Drugs for Hypertension - Part 1 & 2 Flashcards
What are the 3 main takeaways from the Prevalence of Hypertension trends?
- There is a sex difference (as we age & woman enter post menopause it becomes more similar of m/f)
- Age difference (rates increase with age for both m/f)
- Race & ethnicity factor (ex: increase rates for non-hispanic black people)
What long-term health risks are associated with hypertension?
➢ Cardiovascular disease
➢ Retinopathy
➢ Cerebrovascular disease ➢ Dementia
➢ Ischemic heart disease
➢ Left ventricular hypertrophy
➢ Atrial fibrillation
➢ Heart failure
➢ Chronic kidney disease
➢ Peripheral vascular disease
What is hypertension often referred to as?
“silent killer” - often gets undiagnosed & then long-term health risks dev.
List Modifiable Risk Factors common in patients with hypertension
- Current cigarette smoking, secondhand smoking
- Diabetes mellitus
- Dyslipidemia/ hypercholesterolemia
- Overweight/obesity
- Physical inactivity/low fitness
- Unhealthy diet
(Factors that can be changed and, if changed, may reduce CVD risk)
List Relatively Fixed Risk Factors
- Chronic Kidney Disease
- Family history
- Increased age
- Low socioeconomic/educational
status - Male sex
- Obstructive sleep apnea
- Psychosocial stress
(Factors that are difficult to change (CKD, low socioeconomic/educational status, obstructive sleep apnea, cannot be changed (family history, increased age, male sex), or, if changed through the use of current intervention techniques, may not reduce CVD risk (psychosocial stress).
CKD indicates chronic kidney disease; and CVD, cardiovascular disease.)
What is blood pressure?
BP = CO x TPR
- Cardiac output (CO)
- Total peripheral resistance (TPR)
- Chronic increases in BP are normally due to increased arterial resistance (TPR)
- As arteries constrict resistance increases
- Smooth muscle constriction and arterial elasticity
- Subject to a balance of vasoconstriction and vasodilatory signals
– Sympathetic activity constricts peripheral arteries – Nitric oxide synthesis dilates arteries
Sympathetic activity ____ peripheral arteries
constricts
Nitric oxide synthesis ____ arteries
dilates
Decrease BP:
___ renin
___ Ang-II
___ aldosterone release
___ SNA
___ retention
increase
increase
increase
increase
Three (3) major compensatory responses to a decrease in BP regardless of cause may be:
- physiologically useful (dehydration, hemorrhage, early heart failure,
- pathophysiologically harmful (renal artery stenosis, decompensated heart failure).
What is normal BP in adults?
s: <120 mm Hg
d: <80 mm Hg
What is elevated BP in adults?
s: 120-139 mm Hg
d: <89 mm Hg
What should you do if you have normal or elevated BP?
manage risk factors
lifestyle modification (promote) for normal
nonpharmacologic therapy for elevated
reassess in 1 y for normal
reassess in 3-6 mo for elevated
What is stage 1 hypertension in adults?
s: 140-159 mm Hg
d: 90-99 mm Hg
What is stage 2 hypertension in adults?
s: >/ 160 mm Hg
d: >/ 100 mm Hg
What is emergency hypertension in adults?
s: >/ 180 mm Hg
d: >/ 120 mm Hg
What should you do if you have stage 1 or stage 2 hypertension?
manage with medications
lifestyle modifications
reassess in 3-6 mo or 1 mo
What should you do if you have emergency hypertension?
life threatening
may lead to stroke
(hospitalized)
Which laboratory tests should be done in newly diagnosed cases?
Newly diagnosed hypertension
❑Measure hemoglobin or hematocrit, serum electrolytes, serum creatinine, serum glucose, and fasting lipid levels
❑Urinalysis with microscopic examination (access kidney function)
❑12-lead electrocardiography
(see if HTN has been undiagnosed in patient for awhile)
Tests indicated by clinical factors or anticipated treatment
❑Echocardiography (more sensitive than EKG for LVH)
❑Serum uric acid levels (if patient has gout) (esp. if older patient)
❑Microalbuminuria (if patient has diabetes)
Common Causes of Secondary Hypertension With Clinical Indications
- Renal parenchymal disease
- Renovascular disease
- Primary aldosteronism
- Obstructive sleep apnea
- Drug or alcohol induced (may need to stop taking certain meds)
Uncommon Causes of Secondary Hypertension With Clinical Indications
- Pheochromocytoma/paraga nglio ma
- Cushing’s syndrome
- Hypothyroidism
- Hyperthyroidism
- Aortic coarctation (undiagnosed or repaired)
- Primary hyperparathyroidism
- Congenital adrenal hyperplasia
- Mineralocorticoid excess syndromes other than primary aldosteronism
- Acromegaly
What is prehypertension, and what is its proper management?
➢Blood pressure 120/80 to 139/89 mm Hg
➢“Prehypertension” is not in evidence-based guidelines for management of adult high blood pressure
➢Drug therapy is NOT recommended for prehypertension
❑Evidence lacking on whether it decreases or prevents cardiovascular events
❑Focus on lifestyle changes for these patients
What are the recommended
lifestyle modifications for
treating hypertension?
➢Salt restriction (*1 of the best things)
➢Weight loss (to <20% above ideal weight for height)
➢Exercise (≥30 minutes aerobic exercise most days)
➢Smoking cessation
➢Alcohol intake limited to no more than 2 drinks daily
What are the Best Proven Nonpharmacological Interventions for Prevention and Treatment of Hypertensio?
- Weight loss
- Healthy diet
- Reduced intake of dietary sodium
- Enhanced intake of dietary potassium
- Physical activity
- Moderation in alcohol intake
What are the major/minor classes of drugs to treat hypertension?
4 Major Classes - approved as 1st line single treatment
- diuretic
- ACEi, ARB
- calcium channel blocker (CCB)
- B-adrenergic receptor antagonist
3 Minor Classes
- added on when above fail
- a1-adrenergic receptor antagonist
- a2-adrenergic receptor agonist
- vasodilators
Pulmonary Arterial Hypertension
List the diuretics for hypertension
- hydrochlorothiazide
- metolazone
- furosemide
- spironolactone
List the ACEi, ARB for hypertension
- enalapril
- losartan
- valsartan
List the calcium channel blocker (CCB) for hypertension
- verapamil
- nifedipine
List the B-adrenergic receptor antagonist for hypertension
- carvedilol
- metoprolol
List the a1-adrenergic receptor antagonist for hypertension
Prazosin
List the a2-adrenergic receptor agonist for hypertension
Clonidine
List the vasodilators for hypertension
- sodium nitroprusside
- hydralazine
List the Pulmonary Arterial Hypertension for hypertension
- sildenaphil
- bosentan
- epoprostenol
What are the three main physiologic mechanisms for antihypertensive drugs?
BP = CO x TPR
- Decrease blood volume–decrease CO
- Relax blood vessels (mainly arterial) – decrease TPR
- Decrease stimulation of the heart – decrease in CO
Which antihypertensive drugs “Decrease blood volume–decrease CO”?
- diuretics (hydrochlorothiazide, furosemide)
- interrupt renin angiotensin aldosterone system (spironolactone)
Which antihypertensive drugs “Relax blood vessels (mainly arterial) – decrease TPR”?
- interrupt renin ANGIOTENSION aldosterone system
- ACEIs (enalapril)
- ARB (losartan)
- CCB (nifedipine)
Which antihypertensive drugs “Decrease stimulation of the heart –decrease in CO”?
- B-adrenergic receptor antagonist (carvedilol, metoprolol)
- CCB (verapamil)
What is diuresis?
- Increased production of urine by the kidneys
- Drinking water produces mild diuresis to maintain fluid- electrolyte balance (increase water, remove excess water from body)
What are diuretics?
- Substance that increases the production of urine
- patients with heart failure and kidney failure need diuretic medications to help the kidney deal with fluid overload of edema
- Treat hypertension by decreasing blood volume (if you can decrease BV by diuretics, you can decrease BP)
- Treat electrolyte imbalances
What are clinical uses of diuretics?
used for EDEMA forming conditions and ARTERIAL HYPERTENSION
- Hypertension
- Tissue Edema
- Hepatic cirrhosis
- Cardiac failure
How are diuretics used for hypertension?
- 1st line single therapy (thiazide diuretic)
- but possible ↑ LDL, ↑ plasma glucose (not metabolically neutral)
- good as second medication to treat sodium and water retention (may not be good for someone with hyperedemia or diabetes)
- common side effect of other anti-hypertensives (can help restore electrolyte balance)
How are diuretics used for tissue edema?
- fluid shift into the extra cellular space has exceeded 3 to 4L
- due to salt and water retention
- Loop diuretic (FUROSEMIDE) preferred, if no response to the Loop diuretic, add a thiazide – normally metolazone
- fluid excreted in urine is taken from the “vascular space” (bloodstream), allow time for this to be replaced by the interstitial (edematous) fluid
- otherwise cardiovascular collapse
How are diuretics used for hepatic cirrhosis?
- sodium/water accumulates in the abdomen and/or tissue
- abdominal fluid movement into vascular space may be a concern
- slower than fluid movement from interstitial to vascular space
- aggressive treatment will remove fluid faster from the vascular space than can be replaced by the abdominal fluid
How are diuretics used for cardiac failure?
- fluid retention increases vascular volume
- helps to increase preload and stimulate the heart - as failure continues so does fluid retention
- preload increases to levels causing edema
- diuretics decrease vascular volume
- successful treatment of heart failure requires adequate control of vascular volume
Describe Kidney Reabsorption
PROXIMAL TUBULE reabsorbs almost all glucose and amino acids and about 60% of Na+ (back into bloodstream)
* Na+ is reabsorbed through a Na+/K+ ATPase
* Cl- exchanged for formate or oxalate anions
* Water follows passively to maintain osmolarity
ASCENDING LOOP of Henle is IMpermeable to water
* Na+/K+/2 Cl- co-transporter reabsorbs 30% of these ions
DISTAL CONVULATED TUBULE is IMpermeable to water
* Na+/Cl- reabsorbed and Ca2+ excreted
COLLECTING TUBULE AND DUCT reabsorb Na+ and water from the urine and excrete K+
* Na+/K+ ATPase performs this function
Where ___ goes, water will follow
Na+
What is the definition of diuretics?
agents which increase urine flow
What is the clinic use of diuretics?
Clinically: interest is in renal solute excretion (sodium and water)
- block sodium absorption → water will follow later
What is the aim of therapy for diuretics?
- only need to decrease sodium reabsorption a few % - change of 5% has a great effect
99.6% of Na reabsorbed (goes back into bloodstream)
Main point: if Na reabsorption decreases only by 5%…
- then 1250 mmol/day of Na is excreted
- this would represent 9 liters of extracellular fluid loss
- potential for severe cardiovascular problems
Which drugs are used on the proximal tubule?
-mannitol
- acetazolamide
- dapagliflozin
Which drugs are used on the loop of henle?
loop diuretics
Which drugs are used on the distal tubules?
thiazide diuretics
Which drugs are used on the collecting tubule?
potassium sparing
Which drugs are used on the collecting duct?
tolvaptan
Which drugs are the Loop Diuretics?
- FUROSEMIDE
- bumetanide
- ethacrynic acid (non-sulfonamide)
What do Loop Diuretics do?
- inhibit the Na+/K+/2 Cl- co-transporter in the ascending loop of Henle
- very potent and efficacious - high ceiling diuretics
- up to 20% of filtered load excreted (dangerous!!)
(if we dose it too high it can cause CV problems) - Increases prostaglandin production (vasodilation?)
(separate function) - increases Na, Cl, K, Mg, Ca2+ excretion (note Ca effect)
What effects do Loop Diuretics have?
INCREASED urinary excretion
- Na+
- K+
- Ca2+
- Volume of urine
Loop diuretics have a much _____ effect on urine volume and sodium excretion than ____ diuretics.
GREATER
THIAZIDE
Loop diuretics effect on calcium is ______ of what thiazide diuretics do to calcium.
opposite
- by increasing its urinary excretion
What are problems with Loop diuretics?
(in addition to electrolyte imbalances)
- deafness and kidney damage- never combine with aminoglycoside antibiotics (e.g.- kanamycin/streptomycin)
- interaction with the anti-arrhythmic agent amiodarone leads to a more irregular heartbeat
What are uses of Loop diuretics?
- preferred in renal insufficiency
- glomerular filtration rate < 30 ml/min
- Heart failure
- Edema (pulmonary)
- Hypertension
- NOT as first-line hypertension treatment (more for an add-on medication)
- NOT as sole medication
- Electrolyte imbalances
- hypercalcemia (opposite to thiazides diuretics)
Which drugs are the Thiazide Diuretics?
- METOLAZONE
- HYDROCHLOROTHIAZIDE
- similar mechanism(s), parallel dose response curves
(1st line treatment)
What do Thiazide Diuretics do?
similar mechanism(s), parallel dose response curves
distal tubule is primary site of action
- inhibit Na /Cl transporter
- ↓ Na/Cl reabsorption (↑ Na+ excretion )
- ↑ Ca2+ reabsorption (↓ Ca2+ excretion )
Secondary site of action at the proximal tubule
- Additional diuretic effect when combined with loop
diuretic
- Not usually important because of compensation in loop of Henle
+-
- inhibit Na /Cl transporter
- Na/Cl reabsorption ( Na+ excretion ) - Ca2+ reabsorption ( Ca2+ excretion )
Secondary site of action at the proximal tubule
- Additional diuretic effect when combined with loop
diuretic
- Not usually important because of compensation in loop
of Henle
** may decrease blood pressure without perceivable volume loss - low dose may be effective
(also decreased toxicity)
If refractory to a Loop diuretic add a _____ (proximal tubule effect may help)
thiazide
Where is hydrochlorothiazide’s site of action?
primary - NaCl transporter on distal tubule (blocking Na+ retention/reabsorb so you get more excreted)
secondary - Na transporter on proximal tubule
Where is furosemide site of action?
ascending loop of henle
(isn’t as effective so we add the hydrochlorothiazide)
Which are the Thiazide Diuretics?
- HYDROCHLOROTHIAZIDE
- METOLAZONE
Where do the Thiazide Diuretics act?
- distal tubule (primary site of action)
- inhibit Na+/Cl- transporter
What do Thiazide Diuretics do?
↓ peripheral resistance & ↓ sodium, water retension which ↓ BV & ↓CO
both ↓BP
At higher doses of Thiazide Diuretics, patients…
at higher doses - patient perceives need to urinate - “pee pill”
At lower does of Thiazide Diuretics, patients…
seen at lower doses - may not perceivably increase urine flow - but takes time to be effective (months)
What effects do Thiazide Diuretics have?
INCREASED URINARY EXCRETION:
- Na+
- K+
- Volume of urine
DECREASED URINARY EXCRETION:
- Ca2+
Thiazide Diuretics effect on calcium is ____ of what loop diuretics do to calcium.
opposite
- decreasing excretion of Ca2+
What are problems with Thiazide Diuretics?
- hypokalemia – increased Na+ in urine at distal tubule causes more K+ to be exchanged for Na+ causing loss of K+ from body
- hyperglycemia - problem for type 2 diabetes
- (↓ insulin release; ↓ tissue utilization)
- ↑ LDL levels (bad cholesterol - must monitor)
- less effective than RAS blockers in reducing CVD events
- decrease GFR so less effective in CKD patients
- interaction with the anti-arrhythmic agent amiodarone can lead to a more irregular heartbeat
What are the uses of Thiazide Diuretics?
- edema, hypertension
What are the advantages of Thiazide Diuretics?
- orally active
- no postural hypotension, low toxicity
- potentiate other anti-hypertensive medications (good to use in combo with others)
What drugs are Potassium Sparing Diuretics?
SPIRONOLACTONE (less common –> often used in combo with other diuretics b/c they are weak diuretics)
What do Potassium Sparing Diuretics (i.e. Spironolactone) do?
aldosterone receptor antagonist
prevents aldosterone from binding to receptor
- decreases sodium reabsorption
- decreases potassium excretion
Potassium Sparing Diuretics are…
weak diuretics
What are Potassium Sparing Diuretics used in?
- Used in treatment of heart failure, resistant hypertension, hyperaldosteronism, hypokalemia
- give with other diuretics to decrease potassium loss
- may cause hyperkalemia
- never combine with K+ supplements* (b/c of the 2 points above)
What effects do Potassium Sparing Diuretics have?
INCREASED URINARY EXCRETION:
- Na+
- Volume of urine
DECREASED URINARY EXCRETION:
- K+
Potassium Sparing Diuretics have a ___ effect on sodium excretion and urine volume.
weaker
Potassium Sparing Diuretics _____ potassium excretion (_____ to loop and thiazide diuretics).
decreases
opposite
(why its called K+ sparing diuretics)
Describe Electrolyte Disturbances – loop and thiazide diuretics
Potassium depletion due to thiazide and/or loop diuretics - not a problem in “healthy patients”
- more a problem if low potassium already a problem in for eg. heart failure, cirrhosis, etc
What are two major causes of Electrolyte Disturbances – loop and thiazide diuretics?
- secondary hyperaldosteronism (due to plasma volume depletion) - ↑ renin → ↑ Ang-II → ↑ aldosterone
- Na reabsorption at expense of K (and H) loss - increased distal delivery
- ↑ distal delivery - due to inhibition of Na reabsorption in loop and distal tubule
- collecting tubules therefore increase Na reabsorption
- to conserve sodium
What is the Potassium Depletion Treatment (for electrolyte disturbances)?
- dietary intake - apricots, bananas, etc
- potassium chloride tablets-chloride salt - dilute solution 3. slow-potassium tablets -ulceration
- emergencies
- iv KCl - 40 mEq - repeat cautiously until potassium rises 5. potassium sparing diuretics - SPIRONOLACTONE
- weak diuretics
- give with other diuretics to decrease K loss - may cause hyperkalemia
- * never combine with K supplements*
What is the Extracellular Volume Depletion (for Electrolyte Disturbances)?
- loop diuretics - kidney unable to concentrate or dilute
- excrete an isotonic urine (not excreting the electrolytes you should be)
- inability to concentrate urine
- drink more water to excrete solutes
- inability to dilute urine
- excess water consumption is excreted as an isotonic urine
- ingest hypotonic solution - excrete isotonic urine (drink water that doesn’t have a lot of electrolytes in it)
- net loss of electrolytes including plasma sodium
- chronic dilutional hyponatremia
Describe the calcium & volume depletion and increased proximal tubule reabsorption for electrolyte disturbances?
Calcium
- thiazides ↓ calcium excretion
- good for hypocalciuria
- furosemide ↑ calcium excretion
- good for hypercalcemia
Volume depletion and increased proximal tubule reabsorption
- uric acid excretion (b/c diuretics cause more urinary secretion of solutes)
– initially increased
- decreased with chronic administration (gout?)
- lithium - increased proximal tubule reabsorption
- toxicity
What are ACE Inhibitors?
Inhibits the Angiotensin Converting Enzyme (ACE)
- treat HTN
Why decrease formation of angiotensin II?
- Hypertension involves activation of the renin-angiotensin-
aldosterone system (RAAS) - RAAS induces vasoconstriction and blood volume retention
- ACE inhibitors (eg. ENALAPRIL)
-decreased constriction in arteries and veins - decreased aldosterone by decreased angiotensin II
- decreased blood volume (and decreased venous return)
What are ACEi (ex: ENALAPRIL)?
-decreased constriction in arteries and veins
- decreased aldosterone by decreased angiotensin II
- decreased blood volume (and decreased venous return)
What are the uses of ACEi?
hypertension, heart failure, kidney disease with albuminuria
ACEis or ARBs…
would decrease preload and afterload
Angiotensin Receptor Blockers (ARBs)
LOSARTAN
VALSARTAN
- both of heart & BVs
Angiotensin Receptor Blockers (ARBs):
- Blocks binding of Angiotensin-II to its receptor
- decreased constriction in arteries and veins
- decreased aldosterone by decreased angiotensin II
- Ultimate action is similar to ACEi but without increasing bradykinin
- No cough
- Similar complications to those seen with ACEi
- Originally marketed as ACEi without the cough
Angiotensin Converting Enzyme Inhibitors
Angiotensin Receptor Blockers – Side Effects and contraindications
use with caution if plasma Ang-II levels elevated -renal artery stenosis, volume depletion, diuretic use
ACEis produce non productive (dry) cough - less with ARBs
decreased aldosterone - decreased K excretion – do not use with potassium sparing diuretics –> hyperglycemia
only certain ACEIs
may decrease BP too much!! - use in combination with diuretics with caution
Both ACEIs and ARBs contraindicated in pregnancy and lactation - birth defects
(dry cough, hyperkalemia, skin rash, hypotension, fever)
