Autocoids

Cardiovascular Pharmacology

ANTI-ARRHYTHMICS:

• NORMAL RHYTHM:
  • Phase-4 Depolarization results in automaticity of the cardiac action potential, in normal SA nodal cells.
    • AV nodal cells and Purkinje fibers also have spontaneous Phase-4 depolarization, but their automaticity is slower than SA node, thus under normal circumstances, they are already depolarized before reaching the automatic depolarization.
    
    
    
  • Reentrant Excitation: Retrograde conduction and unidirectional block are required for reentrant excitation to occur.
    • Anti-Arrhythmics stop reentry excitation by prolonging the refractory period at the ectopic site. In this way the unidirectional block becomes a bidirectional block, and the cycle is stopped.
• GENERAL EFFECTS of ANTI-ARRHYTHMICS: Anti-arrhythmics also cause arrhythmias. All anti-arrhythmics also have local anesthetic effects.
  • Reduce the slope of Phase-4 Depolarization ------> reduce automaticity.
  • Decrease conduction velocity.
  • Reduce threshold potential.
  • Terminate reentrant excitation, by prolonging the refractory period of the initiation point.
• DRUGS:
  • CLASS-IA: Na⁺-Channel Blocker: Quinidine, Procainamide, Disopyramide, Amiodarone
    • GENERAL PROPERTIES:
      • Prolongs action potential duration. Prolonged QT-interval is the consequence of this on the ECG.
      • Prolongs the effective refractory period of the action potential.
      • Affects both atrial and ventricular arrhythmias.
    • QUINIDINE: alkaloid.
      • EFFECT: Blocks Na⁺ channels ------> reduce cardiac excitability and contractility, especially in atria and AV node.
        • Anti-Cholinergic effects ------> enhance AV transmission.
          • Digitalis antagonizes blocks AV transmission and thus antagonizes this effect.
        • Hyperkalemia: It potentiates the cardiotoxic effects of quinidine. This effect of K⁺ is opposite to what it is in the case of digitalis.
        • Effects on Heart Rhythm:
          • Suppresses ectopic pacemakers.
          • Lengthens the refractory period of the myocardium.
          • Increases ventricular filling rates in the face of atrial fibrillation.
        • EKG: Shows widened QRS-complexes
      • INDICATIONS: Usually given PO. IM and IV also available.
        • Atrial fibrillation
        • Premature Systole
      • ADVERSE EFFECTS: Nausea, vomiting, diarrhea.
        • Cinchonism: "Quinidine or Quinine poisoning." Syndrome consists of tinnitus, deafness, blurred vision, color disturbances, GI upset, Torsades de Pointes.
        • Torsade de Pointes: Characteristic ECG findings with Quinidine toxicity. Long QT-interval, with "short-long'short" sequence in the beat preceding its onset. Also called "cardiac ballet."
        • Thrombotic Thrombocytopenia Purpura (TTP)
        • Embolism: Especially fatal arterial embolisms from the atrial wall, resulting from continued atrial fibrillation.
        • Paradoxical ventricular tachycardia.
        • Sudden death, due to myocardial depression (heart block).
      • TOXICITY: Cardiotoxicity can be potentiated by digitoxin, phenytoin, KCl, and lidocaine.
      • CONTRAINDICATIONS:
        • Not used in ventricular fibrillation -- only in atrial fibrillation.
        • Complete or incomplete AV-Block
        • Digitalis intoxication, CHF
        • History of TPP
        • Hypotensive states.
    • PROCAINAMIDE: Similar to procaine.
      • EFFECTS: Similar to quinidine. Also has anti-acholinergic activity. Also, procainamide produces less depression of contractility.
      • ADVERSE EFFECTS:
        • Fever and rash.
        • Lupus-lie syndrome in 20%
        • Agranulocytosis, 0.5%
      • INDICATIONS: Similar to quinidine. Given PO, IM, or IV.
    • AMIODARONE: Has the hallmark toxic effect of pulmonary fibrosis.
  • CLASS-IB: Na⁺-Channel Blocker. Lidocaine, mexiletene, tocainide, phenytoin.
    • GENERAL PROPERTIES:
      • Lower action-potential duration.
      • Affects inschemic or depolarized myocardial tissue.
      • INDICATIONS: Post-MI arrhythmias, digitalis toxicity.
    • LIDOCAINE:
      • EFFECT: Acts mainly on purkinje fibers:
        • Depress automaticity
        • Shorten refractory period. Reduce action potential duration.
      • INDICATIONS: Usually given as IV loading dose, plus continuous IV infusion. Indicated primarily for ventricular arrhythmias.
        • Abolishes reentry dysrhythmias by (1) converting unidirectional block to bidirectional block, and (2) improving slow conduction.
        • Depresses automaticity in ectopic pacemakers.
      • ADVERSE EFFECTS: Few adverse effects at therapeutic levels.
        • CNS effects predominate: drowsiness, stimulation, seizures, paresthesias, decreased auditory acuity.
    • PHENYTOIN: Given IV for arrhythmias. Resembles lidocaine.
      • INDICATIONS: Especially effective in digitalis toxicity.
      • ADVERSE EFFECTS: Drowsiness, vertigo, ataxia.
  • CLASS-IC: Na⁺-Channel Blocker. Flecainide, Encainide, Propafenone
    • GENERAL PROPERTIES: They are last ditch drugs because of their toxicities.
      • No effect on action potential duration.
      • INDICATIONS:
        • Ventricular tachycardia that progress to ventricular fibrillation.
        • Intractable supraventricular tachycardia.
      • TOXICITY: CNS stimulation, causes arrhtymics.
  • CLASS-II: beta-Blocker: PROPANOLOL, ESMOLOL
    • CARDIAC EFFECTS: Blocks effects of Epinephrine and Norepinephrine on the heart, slowing heart-rate and rate of conduction.
      • Effects are similar to quinidine.
    • INDICATIONS: Supraventricular arrhythmias, Premature Ventricular Contractions (PVC's), digitalis-induced arrhythmias.
    • ADVERSE EFFECTS: Precipitate asthma attack, cause heart-block.
  • CLASS-III: K⁺-Channel Blocker: Bretylium, Sotalol, Amiodarone
    • GENERAL PROPERTIES:
      • Higher action potential duration.
      • Higher effective refractory period.
  • CLASS-IV: Ca⁺²-Channel Blocker: Verapamil, Diltiazem, Bepridil
    • CARDIAC EFFECTS:
      • Reduce the rate of SA nodal discharge.
      • Slow conduction through AV node.
      • Prolong AV node refractory period. Manifests on ECG as prolonged PR interval.
    • INDICATIONS: Paroxysmal Supraventricular Tachycardia, Atrial Fibrillation.
    • ADVERSE EFFECTS: Hypotension, dizziness, AV block, heart failure.

LIPOPROTEINS:

• Chylomicrons: Largest lipoproteins, they carry cholesterol and triglycerides from the intestine to the liver.
  • 80-90% triglyceride.
  • Formed in the intestine
  • Normally not present in the serum of fasting patients.
• Very-Low Density Lipoproteins (VLDL's):
  • 60% triglyceride. Half-life = only a few hours.
  • Secreted by the liver
  • These are the initial lipoproteins to carry triglycerides from the liver to target tissues. These triglycerides originate mostly from carbohydrates.
  • They are hydrolyzed by lipoprotein lipase once they reach target tissues.
• Intermediate Density Lipoproteins (IDL's): Transient lipoprotein.
  • VLDL's become IDL's when they lose the triacylglycerol component.
• Low-Density Lipoproteins (LDL's): Formed from IDL's, after they lose the Apo-E protein.
  • Contain about 50% cholesterol.
  • Carry endogenous cholesterol to target tissues.
  • Stick around the longest.
• Lp(A) Lipoproteins: Composed of an LDL particle combined with an additional protein, Lp(a) specific protein.
  • Elevated levels have been identified as a risk factor for coronary artery disease.
• High Density Lipoproteins (HDL's): Secreted by liver, facilitate cholesterol removal from target tissues, and return of cholesterol to liver.

CHOLESTEROL LEVELS:

• < 200 mg/dL: Normal total cholesterol
• 200-240 mg/dL: Borderline high cholesterol
• > 240 mg/dL: High total cholesterol

HYPERLIPIDEMIC DISEASES and TERMS:

• DEFINITIONS:
  • Hyperlipemia, Hyperlipidemia: Elevated plasma triglycerides. High fasting lipid-levels in blood.
  • Hyperlipoproteinemia: Elevated plasma lipoproteins. High fasting lipid-levels in blood.
• SYMPTOMS: Acute pancreatitis, atherosclerosis, xanthomatosis are the symptoms found generally in all of the diseases.
• FAMILIAL LIPOPROTEIN LIPASE DEFICIENCY (Type-I Hyperlipidemia): Affects only chylomicrons.
• FAMILIAL HYPERCHOLESTEROLEMIA (Type-IIa Hyperlipidemia): Defect in LDL Receptor.
  • SYMPTOMS:
    • Tendinous Xanthomatosis
    • Arcus Corneae: Opaque grayish ring in periphery of cornea, lipid deposits.
    • Xanthelasma: xanthoma planum of the neck, trunk, extremities, and eyelids in patients with normal plasma lipid levels.
    • Premature coronary atherosclerosis
  • HETEROZYGOUS HYPERCHOLESTEROLEMIA:
    • TREATMENT = niacin, resin, lovastatin
  • HOMOZYGOUS HYPERCHOLESTEROLEMIA:
    • TREATMENT = niacin or probucol
• FAMILIAL COMBINED HYPERLIPOPROTEINEMIA (Type-IIb Hyperlipidemia): Elevated VLDL, LDL, or both.
  • SYMPTOMS:
    • Moderate elevation of cholesterol and triglycerides.
    • Usually no xanthomas
  • TREATMENT: Aimed to prevent the onset of atherosclerosis
    • Elevated VLDL: Use Niacin, Clofibrate
    • Elevated LDL: Niacin, resin, Lovastatin
    • Elevated VLDL + LDL: Niacin alone, or combined with Resin, Lovastatin
• FAMILIAL DYSBETALIPOPROTEINEMIA (Type-III Hyperlipidemia):
  • CHARACTERISTICS:
    • Accumulated remnants of chylomicrons and VLDL
    • Reduced LDL levels
    • Increased serum cholesterol and triglycerides
  • SYMPTOMS:
    • Obese patient
    • Impaired glucose tolerance
    • Tuberous or plantar xanthomas
    • Hypothyroidism
    • Increased frequency of coronary atherosclerosis.
  • TREATMENT: Clofibrate is the main treatment
    • Niacin
• FAMILIAL HYPERTRIGLYCERIDEMIA (Type-IV Hyperlipidemia): Increased chylomicrons and VLDL.
  • SYMPTOMS: May be severe or moderate
    • Centripetal pattern of obesity
    • Eruptive xanthomas
    • Lipemia Retinalis
    • Epigastric pain
    • Overt pancreatitis
  • TREATMENT:
    • Dietary restrictions: restrict fat, avoid alcohol, reduce body weight
    • Niacin
    • Clofibrate
• PRIMARY CHYLOMICRONEMIA (Type-V Hyperlipidemia): Increased chylomicrons and VLDL.
  • SYMPTOMS:
    • Eruptive xanthomas
    • Hepatosplenomegaly
    • Lipid-laden foam-cells in marrow, liver, spleen.
  • TREATMENT: Restrict dietary fat. Clofibrate.
• LP(A) HYPERLIPOPROTEINEMIA: Increased Lp(A) Lipoprotein
  • TREATMENT = niacin alone or with lovastatin
    • Dietary Management: Restrict cholesterol and saturated fats, provide calories to maintain ideal body weight.
      • Total fat from calories = 20-25%
      • Saturated fat < 8%
      • Cholesterol < 200 mg / day

HYPOLIPIDEMIC DRUGS:

• NIACIN
  • ACTIONS:
    • Inhibits VLDL secretion ------> lower plasma VLDL and LDL.
    • Inhibits hepatic formation of cholesterol (cholesterogenesis).
  • INDICATIONS: Counteract increased VLDL and LDL. Types IIa, IIb, III, IV, and V
    • Familial Hypercholesterolemia (IIa), heterozygous, when combined with bile-acid binding resin. Very effective.
    • Familial Combined Hyperlipoproteinemia (IIb)
    • Familial Dysbetalipoproteinemia (III)
    • Familial Hypertriglyceridemia (IV)
  • SIDE-EFFECTS: Generally mild
    • Pruritus and flushing: most common side-effect. Warm sensation and cutaneous vasodilation.
    • Nausea
    • Dry skin
    • Elevated serum transaminase, alkaline phosphatase, hyperuricemia
    • Impaired glucose tolerance
    • Severe hepatotoxicity, rarely.
• FIBRIC ACID DERIVATIVES: Clofibrate, Gemfibrozil
  • ACTIONS: Increase lipoprotein lipase activity ------> promote catabolism of VLDL.
    • May decrease hepatic synthesis and secretion of VLDL. They decrease triglycerides secondarily, by decreasing VLDL levels.
    • Inhibit hepatic cholesterogenesis ------> reduce plasma cholesterol.
    • Increase lipoprotein lipase activity ------> increase breakdown of triglycerides.
  • INDICATIONS: Counteract increased VLDL. Types IIb, III, IV, V.
    • Familial Dysbetalipoproteinemia (III): Most efficacious drug for this disease.
    • Familial Hypertriglyceridemia (IV)
    • Do not use with hypercholesterolemia (IIa). Instead treat with lovastatin.
  • SIDE-EFFECTS:
    • Nausea
    • Myalgia, elevated creatinine kinase
    • Increased incidence of gallstones.
    • Allergic: Cutaneous reactions, leukopenia
    • Decreased libido and impotence
  • DRUG-INTERACTION: Potentiate the action of anti-coagulants by displacing them from albumin: warfarin, coumarin.
• BILE-ACID BINDING RESINS: Colestipol, Cholestyramine. Large cationic exchange resins, with unpleasant sandy, gritty quality.
  • ACTION: Binds bile acids and prevents their intestinal absorption ------> lower absorption of cholesterol and triglycerides.
    • Secondarily increases LDL receptors, uptake of LDL lipoproteins, and thus reduces LDL and plasma cholesterol.
    • VLDL remains unchanged or may actually increase.
  • INDICATIONS: Counteract increased LDL. Type IIa, IIb.
    • Familial Hypocholesterolemia (IIa)
    • Familial Combined Hyperlipoproteinemia (IIb)
  • ADVERSE EFFECTS:
    • Safest hypolipidemics because they are not absorbed.
    • Most common: Constipation and bloating
    • Steatorrhea may occur in patients with cholestasis, but risk of gallstones is not increased.
    • Acute pancreatitis, rarely.
    • Vitamin-K malabsorption ------> clotting problems
    • Impaired absorption of lipophilic drugs: digitalis, thiazides, tetracycline, thyroxine, aspirin
• NEOMYCIN: Aminoglycoside antibiotic
  • ACTIONS:
    • Lowers LDL by inhibiting intestinal absorption of cholesterol and bile acids.
    • Variable effects on VLDL.
  • INDICATION: Familial hypercholesterolemia (IIa)
  • ADVERSE EFFECTS: Severe
    • Nausea, abdominal cramps, vomiting, malabsorption
    • Impaired absorption of digitalis
    • Possible enterocolitis due to bacterial overgrowth.
• HMG-CoA REDUCTASE INHIBITORS: Lovastatin, Pravastatin, Simvastatin
  • PHARMACOKINETICS: Inactive lactone prodrugs are hydrolyzed in gut to form active beta-hydroxyl derivatives.
  • ACTION: Inhibit HMG-CoA Reductase ------> inhibit synthesis of cholesterol.
    • Reduce LDL, increase LDL receptors
    • Increase HDL
    • Decrease plasma triglycerides
  • INDICATIONS: Lower LDL. Type IIa, IIb.
    • Familial Hypercholesterolemia (IIa)
    • Familial Combined Hyperlipoproteinemia (IIb)
  • ADVERSE EFFECTS: Hepatotoxicity, skeletal muscle pain and increased creatinine phosphokinase.
• DEXTROTHYROXINE: Dextrorotary thyroxine.
  • ACTION: Enhances removal of LDL and increases fecal excretion of fat and cholesterol.
    • Also causes increased hepatic cholesterol synthesis, but this doesn't counteract its LDL-lowering effect.
  • TOXICITY: Hypermetabolism.
    • Contraindicated in CAD, HTN, arrhythmias.
    • Contraindicated in hepatic / renal dysfunction.
  • DRUG INTERACTIONS: Potentiates warfarin and may be the cause of Digitalis Intoxication.
• DRUG COMBINATIONS: Use drug combinations when:
  • Treatment of hypercholesterolemia with a binding-resin yields significantly increased VLDL
    • Then, give a second drug to treat VLDL: Fibric Acid derivatives
  • LDL and VLDL are both elevated clinically.
  • LDL levels cannot be normalized using a single drug.

CONGESTIVE HEART FAILURE (CHF):

• EPIDEMIOLOGY:
  • Most common cause of hospitalization over 65 years of age.
  • Afflicts more than 2 million Americans annually.
  • 900,000 hospitalization per year.
  • PROGNOSIS: Poor
    • Untreated, 82% of men die within 6 years of onset.
    • Untreated, 67% of women die within 6 years of onset.
    • Treated, mortality was reduced to 40%
• SUBTYPES:
  • HIGH-OUTPUT FAILURE: Glycosides are not effective in treating it.
    • Causes: Hyperthyroidism, Beriberi, anemia, arteriovenous shunts.
  • LOW-OUTPUT FAILURE: Glycosides are effective in treating it.
    • Causes: Myocardial Infarction, hypertension, coronary artery disease.
• HEMODYNAMIC PROPERTIES: Consequences of CHF
  • Subnormal Cardiac Output ------> decreased exercise tolerance, tachycardia, pulmonary edema, cardiomegaly
  • Neurohumoral Reflexes: Reflex tachycardia, increased sympathetics, increased Renin.
  • Myocardial Hypertrophy occurs, to maintain cardiac performance.
    • Ventricular dilation helps to maintain cardiac output to an extent (due to Starling's Law), but past a certain point it can no longer help.
  • Factors affecting cardiac performance:
    • Higher preload: due to increased blood volume and venous tone.
    • Higher afterload: due to hypertension, increased arterial tone.
    • Lower contractility ------> lower inotropic state
    • Higher heart rate, due to reflex tachycardia
  • Ventricular Function Curve: CHF makes the ventricular function cruve shift downward.
  • Edema: Especially pulmonary edema, but also peripheral. Results from decreased Cardiac Output, by two mechanisms:
    • Decreased CO ------> impaired venous return ------> higher capillary hydrostatic pressure
    • Decreased CO ------> decreased renal perfusion ------> activate RAS ------> aldosterone causes higher Na⁺ and fluid retention.
• TREATMENT:
  • CARDIAC GLYCOSIDES: See below.
  • ACE INHIBITORS: They have significantly decreased mortality due to CHF.
    • ACTION: They inhibit the activation of the renin-angiotensin system, which is hyperactive in CHF, due to increased sympathetics.
      • They reduce afterload: Reduce circulating levels of Angiotensin-II
      • They reduce preload: Reduce Aldosterone ------> reduce blood volume.
    • INDICATIONS: ACE Inhibitors are recommended in the following patients:
      • All patients with symptomatic CHF due to LV systolic dysfunction.
      • Asymptomatic patients with severe LV systolic dysfunction, HTN, or valvular regurgitation (aortic incompetence, mitral regurgitation).
      • Post-MI patients at risk for complications.
  • VASODILATORS:
    • Sodium Nitroprusside: IV, used to treat acutely decompensated CHF, where brain and kidney perfusion is compromised.
    • Hydralazine: It maintains renal blood flow. Used to treat CHF in the presence of kidney dysfunction.
  • LOOP DIURETICS: Goal in this case is to reduce blood volume, not reduce blood pressure.
  • XANTHINES: Theophylline can produce coronary vasodilation and bronchodilation, both of which can be therapeutic in CHF.

CARDIAC GLYCOSIDES (DIGITALIS): Inotropic agents used for CHF.

• STRUCTURE: Steroid nucleus
  • Aglycone, responsible for biological activity
  • Digitoxose sugar molecules. 3 sugar molecules, which affect absorption, half-life, and metabolism.
• ACTIONS:
  • MECHANISM: Inhibit Na⁺/K⁺-ATPase Pump ------> increased intracellular Na⁺ in myocardium ------> decreased expulsion of Ca⁺² in myocardium ------> tonically higher levels of intracellular Ca⁺² ------> increased myocardial contractility
  • MECHANICAL ACTION on HEART:
    • Increased myocardial contractility
    • Bradycardia, due to reduced sympathetics.
    • Increased Cardiac Output, due to reduced TPR (from reduced sympathetics) and increased inotropic state.
  • ELECTRICAL ACTION on HEART:
    • Direct Effect on AV Node: Increase risk of heart block
      • Decrease the rate of rise of Phase-0 depolarization at AV node.
      • Prolong refractory period at AV-Node
      • Decrease conduction velocity at AV-Node.
    • Direct Effect on Purkinje Fibers:
      • Increase automaticity ------> increased risk of arrhythmias. This occurs by two mechanisms:
        • Increase the slope of Phase-4 depolarization.
        • Elevate the resting membrane potential of the SA-Node, as a consequence of inhibiting the Na⁺/K⁺-ATPase
      • Decrease conduction velocity
    • Parasympathomimetic Effects: Digitalis increases vagal stimulation, by three mechanisms:
      • Baroreceptor Sensitization
      • Central Vagal Stimulation
      • Facilitate muscarinic transmission at myocardial cells
    • Hypokalemia potentiates the cardiotoxic effects of Digitalis, since digitalis deprives cardiac cells of K⁺. This effect of K⁺ is opposite to the effect seen with quinidine.
  • KIDNEY DIURESIS: Digitalis effect on kidney is indirect -- resulting from improved cardiac output. If cardiac output does not improve, then there will be no diuresis.

• INDICATIONS: CHF
  • Also indicated for treatment of atrial fibrillation. It can be given with other anti-arrhythmics, to prevent the paradoxical ventricular tachycardia that sometimes occurs with treatment.
• PHARMACOKINETICS:
  • IV Administration: Ouabain or Digoxin can be administered IV for emergencies. They are diluted with saline solution and injected slowly.
  • DIGITALIZATION: Goal = attain the maximum cardiac effects as quickly as possible, without producing toxicity.
    • Loading doses can be given for Digoxin, to help attain the steady state faster. Must be careful to avoid arrhythmias when giving loading dose.
    • Or, you can give smaller maintenance doses not preceded by a loading dose. 6-8 maintenance doses per loading dose.
  • The half-life of the drug determines its duration of action:
    • Digoxin: Takes about 1 week to attain steady state, without a loading dose.
    • Digitoxin: Takes about 3 to 4 weeks to attain steady state, without a loading dose.

• TOXICITY: Incidence has been declining, due to blood monitoring. Digitalis has a very narrow margin of safety.
  • RISK-FACTORS: 20% of patients will show toxicity. At-risk situations include:
    • Renal Insufficiency
    • Geriatric Patients
    • Excessive Dosing
    • Hypokalemia as induced by diuretics ------> fatal arrhythmias. Digitalis has additive effects in depleting cardiac cells of K⁺.
    • Hypothyroidism: decreases the necessary dose.
  • ADVERSE EFFECTS: GI and neurologic symptoms usually occur before CV symptoms. This gives us a warning of impending toxicity.
    • CV: Fatal arrhythmias can result from toxicity. This usually is secondary to severe hypokalemia in the cardiac tissue.
      • Sinus bradycardia
      • Ectopic beats (ventricular or AV node)
      • AV block, sinus arrest.
    • GI: Usually the earliest-appearing symptoms.
      • Anorexia, nausea, vomiting diarrhea
    • CNS:
      • Stimulate medullary chemoreceptor trigger zone ------> vomiting
      • Disorientation, hallucinations in the elderly.
      • Color and visual disturbances.
    • Gynecomastia: Rare. Due to estrogenic effects of the steroid nucleus.
  • TREATMENT:
    • Discontinue digitalis
    • Oral or intravenous potassium
    • Treatment with anti-arrhythmic agents: phenytoin, lidocaine, propanolol
• DRUG INTERACTIONS:
  • Quinidine: Displaces digoxin from binding proteins ------> increase circulating levels of digoxin. Do not use quinidine to treat digitalis-induced arrhythmias
  • Catecholamines: Sensitize the heart to the effects of digoxin.
  • Cholestyramine, Neomycin, Sulfa drugs: Can reduce digoxin absorption.
  • Hypokalemia will amplify digoxin-related arrhythmias. Thus do not use Digoxin with diuretics that excrete K⁺, at least not without replacing the lost K⁺.
  • Captopril, Ca⁺²-blockers, other drugs, may increase serum digoxin levels.

BIPYRINES: Phosphodiesterase inhibitor ------> increase cAMP and Ca⁺² ------> higher inotropic state of the heart.

• Less likely than digoxin to cause arrhythmias.
• ADVERSE EFFECTS:
  • Have increased mortality, so only used for short time.
  • Nausea, vomiting
  • Liver enzyme changes

HYPERTENSION:

• SEVERITY
  • Mild Hypertension: 140-159 / 90-99
  • Moderate Hypertension: 160-179 / 100-109
  • Severe Hypertension: 180-209 / 110-119
  • Very Severe Hypertension: > 210 / > 120
• LIFESTYLE CHANGES:
  • Weight reduction
  • Diet: moderate salt and alcohol intake
  • Avoid tobacco
  • Increased physical activity
• TREATMENT: General modes of therapy
  • Reduce blood volume: diuretics
  • Interrupt sympathetic tone: sympatholytic
  • Reduce peripheral resistance: ACE-Inhibitors, Vasodilators, Ca⁺²-blockers
• LIMITS: Do not lower blood pressure below diastolic of 90 mm Hg, as coronary perfusion can become compromised.

ANTI-HYPERTENSIVE DRUGS:

• ORAL DIURETICS:
  • SUBTYPES:
    • THIAZIDE DIURETICS: Most commonly used for HTN. Hydrochlorothiazide, Chlorthalidone, Indapamide
      • ACTION: Lowers blood volume by depleting body Na⁺ stores, by increasing Na⁺ excretion in the kidney.
    • LOOP DIURETICS: Rarely used for HTN, often used for CHF.
    • POTASSIUM-SPARING DIURETICS: Weak; used in conjunction with thiazides to help alleviate hypokalemia.
  • PATIENT POPULATION: Thiazides can be used as monotherapy.
    • Old, black males respond best to Thiazide diuretics.
    • Cheap drug
    • For patients with moderate HTN, and normal kidney and cardiac function.
  • SIDE EFFECTS:
    • Sexual impotence, as is potentially true with any anti-hypertensive
    • Hyperuricemia, gout
    • Reflex increase in renin secretion (can be counteracted with ACE Inhibitor)
    • Potassium depletion: Can be potentially countered with (1) supplemental potassium, or (2) potassium-sparing diuretic
      • Muscle cramps
      • Arrhythmias
    • Impaired glucose tolerance, hyperinsulinemia.
    • Atherogenesis: Thiazides increase LDL and increase the LDL/HDL ratio.
      • Hyperlipidemia
  • DOSING: Very low dose (6-12 mg/day) is required for lowering blood pressure, as compared to that which is required for diuresis (100-200 mg/day). This helps to alleviate side-effects.
• SYMPATHOLYTICS:
  • CENTRALLY ACTING: alpha₂-agonists. Clonidine, Guanabenz, Guanfacine, Methyldopa.
    • ADVERSE EFFECTS: Not recommended for monotherapy.
      • CNS: Dizziness, sedation, nightmares, depression
      • Dry Mouth
  • GANGLIONIC BLOCKERS: Trimethaphan.
    • ACTION: Block all nicotinic ganglionic receptors.
    • INDICATIONS: No longer used, except in two circumstances: (1) hypertensive crisis, and (2) controlled hypotension during neurosurgery.
  • ADRENERGIC NEURON BLOCKERS: "NE-depleting agents"
    • ACTION: Bind to NE vesicles in neurons and prevent their release ------> vasodilation and lower blood pressure.
• beta-BLOCKERS:
  • CLASSES: Non-selective (beta₁, beta₂), cardioselective (only beta₁), partial agonists.
  • MECHANISM: Blocks beta-receptors in 3 places:
    • Block beta₁-receptors on heart: Reduce heart rate and inotropic state.
    • Block beta₁-receptors on kidneys: Reduce renin secretion.
    • Block beta-receptors in CNS: Reduce sympathetic outflow ------> reduce vasomotor tone.
  • INDICATIONS:
    • Lower blood pressure
    • Improve myocardial oxygen supply ------> treat angina
      • They do not, however, increase blood supply to the myocardium.
      • Often combined with nitrates.
      • Do not use with variant angina. beta-blockers slow heart rate ------> prolonged ejection time and increased LVEDV ------> increased myocardial oxygen supply.
    • Normalize heart rate
    • Prevent myocardial infarct (less O₂ demand of myocardium)
    • Limit the size of myocardial infarct
  • PATIENT POPULATION: Young or middle-aged white males is the most responsive patient to beta-blockers.
  • DRUG COMBINATIONS:
    • Recommended as monotherapy for young or middle aged white males.
    • Used in combination with Thiazides to prevent reflex secretion of renin.
    • Used in combination with ACE inhibitors to prevent reflex tachycardia.
  • ADVERSE EFFECTS: Mainly GI and CNS
    • GI: Diarrhea, constipation, nausea, vomiting
    • CNS: Insomnia, lassitude, nightmares, depression.
    • Atherogenesis: Increase plasma triglycerides and decrease HDL
    • Hypoglycemia: beta-blockers impair the epinephrine-mediated response to hypoglycemia, thus they should not be used with insulin and should be used with caution in Diabetics.
    • Arrhythmias, especially heart-block, can be caused by overdose.
  • CONTRAINDICATIONS: Diabetes, Congestive Heart Failure, Heart Block, Asthma
• alpha-BLOCKERS: Only alpha₁-selective blockers (Prazosin, Terazosin, Doxazosin) are used to treat HTN.
  • MECHANISM: Block alpha₁ receptors ------> decreased vasomotor tone.
    • alpha₁-selective: reflex tachycardia is mitigated, because alpha₂-receptors are not also blocked.
  • ADVERSE EFFECTS: Orthostatic Hypotension is the only big one
    • Orthostatic Hypotension: It may be particularly pronounced with first dose
    • CNS: Drowsiness, dizziness, headache
    • Palpitations
    • Easy fatigability
• VASODILATORS:
  • CLASSES:
    • ORAL: Minoxidil, Hydralazine, given for chronic HTN treatment.
    • IV: Sodium nitroprusside, diazoxide, given for hypertensive emergencies.
  • ACTION: Directly cause relaxation in arteriolar smooth muscle ------> markedly decreased peripheral resistance.
    • TOLERANCE: Effects diminish with time, as reflex tachycardia and renin secretion counteract the decreased TPR.
      • Oral nitrates are no longer used for hypertension because tolerance develops.
  • DRUG COMBINATIONS: These drugs are usually combined with other drugs to alleviate the adverse effects.
    • Diuretic is given with them, to avoid fluid retention.
    • beta-blocker can be given with them, to mitigate reflex responses.
  • ADVERSE EFFECTS:
    • Reflex Responses: Tachycardia, increased renin secretion, palpitations
    • Fluid Retention
    • Headaches: Due to increased intracranial pressure, due to increased blood volume in cranium
    • Flushing
    • Dizziness
• Ca⁺²-CHANNEL BLOCKERS:
  • ACTION: Block slow L-Type Ca⁺² channels in (1) vasculature and (2) heart ------> decrease (1) TPR and (2) the inotropic state and AV channel conduction ------> decrease blood pressure.
    • VASCULAR EFFECT: Vasodilation.
    • CARDIAC EFFECTS: They decrease myocardial oxygen demand ------> treatment for angina.
      • Slow AV channel conduction
      • Reduced impulse generation in SA node
      • Decrease contractility
  • PATIENT POPULATION: Effective as monotherapy in mild to moderate HTN, elderly blacks (most responsive group).
  • DRUG CLASSES:
    • DIHYDROPYRIDINES (NIFEDIPINE): Strongest vasodilator, most specific to vasculature.
      • ADVERSE EFFECTS:
        • Reflex tachycardia is most pronounced with this group, because vascular effects are strongest and cardiac effects are minimal.
        • Vascular Effects (increased volume): Headache, flushing, dizziness, peripheral edema
    • VERAPAMIL: Strongest (most specific) cardiac effects.
      • PHARMACOKINETICS:
        • 90% protein bound. Very fast effect after IV administration, but only 10-20% oral availability.
        • Metabolized by liver
        • Excreted by kidneys biexponentially (with early and late phase of excretion).
      • ADVERSE EFFECTS:
        • Reflex tachycardia does not occur.
        • Bradycardia, due to slowed AV conduction.
        • Constipation is common.
        • Inhibit insulin secretion.
        • Interfere with platelet aggregation (longer bleeding times), due to blocked Ca⁺².
    • DILTIAZEM: Has well-balanced effects between vascular and cardiac effects, in-between Nifedipine and Verapamil.
      • ADVERSE EFFECTS:
        • Reflex tachycardia is not as bad.
        • Bradycardia, due to slowed AV conduction.
  • CONTRAINDICATIONS: Ca⁺²-blockers toxicities may precipitate CHF, AV-block, and cardiac arrest. Do not use in cases of:
    • Patients with Left Ventricular Hypertrophy.
    • Patients with bradyarrhythmias (heart block).
    • Patients with CHF.
• ACE-INHIBITORS:
  • ACTIONS: They inhibit ACE ------> reduce vascular tone and blood pressure.
    • They work well, despite the fact that Angiotensin levels are not always changed appreciably in patients taking the drug.
  • PATIENT POPULATION: Recommended for monotherapy for mild to moderate hypertension in any population.
    • The drugs are expensive.
    • They are less effective in elderly black man. Use thiazides for them.
  • ADVERSE EFFECTS:
    • Dry Cough: 5-20% of patients. Thought to be due to bradykinin.
      • ACE also catalyzes the breakdown of bradykinin. Inhibit ACE ------> increase levels of bradykinin.
      • Bradykinin may also contribute to the anti-hypertensive effects of the drug.
      • The cough does not get worse with increased doses.
    • No lipidemia changes.
    • Hyperkalemia: Due to inhibited aldosterone secretion. Do not give this drug with a potassium sparing diuretic!
    • Pregnancy: May cause fetal injury and death.
    • Immune reactions:
      • Angioneurotic edema: 0.1-0.2%. Edema related to scratching, related to bradykinin.
      • Anaphylaxis: 0.1-0.2%
      • Non-allergic, pruritic, maculopapular rash (probably due to bradykinin)
    • Renal: Contraindicated in patients with renal insufficiency.
      • Slow deterioration of renal function
      • Leukopenia, in patients with renal insufficiency.
    • Disturbances in taste
  • DRUG COMBINATIONS: Often used with diuretics.
    • They attenuate the secretion of aldosterone, thereby improving the diuresis and natriuresis (Na⁺ excretion) of diuretic drugs.

ANTI-ANGINAL DRUGS:

• TYPES OF ANGINA:
  • Classic Angina: Stress-induced crushing chest pain. Higher oxygen demand induces angina.
  • Variant Angina: Reduced oxygen supply due to vasospasm of coronary vessels.
    • Best treated with combination of nitrates and calcium-channel blockers. Do not use beta-blockers!
  • Unstable Angina: Crushing chest pain while at rest. MI is imminent.
• MYOCARDIAL OXYGEN SUPPLY: Oxygen extraction is already maximal in the heart.
  • Coronary Blood-flow can be increased to relieve angina:
    • Increase perfusion pressure (diastolic pressure)
    • Increase the duration of diastole (slower heart rate)
  • Lower preload relieves angina. Increase venous capacitance ------> decrease myocardial oxygen demand.
• NITRATES and NITRITES:
  • ACTIONS:
    • MECHANISM: Release NO₃^- ion ------> NO ------> increase cGMP ------> relaxation of all smooth muscle.
      • MAJOR EFFECT: Venous vasodilation ------> Increased venous capacitance ------> decreased preload ------> decreased myocardial oxygen demand.
      • MINOR EFFECT: Arteriolar vasodilation ------> decreased peripheral resistance ------> decreased afterload ------> decreased myocardial oxygen demand.
    • Large Veins are preferentially dilated by nitrites. Decreased preload is the primary mechanism by which myocardial oxygen demand is decreased.
    • Reflex sympathetic activity occurs with treatment.
    • Coronary Blood-flow: Total flow is not increased, but regional flow may be redistributed from well-supplied areas to more ischemic areas.
  • TOLERANCE: It appears quickly and disappears quickly.
    • Metabolic Tolerance: Nitrates are rapidly degraded by hepatic organic nitrate reductase. Derivatives are then excreted by kidneys
    • Physiologic and/or pharmacologic tolerance may develop with prolonged use.
  • ADVERSE EFFECTS:
    • Smooth Muscle Relaxation: Relaxation of bronchial, GI and GU muscle occurs, in addition to relaxation of vascular muscle.
    • Orthostatic hypotension
    • Tachycardia
    • Methemoglobinemia: Methylation of hemoglobin results only from nitrites (sodium and amyl nitrite), when given in high doses.
    • Throbbing headache, due to increased blood volume in cranium.
• Ca⁺²-CHANNEL BLOCKERS: See Anti-HTN above.
• beta-BLOCKERS: See Anti-HTN above.