1. Pharmacology of Hypertension
Vicki Groo, Pharm.d.
Clinical Associate Professor
Clinical pharmacist, heart center

2. 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

4. CLASSIFICATION SBP DBP Normal < 120 and < 80 Prehypertension or
80-89
Hypertension
Stage 1
90-99
Stage 2
≥ 160
≥ 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:

5. 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

6. National Health & Nutrition Examination Survey
81%
73%
50%

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:

8. 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:

9. 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
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)
Stage 1 Hypertension (SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.
Without Compelling Indications
Drug(s) for the compelling indications
Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.
With Compelling Indications
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:

10. Drug Therapy Considerations
Clinical trial data
Over 2/3 of patients will require ≥2 drugs
Cost/ adverse effects
JAMA 2003;289:

11. Lifestyle Modifications Limit salt intake Physical activity
DASH eating
Plan
Lose weight
Limit alcohol intake

12. 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

13. Diuretic moa

14. Diuretic Comparison HCTZ CTD Indapamide benzothiadiazine thiazide-like
Non-thiazide
sulfonamide VD
2.5 L
3-13 L
25 L
T ½
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 = and for 24 hr and pm BP respectively
Indapamide
Hypertension 2004;43:4-9,

15. Diuretic ConsiderationsK
Dose
Other
Thiazides:
1st line choice
Hydrochlorothiazide ↓
mg/d
Chlorthalidone ↓↓
mg/d
Metolazone
↓↓↓
mg/d
Reserve for resistant edema
Indapamide
---
mg/d
1st line choice elderly
Aldosterone Antag
Reserve for resistant HTN or HF
Spironolactone ↑
avoid K > 5.0 or CrCl < 30
Eplerenone
mg/d
K sparing
Caution, ACE/ARB, renal failure
Amiloride
5- 20 mg/d
Use in combo to counteract K loss
Triamterene
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
Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition:

16. 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

17. Mechanism of Action

18. ACE Inhibitors ARBs Drug Dose Captopril 12.5-50 mg tid Enalapril
mg/day
Lisinopril
5-40 mg/day
Benazepril
5-80 mg/day
Fosinopril*
10-80 mg/day
Moexipril
mg/day
Quinapril
Ramipril
mg/day
Perindopril
2-16 mg/day
Trandolapril
1-8 mg/day
Drug
Dose
Candesartan (Atacand)*
4-32 mg/d
Eprosartan (Tevetan)*
mg/d
Irbesartan (Avapro)*
mg/d
Losartan (Cozaar)*
mg/d
Omelsartan (Benicar)
20-40 mg/d
Telmisartan (Micardis)
40-80 mg/d
Valsartan (Diovan)
mg/d
* generic
Combining with thiazide usually more effective than dose increase
Direct Renin Inhibitors
Aliskiren (Tekturna)
mg/day
As effective as ACE or ARB in HTN
* Dual elimination: liver & kidney
Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition:

19. ACE Inhibitors and ARB Compelling Indications Systolic Heart FailureDM
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

20. Beta Blockers MOA: Sympatholytic  ↓ HR and CO / ↓ release of renin
Receptor
Affinity
Lipid
Solubility
Renal
Elimination
Dose
Atenolol β1
Low
Yes
mg/d
Bisoprolol No
mg/d
Carvedilol
β1, β2, α
Mod
mg bid
Labetalol
mg bid
Metoprolol tartrate
Metoprolol succinate
mg bid
mg/d
Nebivolol
5-40 mg/d
Propranolol
β1, β2
High
mg bid
Avoid sudden discontinuation Rebound HTN d/t up regulation of ᵦ receptors
Goodman and Gilmans: The Pharmacologic Basis of Therapeutic 12th edition:

21. 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

22. Calcium channel blockers

23. CCB Considerations AV Node SA Node Contractility Vasodilation DHP
Nifedipine^ 1 5
Amlodipine
Felodipine
Nicardipine
Non-DHP#
Diltiazem^ 4 2 3
Verapamil^
^ 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:

24. 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)

25. 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

26. 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

27. 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 mg daily; max 100 mg daily
Rare but serious SE: Stevens-Johnson syndrome
Hypertrichosis — used topically to promote hair growth
Headache, edema, tachycardia, paresthesia

28. Vasodilators: direct Caution: Increased myocardial work
Use in combination with B-blocker / diuretic to combat these effects

29. 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

30. 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 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

31. Hyperkalemia, dry cough
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

32. 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
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)
Stage 1 Hypertension (SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.
Without Compelling Indications
Drug(s) for the compelling indications
Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.
With Compelling Indications
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:

33. 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

34. 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:

35. 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:

36. 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

37. Hypertensive crisis

38. 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

39. 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

40. Treatment for Hypertensive Emergencies
Goal:
Lower MAP no greater than 20-25% in a few hours
Maintain DBP mmHg
Too rapid or too much  cerebral hypoperfusion
Continuous BP monitoring
IV Vasodilators
Sodium Nitroprusside
Nicardipine
Nitroglycerin
Enalaprilat
Fenoldopam
Hydralazine
IV Adrenergic Inhibitors
Labetalol
Esmolol
Phentolamine

41. IV vasodilators MOA Indication Nitroprusside Vasodilator*
Most HTN emergencies
Caution high ICP or azotemia
Nicardipine
CCB
Except acute heart failure
Caution coronary ischemia
Nitroglycerin
Coronary Ischemia
Enalaprilat
ACE inhibitor
Acute heart failure
Avoid in acute MI
Fenoldopam
Dopamine 1 agonist*
Caution glaucoma
Hydralazine
Direct vasodilator
Eclampsia
* See next slide

42. 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

43. IV vasodilators Dose Onset Adverse Effects Nitroprusside
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
mg q6h
15-30 min
High renin states: ↓↓↓ BP
Variable response
Fenoldopam
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

44. 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

45. 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
(min)
Adverse
Effects
Labetalol
20-80 mg q 10 min
mg/min
5-10
Heart block
Esmolol
ug/kg/min x 1 min
ug/kg/min x 4 min
1-2
Hypotension, nausea
Phentolamine
5-15 mg
↑ HR, HA, flushing
Duration of action varies from min to 6 hours