PHARM 331 Drug actions, effects, and etc

How diuretics work: Mechanism of action

Blockade of sodium and chloride reabsorption

•Site of action = Proximal tubule produces greatest diuresis

•Adverse effects = Hypovolemia (cause getting rid of fluids), Acid-base imbalance (solutes, K, Na), and Electrolyte imbalances 

Classification of diuretics

•Loop: Furosemide (lasix…??? - last 6 hrs) 

•Thiazide: Hydrochlorothiazide 

•Osmotic: Mannitol

•Potassium-sparing: Two subcategories (rid of sodium only, the other diuretics get rid of sodium AND potassium ) 

•Aldosterone antagonists (spironolactone)

•Nonaldosterone antagonists (triamterene)

•Fifth group = Carbonic anhydrase inhibitors (not common)

Loop Diuretics

•Furosemide (Lasix): Most frequently prescribed loop diuretic

•Mechanism of action = Acts on ascending loop of Henle to block reabsorption

•Pharmacokinetics = Rapid onset (PO 60 minutes; IV 5 minutes)

• Cannot control urine 

•Therapeutic uses = Pulmonary edema, Edematous states, Hypertension

• Goal is to get of fluid for pressure to go down 

Furosemide [Lasix]

•Adverse effects = Hyponatremia, hypochloremia, and dehydration

•Hypotension

•Loss of volume

•Relaxation of venous smooth muscle

•Hypokalemia 

•Ototoxicity (rare) - hearing of the ears 

Furosemide [Lasix] Drug interactions

•Digoxin when K+ levels are low 

•Ototoxic drugs

•Potassium-sparing diuretics

•Other loop diuretics

Thiazides and Related Diuretics

•Effects similar to those of loop diuretics

• Increase renal excretion of sodium, chloride, potassium, and water (monitor them, NGFAR, creatine levels) 

• Elevate levels of uric acid and glucose

•Maximum diuresis is considerably lower than with loop diuretics

•Not effective when urine flow is scant (unlike with loop diuretics)

Hydrochlorothiazide

•Most widely used

•Action: Early segment distal convoluted tubule

•Peaks in 4 to 6 hours

Therapeutic uses

• Essential hypertension = majority of the population (HTN occurs typically occur from 8:00 am- 2:00 pm) 

• Edema

Hydrochlorothiazide Adverse Effects

•Hyponatremia, hypochloremia, and dehydration

•Hypotension

•Hypokalemia

•Ototoxicity

•Hyperglycemia- idea that resorption in kidneys and reabsorb glucose 

•Hyperuricemia - if someone has gout, the meds led to it 

•Effects on lipid levels

•Use in pregnancy and lactation

•Impact on lipids, calcium, and magnesium (make sure to monitor them) 

Hydrochlorothiazide drug interctions

•Digoxin

•Augments effects of hypertensive medications

•Lithium

•NSAIDs may blunt diuretic effect with chronic use 

•Can be combined with ototoxic agents without increased risk of hearing loss

Potassium-Sparing Diuretics

•Useful responses

• Modest increase in urine production

• Substantial decrease in potassium excretion

•Rarely used alone for therapy

•Aldosterone antagonist

• Spironolactone

•Nonaldosterone antagonists

• Triamterene

• Amiloride

Spironolactone [Aldactone]

Mechanism of action

•Blocks aldosterone in the distal nephron

•Retention of potassium

•Increased excretion of sodium

Therapeutic uses

•Hypertension

•Edematous states

•Heart failure (decreases mortality in severe failure)

Adverse effects

•Hyperkalemia

•Endocrine effects

Spironolactone [Aldactone] interactions

•Thiazide and loop diuretics = worry of hypovolemia leads to hypotension which leads to orthostatic which leads to fall, which we don’t want for pts. DONT USE MULTIPLE DURETIC AT ONCE.  

•Agents that raise potassium levels

Triamterene [Dyrenium]

Mechanism of action

•Disrupts sodium-potassium exchange in the distal nephron

•Direct inhibitor of the exchange mechanism

•Decreases sodium reuptake

•Inhibits ion transport

Therapeutic uses

•Hypertension

•Edema

Adverse effects

•Hyperkalemia

•Leg cramps

•Nausea

•Vomiting

•Dizziness

•Blood dyscrasias (rare)

Amiloride [Midamor]

Mechanism of action

•Blocks sodium-potassium exchange in the distal nephron

Therapeutic use

•Counteract potassium loss caused by more powerful diuretics

Adverse effects

•Hyperkalemia

Drug interactions

•ACE inhibitors; other drugs with hyperkalemia

Osmotic Diuretic

•Mannitol [Osmitrol]

• Promotes diuresis by creating osmotic force within lumen of the nephron

•Pharmacokinetics

• Drug must be given parenterally

•Therapeutic uses

• Prophylaxis of renal failure

• Reduction of intracranial pressure

• Reduction of intraocular pressure

Mannitol [Osmitrol]

•Adverse effects

• Edema

• Precipitate heart failure

• Precipitate pulmonary edema

ACE Inhibitors

•Reduce levels of angiotensin II

•Increase levels of bradykinin (causes coughing frfr, dry cough, not the phlegm, give Angiotensin blocker) 

• Retains K+ 

ACE Inhibitors Pharmacokinetics

Ends in -pril= means ACE inhibitors

• Nearly all orally. The only exception is enalaprilat (the active form of enalapril), which is given intravenously (IV) with FOOD

Therapeutic uses

•Hypertension

•Heart failure

•Myocardial infarction (MI)

•Diabetic and nondiabetic nephropathy

•Prevention of MI, stroke, and death in patients at high cardiovascular risk

ACE Inhibitors adverse effects

•First-dose hypotension

•Fetal injury

•Cough

•Angioedema

• ACE inhibitors can cause angioedema, a potentially life-threatening reaction. If patients report edema of the tongue, lips, or eyes, emergency care should be sought immediately. The patient must never take ACE inhibitors again.

•Hyperkalemia

•Renal failure

•Neutropenia

ACE Inhibitors drug interactions

•Diuretics

•Antihypertensive agents

•Drugs that raise potassium levels

•Lithium

•Nonsteroidal anti-inflammatory drugs

Preparations, dosage, and administration

•Except for enalaprilat, all ACE inhibitors are administered orally

•All are available in single-drug formulations

•Except for captopril and moexipril, all oral formulations may be administered without regard to meals

Angiotensin II Receptor Blockers

•Block access of angiotensin II

•Cause dilation of arterioles and veins

•Prevent angiotensin II from inducing pathologic changes in cardiac structure

•Reduce excretion of potassium

•Decrease release of aldosterone

•Increase renal excretion of sodium and water

•Do not inhibit kinase II

•Do not increase levels of bradykinin

Angiotensin II Receptor Blockers therapuetic uses/adverse effects

•Hypertension, heart failure, myocardial infarction

•Diabetic nephropathy

•Patient unable to tolerate ACE inhibitors: Protection against MI, stroke, and death from cardiovascular (CV) causes in high-risk patients

•May prevent development of diabetic retinopathy

•New data show that ACE inhibitors and angiotensin II receptor blockers (ARBs) are not effective for primary prevention of nephropathy in normotensive diabetic patients

• Potassium levels will increase with usage of ARB. 

Adverse effects

•Angioedema

•Fetal harm

•Renal failure

•ARBs do not promote accumulation of bradykinin in the lung and therefore have a lower instance of cough

Direct Renin Inhibitors

•Aliskiren [Tekturna] 

•Binds tightly with renin and inhibits the cleavage of angiotensinogen to angiotensin I

Side effects

• Angioedema, cough, GI effects, hyperkalemia, fetal injury, and death

Aldosterone Antagonists

•Eplerenone [Inspra]

• Mechanism of action

• Selective blockade of aldosterone receptors

•Therapeutic uses

• Hypertension

• Heart failure

•Pharmacokinetics

• Absorption is not affected by food

•Adverse effects

• Hyperkalemia

•Drug interactions

• Inhibitors of CYP3A4 -> 80%

• Drugs that raise potassium levels

• Use with caution when combined with lithium

Spironolactone [Aldactone]

Mechanism of action

• Blocks aldosterone receptors

• Binds with receptors for other steroid hormones

Therapeutic uses

• Hypertension

• Heart failure

Adverse effects

• Hyperkalemia

• Gynecomastia

• Menstrual irregularities

• Impotence

• Hirsutism

• Deepening of the voice

Calcium Channel Blockers

Physiologic functions and consequences of blockade - In blood vessels, calcium entry causes vasoconstriction; calcium channel blockade, therefore, causes vasodilation.

•In the heart, calcium entry increases the heart rate, atrioventricular conduction, and myocardial contractility; therefore, calcium channel blockade has the opposite effects.

Calcium Channel Blockers types

• Calcium channel blockers: Classification and sites of action

• Verapamil and diltiazem: Agents that act on vascular smooth muscle (VSM) and the heart

• Dihydropyridines: Agents that act mainly on vascular smooth muscle or BP (not arrhythmia) 

Calcium Channel Blockers hemodynamic effects

•Blockade at peripheral arterioles

-Reduces arterial pressure

•Blockade at arteries and arterioles of heart

-Increases coronary perfusion

•Blockade at SA node

-Reduces heart rate

•Blockade at AV node (most important)

-Decreases AV nodal conduction

•Blockade in the myocardium

-Decreases force of contraction

Verapamil

Therapeutic uses

•Angina pectoris

• Vasospastic angina and angina of effort

•Essential hypertension

• Second-line agent after thiazide diuretics

•Cardiac dysrhythmias

• Atrial flutter, atrial fibrillation, paroxysmal supraventricular tachycardia

•Migraine (vasodilation/constriction in the brain, some cases only if everything else fails) 

Adverse effects

•Constipation

• Most common complaint

• Results from blockade of calcium channels in smooth muscle of the intestine

•Especially severe for older adults

•Can be decreased by increasing dietary fiber and fluids

• Dizziness

• Facial flushing (common)

• Headache (common) 

• Edema of ankles and feet (not that common with Verapamil) 

• Gingival hyperplasia

• Heart block

Verapamil Drug interactions, toxicty, and management

•Digoxin - increases contractility of heart 

•Beta-adrenergic blocking agents

• Work of the heart 

Toxicity

•Severe hypotension

•Bradycardia and AV block

•Ventricular tachydysrhythmias

•Gastric lavage and activated charcoal

Management

• IV verapamil for dysrhythmias can cause severe cardiovascular effects

• Blood pressure and ECG should be monitored

• Resuscitation equipment should be kept immediately available

Diltiazem

•Actions and uses

• Blocks calcium channels in the heart and blood vessels (similar to verapamil)

•Lowers blood pressure

• Arteriolar dilation

• Direct suppressant/reflex cardiac stimulation = Little net effect on the heart

Therapeutic uses

•Angina pectoris

•Hypertension

•Cardiac dysrhythmias

•Atrial flutter, atrial fibrillation, paroxysmal tachycardia

Diltiazem adverse effects and interactions

•Similar to verapamil, except for less constipation

•Dizziness

•Flushing

•Headache

•Edema of ankles and feet

•Exacerbates bradycardia, sick sinus syndrome, heart failure, second- or third-degree heart block

Drug interactions

•Digoxin

•Beta-adrenergic blocking agents

Dihydropyridines

• Agents that act mainly on vascular smooth muscle

•Nifedipine [Adalat, Nifedical, Nifediac, Procardia]

• -Pine= dihydropyridines 

• Significant blockade of calcium channels in blood vessels

• Minimal blockade of calcium channels in the heart

• Similar to verapamil in some respects and quite different in others

Nifedipine

-Shell with two holes (one for gastric juice and other for med with shell, shells could be seen in feces after dispelling, medicine was absorbed but not the shell.

•Vasodilation by blocking calcium channels

•Blocks in vascular smooth muscle, relaxation 

•Very little blockade of heart calcium (Ca) channels

•Cannot be used to treat dysrhythmias

•Less likely than verapamil to exacerbate preexisting cardiac disorders

Direct Effects 

Limited to blockade of Ca channels invascular smooth muscle (VSM)

•No direct suppressant effects on:

•Automaticity, AV conduction, or contractile force

Indirect effects 

•Lowered blood pressure (BP) activates baroreceptor reflex

•Primarily with immediate release versus sustained release

• Vasodilation by blocking calcium channels

Nifedipine uses and adverse effects

• Angina pectoris

• Hypertension

• Investigational basis: To relieve migraine headache and to suppress preterm labor

Adverse effects

•Flushing

•Dizziness

•Headache

•Peripheral edema (common in high doses) 

•Gingival hyperplasia

•Chronic eczematous rash in older patients

•Reflex tachycardia

•Increases cardiac oxygen demand

•Can increase pain in angina patients

•Can be combined with a beta blocker for prevention of reflex tachycardia

• Note: Beta blockers decrease the adverse cardiac effects of nifedipine but can intensify the adverse cardiac effects of verapamil and diltiazem

Other Dihydropyridines

•Seven other dihydropyridines available

•All similar to nifedipine

•Produce greater blockade of Ca channels in the VSM than in the heart

• Nicardipine, amlodipine, isradipine, felodipine, nimodipine (common in US), nisoldipine, and clevidipine

*Verapamil and diltiazem are contraindicated for patients with severe hypotension, sick sinus syndrome (in the absence of electronic pacing), and second-degree or third-degree AV block. Use with caution in patients with heart failure or liver impairment and in patients taking digoxin or beta blockers

Digoxin

• The combination of digoxin with verapamil or diltiazem increases the risk of partial or complete AV block.

• Monitor for indications of impaired AV conduction (missed beats, slowed ventricular rate).

•Verapamil (and possibly diltiazem) can increase plasma levels of digoxin. Digoxin dosage should be reduced.

• Also used to treat supraventricular dysrhythmias (inactive against ventricular dysrhythmias)

  • Suppresses dysrhythmias by decreasing conduction through AV node and automaticity in the SA node

  • interval may be shortened

Digoxin [Lanoxin] 

Effects

• Positive inotropic action on the heart

• Increases force of ventricular contraction

• Increases myocardial contractility

Relationship of potassium to inotropic action

• Potassium levels must be kept in normal physiologic range

Hemodynamic benefits

• Increased cardiac output

  • Decreased sympathetic tone

  • Increased urine production

  • Decreased renin release

Digoxin [Lanoxin] other effects

Neurohormonal benefits

• Modulates the activity of the neurohormonal system

• Suppresses renin release in the kidney

• Decreases sympathetic outflow from the CNS

• Increases sensitivity of cardiac baroreceptors

Electrical effects

• Alters electrical properties of the heart

  • Increases firing rate of vagal fibers

  • Increases responsiveness of sinoatrial (SA) node to acetylcholine = Very active in arrhythmias (HTN, congestive HF)  

Digoxin [Lanoxin] adverse effects

• Cardiac dysrhythmias

• Predisposing factors 

  • Hypokalemia

  • Elevated digoxin level

    • Narrow therapeutic range

  • Heart disease

• Diagnosing digoxin-induced dysrhythmias

• Managing digoxin-induced dysrhythmias

• Noncardiac adverse effects

  • Anorexia, nausea, vomiting, fatigue

• Measures to reduce adverse effects

  • Education

*Cardiotoxicity

Digoxin [Lanoxin] drug interactions

changes the concentration of K+ (EKG, K+ levels)

• Diuretics

• ACE inhibitors and ARBs

• Sympathomimetics

• Quinidine

• Verapamil

Pharmacokinetics

• Absorption

• Distributed widely and crosses placenta

• Eliminated primarily by renal excretion

• Half-life about 1.5 days -> blood work after 3 Half lives so times days by 3 

• Ex: 1.5 * 3 Levels changes every 5 days (steady state and dosages depend on Half-life) 

• If pt needs certain meds, may need loading dose (not CHF), injects

*Some metabolize livers or kidneys so monitor where it metabolizes then the heart 

Beta Blockers

•Concurrent use of a beta blocker with verapamil or diltiazem can cause bradycardia, AV block, or heart failure.

• Monitor closely for cardiac suppression. Administer intravenous verapamil and beta blockers several hours apart.

Beta blockers intention and adverse effects

• With careful control of dosage, can improve patient’s status

• Protect from excessive sympathetic stimulation

• Protect against dysrhythmias

Adverse effects

• Fluid retention or worsening of HF

• Fatigue

• Hypotension -> heart pumping less 

• Bradycardia or heart block

Grapefruit Juice (pulp) 

• Grapefruit juice can raise levels of verapamil and diltiazem, although new evidence reveals this is less than originally thought. Nevertheless, toxicity may result. Advise patients that it may be prudent to minimize grapefruit juice consumption.

• One cup is okay but still unsure cause Americans do not drink the can ones (what they study for the interactions) 

• TELL THEM NO!!!!!!!!!!

Managing Acute Toxicity of Dihrdopyridines

Remove unabsorbed drug with gastric lavage followed by activated charcoal. Give IV calcium to help counteract excessive vasodilation and reduced myocardial contractility.

• To raise blood pressure, give IV norepinephrine. IV fluids and placing the patient in modified Trendelenburg position can also help.

• Bradycardia and AV block can be reversed with atropine and glucagon. If these are inadequate, electronic pacing may be required.

Vasodilators

•Can be produced with a variety of drugs

•Some act primarily on veins or arterioles; others act on both types of vessels

•Wide variety of therapeutic applications

Basic Concepts in Vasodilator Pharmacology

•Selectivity of vasodilatory effects

•Selective dilation of arterioles

- Hydralazine (vasodilator) 

•Selective dilation of veins

- Nitroglycerin (vasodilator) 

• Adverse effect is headaches if pt leave the patch on after 10 hrs

•Dilation of arterioles and veins

-Prazosin

Vasodilators uses and adverse effects

•Essential hypertension

•Hypertensive crisis

•Angina pectoris

•Heart failure

•Myocardial infarction

•Pheochromocytoma

•Peripheral vascular disease

•Pulmonary arterial hypertension

•Production of controlled hypotension during surgery

Adverse effects related to vasodilation

•Postural hypotension

•Teach patients about symptoms of hypotension (lightheadedness, dizziness) and advise them to sit or lie down if these occur. Avoid abrupt transitions from a supine or seated position to an upright position.

•Reflex tachycardia

-Expansion of blood volume

Hydralazine Uses

• Give it more than once a day, 3x a day (compliance is hard) 

Adverse effects 

•Reflex tachycardia

•Increased blood volume

•Systemic lupus erythematosus–like syndrome (rare) 

•Headache, dizziness, weakness, and fatigue

Drug interactions 

•Other antihypertensive agents

•Avoid excessive hypotension

•Combined with beta blocker to protect against reflex tachycardia and with diuretics to prevent sodium and water retention and expansion of blood volume

Minoxidil (grew hair) 

Selective dilation of arterioles

•More intense dilation than hydralazine, but causes more severe adverse reactions

•Used for severe hypertension unresponsive to safer drugs

Adverse effects

•Reflex tachycardia

•Sodium and water retention

•Hypertrichosis

•Pericardial effusion

•Other

Sodium Nitroprusside [Nitropress]

•Fastest-acting antihypertensive agent

•Causes venous and arteriolar dilation

•Administration: IV infusion

•Onset: Immediate (BP returns to pretreatment level in minutes when stopped)

• Only Used for hypertensive emergencies

Adverse effects

•Excessive hypotension

•Cyanide poisoning -> you become a smurf (stop med, slowing the drip) 

•Thiocyanate toxicity

Drugs for Hypertensive Emergencies

•Sodium nitroprusside (remember SMURF) - inject 

•Fenoldopam

•Labetalol - inject 

•Diazoxide

•Clevidipine

Drugs for Hypertensive Disorders of Pregnancy

Chronic hypertension and pregnancy

•ACE inhibitors, ARBs, and DRIs are contraindicated during pregnancy

•Most other antihypertensives can be continued during pregnancy

Preeclampsia and eclampsia

•Hydralazine

•Magnesium sulfate (anticonvulsant)

Classes of antihypertensive drugs

Diuretics

• Thiazide diuretics

• Loop diuretics

• Potassium-sparing diuretics

Sympatholytics (antiadrenergic drugs)

• Beta-adrenergic blockers

• Alpha₁ blockers

• Alpha/beta blockers: Carvedilol and labetalol

• Centrally acting alpha₁ agonists

• Adrenergic neuron blockers

•Direct-acting vasodilators: Hydralazine and minoxidil

•Calcium channel blockers

Drugs that suppress RAAS

• ACE inhibitors best used for HTN

• Angiotensin II receptor blockers

• Aldosterone antagonists

• Direct renin inhibitors: Type 2 diabetes mellitus precautions

Ivabradine (Corlanor) - third line

For use in patients with stable, symptomatic heart failure with:

• LVEF <35% Left ventricle ejection fraction  

• Sinus rhythm -> fix the dysrhythmia 

• Heart rate > 70 BPM

*Can be used for patients who have a contraindication to beta blocker use

Digoxin and Cardiac Glycosides

• Positive inotropic actions 

• Increase myocardial contractile force

• Alter electrical activity of the heart -> need K+ levels to be in normal limits (need K+ to be over 3.5 or else will have digoxin toxicity) 

  • Nausea (is first) is adverse affect, visionary disorders (yellow hallo) 

  • ALWAYS THINK OF POTASSIUM LEVELS WHEN PT HAS MUSCLE WEAKNESS

• Favorably affect neurohormonal systems

Inotropic Agents 

• Sympathomimetics

  • Dopamine [Intropin]

    • Catecholamine

    • Activates beta1-adrenergic receptors in the heart, kidney, and blood vessels

    • Increases heart rate

    • Dilates renal blood vessels

    • Activates alpha1 receptors - does not block the receptors, causes constriction, enhancing the effects which makes the receptors better

Inotropic Agents Pt2

• Dobutamine

  • Synthetic catecholamine

  • Selective activation of beta1-adrenergic receptors

• Phosphodiesterase inhibitors

  • Milrinone [Primacor]

  • Inodilator: Increases myocardial contractility and promotes vasodilation

  • Reserved for patients with severe reduction in cardiac output resulting in decreased organ perfusion

  • Arrhythmias, myocardial ischemia 

• Vasodilators

• Isosorbide dinitrate plus hydralazine

• Cardiac (Digitalis) Glycosides

• Digoxin [Lanoxin]

Class IA Agents 

Quinidine

• Effects on the heart

  • Blocks sodium channels

  • Slows impulse conduction

  • Delays repolarization

  • Blocks vagal input to the heart

• Effects on the ECG

  • Widens the QRS complex

  • Prolongs the QT interval

Class 1A Agent uses and effects

• Therapeutic uses

  • Used for supraventricular and ventricular dysrhythmias

• Adverse effects (Delentones are used for seizures, also could use for arrhythmias) 

  • Diarrhea

  • Cinchonism

  • Cardiotoxicity

  • Arterial embolism

  • Alpha-adrenergic blockade, resulting in hypotension

  • Hypersensitivity reactions

• Drug interactions

  • Digoxin

Class IB Agents 

• Lidocaine [Xylocaine] for pain

  • Effects on the heart and ECG

    • Blocks cardiac sodium channels

      • Slows conduction in the atria, ventricles, and His-Purkinje system

    • Reduces automaticity in the ventricles and His-Purkinje system

    • Accelerates repolarization

  • Adverse effects

    • CNS effects

    • Drowsiness

    • Confusion

    • Paresthesias

Class IC Agents

• Block cardiac sodium channels

• Delay ventricular repolarization

• All class IC agents can exacerbate existing dysrhythmias and create new ones

• Two class IC agents

  • Flecainide

  • Propafenone

Class II: Beta Blockers ( ends with -ol) 

• Beta-adrenergic blocking agents

  • Only four approved for treating dysrhythmias, not for CHF 

    1. Propranolol

    2. Acebutolol

    3. Esmolol

    4. Sotalol

Propranolol (non-selective BB)

• Effects on the heart and ECG

  • Decreased automaticity of the SA node

  • Decreased velocity of conduction through the AV node

  • Decreased myocardial contractility

• Therapeutic use

  • Dysrhythmias caused by excessive sympathetic stimulation

  • Supraventricular tachydysrhythmias

    • Suppression of excessive discharge

    • Slowing of ventricular rate

• Adverse effects

  • Heart failure

  • block

  • Sinus arrest

  • Hypotension -> flushing (pts cannot handle constipation) 

  • Bronchospasm (in asthma patients) 

    • Beta 2 -> will be blocked due to the blocked receptors of B1 and 2

Class III: Potassium Channel Blockers

• Amiodarone [Pacerone]

  • Therapeutic use

    • For life-threatening ventricular dysrhythmias only

    • Recurrent ventricular fibrillation

    • Recurrent hemodynamically unstable ventricular tachycardia

  • Effects on the heart and ECG

    • Reduced automaticity in the SA node

    • Reduced contractility

    • Reduced conduction velocity

    • QRS widening

    • Prolongation of the PR and QT intervals

Potassium Channel Blockers adverse effects

• Adverse effects

  • Protracted half-life

  • Pulmonary toxicity

  • Cardiotoxicity (big no no) 

  • Thyroid toxicity (big no no)

  • Liver toxicity

  • Ophthalmic effects

  • Toxicity in pregnancy and breast-feeding

  • Dermatologic toxicity

• Drug interactions (increases levels)

  • Quinidine

  • Procainamide

  • Phenytoin

  • Digoxin

  • Diltiazem

  • Warfarin

  • Cyclosporine

  • Lovastatin, simvastatin, atorvastatin

  • May have to reduce the dosages of these meds

Other factors on K+ channel blockers

• Amiodarone levels can be increased by grapefruit juice and by inhibitors of CYP3A4. Toxicity can result.

• Amiodarone levels can be reduced by cholestyramine (which decreases amiodarone absorption) and by agents that induce CYP3A4 (eg, St. John’s wort, rifampin).

• The risk of severe dysrhythmias is increased by diuretics (because they can reduce levels of potassium and magnesium) and by drugs that prolong the QT interval, of which there are many 

• Combining amiodarone with a beta blocker, verapamil, or diltiazem can lead to excessive slowing of the heart rate

• Muscle weakness -> think about K+ levels 

Class IV: Calcium Channel Blockers 

• Verapamil [Calan, Verelan] and diltiazem [Cardizem, Tiazac]

  • Reduce SA nodal automaticity

  • Delay AV nodal conduction

  • Reduce myocardial contractility

  • Therapeutic uses

    • Slow ventricular rate (atrial fibrillation or atrial flutter)

    • Terminate SVT caused by an AV nodal reentrant circuit

  • Adverse effects

    • Bradycardia

    • block

    • Heart failure

    • Hypotension

    • Peripheral edema

    • Constipation

    • Can elevate digoxin levels

    • Increased risk when combined with a beta blocker = same effect so risk of arrhythmia unless pt is not at risk 

    • Propranolol -> you see trouble 

Adenosine [Adenocard]

Other Antidysrhythmic Drug

• Effects on the heart and ECG

  • Decreases automaticity in the SA node

  • Slows conduction through the AV node

  • Prolongs PR interval

• Therapeutic use: Termination of paroxysmal SVT

• Adverse effects

  • Sinus bradycardia

  • Dyspnea

  • Hypotension

  • Facial flushing

  • Chest discomfort

• Drug interactions

  • Methylxanthines

  • Dipyridamole

HMG-CoA Reductase Inhibitors (Statins)

NUMBER 1

• Most effective drugs for lowering LDL (plaque stability) 

• Reduction of LDL cholesterol

• Elevation of HDL cholesterol

• Reduction of triglyceride levels

• Nonlipid beneficial cardiovascular actions

  • Promote plaque stability

  • Suppress production of thrombin

HMG-CoA Reductase Inhibitors (Statins) uses and actions

• Mechanism of cholesterol reduction

• Clinical trials

• Therapeutic uses

  • Hypercholesterolemia

  • Primary and secondary prevention of CV events

  • Post-MI therapy

  • Diabetes 

  • Potential uses

• Beneficial actions

  • Reduction of LDL cholesterol

  • Elevation of HDL cholesterol

  • Reduction of triglyceride levels

  • Nonlipid beneficial cardiovascular actions

*May affect glucose levels

HMG-CoA Reductase Inhibitors (Statins) adverse effects

• Common

  • Headache

  • Rash

  • Memory loss (not really)

  • disturbances

• Rare 

  • Myopathy/rhabdomyolysis (Major for some pts, dark urine, extremities pain,) -> considered an allergy (not really, more adverse effect) -> if they have a reaction to one, they will have reaction to everyone

  • Hepatotoxicity- have to monitor liver enzyme, AST, ALT 

    • ANATERONE?= levels go higher -> toxicity 

  • New-onset diabetes

HMG-CoA Reductase Inhibitors (Statins) drug interactions and dosing

• Drug interactions

  • Most other lipid-lowering drugs (except bile-acid sequestrants)

  • Drugs that inhibit CYP3A4

  • Use in pregnancy

• Dosing: Once daily in the evening

• Endogenous cholesterol synthesis increases during the night

• Statins have greatest impact when given in the evening, works at night since Cholesterol is made at night 

• Long Half-life = duration is long so if you take it in the morning it will work at night too expect avortastin and overostatin 

Bile-Acid Sequestrants

• Previously were first-line drugs (bile- acid was the reason why its not first line anymore, pulls cholesterol out) 

• Now primarily used as adjuncts to statins

• Cholestyramine

• Colestipol

• Colesevelam

  • Newest and better-tolerated drug

  • Does not decrease uptake of fat-soluble vitamins (as other bile sequestrants do)

  • Does not significantly reduce the absorption of statins, warfarin, digoxin, and most other drugs studied

  • Reduces LDL cholesterol

  • Increases VLDL levels in some patients

  • Mechanism of action

    • Increases LDL receptors on hepatocytes

    • Prevents reabsorption of bile acids

  • Therapeutic use

    • Reduces LDL cholesterol (in conjunction with modified diet and exercise)

  • Adverse effects

    • Constipation, need to take with food/water and 2 hrs after or before after other meds?

Ezetimibe

• Mechanism of action and impact on plasma lipids

  • Inhibits cholesterol absorption

• Therapeutic use

  • Reduces total cholesterol, LDL cholesterol, and apolipoprotein B

  • Approved for monotherapy and combined use with statins

• Adverse effects

  • Myopathy

  • Rhabdomyolysis

  • Hepatitis

  • Pancreatitis

  • Thrombocytopenia

• Drug interactions

  • Statins

  • Fibrates

  • Bile-acid sequestrants

  • Cyclosporine

Fibric Acid Derivatives (Fibrates)

• Most effective drugs available for lowering TG levels

• Can raise HDL cholesterol

• Little or no effect on LDL cholesterol

• Can increase the risk for bleeding in patients taking warfarin 

• Can increase the risk for rhabdomyolysis in patients taking statins

• Three drugs in the United States

  • Gemfibrozil [Lopid]

  • Fenofibrate [Tricor, others]

  • Fenofibric acid [TriLipix]

Gemfibrozil

• Effects on plasma lipoproteins

  • Decreases plasma TG content

  • Lowers VLDL levels

  • Can raise HDL cholesterol

• Mechanism 

• Drug interactions

  • Displace warfarin from plasma albumin

  • Measure international normalized ratio (INR) frequently

• Therapeutic uses

  • Reduces high levels of plasma triglycerides (VLDLs)

  • Treatment reserved for patients who have not responded to diet modification

  • Less effective than statins in reducing LDL

  • Can raise HDL (not approved for this use)

• Adverse effects

  • Rashes

  • Gastrointestinal disturbances

  • Gallstones

  • Myopathy

  • Liver injury (hepatotoxic)

Used to Alter Plasma Lipid Levels 

• Fish oil

• Lovaza (also fish oil) 

• Plant stanol and sterol esters

• Cholestin

Drugs for Angina Pectoris 

• Three families of antianginal agents

  • Organic nitrates

    • Nitroglycerin - vasodilate 

  • Beta blockers

    • Example: Metoprolol (Specific beta 1- calcium channel blocker) 

  • Calcium channel blockers

    • Example: Verapamil

• Ranolazine (vasodilate)

  • Newer drug with limited indications

  • Can be combined with other drugs

Organic Nitrates: Nitroglycerin actions and adverse effects

• Stable and variant angina

• Vasodilator

• Acts directly on vascular smooth muscle (VSM) to promote vasodilation

• Adverse effects

  • Headache (common) 

  • Orthostatic hypotension (common) 

  • Reflex tachycardia

Organic Nitrates: Nitroglycerin drug interactions

• Drug interactions -other medications that cause hypertension 

• Hypotensive drugs

• Phosphodiesterase type 5 inhibitors

• Beta blockers, verapamil, and diltiazem

Organic Nitrates: Nitroglycerin tolerance and uses

• Can develop rapidly

• Cross-tolerance to all other nitrates

• minimize, use the lowest effective dose

• Long-acting formulas: 8 drug-free hours per day, night take it off and put it on in morning 

• Therapeutic uses

  • Acute anginal therapy

  • Sustained anginal therapy

  • for perioperative control of blood pressure and treatment of heart failure with myocardial infarction (MI), unstable angina, and uncontrolled exacerbations of chronic angina

Isosorbide mononitrate and isosorbide dinitrate

• Actions identical to those of nitroglycerin

• Used for angina; taken orally; produce headache, hypotension, and reflex tachycardia 

Propranolol, metoprolol actions and adverse effects

Betablockers

• decrease cardiac O2 demand

• Adverse effects

  • Bradycardia

  • Decreased atrioventricular (AV) conduction

  • Reduction of contractility

  • Asthmatic effects

  • Use with caution in patients with diabetes

  • Insomnia

  • Depression

  • Bizarre dreams

Verapamil, diltiazem, nifedipine uses and adverse effects

CCB

• Block calcium channels in vascular smooth muscle

• Used for stable and variant angina

• Adverse effects

  • Dilation of peripheral arterioles

  • Reflex tachycardia

  • Hypotension

  • Beta blockers

  • Bradycardia

  • Heart failure

  • block

Ranolazine

• Belongs to first new class of antianginal agents approved in more than 25 years

  • Benefits are modest and greater in men than in women

  • Does not reduce heart rate, blood pressure, or vascular resistance

  • Can prolong QT interval; multiple drug interactions

• Exact mechanism unknown

• a first-line therapy; combine with first-line agents for inadequate response to other first-line medications for angina