10) Hypertension and Anti-Hypertensives Flashcards
Hypertension is recognized as a major risk factor for several potentially lethal cardiovascular conditions, including
- Myocardial infarction
- Heart failure
- Stroke
Elevated systolic pressure is considered
- 120-130 mmHg
Stage 1 hypertension systolic pressure
- 130/80 to 140/89 mmHg
Stage 2 hypertension systolic pressure
- 140/90 mmHg +
Systemic vascular resistance (SVR)
- Resistance to blood flow offered by all of the systemic vasculature
- Excluding the pulmonary vasculature
- AKA total peripheral resistance
SVR is determined by mechanisms that cause
- Vasoconstriction which increase SVR
- Vasodilation which
decrease SVR
Although SVR is primarily determined by changes in blood vessel diameters, changes in
- Blood viscosity also affect SVR
Cardiac output (CO)
- Amount of blood pumped by the heart per minute
- Amount of work performed by the heart in response to the body’s need for oxygen
Drugs used in hypertension
- Diuretics
- Sympathoplegics
- Vasodilators
- Angiotensin antagonists
- Renin inhibitors
Sympathoplegics are blockers of
- A/B receptors
- Nerve terminals
- Ganglia
- CNS sympathetic outflow
Vasodilator examples
- Calcium blockers
- Parenteral vasodilators
- Older oral vasodilators
Angiotensin antagonist examples
- ACE inhibitors
- Receptor blockers
The diuretics most important for treating hypertension are
- Thiazides (eg, chlorthalidone, hydrochlorothiazide)
- Loop diuretics (eg, furosemide)
Nephron (basic structural unit of the kidney) function
- Regulate concentration of water and soluble substances (like Na+) by filtering the blood
- Reabsorbs what is needed
- Excretes the rest as urine
Segments of the nephron
- PCT: Proximal convoluted tubule
- TAL: Thick ascending loop of Henle
- DCT: Distal convoluted tubule
- CCT: Cortical collecting duct
Diuretics acting on PCT
- Carbonic anhydrase inhibitors (acetazolamide)
Diuretics acting on TAL
- Loop diuretics (furosemide)
Diuretics acting on DCT
- Thiazides (hydrochlorothiazide)
Diuretics acting on CCT
- K+ sparing diuretics (spironolactone)
Duretics modify
- Salt secretion
Drugs that modify water excretion
- Osmotic diuretics (mannitol: also modifies salt excretion)
- ADH agonists (desmopressin)
- ADH antagonists (conivaptan)
Loop diuretics
- Furosemide, Bumetanide, Torsemide (all sulfonamide derivatives)
- Ethacrynic acid (not a sulfonamide)
Loop diuretics usually induce
- Hypokalemic metabolic alkalosis
- Large amounts of sodium are presented to the collecting tubules, potassium wasting may be severe
Loop are very efficacious. They can cause
- Hypovolemia
- Cardiovascular complications
Distal convoluted tubule
- Pumps Na+/Cl- out of the lumen of the nephron via the
Na+/Cl– carrier (NCC) - Channel is target of thiazide diuretics
Calcium is also reabsorbed in the DCT under the control of
- Parathyroid hormone (PTH)
Thiazides are sulfonamide derivatives; the ones that lack typical thiazide ring in their structure are therefore considered
- Thiazide-like which also contain sulfonamide
Because they act in a diluting segment of the nephron, thiazides may reduce
- Excretion of water and cause dilutional hyponatremia
Loop diuretic names
- Bumetanide
- Bumex
- Furosemide
- Lasix
- Torsemide
- Ethacrynic acid
Bumetanide and Bumex metabolism
- Partially hepatic, then urine excreted
Furosemide and Lasix metabolism
- Mainly renal
Torsemide metabolism
- Mainly hepatic
Ethacrynic acid metabolism
- Partially hepatic
Thiazide diuretic names
- Chlorothiazide
- Hydrochlorothiazide
Chlorothiazide and hydrochlorothiazide metabolism
- Not metabolized
- Excreted unchanged in urine
Thiazide-like diuretic names
- Chlorthalidone
- Indapamide
- Metolazone
Chlorthalidone and Metolazone metabolism
- Not metabolized
- Excreted unchanged in urine
Indapamide metabolism
- Hepatic
Loop diuretic side effects
- LFT increased
- Hypomagnesemia
- Hypokalemia
- Hypocalcemia
- Photosensitivity
- Nephrotoxicity
- Ototoxicity (dose-related)
Thiazide-like diuretic side effects
- Hypokalemia
- Hypercalcemia
- Hypercholesterolemia
- Hypertriglyceridemia
- Increase LDL
- Azotemia
Diuretic side effects (shared by both kinds)
- Fluid and electrolyte loss
- Hypovolemia (dehydration)
- Hypotension
- Hyperglycemia
- Hyperuricemia
- Hypochloremia
- Hyponatremia (dilutional)
- Metabolic alkalosis
Final segment of the nephron
- Cortical collecting tubule
- Controlled by aldosterone
Aldosterone
- Steroid hormone secreted by the adrenal cortex
- Responsible for sodium reabsorption (2–5%)
The reabsorption of sodium occurs via
- Epithelial sodium channels (ENaC)
- Accompanied by loss of potassium or hydrogen ions
The collecting tubule is the primary site of
- Acidification of the urine
- Last site of potassium excretion
The aldosterone receptor and the sodium channels are sites of action of the
- Potassium-sparing diuretics
Reabsorption of water occurs in the
- Collecting tubule
- Under the control of antidiuretic hormone (ADH)
Most diuretics act from the
- Luminal side of the membrane (except aldosterone receptor antagonist group)
Aldosterone receptor antagonist group (diuretics)
- Spironolactone and eplerenone
- Enter the collecting tubule from the basolateral side
- Bind to cytoplasmic aldosterone receptor
Carbonic anhydrase inhibitor (Acetazolamide) method of action
- Inhibit carbonic anhydrase
- In proximal tubule, bicarbonate reabsorption is blocked and Na+ is
excreted with HCO-
Carbonic anhydrase inhibitor (Acetazolamide) toxicities/interactions
- Metabolic acidosis
- Hyperammonemia in cirrhosis
Loop diuretics
(furosemide, bumetanide and torsemide, ethacrynic acid) method of action
- Inhibit Na+/K+/2Cl- transporter in thick ascending limb of loop of Henle
- Cause powerful diuresis and increased Ca2+ excretion
Loop diuretics (furosemide, bumetanide and torsemide, ethacrynic acid) toxicities/interactions
- Metabolic hypokalemic alkalosis
- Ototoxicity
- Hypovolemia
- Efficacy reduced by nonsteroidal anti- inflammatory drugs
- Sulfonamide allergy
Thiazide diuretics Hydrochlorothiazide, chlorthalidone (thiazide-like) method of action
- Inhibit Na+/Cl- transporter in distal convoluted tubule
- Cause moderate diuresis and reduced excretion of calcium
Thiazide diuretics Hydrochlorothiazide, chlorthalidone (thiazide-like) toxicities/interactions
- Metabolic hypokalemic alkalosis
- Early hyponatremia
- Increased serum glucose, lipids, uric acid
- Efficacy reduced by nonsteroidal anti-inflammatory drugs
- Sulfonamide allergy
K+- sparing diuretics (Spironolactone, eplerenone) method of action
- Steroid inhibitors of cytoplasmic aldosterone receptor in cortical collecting ducts
- Reduce K+ excretion
K+- sparing diuretics (Spironolactone, eplerenone) toxicities/interactions
- Hyperkalemia
- Gynecomastia (spironolactone only)
K+- sparing diuretics (Amiloride, triamterene) method of action
- Inhibitor of ENaC epithelial sodium channels in cortical collecting duct
- Reduces Na+ reabsorption and K+ excretion
K+- sparing diuretics (Amiloride, triamterene) toxicities/interactions
- Hyperkalemia
Osmotic diuretics (Mannitol) method of action
- Osmotically retains water in tubule by reducing reabsorption in proximal tubule, descending limb of Henle’s loop, and collecting ducts
- In the periphery, mannitol extracts water from cells
Osmotic diuretics (Mannitol) toxicities/interactions
- Hyponatremia followed by hypernatremia
- Headache, nausea, vomiting
Angiotensin converting enzyme inhibitor (ACEI) names
- Enalapril
- Captopril
- Ramipril
- Lisinopril
- Benazepril
- Trandolapril
- Others
There is sufficient evidence that proves that ACEI and ARB reduce
- Progression of CKD (chronic kidney disease)
ACE inhibitors reduce the activity of
- Renin-angiotensin-aldosterone system (RAAS)
RAAS is activated in response to
- Fall in blood pressure (hypotension) or salt-water
imbalance of the body
Renin
- Released by kidney
- Enzyme that changes angiotensinogen (a protein made in the liver)
to angiotensin I
ACE (Angiotensin converting enzyme) converts
- Angiotensin I into angiotensin II
The system increases blood pressure by
- Increasing the amount of salt and water the body retains
- Action of angiotensin as a vasoconstrictor
Inhibition of ACE side effects
- Hypotension /dizziness
- Increase serum creatinine/ renal impairment
- Hyperkalemia
Inhibition of enzymes other than ACE side effects
- Cough caused by elevated bradykinin level due to ACE inhibition can be a cause of dry cough, angioedema and/or rash, hypotension, and inflammation-related pain
Other side effects of ACEI
- Neutropenia, agranulocytosis
- GI: N/V/D
- Impotence
- Taste change
Angiotensin II receptor blockers (ARB) names
- Valsartan
- Telmisartan
- Losartan
- Irbesartan
- Olmesartan
- Candersartan
- Others
ARBs are AT1-receptor antagonists
- Block the activation of angiotensin II AT1 receptors
Blockage of AT1 receptors directly causes
- Vasodilation
- Reduces secretion of vasopressin
- Reduces production and secretion of aldosterone
Hepatically metabolized ARBs
- Losartan
- Valsartan
- Irbesartan
- Telmisartan
- Eprosartan
Hepatically mixed with renally metabolized ARBs
- Candesartan
- Olmesartan
- Azilsartan
Clinical effects of ACEI and ARB
- Relax the efferent arteriole
- Lowers intra-glomerular pressure
- Reduces GFR
Advantage of ARB over ACEI
- Doesn’t block type II AgII receptors
- Maintains antiproliferative effect
- Bradykinin is converted to kinin, so no dry cough as side effect
Blockage of AT1 receptor side effects
- Hypotension /dizziness
- Increase serum creatinine/ renal impairment
- Hyperkalemia
Aliskiren (Tekturna)
- Direct renin inhibitor
- Taken once a day
Aliskiren (Tekturna) method of action
- Renin inhibitor
- Renin is the first enzyme in the RAAS that cleaves angiotensinogen to
angiotensin I
Aliskiren (Tekturna) side effects
- Hyperkalemia
- Angioedema
- Low blood pressure
- Cough, diarrhea and headaches
Aliskiren (Tekturna) metabolism
- Unchanged in urine and feces
Sympathoplegics that act in CNS
- Alpha2-selective agonists (eg, clonidine, methyldopa)
Alpha 2-selective agonists (eg, clonidine, methyldopa) cause a decrease in
- Sympathetic outflow by activation of α2 receptors in the CNS
- Both drugs may cause sedation
Alpha 2-selective agonist CNS activity
- Readily enter the CNS when given orally
Alpha 2-selective agonists reduce blood pressure by
- Reducing cardiac output and vascular resistance
Major compensatory response of alpha 2-selective agonists
- Salt retention
Sudden discontinuation of clonidine causes
- Rebound hypertension
- May be severe
Methyldopa occasionally causes
- Hematologic immunotoxicity
- Hemolytic anemia
Hemolytic anemia
- Disorder in which red blood cells are destroyed faster than they can be made
Adrenoreceptor blockers
- Alpha-1 blockers
- Beta blockers
Alpha1-selective agents (eg, prazosin, doxazosin, terazosin)
- Moderately effective antihypertensive drugs
- Reduce vascular resistance and venous return
Alpha 1 receptor is found in
- Blood vessels
- Sphincters of the GI
- Eye
- Genitourinary (uterus)
Nonselective α blockers (phentolamine, phenoxybenzamine) are of no value in
- Chronic hypertension because of excessive reflex tachycardia
Alpha 1-selective adrenoceptor blockers cause
- Orthostatic hypotension, especially with the first few doses
- Also relax smooth muscle in the prostate (useful in benign prostatic hyperplasia)
Beta blockers are used very heavily in the treatment of
- Hypertension
Beta blocker examples
- Propranolol is the prototype
- Atenolol, metoprolol, and carvedilol are among the most popular
Beta blocker effects
- Reduce cardiac output
- Chronic use may decrease vascular resistance
Chronic use of beta blockers may cause a decrease in vascular resistance as a result of
- Reduced angiotensin levels
- β blockers reduce renin release from the kidney
Vasodilators
- Drugs that dilate blood vessels by acting directly on smooth muscle cells
Vasodilators act by four major mechanisms
1) Blockade of calcium channels
2) Release of nitric oxide
3) Activation of D1 dopamine receptors through Gs
4) Opening of potassium channels (which leads to hyperpolarization)
4 major vasodilators
1) Calcium channel blockers
2) Nitrates, Nitroprusside, hydralazine
3) Fenoldopam
4) Minoxidil, diazoxide
Effective vasodilators
- Calcium channel blockers
- Verapamil and diltiazem also reduce cardiac output in most patients
Two types of CCB
- Dihydropyridine (DHP) with nifedipine as the prototype
- Non-DHP
DHP names
- Amlodipine
- Felodipine
- Isradipine
- Nicardipine
- Nifedipine
- Nimodipine
- Nitrendipine
DHP mechanism
- High vascular selectivity (reduces SVR and BP)
- Can lead to reflex cardiac stimulation (tachycardia and increased inotropy)…can offset beneficial effects
DHP side effects
- Flushing
- Headache
- Excessive hypotension
- Edema
- Reflex tachycardia
- Long-acting dihydropyridines (e.g., extended release nifedipine, amlodipine) reduce reflex responses
Non-DHP names
- Verapamil
- Diltiazem
Verapamil (non-DHP) mechanism
- Selective for the myocardium, less effective as a systemic vasodilator drug
- Indication for treating angina (by reducing myocardial oxygen demand)
Diltiazem (non-DHP) mechanism
- Intermediate between verapamil and dihydropyridines in its selectivity for vascular calcium channels
- Able to reduce arterial pressure without producing the same degree of reflex tachycardia of dihydropyridines
Non-DHP side effects
- Bradycardia
- Impaired electrical conduction (e.g., atrioventricular nodal block)
- Depressed contractility
Hydralazine and Minoxidil
- Older vasodilators
- More effect on arterioles than veins
Hydralazine
- Acts through the release of nitric oxide from endothelial cells
- Rarely used at high dosage
Hydralazine is rarely used at high dosage because of
- Hydralazine-induced lupus erythematosus
- Reversible upon stopping the drug
Minoxidil
- Potassium channel opener that hyperpolarizes and relaxes vascular smooth muscle
Minoxidil can cause
- Hirsutism, so it is also available as a topical agent for the treatment of baldness
Minoxidil use/mechanism
- Extremely efficacious
- Reserved for severe hypertension
- Diazoxide has the same mechanism of action, but is less preferred because of the high side effects
Hydralazine metabolism
- Hepatic
- DOA = 12h
Hydralazine side effects
- Hydralazine-induced Lupus like syndrome
- Blood dyscrasias
- Hypotension
- Peripheral neuritis (pyridozine treatment is needed here)
- Flushing; orthostatic hypotension
Minoxidil metabolsim
- Hepatic
- DOA = 2-5 days
Minoxidil side effects
- Fluid retention; sodium/ water retention; weight gain
- Increase serum creatinine and liver enzymes
- US Box warning: pericarditis
- Syncope; sinus tachycardia
- Hypertrichosis
Diazoxide (thiazide derivative but lacks diuretic properties) DOA
- Less than 8h
Diazoxide side effects
- Hyperosmolar coma
- Hypotension, tachycardia
- Headache
- Pancreatitis
- Hirsutism
- Hyperglycemia
- Sodium retention
- Blood dyscrasias (thrombocytopenia; neutropenia; decrease hematocrit
- Blurred vision
- Gout
Parenteral vasodilators used in hypertensive emergencies
- Nitroprusside
- Diazoxide
- Fenoldopam
Nitroprusside mechanism
- Releases nitric oxide (from the drug molecule itself) - Increases cyclic guanine monophosphate (cGMP) concentration
- Increases relaxation in vascular smooth muscle
- Dilates arterial resistance vessels more than venous vessels
Dopamine D1 receptor activation by fenoldopam causes
- Prompt, marked arteriolar vasodilation
Nitroprusside properties
- Brand = Nitropress
- DOA = 10 min
- Short-acting agent
- Light-sensitive
Fenoldopam properties
- Brand = Cortopam
- DOA = 1h
- Metabolism = hepatic
Nitroprusside and Fenoldopam shared side effects
- Flushing
- Headaches
- Hypotension
- Tachycardia
Nitroprusside side effects
- Methemoglobinemia
- Hypothyroidism
- Can release cyanide ions
Fenoldopam side effects
- Increase liver enzyme
