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73 Cards in this Set

  • Front
  • Back
Non-pharmacologic therapy for HTN?
1. Lose weight
2. Reduced salt intake
3. Reduced alcohol intake
4. Physical exercise
What are the first-line drugs in the treatment of HTN?
1. Thiazide diuretics
2. ACEi
3. Orally-active ATII receptor antagonists
4. CCAs
5. B-blockers
6. A-adrenoceptor antagonists
Name other drugs used for HTN treatment?
1. combined a- and b- receptor antagonists
2. centrally acting agents
3. Vasodilating agents
-- arterial
-- arterial and venous
What is the first-line diuretic used?
HCTZ use, hemodynamic and renal effects?
1. used as monotherapy and to prevent/reverse ths salt and water retention caused by other antihypertensive drugs

2. Hemodynamic and renal effects
- initial saluresis lowers ECF volume and thus CO; BP falls
- CO eventually returns to pretreatment value and the fall in BP results from a decline in TPR
- ECF volume remains slightly reduced (about -5%), so plasma renin activity (PRA) and Aldo are persistently elevated
- HR is unchanged or increases slightly
- prolonged therapy reverses LVH by 5%
unknown; fall in BP is dependent on maintaining a negative Na balance b/c high salt intake reverses the hypertensive effect
Clinical use HCTZ?
- most frequently used anti-HTN agent in the U.S.
- BP falls by about -20/-10mmHg, and this response takes 2-4 wks to develop fully

- AntiHTN effect occurs at small doses, which produce only a mild natriuresis
-- Increasing the dose above this value does not cause a greater fall in BP but will increase the incidence of metabolic abnormalities

- Modest salt restriction prevents need for larger doses and limits K loss (directly proportional to amt of Na delivered to the distal tubule

- Plasma Aldo rises secondary to increased plasma renin activity (PRA) and plasma ATII. This secondary hypoaldosteronism contributes to hypokalemia

- No effect in BP of patients w/ GFR <30

- used routinely to prevent/reverse the salt and water retention caused by other antiHTN drugs (arterial vasodilators, A- and B-adrenoceptor antagonists, and centrally acting sympatholytic drugs
HCTZ toxicity?
1. Hyperuricemia - usually asymptomatic; may precipitate gout

2. Hyperglycemia (DMII) - low incidence; thiazides directly inhibit insulin secretion

3. Hypokalemia
- no evidence that hypoK causes dysrhythmias in pts whose only cardiac abnormality is LVH
- special care to correct hypoK in pts receiving cardiac glycosides (digoxin) since hypoK predisposes to digoxin-induced dysrhythmias
- hypoK appears to account for the disturbances in glucose metab (decreased insulin sensitivity) and symptoms of muscle weakness and fatigue encountered in some patients

4. Hyperlipoproteinemia
How do you lessen HCTZ hypokalemia?
1. use low dose HCTZ w/ modest Na restriction

2. cotreat w/ K-sparing diuretics amiloride, spironolactone, triamterene

3. cotreat w/ ACEi

4. cotreat w/ angiotensin receptor antagonist (ARB)

5. cotreat w/ B-blocker

6. cotreat w/ oral K supplement
Name the ACE inhibitors?
ACEi use and hemodynamic/renal effects?
Used as monotherapy or combined w/ thiazide for increased efficacy

- MAP falls b/c TPR reduced
- In addition to the dilation of resistace arterioles, drugs increase compliance of large arteries thus causing further fall in SBP; increase compliance appears to result from reversal/prevention of ATII trophic effect on protein synth in small and large arteries
- SBP, DBP, and MAP are decreased
- CO is little changed, although SV and CO may be reduced slightly via venodilation
- HR is unchanged, or may fall somewhat, but this lack of tachy does not result from impaired baroreflexes
- RBF is uniformly increased by dilation of both the aff and eff arterioles, but GFR is unchanged; FF is reduced, so salt/water retention does not occur
- blood flow in cerebral and coronary beds is well maintained
- prevent/reverse vascular/cardiac remodeling caused by ATII
- prevents conversion of ATI to ATII (also prevents brkdwn bradykinin)

- Initial fall in BP is related to pretreatment value of PRA, bit long-term antiHTN response does not correlate w/ PRA pretreatment. No effect on BP in anephric pts.

- Plasma ATII falls, but plasma Aldo is maintained by ACTH and plasma K concentration
Clinical use of ACEi?
- lower BP in about 50% of HTN patients, so their efficacy as a single agent is comparable to the thiazide diuretics and B-adrenoceptor antagonists

- 80% patients show response when thiazide added

- Also used to trt malignant HTN, renovascular HTN, and the HTN crisis of scleroderma

- Long term tx reverses (-15%) the hypertensive cardiac hypertrophy

- DOCs for patients w/ HF, LVH, and DM (protects the kidneys) and pts w/ systolic dysfxn after MI

- Cardiovascular reflexes are maintained, so postural HTN is rare

- No hypoK, hyperuricemia, hyperglycemia or hyperlipidemia

- prevent or reverse both the hypoK and the adverse changes in plasma lipid profile, produced by thiazide diuretics

- fatigue, weakness, sexual dysfxn rare
ACEi toxicity?
-- "first dose" hypotension, expecially in thiazide-treated pts
-- Renal insufficiency - in pts w/ bilateral renal a. stenosis or stenosis of solitary kidny; marked dilation of efferent arterioles causes glomerular hydrostatic P to fall dramatically
-- HyperK - only in pts receiving K-sparing diuretics or oral K supplements
-- Angioedema - not dose-related and can be life-threatening. May occur months after trtmt started
-- Skin rash - dose-related
-- loss of taste or abnormal taste
-- Dry cough (7-15%) - dose related; one aspirin/day prevents the cough in many patients
-- Neutropenia - incidence in total pt population is 0.2%, but occurs 0.5% in pts w/ renal dysfxn (GFR<30) and 7.5% pts w/ renal dysfxn and collagen vascular disease
-- DO NOT USE DURING PREGNANCY! - teratogenic throughout and can cause oligohydramnios, fetal calvarial hypoplasia, fetal pulminary hypoplasia, fetal growth retardation, neonatal anuria, and neonatal death
Name the orally active ATII receptor antagonists (ARBs).

BALANCED vasodilators
ARB use, hemodynamic and renal effects?
Use as monotherapy or combined w/ thiazide for increased efficacy

- hemodynamic and renal effects essentially same as those caused by ACEi
- also increase compliance of both small and large arteries by a mech independent of the decrease in BP caused by these drugs (like CEIs)
- produces competitve blockade of AT1 receptors, thus blocking all the cardiovasc effects of AngII
ARB clinical use?
Approved for HTN
- dose-response curve for drugs is shallow
- if addtl fall in BP desired, better to add small dose HCTZ than to increase dose of ARB

May be beneficial for CHF trtmt, but not yet approved; will probably be developed for use in pts. w/ CHF who develop toxicity on an ACE inhibitor
ARB toxicity?


3. No dry cough

4. Agioedema can occur, espec in pts who have developed angioedema on an ACEi

5. Can cause less HTN

6. HyperK
Name the CCAs.

All above are DHPs

(verapamil and diltiazem are also CCAs - nonDHP - but used prim for angina, dysrhythmias)
Block L-type Ca channels in vascular smooth muscle and cardiac muscle
CCA Pharm effects on BP?
1. greatest fall in BP------least
DHPs (nefedipine) > verapamil>diltiazem

2. All the CCAs are effective in the trtmt of HTN, but the DHPs are used when the sole aim of therapy is to treat HT
CCA Pharm effects on the kidney?
1. tend to dilate preglomerular arterioles and thus decrease GFR

2. No change in renin release

3. CCAs promote salt/water excretion, perhaps by a direct inhibitory effect in the renal tubule.

4. Reduce proteinuria in pts w/ DMII, but an ACEi remains the DOC for preventing glomerular damage in these pts
CCA hemodynamic and renal effects?
1. BP falls as TPR is dilated. Dilate arterioles but not venules

2. SBP, DBP, and MAP are reduced

3. Large arteries are relaxed; increases Windkessel fxn of these conduit arteries which in turn causes an additional fall in SBP

4. CO may be increased slightly by nifidipine and the other DHPs

5. DHP can produce slight tachy

6. RBF and GFR may increase, decrease, or remain unchanged, but salt and water retention do not occur b/c these drugs exert a direct natriuretic effect at the renal tubules (mech unknown

7. PRA, plasma ATII and Aldo conc are unchanged
Clinical use of the CCAs?
The DHPs are first-line drugs in trtmt of mild to moderate HT

-- use extended release prep for drugs w/ short half-life
-- unlike most other classes of first-line drugs, CCAs do not cause Na/water retention b/c they exert direct natriuretic effects which persist throughout therapy
-- effective in trtmt systolic HTN b/c they cause greater fall in SBP than DBP
-- well-suited for use in pts w/ asthma, DM, renal dysfxn, gout, hyperlipidemia
CCA toxicity?
1. Excessive vasodilation
-- hypotension, dizziness, headache w/ a pounding pulse, facial flushing, lower leg edema
-- sympt may disappear if decrease dose
-- usually not seen in slow release form or w/ long half-lives

2. Pedal edema
-- NOT a result of expansion of ECF volume
-- dilataion of precep sphincters causes excessive filt of fluid into interstit space of ankles
-- most likely to occur w. DHPs

3. do not suppress AV conduction or CO


5. parodoxical angina from "coronary steal:
Name the B-blockers used to decrease HTN.
B-blocker use?
1. Cheap, effective way to manage HTN, but the fall in renal perfusion pressure can lead to increase in filtration fraction which causes slowly developing water/salt retention
-- volume expansion limits the antiHTN effect and is called "pseudotolerance"

2. Thiazide often added to B-blocker b/c causes further BP reduction and prevents salt/water retention which may occur in response to the fall in renal perfusion pressure
B-blocker MOA?
unknown how they reduce TPR
Name the combined a- and b-adrenoceptor blockade drug.
Labetalol use, hemodynamic and renal effect?
Used primarily for trtmt of HTN emergency
- MAP falls as TPR declines
- CO is unchanged
- basal HR falls: exercised induced tachy is attenuated
- fall in renal perfusion pressure can lead to increased filtration fraction which causes slow retention of salt/water
- PRA and plasma angII are unchanged
Labetalol MOA?
Blocks B1-adrenoceptors in heart

Blocks a1-adrenoceptors in the arterioles and venules

Partial agonis at vascular B2 receptors
Clinical use of labetalol in HTN emergency?
1. AntiHTN effect after i.v. injection is smooth with an onset of 2-4 min, a peak at 10-15 min, and a duration of 24h

2. HR unchanged or reduced slightly

3. CO unchanged via BALANCED VASODILATION, so cerebral, coronary and RBF are maintained

4. Poorly lipid soluble, so little effect on fetus in pre-eclampsia

5. After control of BP is obtained w/ i.v. prep, p.o. therapy w/ labetalol can be started
Labetalol toxicity?
1. orthostatic HTN
2. headaches
3. fatigue
4. reduced sexual fxn
a-methyldopa use?
**centrally-acting agent

Previously a first-line agent for mild to moderate HTN, but concomitant admin of a diuretic agent is usually req'd and adverse S/Es limit its usefulness

-- can be used in pediatric HTN and HTN during pregnancy

-- In HTN emergency, the slow fall in BP prevents MI/CVA
a-methyldopa toxicity?
dry mouth
rebound HTN
flu-like syndrome (drug fever)
positive Coomb's test
clonidine use, hemodynamic and renal effects?
**centrally-acting agent

Usually used w/ diuretic drug in trtmt of mild to moderate HTN

-- Standing position, BP is lowered by decline in TPR (passive vasodilation due to w/d of sypmathetic tone)
-- Seated position, venodilation and subseq reduction in venous return tend to decrease CO
-- FF may be increased in response to fall in renal perfusion pressure, so salt/water retention develop slowly
-- plasma renin activity and ATII conc are suppressed
clonidine MOA?
highly lipid-soluble cmpd is an a2-adrenoceptor agonist which enters the brain and reduces sympth outflow by stim of postsynaptic a2-adrenoceptors in the rostral ventrolateral medulla

- sympathetic reflexes are attenuated, but not blocked
clinical uses clonidine?
mild to moderate HTN, but progressive salt/water retention limits fall in BP (pseudotolerance)
clonidine toxicity?
1. Sedation - may lessen after several weeks therapy, bud decreased mental acuity and chronic forgetfullness may persist

2. Dry mouth - 25-50% of patients; may be accomp by dry nasal mucosa, dry eyes, and swelling of parotid glands

3. CNS - vivid dreams, restlessness, depression

4. CV - orthostatic intolerance, bradycardia, and slowing of AV conduction

5. Withdrawal syndrome - headache, apprehension, tremor, abdom pain, sweating, tachy, and increased BP result from rebound increase sympt activity
Name the arterial vasodilators.
hydralazine, minoxidil, diazoxide
H, M, and D use?
1. NOT first-line drugs in trtmt of HTN
-- reserved for pts w/ severe HT resistant to combined therapy of first-line drugs
-- DIAZOXIDE used only in trtmt of HTN emergency
H, M, and D hemodynamic and effects?
1. only vascular smooth muscle of arterioles is relaxed

2. arteriodilation lowers TPR: BP falls

3. Decrease in BP elicits a baroreflexly mediated increase in sympth discharge to heart, vasculature, kidney

4. reduction in BP per se, and increased a-adrenoceptor and ATII stimulation in renal tubules also contrib to the retention of salt/water
What occurs in the heart, vasculature, and kidney when H, M, and D-related dip in BP elicits a baroreflexly mediated increase in sympathetic discharge?
1. Heart responds w/ increased rate and dp/dt

2. Venous response is decreased venous capacitance

3. NET effect is large increase in CO

4. increase in sympth activity cannot constrict the arterioles b/c of the overwhelming pharm effec of the venodilating drug

5. Renal B1-adrenoceptor stim increses renin release. Increased plasma ATII elevates plasma Aldo which produces progressive Na/water retention
H, M, and D mechanism of action?
1. all three relax arteriolar sm muscle by reducing availability of intracellular Ca for excitation-contraction coupling, but the mech has not been established

2. HYDRALAZINE - may degrade to form NO or hyperpol sm muscle cells by opening K channels

3. MINOXIDIL's active metabolite, minoxidil sulfate (produced by liver) hyperpol VSM cells by increasing K conductance

4. DIAZOXIDE hyperpol vasc smooth muscle cells by increasing K conductance
Clinical use of hydralazine and minoxidil?
- reserved for use in severly HTN pts, but they cannot be used as single agents b/c of tachy and ECF volume expansion

- combo w/ b-blocker prevents the tachy and lessens the increase in CO and myocardial oxygen demand; also blocks symth-mediated renin release, thus preventing secondary hyperaldosteronism

HYDRALAZINE -- rapid onset
MINOXIDIL -- very slow onset (must be bioactivated by the liver)
Hydralazine and minoxidil toxicities?
1. tachy, cardiac palps, headache, edema, angina
2. SLE-like syndrome
-- fever, arthralgia, arthritis, malar rash
-- slow acetylators more at risk for syndrome
-- syndrome remits after drug stopped, but corticosteriod therapy might be req'd
3. can cause a pyridoxine-responsive polyneuropathy

1. tachy, edema, angina, and global hypertrichosis
2. topical used to treat baldness (can cause large amt hair growth everywhere when used systematically)
Clinical use of diazoxide?
**used exclusively in ER - HTN emergency

- given by minibolus injections to circumvent the problem of avid binding to plasma proteins
Toxicity of diazoxide?
1. Tachy, edema, angina

2. hyperglycemia (directly inhibits insulin release)
-- DMII treated w/ orally active hypoglycemic agents are at greatest risk for hyperglycemia
-- can use to treat insulinoma

3. relaxes uterine smooth muscle and may arrest labor if given to treat pre-eclampsia
Name the arterial and venous dilator.
Sodium nitroprusside
Hemodynamic and renal effects of sodium nitroprusside?
1. Only given to SUPINE patients

2. used for HTN emergencies in hospital -- must be prepared fresh in sterile 5% dextrose water (D5W) and given by slow i.v. infusion

-- DBP falls as TPR is reduced
-- venodilation decreases venous return, so CO is decreased
-- HR is elevated slightly, via the carotid barorefles in response to fall in BP
-- elim half-life is only 30sec, so dose titration based on hemodynamic response
-- usually not given long enough to cause salt/water retention
-- when used in pts w/ CHF, increase in CO usually causes a hemodynamic saluresis
sodium nitroprusside MOA?
When it comes in contact w/ RBCs, NO is released causing vasodilation and inhibition of platelet aggregation via stimulation of guanyl cyclase

Increased cGMP relaxes vascular smooth muscle
Sodium nitroprusside clinical use?

- HTN emergencies
- Controlled hypotension during surgery and to halt acute dissecting aneurysm
- Increases CO in CHF and reduces myocardial oxygen demand after MI
Sodium nitroprusside toxicity?
1. CV - tachy, headache, palpitations

2. Thiocyanate intoxication
-- anorexia, nausea, delirium, hallucinations, psychosis
-- occurs after several days of therapy and often assoc w/ decreased renal fxn
-- earliest signs of thiocyanate intox are a mental disorientation and metabolic acidosis in assoc w/ increased dose reqmt
-- to treat, d/c the drug and give furosemide to improve renal fxn
Normal metabolism of sodium nitroprusside
What is the goal of therapy?
To lower DBP below 85mmHg
AntiHTN drugs are chosen on the basis of...?
1. cost
2. efficacy in a subgroup of HT patients
3. side effect profile
4. effects on quality of life
First-line agent: thiazide diuretics
- effective in most pts, especially in older, and volume dependent pts (obese or black)

- avoid in pts w/ hyperuricemia, hyperglycemia, hyperlipidemia, and hypokalemia

- do not appear to reverse LVH as well as other drug classes
First-line agent: ACEi or ARBs
1. DOC for pts w/ DM (even if normotensive), LVH, or HF assoc w/ diastolic or systolic dysfxn

2. Tend to work better in young, caucasian pts (<50y.o.)

3. Will work in older and black if combined w/ thiazide

4. Used in pts who cannot tolerate thiazides or B-adrenoceptor antagonists

5. Used in pts w/ CHF, DM, hyperuricemia, hyperlipidemi, hyperglycemia, or hypoK. Also safe in pts w/ hx of dysrhythmias

6. Use ARBs in pts w/ cough on ACEi
First-line agent: CCA
Use extended release or drugs w/ long half-lives

1. use in pts who cannot tolerate thiazides, b-blockers, or ACEi

2. more effective in pts w/ low PRA (black, elderly)

3. can use in pts w/ pulmonary disease, signif LVH, peripheral vascular disease, or hx of cardiac dysrhythmias
First-line agent: B-blockers
1. well-suited for young pts w/ hx of angina pectoris, MI, dysrhythmias, or MV prolapse

2. black and older tend to respond poorly

3. avoid use in pts w/ DMII, peripheral vascular disease, asthma, COPD, and CHF

**decreases ability to exercise
What do you do when pts have an inadequate response to a single agent?
1. Try therapy w/ a different class of first-line agents

2. If still not successful, add a second drug from another class of first-line drugs.
-- HCTZ enhances the antiHTN effects of B-blockers, CCAs, ACEi, and ARBs

3. If two first-line drugs do not provide an adequate response, you may add a third class of first-line drugs, but first consider possibility of:
-- noncompliance
-- inapprop dosages
-- volume expansion
-- excessive alcohol intake
-- progression of renal disease
How compliant are patients when taking antiHTN drugs?
Less than 10% of patients discontinue antiHTN drugs b/c of adverse S/Es
How do we approach trtmt of systolic HTN in the elderly?
**defined as fixed BP greater than 160/90mmHg

- encountered in elderly pts w/ decreased arterial compliance
- these patients are at greater risk for CV events (MI, CVA, HF)
- the control of SBP is more important than the control of DBP

1. SHEP program indicates that trtmt w/ low doses thiazide diuretic drugs given singly or in combo w/ B-blocker or reserpine did produce significant decreases in non-fatal strokes, MI, and LVF after 4.5 yrs trtmt
An extreme elevation of BP can be associated with...?
Extreme BP elevation can be associated w/ hypertensive encephalopathy, intracranial hemorrhage, acute LVF, pulmonary edema, unstable angina, acute MI, dissecting aortic aneurysm, eclampsia, head trauma, and extensive burns
How do we approach treatment of hypertensive emergency?
Rapid acting drug given i.v. to treat the HTN
-- labetalol
-- esmolol
-- nicardipine
-- diazoxide
**single-dose i.v. given SLOWLY
-- sodium nitroprusside (try to stay away from b/c of short half-life)

SAER uses p.o. clonidine
- nice slow fall in P
- okay as long as also eventually treat with something else later
Why must we lower BP slowly?
When pts suffer from HTN encephalopathy (very high BP), BP must not be lowered too rapidly b/c ischemic stroke or MI may result

-- lower BP about 15% immediately followed by a more gradual decline over the next 24h
-- oral therapy w/ a first-line drug should be started during emergency treatment
How do approach treatment to preeclampsia?
1. MAGNESIUM SULFATE given by i.v. infusion to prevent seizures may also lower BP some, but either LABETALOL or NICARDIPINE usually must be given by i.v. infusion to control BP

2. Do not lower BP to less than 130/80 b/c hypoperfusion of the placenta and fetus may occur

3. DO NOT use DIAZOXIDE ( may halt uterine contractions) or SODIUM NITROPRUSSIDE (causes fetal cyanide poisoning)
Which antiHTN drugs will increase ECF volume?
arterial vasodilators
a-adrenoceptor antagonists
Which antiHTN drugs will cause the ECF volume to be unchanged or decreased?
diuretic drugs
Which vasodilators will increase CO?
venous dilation = decreased VR

Which vasodilators will cause CO to be unchanged?
arterial/venous balanced vasodilation = decreased VR and DBP

a1-adrenoceptor blockers
sodium nitroprusside
a-methyldopa, clonidine
Which vasodilators will cause CO to be increased?
arterial dilation = increased VR and decreased DBP

nifedipine (DHPs)