Great Syndromes PBL 20

Amphotericin B

gspbl20 — Thu, 08 May 2008 15:35:54 +0000

Drug: Amphotericin B

Class: Polyene antifungal

Treatment For: A variety of systemic mycoses (Cryptococcus, Blastomyces, Coccidioides, Aspergillus, Histoplasma, Candida, Mucor, etc.), visceral leishmaniasis, Naegleria fowleri meningoencephalitis, and fungal meningitides (Cryptococcus, etc.).

Primary Molecular Target: Binds ergosterol in the fungal membrane

Mechanism of Action: The drug forms pores in the fungal cell membrane, which allows leakage of electrolytes (K+), and, eventually, causes cell death.

Primary site of Metabolism: Details on possible metabolic pathways are not known, although a large proportion is altered from its biologically active form. The drug is mainly excreted by the kidneys.

Drug Interactions/Adverse Events: Fever/Chills, hypotension, nephrotoxicity (avoid other nephrotoxic drugs, such as aminoglycosides and cyclosporine), hypokalemia (can be toxic with Digitalis, skeletal muscle relaxants, potassium wasting diuretics), arrhythmias, renal tubular acidosis, nephrocalcinosis, anemia, IV phlebitis, anorexia, nausea, headache. Toxicity can be reduced by concomittant administration with aspirin, antipyretics, and corticosteroids to decrease fever/chills (although it has been reported that corticosteroids could predispose to hypokalemia and cardiac effects); antihistamines to prevent hypotension; heparin to lessen thrombophlebitis; and antiemetics to counteract the nausea.

Gentamicin

gspbl20 — Thu, 08 May 2008 03:33:13 +0000

Drug: Gentamicin

Class: Aminoglycoside antibiotic

Treatment For: Many staphylococci, add a beta-lactam to treat neonatal enterococci, endocarditis, pseudomonas, proteus, klebsiella, serratia, stenotrophomonas, and other gram-negative antibiotic resistant bacteria.

Primary Molecular Target: Binds the 30S subunit ribosomal proteins to cause misreading of mRNA .

Mechanism of Action: Inhibits protein synthesis in three ways; Interference with the initiation complex, incorporation of incorrect amino acids into the peptide resulting in either a toxic or nonfunctional protein, and breaking up of polysomes into nonfunctional monosomes.

Primary site of Metabolism: Gentamicin is not metabolized, but is filtered and excreted by the kidney in its active form.

Drug Interactions/Adverse Events: Ototoxicity, nephrotoxicity, neuromuscular blockade (especially in association with anesthesia or other neuromuscular blockers). Should not be used concurrently with loop diuretics or other nephrotoxic antimicrobials (vancomycin, amphotericin, etc.) as this my accelerate kidney damage.

Imipenem-Cilastatin

gspbl20 — Wed, 07 May 2008 19:22:55 +0000

Drug: Imipenem-Cilastatin

Class: Imipenem- Carbapenem (Beta-lactam antibiotic)

Treatment For: Broad spectrum anti-microbial; Streptococci (including penicillin-resistant S. pneumoniae), enterococci (excluding E. faecium and non-β-lactamase-producing penicillin-resistant strains), staphylococci (including penicillinase-producing strains), and Listeria all are susceptible. Some strains of methicillin-resistant staphylococci are susceptible, many strains are not. Excellent activity against the Enterobacteriaceae, including organisms that are cephalosporin-resistant by virtue of β-lactamases. Most strains of Pseudomonas and Acinetobacter are inhibited. X. maltophilia is resistant. Anaerobes, including B. fragilis, are highly susceptible.

Primary Molecular Target: Imipenem: Binds to penicillin binding proteins Cilastatin: Renal tubular dihydropeptidase I

Mechanism of Action: Imipenem: Binds to penicillin binding proteins thereby inhibiting bacterial cell wall synthesis Cilastatin: reversibly and competitively inhibits dehydropeptidase I (DHP I). Imipenem is hydrolyzed in vivo to a microbiologically inactive metabolite by DHP I present on the brush border of proximal renal tubular cells; concurrent administration of cilastatin prevents this renal metabolism of the antibiotic.

Primary site of Metabolism: Imipenem: Renal Cilastatin: Renal

Drug Interactions/Adverse Events: Nausea/Vomiting most common; GI upset will also occur due to drugs actions against normal flora. Can lower seizure threshold, patients especially at risk include patients with meningitis or CNS lesions and those with renal insufficiency. Low incidence of hypersensitivity but may occur in patients with a beta-lactam allergy. Can induce cephalosporinases.

Ibuprofen (Motrin, Advil)

gspbl20 — Wed, 07 May 2008 00:15:27 +0000

Drug: Ibuprofen

Class: Nonselective nonsteriodal anti-inflammatory drug

Treatment for: Mild to moderate pain for dysmenorrhea; inflammatory disorders, including osteoarthritis and rheumatoid arthritis

Primary Molecular Target: COX-1, COX-2 isoenzymes

Mechanism of Action: Inhibits cyclooxygenase-1 and cyclooxygenase-2 isozymes and synthesis of prostaglandins causing pain, fever, and inflammation

Metabolism: via hepatic oxidation by cytochrome P450 2C9 to two inactive metabolites. Plasma half-life

is between 2 and 4 hours. Ibuprofen is excreted in the urine, 50—60% as metabolites and approximately 10% as unchanged drug. Some biliary excretion may occur. Excretion is usually complete within 24 hours of oral administration.

Special Considerations: Reduces risk of colon, breast, lung, prostate, and other cancers

Adverse effects: Gastrointestinal bleeding; nausea; vomiting; dyspepsia; allergic reactions; rarely hepatitis and renal failure

Drug Interactions: adverse GI effects increased by other nonsteroidal anti-inflammatory drugs; use with acetaminophen increases renal toxicity; decreases effect of antihypertensive agents; increases lithium levels and toxicity; use with aspirin decreases effects of both drugs

Digoxin

gspbl20 — Mon, 05 May 2008 03:19:07 +0000

Drug: Digoxin

Class: Digitalis glycoside

Treatment for: Heart failure; used to slow ventricular rate in atrial fibrillation

Primary Molecular Target: Na⁺/K⁺- ATPase

Mechanism of Action: Inhibits Na⁺/ K⁺- ATPase; increases intracellular Ca2+ and cardiac contractility; slows atrioventricular conduction and increases atrioventricular refractory period

Metabolism: sequential sugar hydrolysis in the stomach or by reduction of lactone ring by intestinal bacteria (in ~10% of population, gut bacteria may metabolize up to 40% of digoxin dose); metabolites may contribute to therapeutic and toxic effects of digoxin; metabolism is reduced with CHF

Special Considerations: Serum levels are used to assess dosage or confirm toxicity and should be in the range of 0.5 to 2 nanograms/mL

Adverse effects: nausea and vomiting; blurred vision, yellow/green halos; mental status changes; changes on EKG: decreased QT interval, increased PR interval, ST-segment depression, all types of arrhythmias (most serious signs of intoxication)

Drug Interactions: Amiodarone, quinidine, cyclosporine, diltiazem, and verapamil increase serum levels; diuretic-induced hypokalemia increases effects and toxicity.

Prednisone

gspbl20 — Mon, 05 May 2008 05:40:08 +0000

Drug	Prednisone
Class	Glucocorticoid
Treatment for	Adrenal insufficiency; Immunosupression (autoimmune diseases, excessive inflammation; transplantation); maligancy (breast, lymphoma)
Primary Molecular Target (e.g. Receptor, enzyme)	Binds glucocorticoid receptors (intracellular)
Mechanism of Action	Prednisone-glucocoroticoid receptor complex actively transported into nucleus, as a homodimer binds to glucocorticoid response elements in the promotor regions of responsive genes. Can also interact with other transcription factors, regulating the transcription of additional genes. Broad impact on the expression of cytokines, growth factors, etc. Prednisone exerts minimal effects via mineralocorticoid receptors.
Primary site of Metabolism	The metabolism of steroid hormones involves sequential additions of oxygen or hydrogen atoms, followed by conjugation. Reduction of the 4,5 double bond occurs at both hepatic and extrahepatic sites whereas reduction of the 3-ketone is only in the liver. The 3-hydroxyl group is conjugated with sulfate or glucuronide by enzymatic reactions that take place in the liver, and to a lesser extent in the kidney. The products are excreted in urine.
Case-relevant Drug Interactions or Adverse Events	Immunosuppresion can decrease ability of body to clear infections

Metoprolol

gspbl20 — Fri, 25 Apr 2008 06:03:36 +0000

Drug: Metoprolol

Class: Beta1-selective adrenergic blocking agent

Treatment for: hypertension, angina, acute myocardial infarction, congestive heart failure. Also been used for supraventricular and ventricular tachyarrhythimias, and migraine prophylaxis

Primary Molecular Target: Beta1-adrenergic receptor at low doses (Note: high does my elicit Beta2 receptor antagonism of bronchial and vascular musculature)

Mechanism of Actions:

1. HT: unknown. Proposed mechanisms include 1) competative antagonsim of catecholamines at peripheral adrenergic neuron sites, leading to decreased cardiac output; 2) central effect leading to reduced sympathetic outflow to the periphery; 3) suppression of renin activity.

2. Angina Pectoris: blocking of catecholamine-induced increases in heart rate, in velocity and exten of myocardial contraction, and in blood pressure, the drug reduces the O2 requirements of the heart.

Primary site of metabolism: primarily in the liver, which is characterized by extensive first-pass metabolism. Metoprolol is primarily metabolized by cytochrome P450 2D6. The rate of metabolism is dependent partly on the genetic polymorph that determines the rate of hepatic hydroxylation. In most subjects, hydroxylation occurs relatively rapidly, and the half-life of metoprolol is about 3—4 hours; in slow hydroxylators, the half-life is prolonged to about 7 hours. The drug is excreted mainly via the kidney as metabolites, with 95% of an oral dose excreted renally, primarily via glomerular filtration, within 72 hours.

Special Considerations: Metoprolol is widely distributed throughout the body. Metoprolol is moderately lipid soluble; it is more lipid-soluble than atenolol, but less lipid-soluble than propranolol or betaxolol. Metoprolol crosses the blood-brain barrier, with 78% of plasma concentration distributing to CSF fluid. Metoprolol also crosses the placenta, and is concentrated in breast milk. Although the drug is not extensively bound to plasma proteins, the hypotensive effects of metoprolol can last up to 1 month after discontinuation of the drug, possibly because of extensive tissue binding or CNS distribution.

Adverse effects: dizziness, lightheadedness, drowsiness, tiredness, diarrhea, unusual dreams, trouble sleeping, vision problems, reduction of peripheral blood flow, persistent dizziness, fainting, unusual fatigue, bluish discoloration of the fingers and toes, numbness/tingling/swelling of the hands or feet, decreased sexual ability, reversible hair loss, mental/mood changes, trouble breathing, cough, unexplained or sudden weight gain, increased thirst, increased urination.

Serious side effects include easy bruising or bleeding, persistent sore throat or fever, jaundice, stomach pain, dark urine, persistent nausea.

Hypersensitivity reaction leading to rash, urticaria, edema, severe dizziness, and/or dyspnea.

Drug Interactions: Calcium channel blockersand digoxin can lower of blood pressure and heart rate to dangerous levels when administered together with metoprolol. Metoprolol can mask the early warning symptoms of hypoglycemia and should be used with caution in patients receiving treatment for diabetes type II.

Warfarin (Coumadin)

gspbl20 — Fri, 25 Apr 2008 02:53:09 +0000

Drug: Warfarin (Coumadin)

Class: Anticoagulant

Treatment for: Prophylaxis for venous thrombosis and pulmonary embolism, atrial fibrillation, dilated cardiomyopathy, left ventricular aneurysm, thrombus formation prevention in patients with mechanical heart valves.

Primary Molecular Target: Epoxide reductase.

Mechanism of Action: Inhibits the enzyme epoxide reductase in the liver, which notmally converts vitamin K from its inactive epoxide form to its active quinone form. This effectively leads to a vitamin K deficiency. Without vitamin K, clotting factors II, VII, XI, and X, and proteins C and S (all of which are calcium-dependent clotting factors) will not be caboxylated forms which more efficiently interact with calcium. This will cause the PT to rise.

Primary site of metabolism: There are two enantiomers of warfarin: R and S-warfarin. Both are metabolized in the liver. R-warfarin is metabolized primarily by CYP1A2, CYP3A4, and then by carbonyl reductases. S-warfarin is metabolized primarily by CYP2C9.

Drug Interactions or adverse effects: The major side effect of warfarin is hemorrhage, which can be avoided by monitoring the INR. Very rarely, warfarin can cause a necrotic condition related to an early deficiency in protein C (an anticoagulant) owing to its short half-life compared to the other clotting factors. This causes a temporary hypercoagulable state, which may lead to many small areas of diminished blood flow, and, eventually, necrosis of the affected tissue. Warfarin has also been linked to osteoporosis.

Benazepril

gspbl20 — Thu, 24 Apr 2008 04:48:58 +0000

Drug: Benazepril

Class: ACE inhibitor

Treatment for: Hypertension, CHF, ischemic heart disease, reduces proteinuria and progression of nephropathy in diabetics.

Primary Molecular Target: Angiotensin-converting enzyme

Mechanism of Action: Inhibition of angiotensin-converting enzyme. This prevents angiotensin I from being converted into angiotensin II, which effectively blocks the renin-angiotensin-aldosterone axis. Angiotensin II is a potent vasodilator, so decreasing the amount of angiotensin II in the blood effectively vasodilates, which lowers blood pressure. Also, by blocking the renin-angiotensin-aldosterone system, the juxtaglomerular apparatus is no longer able to react to decreasing sodium in the tubule. The leads to a relative natriuresis. Benazepril also prevents the inactivation of bradykinin, which is a vasodilator. Benazepril is a long-acting ACE inhibitor in prodrug form.

Primary site of metabolism: First it is hydrolyzed by esterases in the liver to its active form, benazeprilat. Benazeprilat is later metabolized in the liver by cytochrome P450 3A4.

Drug Interactions or adverse effects: Benazepril may cause hypotension, cough, angioedema, rash, and acute renal failure and hyperkalemia. Although I don’t think we are concerned as much about the risk of our patient becoming volume depleted to the point of hypotension, the cough, angioedema, and natriuresis may possibly present complications.

NPH Insulin/Spironolactone

gspbl20 — Wed, 23 Apr 2008 22:55:20 +0000

Drug	Spironolactone	NPH Insulin
Class	Aldosterone antagonist; K⁺sparing diuretic	Intermediate acting Insulin
Treatment for	Volume overload; primary/secondary hyperaldosteronism	Type I and some Type II Diabetes Mellitus
Primary Molecular Target (e.g. Receptor, enzyme)	Mineralcorticoid receptor (MR)	Insulin receptor (tyrosine kinase receptor)
Mechanism of Action	Competitive inhibition of aldosterone at the MR	Autophosphorylation of tyrosine kinase receptor initiates downstream signalling cascade: effects include translocation of GLUT-4 to cell membrane (increased glucose uptake in skeletal muscle); various anabolic effects -glycogen synthesis, lipogenesis and fat storage, protein synthesis, activates transcription factors that enhance DNA synthesis and cell growth/division
Primary site of Metabolism	Hepatic metabolism; eliminated in urine/bile	Injected insulin – Kidney (60%); Liver (40%) [Endogenous insulin - Liver (60%) Kidney (40%)]
Case-relevant Drug Interactions or Adverse Events	In general: Hyperkalemia, non-anion gap acidosis, gynecomastia This Case: Gastritis/Ulcers – Contraindicated in patients with peptic ulcers	Hypoglycemia; insulin hypersensitity or anti-insulin antibodies (rare)