Anti-Hypertensive Drugs Flashcards
Etiology of Hypertension
> 90% of patients have essential hypertension
Risk Factors: Family history, obesity, diet, age, physical inactivity, smoking, African Americans (4x more likely), middle age men > females
Hypertension guidelines
sustained systolic BP > 130 mmHg
or
sustained diastolic BP > 80 mmHg
** results from: increased peripheral vascular smooth muscle tone –> increased arteriolar resistance and reduced capacitance on the venous system
Hypertension Categories (4)
Normal: < 120 and < 80 Elevated 120-129 and < 80 Stage 1: 130-139 or 80-89 Stage 2: > 140 or > 90 ** current guideline goals is to reduce BP to < 130/80 mmHg
BP control
Arterial BP: directly proportional to CO and PVR
CO and PVR: controlled by baroreflexes (SNS and RAAS)
** Antihypertensive drugs reduce either or both
Anatomical Sites of BP control (4)
1) Resistance of arterioles
2) Capacitance of Venules
3 Pump output of the Heart
4) Volume (kidneys)
Compensatory Response to Decrease BP
Decreased blood pressure will compensate via two reflex mechanism:
1) Increased sympathetic outflow = tachycardia
2) Increased Renin release = Salt and water retention (increase plasma volume)
Both will lead to Increase BP
** not all hypertensive drugs result in a reflex.. generally drugs that work on the vessels cause reflexes
Stage 1 vs Stage 2 control of Hypertension
how many drugs prescribed
Stage 1: Often controlled with a single drug
Stage 2: Often requires multiple drugs
** life-style changes are the first recommendation to all patients with pre-hypertension and Stage 1 hypertension
Current Recommendations for Treatment
Initiation of pharmacotherapy
- most patients can be started on a single drug (should consider giving 2 drugs of different classes to patients with Stage 2 hypertension)
Stage 2 Hypertension:
- 2 first line drugs of different classes (patients with stage 2 hypertension and average BP of 20/10 mmHg above the BP target)
If BP is still not controlled: vasodilator given
First-Line agents, Second-Line agents, and Other agents
First Line: ACE inhibitors, ARBs, Calcium Channel blockers, and Thiazide diuretics
Second Line: Beta-blockers, aldosterone antagonist
Other: Loop diuretics, alpha-blockers, direct vasodilators, central alpha 2-agonist, renin inhibitors
ACE Inhibitor Drugs
Captopril
Enalapril
Lisinopril
ACE Inhibitor MOA
First Line agent (particularly for diabetics and patients with CKD)
- Decrease BP by decreasing PVR
- inhibits ACE - converts angiotensin I –> Angiotensin II (vasoconstrictor)
- *** blockage of ACE leads to Increased Renin and Angiotensin I due to lack of feedback inhibition
- Decreases Na+ and H2O retention
- Increases bradykinin levels (ACE metabolizes bradykinin) - which leads to decrease BP and mild vasodilation
- DO NOT reflexively increase CO or HR
ACE Inhibitors- Clinical Applications
Hypertension (most effective in white or young patients or can be given with a diuretic to = same effectiveness in black patients
Preserves renal function in patients with nephropathy (diabetic or non-diabetic) – angiotensin II constricts renal efferent arterioles - thus blocking allows arterioles to dilate and decrease GFR (dec. hyper-filtration) ** UNILATERAL
Effective for treating Chronic HF
Standard of care for patients following MI (started 24 hrs after end of infarction)
ACE inhibitors AE
Dry hacking cough (due to increase Bradykinin)
Hyperkalemia - effects due to blocking of aldosterone
Hypotension
Angioedema (rare but life-threatening) < 1%
Acute Renal Failure (patients with bilateral renal artery stenosis) - in bilateral vasoconstriction the efferent arteriole is maintaining GFR and ACE inhibitor will cause a plummet in GFR = Death
Rash, fever, altered taste
ACE Inhibitors Contraindications
Pregnancy
- 1st trimester - Inc. risk of malformations
- 2nd and 3rd trimester - risk of fetal hypotension, anuria, and renal failure
Patients with bilateral renal stenosis
Patients with a history of angioedema related to previous ACEI treatments or hereditary idiopathic angioedema
ARB Drugs
Losartan
Valsartan
ARB MOA
Angiotensin II receptor Blocker (blocks AT1 Receptor)
*** Increased levels of angiotensin II, angiotensin I, renin do to lack of feedback mechanism
First line agent
Alternatives to ACEI (does not produce dry cough)
Dec. in BP causing arteriolar and venous dilation
blocks aldosterone secretion: Dec Na+ and H2O retention
Dec. Diabetic Nephrotoxicity
Does Not Increase Bradykinin Levels
ARB AE
Similar to those of ACE inhibitors
Dry cough does not occur
Angioedema risk is significantly lower than with ACEI
** Losartan reduces plasma uric acid levels by inhibiting URAT1 transporter- useful in patients that also have gout
ARB Contraindications
Pregnancy
Patients with bilateral renal stenosis
Renin Inhibitor
MOA
End Result
Aliskiren
Alternative agent in the treatment of hypertension
** Not clinically as effective than ARB or ACEI
MOA: Inhibits the enzyme activity of Renin and prevents the conversion of angioteninogen to angiotensin I
End Result: Inhibits theA production of angiotensin II and aldosterone
Renin Inhibitor AE
Similar to those of an ACEI
No dry cough
Decreased risk of angioedema than with ACEI
Calcium channel blockers
Verapamil (non-dihydropyridines)
Diltiazem (non-dihydropyridines)
Nifedipine (dihydropyridine)
Amlodipine (dihydropyridine)
First line agent (particularly black and/or the elderly)
Separated into two classes: (non-dihydropyridines or dihydropyridines)
Verapamil and Diltiazem
Verapamil:
Least selective Ca2+ channel blocker
significant effects in cardiac and vascular smooth muscle - relaxation and decrease contractility and HR
Uses:
- treat angina, supra ventricular tachyarrhythmias, hypertension, migraine, and cerebral vasospasm
Diltiazem:
Effects cardiac and vascular smooth muscle (less effective on cardiac then verapamil)
Good side-effect profile
Uses:
- treat angina, hypertension, supra ventricular tachyarrhythmias, and cerebral vasospasm
Dihydropyridines
Nifedipine
Amlodipine
Greater affinity for vascular Ca2+ channels than for cardiac channels
Reduces calcium entry into the smooth muscle to causes coronary and peripheral vasodilation and lower BP
Primary use is to treat hypertension, can also be used for angina
** Not used for cardiac arrhythmias
Calcium channel blockers - Clinical App.
Hypertension (Black of elderly patients)
Have intrinsic natriuretic effects (diuretic not needed)
Useful in patients with asthma, diabetes, peripheral vascular disease
Calcium channel blockers- PK
High-doses of short-acting dihydropyridine blockers can increase risk of MI (due to reflex stimulation)
Sustained release preparations are preferred
Calcium channel blockers- AE
Verapamil
- Constipation, negative inotropic signals, gingival hyperplasia
Dihydropyridines
- hypotension, peripheral edema (feet/ankles), dizziness, headache, fatigue, gingival hyperplasia, flushing, REFLEX TACHYCARDIA (short-acting preparations)
Calcium channel blockers Contraindications
Non-dyhyrdopyridines
- contraindicated in patients taking b-blockers or who have a 2nd or 3rd degree AV block, or severe left ventricular systolic dysfunction
Diuretic Drugs and MOA
Thiazide (Hydrochlorothiazide, Metolazone, Chlorthalidone)
First line agent (particularly black and/or elderly patients)
MOA
- Lower BP by increasing Na+ and H2O excretion- decreasing blood volume
- Long term treatment = normal plasma volume but sustained decrease in PVR
Thiazides- Clinical Apps.
Counteract Na+ and H2O retention caused by other anti-hypertensive drugs
Particularly useful in the black and elderly (with normal renal and cardiac function)
Thiazides AE
Hypokalemia Hyperuricemia Hyperglycemia Hypomagnesium Hyperchlosterolemia Sex dysfunction
Loop Diuretics (furosemide)
Act promptly in patients with poor renal function or heart failure
more potent in inducing diuresis and can cause more side effects
used primarily in patients who do not respond to thiazides therapy adequately
causes dec. renal vascular resistance and inc. renal blood flow
K+ sparing Diuretics MOA and uses
Dec. loss of K+ in the urine due to thiazide or loop diuretics
used in combination therapy
Aldosterone Antagonist clinical application
Spironolactone and Eplerenone
- Inhibits Na+ and H2O retention via aldosterone receptor
- reduced K+ excretion - risk for hyperkalemia
- Used in treatment of hypertension and HF
- Can be used as a part of first line therapy in patients with hypertension and severe left ventricular dysfunction
Beta Blocker Drugs and clinical applications
Propranolol (Non-selective)
Metoprolol (B1-selective)
Atenolol (B1-selective)
Pindolol (partial Non-selective agonist) - preferred blocker in pregnancy
Used only as add on therapy to first line agents in primary prevention patients
First line therapy ONLY for patients with CAD, HF, or post MI- plus hypertension
Beta-blockers: MOA and PK
MOA:
Reduce BP by dec. Cardiac Output, contractility, and Heart Rate
Blunt sympathetic reflex with exercise
inhibits both release of NE and Renin (B1 receptors)
PK: May take several weeks to develop full effects
Beta-blockers AE
Bradycardia, CNS effects (fatigue, lethargy, insomnia, hallucinations), hypotension, decrease libido, and impotence
Disturb lipid metabolism (Dec. HDL and Inc. TAGs)
Hypoglycemia (b2)
drug withdrawal effects (quick withdrawal may induce angina, MI or sudden death) –> must be tapered off
Propranolol - contraindicated in patients with COPD or Asthma
Alpha 1 blockers Drugs MOA and effects
Prazosin
Doxazosin
Competitive inhibitor of alpha 1 adrenoreceptors
Dec. PVR and Dec. Arterial BP by relaxing both arterial and venous smooth muscle
Causes minimal changes in CO, renal blood flow, and GFR (no long term tachycardia)
Na+ and H2O retention does occur
Effective in lowering BP but more side effects than any other antihypertensive
Alpha 1-blockers - Clinical Applications
Hypertension (due to side-effect profile and advent of safer antihypertensives, are seldom used in treatment in hypertension.
Generally used for alternative reasons : BPH - DOC to relieve symptoms
Have been used in HF but not commonly
Alpha 1 blockers AE
Orthostatic hypotension (syncope) upon first does or increase in dose
concomitant use of a beta-blocker to blunt initial reflex tachycardia
CNS effects: dizziness, headache, lack of energy, nausea, and palpitations
** Doxazosin shown to increase rate of congestive HF
Mixed Alpha and Beta blocker: PK, advantages, AE
Labetalol (more potent on beta than alpha)
PK:
- oral or parenteral admin.
- used in hypertension management (safe in pregnancy)
- IV = rapid reduction in BP- useful in hypertensive emergencies
Advantages:
- Dec. BP with associated alpha-1 blockade and is not associated with a reflex tachycardia
AE:
Orthostatic Hypotension
Central alpha 2- agonist
Clonidine
Methyldopa
Clonidine: MOA, Uses, AE
MOA:
- Reduces sympathetic outflow (a2 receptor)
- Decreases PVR and CO –> dec. BP
- Does not affect renal blood flow or GFR
Uses:
- Used in hypertension management including hypertension crisis
AE:
- Drowsiness, dry mouth, dizziness, headache, and sexual dysfunction
- Rebound hypertension may occur follow quick withdrawal
** avoid concomitant use with beta blockers
Methyldopa: MOA, Uses, AE
MOA:
- Alpha-2 agonist converted to alpha methyl dopamine and alpha methylnorepinephrine centrally to diminish sympathetic outflow
- Dec. PVR and Dec. BP
- Does not dec. Renal Blood flow or GFR
Uses:
- DOC of pregnancy induced hypertension
- Used in management of hypertension
AE:
- sedation, drowsiness, dizziness, nausea, headache fatigue, and sexual dysfunction
- nightmares, mental depression, and vertigo
- Development of Positive Coombs test (can result in hemolytic anemia, hepatitis, and Drug fever)
Direct Vasodilators
Hydralazine
Minoxidil
Not first line treatment
Direct acting smooth muscle relaxants (arterioles)
produces reflex tachycardia, renin release
Major side effects can be blocked if combined with beta blocker and diuretics
Hydralazine: PK, Uses, AE
PK:
- IV or oral
- acts mainly on the arterioles
Uses:
- to treat pregnancy induced hypertension/pre-eclampsia
- used to manage hypertension as a last line therapy
AE:
- Fluid retention and reflex tachycardia
- reversible lupus like syndrome (metabolized by acetylation)
- Headaches, nausea, sweating, and flushing
** usually admins. with beta blocker and thaizide
Minoxidil: Uses, AE
Causes direct peripheral vasodilation of the arterioles
Uses:
- oral treatment for severe malignant hypertension
AE:
- reflex tachycardia, and fluid retention
- hypertrichosis (baldness treatment)
Pulmonary Hypertension
An increase in BP in the pulmonary artery, vein, or capillaries
Tx:
Prostaglandins
Inhibitors of endothelin synthesis
vasodilators
Epoprostenol
Synthetic PGI2
lowers peripheral, pulmonary, and coronary resistance
Given via continuous IV infusion
AE: flushing, headache, jaw pain, diarrhea, and arthralgias
Bosentan
Non-selective endothelin receptor blocker
Blocks both the initial transient depressor (ETA) and the prolonged pressor (ETB) responses to endothelin
Category X for pregnancy
Sildenafil
Inhibitor of PDE5 (phosphodiesterase 5)
Inc. cGMP = smooth muscle relaxation
AE: headache, flushing, dyspepsia, cyanopsia
Contraindicated with Nitrates
Comorbid condition: None Treatment
First Line: ACEI or ARB, CCB, or thaizide
Second Line: beta blockers, aldosterone antagonist
Comorbid condition: Acute or Chronic CAD Treatment
First Line: beta-blockers + ACEI or ARB
Second Line: Thaizide, CCB
Comorbid condition: Chronic Kidney Disease Treatment
First Line: ACEI or ARB
Second Line: CCB or Thiazide
Comorbid condition: Diabetes treatment
First Line: ACEI or ARB
Second Line: CCB or Thiazide
Comorbid condition: HF treatment
First Line: ACE or ARB + thiazide (or Loop) + beta blocker
Second Line: Aldosterone antagonist, hydrazine/isosorbide dinatrate (black)
Comorbid condition: MI Treatment
First Line: beta blocker the ACEI/ARB
Second Line: Aldosterone Antagonist
Comorbid condition: Prior Ischemic Stroke Treamtne
First Line: ACEI or ARB
Second Line: CCB or Thiazide
Hypertensive Crisis
Clinical syndrome - generally diastolic > 120 mmHg leading to vascular and organ damage
Divided into Two Types:
- Emergencies (target organ damage)
- Urgencies
Hypertensive EMERGENCY
DBP > 150 mmHg in otherwise healthy person
or
DBP > 120 mmHg in individuals with pre-existing complications
Damage of target organs (brain, kidney, heart)
Immediate BP reduction is required (IV drugs)
Hypertensive URGENCY
No target organ damage
Patients should be started of 2 oral drugs and close evaluation continued on an outpatient basis
Hypertensive Emergency Causes
- Essential hypertension
- renal parenchymal disease
- renovascular disease
- pregnancy (eclampsia)
- endocrine dysfunction
- Drugs (cocaine, crack, etc)
- Drug withdrawal
- CNS disorder
- Autonomic hypereactivity
Hypertensive Emergency- Management
Admission into ICE- IV drugs
Arterial line to measure BP
BP should be progressively reduced using short acting titratable drugs
** abrupt dec. in BP can lead to MI, Stroke, and visual changes
Lowe BP no more than 25% with 1 hr. (goal is 100-110 mmHg DBP)
If stable further reduction to (160/100 mmHg SBP/DBP) within 2-6 hrs
Hypertensive Emergency - Treatments
Sodium Nitroprusside Labetalol Fenoldopam Nicardipine Nitroglycerin Diazoxide Phentolamine Esmolol Hydralazine
Sodium Nitroprusside
Always give IV (poisonous oral)
short half life (t1/2= 1-2 min)
requires continuous infusion
Prompt vasodilation and reflex tachycardia
causes peripheral vasodilation by direct effects on arterial and venous smooth muscle
AE:
- hypotension, goose bumps, abdominal cramps, nausea, vomiting, headache
- cyanide toxicity (rare) -metabolite (treat with sodium thiosulfate infusion)
Labetalol
Combined beta and alpha blocker
IV bolus or infusion for hypertensive emergencies
t 1/2 = 3-6 hrs.
DOES NOT cause reflex tachycardia
Contraindications: Asthma, COPD, 2nd or 3rd degree AV blocks, or bradycardia
Fenoldopam
Peripheral Dopamine (D1) receptor agonist
evokes arteriolar dilation
infusion for hypertensive emergencies
t 1/2 = 30 min
Maintains or increases renal perfusion as lowering BP
Promotes natures
safe in all hypertensive emergency (especially in patients with renal insufficiency)
Nicardipine
Calcium channel blocker
IV infusion for hypertensive emergency
t 1/2 = 30 min
evokes reflex tachycardia
Nitroglycerin
Vasodilator (more effect on veins than arteries)
DOC for hypertensive emergencies in patients with cardiac ischemia or angina or after bypass surgery
t 1/2 = 2-5 min
Hypotension = most serious side effect
Diazoxide
Arteriolar dilation
Prevents vascular smooth muscle contraction by opening K+ channels and stabilizing the membrane potential
t 1/2 = 24 hrs
AE:
- Hypotension, reflex tachycardia, Na+ and H2O retention
- inhibits insulin release and can be used to treat hypoglycemia secondary to insulinoma
Other options
Phentolamine:
DOC for patients with catecholamine released emergencies
Esmolol:
Often used for aortic dissection or post-operative hypertension
Hydralazine:
DOC in treating hypertensive emergencies in pregnancy related to eclampsia
