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Questions and Answers
What is a potential consequence of using thiazide diuretics in elderly patients?
Which diuretic is noted for providing more pronounced diuresis compared to thiazides?
What is the conversion ratio for Furosemide from IV to PO administration?
Which of the following statements about calcium channel blockers is true?
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Which of the following is NOT a common effect of loop diuretics?
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What is a common side effect associated with the use of verapamil?
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Which medication is classified as a dihydropyridine calcium channel blocker?
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What is the main mechanism by which loop diuretics exert their effect?
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Which adverse effect is specifically associated with the use of non-dihydropyridines?
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What is a compelling indication for the use of calcium channel blockers?
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Which of the following drugs is less likely to cause cardiac depression?
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What is a significant risk associated with immediate release dihydropyridine agents?
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Which statement about drug interactions involving calcium channel blockers is accurate?
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Which side effect is specifically associated with loop diuretics but not thiazide diuretics?
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What is the primary mechanism of action for potassium-sparing diuretics?
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Which of the following is a common side effect of spironolactone?
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Which drug interaction is particularly concerning when using diuretics?
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Which potassium-sparing diuretic is an aldosterone antagonist?
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What effect do calcium channel blockers (CCBs) have on blood pressure?
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Which condition makes thiazide diuretics ineffective?
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What is a common therapeutic combination involving thiazide diuretics?
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What is the primary mechanism of action for guanethidine in treating severe hypertension?
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Which of the following side effects is associated with reserpine?
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Which statement is true regarding the effects of arterial vasodilators?
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In treating resistant hypertension, what is a necessary combination for using minoxidil?
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What is a significant consequence of reserpine's mechanism of action?
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Which of the following side effects is not typically associated with guanethidine?
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What characteristic differentiates hydralazine in its clinical use for hypertension?
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What is an expected side effect of minoxidil?
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What is a potential risk when using ACEIs or ARBs in patients with renal vascular disease?
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Which of the following agents is typically avoided in the treatment of severe hypertension in pregnancy?
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What is a major consideration for combination therapy in hypertension?
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Which factor is NOT a cause of resistant hypertension?
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What is a recommended method to promote patient compliance in managing hypertension?
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In which condition are thiazide-type diuretics particularly useful?
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Which class of medication should not be used in combination with either ACE inhibitors or ARBs?
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What is a crucial aspect of managing hypertension regarding drug interactions?
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Study Notes
Thiazide Diuretics
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Side effects:
- Hypokalemia: Low potassium levels, which can lead to weakness and impaired insulin release.
- Dehydration: Especially problematic in elderly individuals, leading to postural hypotension.
- Hyperglycemia: May result from the impaired insulin release caused by hypokalemia.
- Hyperuricemia: Thiazides compete with uric acid for tubular secretion, leading to elevated uric acid levels.
- Hyperlipidemia: The mechanism is not fully understood, but cholesterol levels tend to increase slightly.
- Impotence
- Hyponatremia: Can occur after prolonged use due to factors like thirst, sodium loss, or inappropriate ADH secretion, which can cause confusion particularly in the elderly.
Less Common Thiazide Side Effects
- Hypersensitivity: May manifest as interstitial nephritis, pancreatitis, skin rashes, or blood dyscrasias, although these are very rare occurrences.
- Metabolic Alkalosis: An increase in sodium load at the distal convoluted tubule stimulates the sodium/hydrogen exchanger, resulting in enhanced sodium reabsorption and hydrogen ion excretion.
- Hypercalcemia: Increased calcium levels can occur.
- Magnesium Depletion: Thiazides can lead to a deficiency in magnesium.
- Weakness, Lethargy, Muscle Cramps
Loop Diuretics
- Block sodium reabsorption in the loop of Henle by inhibiting the apical Na-K-2Cl cotransporter in the TALH.
- Provide more potent diuresis than thiazides, but have a shorter duration of action and are less effective at lowering blood pressure.
- A better choice for patients with heart failure due to their effectiveness even with reduced glomerular filtration rate.
- Prototype agent: Furosemide, with other notable agents being torsemide, bumetanide, and ethacrynic acid.
- Potency: Torsemide and bumetanide are more potent than furosemide due to furosemide's lower bioavailability (60-65%).
- Allergy caution: Loop diuretics may cause allergic reactions in individuals with sulfonamide sensitivity. Ethacrynic acid may be used as an alternative in such cases.
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Pharmacokinetics:
- Rapidly absorbed from the gastrointestinal tract with bioavailability ranging from 65-100%.
- Can be administered intravenously, intramuscularly, or orally.
- Rapid onset of action.
- Extensively bound to plasma proteins.
- Short half-lives in general.
- Elimination: Excreted unchanged by the kidneys or via conjugation in the liver and secretion in bile.
Loop Diuretics Side Effects
- Similar to thiazide diuretics, but certain differences:
- Hypokalemia, metabolic alkalosis, hypercholesterolemia, hyperuricemia, hyperglycemia, hyponatremia, dehydration and postural hypotension
- Hypocalcemia: In contrast to thiazides, loop diuretics can lead to low calcium levels.
- Magnesium Depletion
- Hypersensitivity
- Ototoxicity: Especially if administered rapidly via intravenous bolus.
Potassium Sparing Diuretics
- Inhibit sodium reabsorption in the collecting tubule in exchange for potassium and hydrogen ions.
- Weak antihypertensive agents when used alone.
- Often used in combination with thiazides to counteract thiazide-induced hypokalemia.
- Prototype agent: Triamterene, with other agents being spironolactone, eplerenone, and amiloride.
- Spironolactone and eplerenone: Aldosterone antagonists, with spironolactone having an active metabolite called canrenone.
Potassium Sparing Diuretics Side Effects
- Hyperkalemia: Caution is advised in patients taking ACE inhibitors.
- Gastrointestinal: Diarrhea
- Photosensitivity
- Gynecomastia: Can occur with aldosterone antagonists.
- Nephrolithiasis: Can occur with triamterene.
- Reversible Azotemia: May happen with triamterene.
Drug Interactions - Diuretics
- Digoxin: Diuretic-induced hypokalemia can increase the risk of arrhythmias caused by digoxin.
- Lithium: Diuretics can lead to increased lithium levels, potentially causing lithium toxicity (weakness, tremor, thirst, confusion).
- NSAIDs: NSAIDs can reduce the diuretic and antihypertensive efficacy of diuretics by decreasing renal prostaglandin production.
- Hypoglycemic agents: Diuretics can decrease insulin sensitivity and increase potassium loss, potentially affecting hypoglycemic agents' effectiveness.
Therapeutic Notes About Diuretics
- Thiazide diuretics are often available in fixed-dose combinations with potassium-sparing agents or other antihypertensive drugs.
- Often used in combination with antihypertensive agents that impair vascular responsiveness, such as vasodilators, as blood pressure can become highly sensitive to blood volume in their presence.
- Potassium supplements may be prescribed to manage thiazide-induced hypokalemia.
- Thiazides are not effective in patients with renal insufficiency where glomerular filtration rate is below 40 ml/min.
Calcium Channel Blockers
- Two main types:
- Dihydropyridines: Amlodipine, nifedipine, nitrendipine, nimodipine, nicardipine, nisoldipine, felodipine, isradipine, lacidipine, lercanidipine, benidipine. Potent vasodilators of peripheral and coronary arteries.
- Non-dihydropyridines: Verapamil, diltiazem. Less potent vasodilators with negative chronotropic and inotropic actions.
- CCBs promote vasodilation by preventing the entry of calcium into vascular smooth muscle, decreasing total peripheral resistance and lowering blood pressure.
- All types (verapamil, diltiazem, and dihydropyridines) are equally effective in lowering blood pressure.
- Dihydropyridines are more selective vasodilators with less cardiac depressant effects than verapamil and diltiazem.
Calcium Channel Blockers - Compelling Indications
- Angina
- Diabetes
- Bronchospasm
- Renal Disease
Calcium Channel Blockers - Side Effects
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Most important adverse effects: Extensions of their therapeutic action.
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Non-dihydropyridines:
- Depression of contractility, heart failure, AV nodal blockade, bradycardia, hypotension.
- Verapamil has a greater impact than diltiazem.
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Dihydropyridines:
- Can cause tachycardia.
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Non-dihydropyridines:
- Common side effects: Flushing, headache, dizziness, fatigue, hypotension, lower extremity edema, constipation, nausea (especially verapamil), gingival hyperplasia (especially verapamil).
- Do not alter: Serum lipids, glucose, uric acid, or electrolytes.
- May not provide as much protection from cardiovascular events as beta-blockers and ACE inhibitors, except in the case of stroke.
- Avoid immediate-release dihydropyridine agents due to the risk of MI, severe hypotension, cerebral ischemia, and death (e.g., short-acting nifedipine).
Amlodipine
- A dihydropyridine.
- Relatively selective vasodilator with less cardiac depression compared to verapamil or diltiazem.
- Used to treat hypertension and coronary artery disease.
- Side effects: Peripheral edema, fatigue, tachycardia, headache, flushing, gingival hyperplasia.
Diltiazem
- Intermediate action on the heart and blood vessels.
- Used to treat hypertension, coronary artery disease, and arrhythmias.
- Side effects: Dizziness, headache, edema, bradycardia.
Verapamil
- Phenylalkylamine class with the greatest effect on the heart.
- Used to treat hypertension, coronary artery disease, arrhythmias, and cluster headaches.
- Side effects: Dizziness, headache, edema, constipation, bradycardia, gingival hyperplasia.
Drug Interactions - CCBs
- CCBs are substrates of CYP3A4, which metabolizes a variety of drugs.
- Drugs or foods (like grapefruit juice) that induce or inhibit this enzyme may affect CCBs' metabolism.
Guanethidine
- Prevents norepinephrine release from nerve terminals.
- Effective but has severe side effects, reserved for severe hypertension.
- Side effects: Marked orthostatic hypotension, diarrhea, bradycardia, impotence. It does not enter the CNS.
- Drug interactions: Tricyclic antidepressants (TCAs).
Reserpine (from Rauwolfia Serpentina)
- Binds to storage vesicles in the CNS and peripheral adrenergic neurons, blocking the ATP-dependent proton pump that transports amines into the vesicle.
- Binding is irreversible, requiring new vesicles to be synthesized.
- The antihypertensive effect likely stems from both central and peripheral actions.
- Binding creates dysfunctional vesicles, leading to impaired concentration and storage of norepinephrine and dopamine in nerve endings.
- Neurotransmitter release is reduced when nerves are depolarized.
Reserpine - Side Effects
- Severe psychological depression, sedation, extrapyramidal effects (resembling Parkinson's disease), diarrhea, peptic ulcers, bradycardia, postural hypotension, nasal congestion.
Reserpine - Drug Interactions
- May potentiate the effects of CNS depressants and MAO inhibitors.
Vasodilators
- Two main types:
- Arterial vasodilators: Directly relax the musculature of precapillary arterioles, lowering total peripheral resistance.
- Arterial and venous vasodilators: Affect both arterial resistance and venous capacity vessels.
Arterial Vasodilators
- Little or no effects on venous capacitance vessels.
- Do not affect the function of the carotid or aortic baroreceptors.
- Agents include hydralazine, minoxidil, diazoxide, and fenoldopam.
Hydralazine
- Interferes with calcium transport in smooth muscle.
- Orally effective, but bioavailability is low.
- Used for treating resistant hypertension and hypertensive emergencies.
- Side effects: Tachycardia, palpitations, aggravation of angina, fluid retention, anorexia, nausea, vomiting, sweating, flushing, headache, rash, lupus-like syndrome.
Minoxidil
- Orally effective; mainly used for resistant hypertension.
- Opens potassium channels in smooth muscle membranes.
- Used in combination with a beta-blocker and a loop diuretic to achieve blood pressure control.
- Issues: Polypharmacy, altered drug metabolism, physiological changes.
General Points About Resistant Hypertension
- Patients often require combination therapy to achieve their blood pressure goals.
- They are susceptible to volume depletion, leading to orthostatic hypotension.
- Cognitive impairment and fixed incomes can pose challenges.
Renal Vascular Disease
- ACE inhibitors or angiotensin II receptor blockers (ARBs) may be used, but caution is advised.
- Can cause a rapid and profound drop in blood pressure, potentially leading to renal failure.
- Avoid using ACEIs or ARBs in cases of bilateral renal artery stenosis.
Pregnancy
- Most cardiovascular drugs are categorized as either risk category C or D in pregnancy.
- Chronic or transient hypertension should be distinguished from preeclampsia.
- Limited data from controlled clinical studies.
- Recommended treatments:
- Methyldopa
- Labetalol
- CCBs
- Hydralazine
- Beta-blockers (with caution)?
- Severe hypertension:
- Intravenous labetalol, oral methyldopa, or oral nifedipine.
- Intravenous hydralazine as a second-line option.
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Avoid:
- ACE inhibitors
- ARBs
- Diuretics?
Combination Therapy
- The combination should be superior to monotherapy in efficacy.
- Each component should contribute to the therapeutic effect.
- Dosage forms should be suitable in terms of bioavailability, absence of unwanted interactions, and careful selection of doses.
- ACE inhibitors and ARBs should not be used together.
Causes of Resistant Hypertension
- Incorrect blood pressure measurement
- Excess sodium intake
- Inadequate diuretic therapy
- Medication-related factors:
- Inadequate doses
- Poor compliance
- Drug interactions
- Over-the-counter medications, herbals, or dietary supplements
- Excessive alcohol consumption
- Identifiable causes of hypertension
Promoting Patient Compliance
- Educate patients on proper medication use and disease state.
- Incorporate social support networks.
- Include patients in decision-making.
- Avoid drugs with numerous side effects.
- Simplify the drug regimen: Minimizing the number of pills, frequency, and inconvenience.
- Provide positive reinforcement.
- Maintain continuity of care.
- Individualize treatment.
Additional Considerations in Antihypertensive Drug Choices
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Potential favorable effects:
- Thiazide diuretics: Slowing demineralization in osteoporosis.
- Beta-blockers: Treatment of atrial tachyarrhythmias/fibrillation, migraines, thyrotoxicosis (short-term), essential tremor, or perioperative hypertension.
- CCBs: Raynaud's syndrome and certain arrhythmias.
- Alpha-blockers: Prostatism.
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