine
5-15 mg/hr
5-10 min
↑ HR, HA, flushing
Nitroglycerin
5-100 ug/min
2-5 min
HA, vomiting
Tolerance with prolonged
use
Enalaprilat
1.25-5 mg q6h
15-30 min
High renin states: ↓↓↓ BP
Variable response
Fenoldopam
0.1-0.3 ug/kg/min
< 5 min
↑ HR, HA, flushing,
nausea
Hydralazine
10-20 mg IV
10-50 mg IM
10-20 min
20-30 min
↑ HR, HA, flushing,
vomiting, angina
Duration of action varies from 1-2 min to 6 hours
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
•
•
•
http://www.biomedcentral.com/content/figures/1471-2253-13-9-1-l.jpg
Anorexia / nausea
Fatigue
Toxic psychosis
IV ADRENERGIC BLOCKERS
MOA
Indication
Labetalol
B1, B2, α blocker
Most HTN emergencies
Except acute heart failure
Esmolol
B1 blocker
Aortic dissection
Perioperative
Phentolamine
α antagonist
Catecholamine excess
Dose
Onset Adverse
(min) Effects
Labetalol
20-80 mg q 10 min
0.5-2.0 mg/min
5-10
Esmolol
250-500 ug/kg/min x 1 min 1-2
50-100 ug/kg/min x 4 min
Hypotension,
nausea
Phentolamine
5-15 mg
↑ HR, HA, flushing
1-2
Duration of action varies from 3-10 min to 6 hours
Heart block