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Factors increasing lipid solubility (increased aborption)
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Factors decreasing lipid solubility (decreased re-aborption in kidney tubules; additions commonly produced by metabolism to enhance excretion) Addition of:
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| Drug: Aspirin |
| Drug Class: example of a weak acid |
| Pharmacokinetics: RCOOH <---> RCOO- + H+. The protonated form of a weak acid is the neutral, more lipid-soluble form. Almost all drugs are filtered by the glomerulus. If a drug is in a lipid-soluble form during passage through the renal tubule, a significant fraction will be reabsorbed by passive diffusion across membranes and back into the blood. Therefore, weak acids are excreted faster in alkaline urine because it causes a greater fraction of drug to be in a charged form. pH differences may also cause trapping or altered absorption in the stomach & small intestine. |
| Drug Interactions: Urinary Alkalinizers (e.g. sodium bicarbonate, potassium or sodium citrate, thiazide diuretics, carbonic-anhydrase inhibitors) decrease aspirin effectiveness by increasing the rate of salicylate renal excretion. |
| Notes: A very large fraction of drugs in use are either weak acids or weak bases. Weak organic acids are well absorbed in the stomach because they are uncharged at stomach pH. Weak bases are better absorbed in the intestines where the pH is higher. |
Reference: Katzung's text & www.rxlist.com |
| Drug: Quinidine |
| Drug Class: example of a weak base |
| Pharmacokinetics: RNH3+ <---> RNH2 + H+. Most weak bases are amine-containing molecules and are less lipid soluble at acidic pH levels that cause them to exist primarily in a charged form. Weak bases will be excreted faster in acidic urine. |
| Major drug interactions: Drugs that alkalinize the urine (carbonic-anhydrase inhibitors, sodium bicarbonate, thiazide diuretics) reduce renal elimination of quinidine. Drugs that acidify the urine (ascorbic acid, aluminum chloride) may increase the renal elimination of quinidine (but the clinical significance is not clear). |
Reference: www.rxlist.com |
Drug's modulating distribution by inhibiting P-glycoprotein
| Drugs: Rifampin & St. John's wort |
| Mechanism of Action: Inducers of Intestinal P-glycoprotein (& hepatic cyt-P450) |
| Background: P-glycoprotein is a membrane-bound protein that is thought to play a protective role, functioning to prevent entry and promote removal of xenobiotics (foreign compounds) from the body by translocating them from intracellular to the extracellular environment. P-glycoproteins have a broad substrate specificty. P-glycoprotein is expressed in intestinal mucosa, renal proximal tubules & in capillary endothelial cells comprising the blood-brain-barrier, and in tumor cells (where it functions as a multi-drug resistance mechanism). |
| Pharmacokinetics: Induction of P-glycoprotein can result in decreased intestinal absorption of cationic drugs, reduced entrance into the CNS across the blood-brain-barrier, and increased secretion of drugs into renule tubules. Cyt-P450 induction by these two drugs also enhances the metabolism of a wide variety of drugs including couramin, oral contraceptives & metoprolol (amongst others). Induction of both mechanisms by rifampin & St. John's wort increases elimination of other drugs from the body. |
Reference: Katzung's text & MedSciMonit, 2004; 10(1):RA5-14 |
| Drugs: Cimetidine & Grapefruit Juice |
| Mechanism of Action: P-glycoprotein inhibitors (& inhibitors of cyt-P450) |
| Pharmacokinetics: Cells in the intestinal tract contain a P-glycoprotein that acts as a reverse transporter which actively pumps drugs out of the cells in the gut wall back into the gut lumen. Inhibition of P-glycoprotein can result in substantially increased drug absorption. |
| Major drug interactions: These compounds can elevate plasma levels of various drugs by inhibiting their metabolism by cyt-P450, and by enhancing their oral bioavailability by inhibiting intestinal P-glycoprotein. They can also increase the fraction of drug crossing the BBB into the CNS. |
Reference: Katzung's text & MedSciMonit, 2004; 10(1):RA5-14 |
Examples of Drugs with Significant First Pass Effect
| Drug: Propranolol: 75-85 % is metabolized by the liver before it can reach the circulation when taken orally. |
| Drug: Morphine:70% metabolized via 1st pass effect if taken orally. Usually given via s.c. injection to bypass this mechanism. |
| Drug: Nitroglycerin: typically taken sublingually (buccal cavity) where it enters the circulation and is delivered to the heart, avoiding the 1st pass effect. |
Examples
| Drug: Quinacrine is largely deposited into the liver and gall bladder. It has an exceptionally high (620 L/kg)"apparent" volume of distribution because most of the drug ends up being in tissues and not in plasma. |
| Drug: Thiopental is highly lipid soluble and rapidly distributes to the brain after a single IV injection. After a single dose, thiopental levels in the brain increase for a few minutes, then decline in parallel with the plasma level. Anesthesia ends rapidly as the drug redistributes to more slowly perfused tissues. If plasma concentration is monitored long enough, a third phase of distribution, in which the drug is slowly released from fat, can be distinguished. With continued administration of thiopental, large amounts may be stored in fat, resulting in prolongation of anesthetic plasma concentrations. Apparent Vd = 2.3 L/kg. |
| Drug: Digoxin is also concentrated in tissues and therefore has a large apparent volume of distribution (Vd 6.3 L/kg) in healthy patients. |
Reference: Katzung's text |
Inhibitors of Cyt-P450
| Drugs: Cimetidine, Erythromycin, Ciprofloxacin, Fluoxetine (Prozac ®), Grapefruit juice |
| Notes: When co-administered, these drugs can alter the metabolism of drugs metabolized by cyt-P450 isoforms (the short list). This process is reversible, depending on the drug's half-life. |
Reference: Katzung's text |
| Drugs: Rifampin, Barbiturates, Phenytoin, Carbamezepine, St. John's wort, (Ethanol in large amounts), Thyroid hormone. |
| Notes: Chronic administration of these drugs will cause increased levels of cyt-P450 by enzyme induction, and will increase the rate of metabolism of drugs metabolized by cyt-P450 isoforms (the short list). This process is slowly reversible. |
Reference: Katzung's text |
Important Drugs Metabolized by Cyt-P450
| Drugs: Warfarin, Theophylline, Oral contraceptives |
| Notes: Approximately half of all drugs are metabolized by cyt-P450. This is just a short list of examples! Warfarin & theophylline have low TI's. |
Reference: Katzung's text |
Other Drug Interactions Resulting from Changes in Drug Metabolism
| Drugs: Sulfa drugs & Phenobarbital |
| Notes: In newborns, sulfa type drugs (e.g. antibiotics) can displace bilirubin from binding sites, leading to jaundice, kernicterus & mental retardation. Coadministering phenobarbital to the mother can induce cyt-P450 mediated conjugation of bilirubin, making it more water soluble and more readily excreted. |
| Drugs: Ethanol & Tolbutamide |
| Notes: Alcoholics have increased cyt-P450. Tolbutamide is a drug taken by diabetics to treat hyperglycemia. Diabetics who abuse alcohol may have inadequate plasma levels of tolbutamide when taking standard doses. |
| Drugs: Phenobarbital & Warfarin |
| Notes: Administration of phenobarbital to a patient (e.g. to calm them down after an MI) can cause induction of cytP40, thus altering the metabolism of warfarin. Withdrawal of phenobarbital will have the opposite effect due to reduced enzyme induction. |
| Drugs: Phenobarbital & Phenytoin |
| Notes: Administration of phenobarbital to a patient (e.g. to help them sleep) taking the anticonvulsant phenytoin (Dilantin ®) will cause increased metabolism of dilantin (by induction of cytP40), thus reducing the plasma level of dilantin, and increasing the chances of seizure in a patient with epilepsy. |
| Drugs: Ethanol & Disulfuram (antibuse) |
| Notes: Disulfuram inhibits aldehyde-dehydrogenase. When ethanol is metabolized, alcohol dehydrogenase rapidly converts acetaldehyde to acetic acid. Disulfuram prevents this breakdown, causing acetaldehyde to accumulate, which makes the patient ill (nausea, vomiting, decreased BP) & hopefully encourages the patient to stop drinking ethanol. |
| Drugs: MAO inibitors & Tyramine containing foods |
| Notes: MAOi antidepressants will prevent the metabolism of tyramine, which is present in blue cheese & beer. Tyramine in such foods is normally metabolized by MAO in the gut before it can be absorbed. MAO inhibitors prevent this breakdown, resulting in elevated tyramine levels after ingestion of such foods. Tyramine can cause a dangerous increase in blood pressure. |
Important Concepts & Equations:
| Why the apparent Vd can be larger than anatomically possible |
| The Two Primary Pharmacokinetic Parameters are Vd & Cl |
| T1/2 = 0.69 Vd / Cl |
| t (0.90) = 3.3 T 1/2 |
| Apparent Vd = Loading Dose/Co |
| Css = Dosing Rate/ Cl |
Pharmacokinetic Drug Profiles:
Drugs with mainly renal clearance:
| Drugs: Gentamicin (generic, Garamycin ®), Tobramycin (generic, Nebcin ®) Vancomycin |
| Drug Class: Selected Antibiotics |
| Pharmacokinetics: These antibiotics are eliminated exclusively by renal clearance, and do not undergo any significant metabolism. They are cleared from the body more slowly than in patients with with immature or impaired renal function compared to patients with normal renal function. The more severe the impairment, the slower the clearance. Dosage must be adjusted to the level of renal function, which is typically determined by estimating creatinine clearance, to prevent nephrotoxicity and ototoxicity. |
Reference: www.rxlist.com (gentamicin, tobramycin, vancomycin) |
Drugs with mainly hepatic clearance:
| Drug: Propranolol |
| Drug Class: Beta-Blocker |
| Pharmacokinetics: Propranolol is almost completely absorbed from the gastrointestinal tract, but undergoes extensive hepatic (first pass) metabolism. It's bioavailability is relatively low (e.g. 30%) but is also dose dependent. Hence the proportion of drug reaching the systemic circulation increases as the dose is increased, suggesting that hepatic extraction mechanisms may become saturated. A major consequence of the low bioavailability of propranolol is that oral administration results in much lower plasma levels compared to those achieved after i.v. administration of the same dose. Because the first pass effect varies amongst individuals, there is great variability in the plasma concentrations acheieved after oral propranolol. Peak effect occurs in one to one-and-one-half hours after oral administration. The biologic half-life is approximately four hours.There is no simple correlation between dose or plasma level and therapeutic effect, and the dose-sensitivity range as observed in clinical practice is wide. The principal reason for this is that sympathetic tone varies widely between individuals. Since there is no reliable test to estimate sympathetic tone or to determine whether total beta blockade has been achieved, proper dosage requires titration. |
Reference: www.rxlist.com & Katzung's text |
| Drug: Lidocaine (Xylocaine ®) |
| Drug Class: Class 1b antiarrhythmic, local anesthetic (amide) |
| Pharmacokinetics: Lidocaine undergoes extensive first pass metabolism (~70%) if taken orally, and only ~30% reaches the systemic circulation. Toxic lidocaine metabolites accumulate if the oral dose of lidocaine were to be increased proportionally, and hence lidocaine cannot be given orally. When given parentally, lidocaine equilibrates rapidly (within minutes) with other body compartments (in contrast to digoxin) and is eliminated primarily by hepatic metabolism (90%), with 10% eliminated unchanged in the urine, half life 1.5-2 hrs. CHF can reduce both the apparent Vd and the Cl of lidocaine. As a result, lidocaine's T1/2 may be relatively normal (see equation above), and can be misleading when chosing the proper infusion rate. A reduced Vd requires a reduction in loading dose, and reduced Cl requires a reduced dosing rate. Hepatic disease can also reduce lidocaine's Cl. |
Reference: www.rxlist.com |
| Drug: Warfarin (generic, Coumadin ®) |
| Drug Class: Anticoagulant |
| Pharmacokinetics: Warfarin sodium is essentially 100% absorbed after oral administration with peak concentration generally attained within the first 4 hours. Warfarin sodium distributes into a relatively small apparent volume of distribution of about 0.14 liter/kg (e.g. equivalent to the "albumin space" because 99% of racemic warfarin is bound to plasma proteins). The levorotatory S-warfarin is four times more potent than the dextrorotatory R-warfarin. The elimination of warfarin sodium is almost entirely by hepatic metabolism. Warfarin sodium is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin sodium alcohols). The Cytochrome P-450 isozymes involved in the metabolism of warfarin sodium include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin sodium. The terminal half-life of warfarin sodium after a single dose is approximately one week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. Very little warfarin sodium is excreted unchanged in urine. Urinary excretion is in the form of metabolites. Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin sodium. No dosage adjustment is necessary for patients with renal failure. Hepatic dysfunction can potentiate the response to warfarin sodium through impaired synthesis of clotting factors and decreased metabolism of warfarin sodium. Pharmacokinetic mechanisms for drug interactions with warfarin include: enzyme induction (barbiturates & rifampin), enzyme inhibition (cimetidine, amiodarone, disulfiram, etc.) and reduced plasma protein binding. Pharmacodynamic mechanisms for interactions also exist (e.g. reduced clotting factor synthesis with hepatic disease, aspirin's effect on platelet function & competitive antagonism by Vit K). |
Reference: www.rxlist.com |
| Drug: Theophylline (generic, Elixophyllin, Slo-Phylliin, Uniphyl, Theo-Dur ® etc.) |
| Drug Class: Methylxanthine, Bronchodilator |
| Pharmacokinetics: Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver. The pharmacokinetics of theophylline vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses (COPD, cystic fibrosis, hyperthyroidism) and alterations in normal physiology (age, diet) and co-administration of other drugs that alter cyt-P450 (smoking, cimetidine, erythromycin, rifampin) can significantly alter the pharmacokinetic characteristics of theophylline. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum theophylline concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter theophylline clearance. |
Reference: www.rxlist.com |
Drugs with Dose-Dependent Kinetics of Elimination
| Drug: Phenytoin |
| Drug Class: Antiepileptic |
| Pharmacokinetics: The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5-7 half-lives) after initiation of therapy with recommended doses of 300 mg/day. When serum level determinations are necessary, they should be obtained at least 5-7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient's next scheduled dose. Peak levels indicate an individual's threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, congenital enzyme deficiency or drug interactions which result in metabolic interference. Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Phenytoin has dose-dependent kinetics of elimination. Phenytoin is hydroxylated in the liver by an enzyme system that is saturable at high plasma levels, hence small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more. |
Reference: www.rxlist.com |
| Drug: Aspirin |
| Drug Class: Antiinflammatory, Analgesic, Antipyretic, Antirheumatic, Anticoagulant |
| Pharmacokinetics: Aspirin (acetylsalicylic acid) is rapidly hydrolyzed primarily in the liver to salicylic acid, which is conjugated with glycine (forming salicyluric acid) and glucuronic acid and excreted largely in the urine. As a result of the rapid hydrolysis, plasma concentrations of aspirin are always low and rarely exceed 20 mcg/ml at ordinary therapeutic doses. The plasma half-life for aspirin is approximately 15 minutes; but the half-life for salicylate lengthens as the dose increases: Doses of 300 to 650 mg have a half-life of 3.1 to 3.2 hours; with doses of 1 gram, the half-life is increased to 5 hours and with 2 grams it is increased to about 9 hours. Salicylates are excreted mainly by the kidney. Studies in man indicate that salicylate is excreted in the urine as free salicylic acid (10%), salicyluric acid (75%), salicylic phenolic (10%) and acyl (5%) glucuronides and gentisic acid (<1%). |
Reference: www.rxlist.com |
| Drug: Ethanol (Jack Daniels, Budweiser, Cuervo Gold ®) |
| Drug Class: CNS Depressant |
| Pharmacokinetics: Peak blood levels are achieved within 30 mins after oral ingestion. Presence of food delays absorption by slowing gastric emptying. Vd is similar to total body water content. Over 90% of ethanol is oxidized in the liver, with the remainder excreted through the lungs & the urine. The rate of metabolism is dose-dependent, but at levels usually achieved in the blood, the rate of oxidation follows zero-order kinetics (i.e. is independent of time & concentration). As a result, ethanol metabolism is capacity-limited and is not proportional to the amount of ethanol present in the bloodsteam. Changes in "dosing rate" may result in disproportionate, non-linear changes in blood levels, and "toxicity" may develop. A typical adult can metabolize 7-10g (150-220 mmol) of ethanol per hour (the equivalent of 10oz of beer, 3.5 oz of wine or 1oz of 80 proof spirits). Chronic ethanol consumption can induce cyt P450; this can increase the hepatotoxicity of acetaminophen due to increased conversion to reactive hepatotoxic metabolites. Acute alcohol use may inhibit the metabolism of other drugs due to decreased metabolism &/or decreased liver blood flow (such as tricyclic antidepressants, phenothiazines & sedative-hypnotic drugs). Pharmacodynamic interactions may also occur with other drugs including CNS depressants |
Reference: Katzung's text |
Drugs with both renal and hepatic clearance:
| Drug: Digoxin (Lanoxin ®) |
| Drug Class: Cardiac glycoside (positive inotrope) |
| Indications: Congestive Heart Failure, Atrial Fibrillation |
| Pharmacokinetics: When given i.v. digoxin distributes slowly from the plasma into body tissues, taking 6-8 hrs to reach an equilibrium between body compartments. This should be kept in mind when interpreting the relationship between plasma drug concentration vs. it's clinical effects. Once it has equilibrated, digoxin is concentrated in tissues and therefore has a large apparent volume of distribution (9.8 liters/kg body weight, or ~686 liters in a 70 kg patient). Serum digoxin concentrations are not significantly altered by large changes in fat tissue weight, so that its distribution space correlates best with lean (i.e., ideal) body weight, not total body weight. Digoxin is primarily eliminated as unchanged drug via the kidney, and only a small percentage (16%) of a dose of digoxin is metabolized. The metabolism of digoxin is not dependent upon the cytochrome P-450 system, and digoxin is not known to induce or inhibit the cytochrome P-450 system. The clearance of digoxin can be primarily correlated with renal function as indicated by creatinine clearance. Elimination of digoxin follows first-order kinetics (that is, the quantity of digoxin eliminated at any time is proportional to the total body content). In healthy volunteers with normal renal function, digoxin has a half-life of 1.5 to 2.0 days. The half-life in anuric patients is prolonged to 3.5 to 5 days. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to tissue and does not circulate in the blood. Digoxin typically has a high bioavailability (90-100%) when taken orally. |
| Reference: www.rxlist.com |
| Drug: Procainamide |
| Drug Class: Antiarrhythmic (Class Ia) |
| Pharmacokinetics: The half-time for elimination of procainamide is three to four hours in patients with normal renal function, but reduced creatinine clearance and advancing age each prolong the half-time of elimination of procainamide. A significant fraction of the circulating procainamide may be metabolized in hepatocytes to N-acetylprocainamide (NAPA), ranging from 16 to 21 percent of an administered dose in "slow acetylators" to 24 to 33 percent in "fast acetylators". Both procainamide and NAPA are eliminated by active tubular secretion as well as by glomerular filtration. |
Reference: www.rxlist.com |
| Drug: Penicllin G (generic, Pentids, Pfizerpen ®) |
| Drug Class: Antibiotic (Beta Lactam) |
| Pharmacokinetics: administered i.v. or i.m. because oral absorption is unreliable (acid labile). Under normal conditions, penicillin G is rapidly eliminated from the body, mainly by the kidney, but in small part in the bile and by other routes. Approximately 60% to 90% of an i.m. dose is elminated in the urine, largely within the first hour after injection. The remainder is metabolized to penicilloic acid. Serum half-life is 35 mins. Approximately 10% of the drug is eliminated by glomerular filtration and 90% by active tubular secretion (probenecid can block this transporter and prolong Pen G's half life). In neonates and young infants, and in individuals with impaired kidney function, excretion is considerably delayed. In renal failure the half life can be as long as 10 hours. |
Reference: www.rxlist.com, Katzung & Goodman & Gilman's text |
Drug-induced Hemolysis in G6PD Deficiency
| Drug: Primaquine (example) |
| Drug Class: Antiprotozoal / Antimalarial |
Hemolytic Anemia: G6PD (Glucose-6-phosphate dehydrogenase) is an enzyme present in the RBC. Deficiency of this enzyme leads to shortening of the red-cell life span and hereditary non-spherocytic hemolytic anemia. Deficiency also results in an increased sensivity to drug-induced hemolysis. Drugs such as primaquine (antimalarial), sulfa drugs, chloramphenicol (types of antibiotics), aspirin & some Vit K analogs can cause hemolytic anemia. Patients should be tested for G6PD deficiency before these drugs are prescribed. There is a high incidence of severe G6PD-deficiency in individuals of Mediterranean (Sardinians, Sephardic Jews, Greeks, Iranians) and Asian ancestry. There is also a higher than normal incidence in those of African ancestry, but they usually have a milder biochemical defect. This difference can be taken into consideration in choosing a treatment strategy. Primaquine should be discontinued if there is evidence of hemolysis or anemia. G6PD deficiency results in reduced GSH levels, which is required for maintaining the structural integrity of RBC membranes. Drug induced hemolysis is greater in the presence of low GSH levels in RBCs. Normal patients have 60 mg% GSH, whereas susceptible patients have ~20 mg% GSH. |
| Other Drugs: Sulfa drugs, Chloramphenicol (types of antibiotics), aspirin & some Vit K analogs can also cause hemolytic anemia. |
Reference: http://www.healthdigest.org/drugs & Katzung's text |
| Drug: Isoniazid (INH) (example) |
| Drug Class: Antimycobacterial |
| Pharmacokinetics: Isoniazid is metabolized primarily by acetylation by liver N-acetyltransferase. The rate of acetylation is genetically determined. Approximately 50 percent of African Americans and Caucasians are "slow acetylaters", and the rest are "rapid acetylaters"; the majority of Eskimos and Asians are "rapid acetylaters." The defect in slow acetylators of isoniazid and similar amines appears to be caused by the synthesis of less enzyme rather than an abnormal form of it. The rate of acetylation does not significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood levels of the drug and thus, to an increase in toxic reactions. The average concentration of isoniazid in the plasma of rapid acetylators is about one third to one half of that in slow acetylators, and average half-lives are less than 1 hour and 3 hours, respectively. |
| Other Drugs: Procainamide (antiarrhythmic), Sulfa drugs (a type of antibiotic) & Dapsone (anti-leprosy) are also metabolized by acetylation & will have higher plasma levels (increased side effects/toxicity) in slow acetylators. |
Reference: www.rxlist.com & Katzung's text |
Atypical Pseudocholinesterase, Malignant Hyperthermia & Succinylcholine
| Drug: Succinylcholine (example) |
| Drug Class: Skeletal Muscle Relaxant |
Atypical Pseudocholinesterase: Succinylcholine should be used carefully in patients with reduced plasma cholinesterase (pseudocholinesterase) activity. Plasma cholinesterase activity may be diminished in the presence of genetic abnormalities of plasma cholinesterase (e.g., patients heterozygous or homozygous for atypical plasma cholinesterase gene). Patients homozygous for atypical plasma cholinesterase gene (1 in 2,500 patients) are extremely sensitive to the neuromuscular blocking effect of succinylcholine. The atypical enzyme has a ~100 fold lower affinity for substrate compared to the normal enzyme. In these patients, a 5-to 10-mg test dose of succinylcholine may be administered to evaluate sensitivity to succinylcholine, or neuromuscular blockade may be produced by the cautious administration of a 1-mg/mL solution of succinylcholine by slow IV infusion. Apnea or prolonged muscle paralysis should be treated with controlled respiration. Adverse reactions to succinylcholine consist primarily of an extension of its pharmacological actions. Succinylcholine causes profound muscle relaxation resulting in respiratory depression to the point of apnea; this effect may be prolonged. Hypersensitivity reactions, including anaphylaxis, may occur in rare instances. The following additional adverse reactions have been reported: malignant hyperthermia, cardiac arrest, arrhythmias (bradycardia, tachycardia), hypertension, hypotension, hyperkalemia, prolonged respiratory depression or apnea, increased intraocular pressure, muscle fasciculation, jaw rigidity, postoperative muscle pain, rhabdomyolysis with possible myoglobinuric acute renal failure, excessive salivation, and rash. Dibucaine test: a test that can be used to identify patients with an abnormal ability to metabolize succinylcholine. Under standardized conditions, a dose of dibucaine (an inhibitor of pseudocholinesterase) will inhibit the normal enzyme by ~80%, as compared to 20-25% in patients homozygous for the atypical enzyme, and by 40-70% in patients heterozygous for the atypical enzyme. The percent inhibition is refered to as the "dibucaine number". 1 in 3000 patients have atypical pseudocholinesterase. |
| Malignant Hyperthermia: can also be triggered by succinylcholine or volatile general anesthetics in individuals having a heterogenetic disorder unrelated to abnormalities in plasma cholnesterase (1 in 10,000 patients). The precise cellular defect responsible for the disorder in these indivduals is unclear, but it is known to involve an increased release of calcium by the skeletal muscle sarcoplasmic reticulum when exposed to certain "triggering agents". The treatment for malignant hyperthermia is dantrolene, which inhibits the release of calcium from the sarcoplasmic reticulum in skeletal muscle. Malignant hyperthermia is commonly fatal if not rapidly treated. |
Reference: www.rxlist.com |
Vampire Syndrome
| Drug: Barbiturates (example) |
| Drug Class: Sedative Hypnotic |
Acute Porphyria: Porphyria Cutanea Tarda (PCT) is caused by a genetic defect in one or more of the enzymes responsible for the synthesis of heme (which occurs mainly in the liver). Patients with this abnormality accumulate porphyrins (that cannot be converted to heme) in various organs, including the skin. When exposed to sunlight, porphyrins aborb light energy and then release it into the skin in photochemical reactions that cause damage to the skin. Blisters and crusting of sun-exposed areas of skin are the most prominent features (hence the connection with vampire lore). It usually develops in middle age, hence, the name tarda which is Latin for late. Acute attacks can be fatal. Certain drugs such as barbiturates, alcohol, birth control pills, hexachlorobenzene, and other drugs with allyl groups (sulfa drugs, chloraquine) can also trigger acute porphyria in patients with this disorder. A common mechanism for this drug reaction is by stimulating an increase in the synthesis of heme and its precursors in the liver (e.g. enzyme induction to make more cytochrome P450). When the liver in a patient with acute porphyria is induced to make more heme, the genetic block in the pathway results in the accumulation of heme precursors instead of heme. Therefore, when a drug causes the liver to make more cytochrome P450 enzymes, it induces the liver to make more heme precursors, and then an exacerbation of a genetic porphyria can follow. |
| Reference: http://www.porphyriafoundation.com |
Hereditary Methemoglobinemia
| Drug: Nitrates & Sulfa drugs (examples) |
Met Hb: RBCs contain two enzymes "methemoglobin diaphorase I & II" which are present to convert methemoglobin (Met Hb) back to hemoglobin. Met Hb (Fe+3) does not carry oxygen or carbon dioxide, causing cyanosis. In hereditary methemoglobinemia patients lack methemoglobin diaphorase I, resulting in the accumulation of Met Hb. Drugs that can oxidize Hb (Fe+2) to Hb (Fe+3) such as nitrates, nitrates, analine dyes, nitroprusside, antimalarials, sulfa drugs & some AIDs medications can make this condition worse. Treatments: removal of causing agent, methylene blue (i.v.), ascorbic acid (oral) |
Reference: www.emedicine.com |
Selective COX-2 Inhibitors (coxibs)
| Drug: Celecoxib (Celebrex ®) |
| Drug Class: NSAID (Nonsteroidal Anti-Inflamatory Drug) |
| Mechanism of Action: inhibition of prostaglandin synthesis, primarily via selective inhibition of cyclooxygenase-2 (COX-2) and at therapeutic concentrations in humans, celecoxib is not highly effective in inhibiting the cyclooxygenase-1 (COX-1) isoenzyme. Cox-2 inhibitors have analgesic, antipyretic & anti-inflammatory effects similar to non-selective NSAIDs, but with fewer GI side effects. In general, coxibs have little impact on platelet aggregation (which is mediated by Cox-1) & therefore have minimal cardioprotective effects. However they have been associated with a higher than normal incidence of stroke. |
| Indications: 1) For relief of the signs and symptoms of osteoarthritis, and 2) rheumatoid arthritis in adults. |
| Contraindications: known hypersensitivity to celecoxib. Patients with severe renal insufficiency (Cox-2 is constitutively active in the kidney). |
| Pharmacokinetics: taken orally. Plasma levels of celecoxib occur approximately 3 hrs after an oral dose. Metabolism is primarily mediated via cytochrome P450 2C9. Plasma half life ~11 hrs. |
| Side Effects: Celecoxib is a sulfonamide & may cause skin rashes. The frequency of other side effects is similar to other NSAIDs. |
| Major drug interactions: NSAIDs may diminish the effects of Angiotensin Converting Enzyme (ACE) inhibitors, furosemide and thiazide diuretics. Fluconazole can double celecoxib levels due to inhibition of cyt P450 2C9. Concomitant administration of aspirin with celecoxib may result in an increased rate of GI ulceration or other complications. It interacts occasionally with warfarin (due to cyt P450 C9 metabolism). |
| Note: Celecoxib is not considered to be a good substitute for aspirin for cardiovascular prophylaxis (e.g. because it has minimal effects on platelet function). |
Reference: www.rxlist.com & Katzung's text |
| Drug: Rofecoxib (Vioxx ®) |
| Drug Class: NSAID |
| Mechanism of Action: inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2) and at therapeutic concentrations in humans, celecoxib produces relatively little inhibition of the cyclooxygenase-1 (COX-1) isoenzyme. |
| Indications: 1) For relief of the signs and symptoms of osteoarthritis. 2) For the management of acute pain in adults. 3) For the treatment of primary dysmenorrhea. |
| Contraindications: known hypersensitivity to rofecoxib |
| Pharmacokinetics: Rofecoxib is taken orally and is eliminated predominantly by hepatic metabolism with little (< 1%) unchanged drug recovered in the urine, and feces (<14%). Metabolism of rofecoxib is primarily mediated through reduction by cytosolic enzymes. Cytochrome P450 plays a minor role in metabolism of rofecoxib. The effective half- life is ~17 hours. |
| Side Effects: at high doses it is associated with occasional edema and hypertension. Other toxicities are similar to those of other coxibs. |
| Major drug interactions: Same as celecoxib (ACE inhibitors, thiazide diuretics, aspirin). In addition, potentially significant interactions with rifampin, methotrexate and warfarin. Patients receiving these agents with rofecoxib should be appropriately monitored. |
Reference: www.rxlist.com & Katzung's text |
| Drug: Aspirin (Acetylsalicylic acid, ASA) (generic) |
| Drug Class: NSAID |
| Mechanism of Action: Aspirin irreversibly inhibits both isoforms of COX. and inhibits platelet aggregation. Aspirin also interferes with the chemical mediators of the kallikrein system, thus inhibiting granulocyte adherence to damaged vasculature, stabilizing lysosomes, and inhibiting the chemotaxis of PMN leukocytes and macrophages. |
Indications: 1) Anti-inflammatory. Aspirin interferes with the chemical mediators of the kallikrein system, thus inhibiting granulocyte adherence to damaged vasculature, stabilizing lysosomes, and inhibiting the chemotaxis of PMN leukocytes and macrophages. 2) Analgesia. Aspirin is effective in reducing pain of mild to moderate intensity through its effects on inflammation and probably because it inhibits pain stimuli at a subcortical (central) site. It is not effective for severe visceral pain. 3) Antipyretic. Aspirin reduces elevated body temperature (but it has little effect on body temperature in normal healthy patients). This effect is probably mediated by both COX inhibition in the CNS and inhibition of IL-1 (which is released by macrophages during episodes of inflammation). 4) Antiplatelet Effects. Single low doses of aspirin (81 mg daily) produce a slightly prolonged bleeding time, which doubles if administration is continued for a week. The change is due to irreversible inhibition of platelet COX, so that aspirin's antiplatelet effect lasts 8-10 days (the life of the platelet). 5) MI Prophylaxis: Aspirin is indicated to reduce the risk of death and/or nonfatal myocardial infarction in patients with a previous infarction or unstable angina pectoris. 6) Transient Ischemic Attacks: Aspirin is indicated for reducing the risk of recurrent transient ischemic attacks (TIAs) or stroke in men who have transient ischemia of the brain due to fibrin emboli. There is currently no evidence that aspirin is effective in reducing TIAs in women, or is of benefit in the treatment of completed strokes in men or women. |
| Contraindications: hypersensitivity to NSAIDs or history of bleeding disorders, such as GI bleeding or hemophelia. Not recommended during pregnancy, but may be valuable in treating preeclampsia-eclampsia. Children and teenagers should not use this medicine for chicken pox or flu symptoms before a doctor is consulted about Reye's syndrome, a rare but serious illness reported to be associated with aspirin. |
| Pharmacokinetics: Aspirin is rapidly hydrolyzed primarily in the liver to salicylic acid, which is conjugated with glycine (forming salicyluric acid) and glucuronic acid and excreted largely in the urine. As a result of the rapid hydrolysis, plasma concentrations of aspirin are always low and rarely exceed 20 mcg/ml at ordinary therapeutic doses. The peak salicylate level for uncoated aspirin occurs in about 2 hours; however with enteric coated aspirin tablets this is delayed. The plasma half-life for aspirin is approximately 15 minutes; that for salicylate lengthens as the dose increases: Doses of 300 to 650 mg have a half-life of 3.1 to 3.2 hours; with doses of 1 gram, the half-life is increased to 5 hours and with 2 grams it is increased to about 9 hours. Salicylates are excreted mainly by the kidney. Studies in man indicate that salicylate is excreted in the urine as free salicylic acid (10%), salicyluric acid (75%), salicylic phenolic (10%) and acyl (5%) glucuronides and gentisic acid (<1%). |
| Side Effects: Expected side effects are dose-dependent. With therapeutic doses, gastric upset, gastric and duodenal ulcers are the most common side effects. With high doses "salicylism" can occur - vomiting, tinnitus, decreased hearing, vertigo (reversible). Even larger doses cause hyperpnea through a direct effect on the medulla. At toxic doses, respiratory alkalosis followed by metabolic acidosis (salicylate accumulation), respiratory depression, and even cardiotoxicity an glucose intolerance can occur. Overdosage of 200 to 500 mg/kg is in the fatal range. |
| Major drug interactions: Aspirin may contribute to increasing bleeding time by decreasing prothrombin in the plasma. Large doses have a hypoglycemic action that can enhance the effect of oral hypoglycemic drugs and affect the diabetic's insulin requirements. Large doses of aspirin are uricosuric, but smaller amounts may decrease the uricosuric effects of probenecid, sulfinpyrazone and phenylbutazone. Therefore aspirin is contraindicated in the treatment of pain & inflammation associated with gout. |
Reference: www.rxlist.com & Katzung's text |
| Drug: Acetaminophen (generic, Tylenol ®, others) |
| Drug Class: Analgesic, Antipyretic |
| Mechanism of Action: A weak COX-1 and COX-2 inhibitor in peripheral tissues and posesses no significant antiinflammatory effects. Recent evidence suggest that it may inhibit a third enzyme COX-3 in the CNS. It has been proposed that COX-3 may be a splice variant of the COX-1 gene (but this is questionable). Acetaminophen produces analgesia by elevation of the pain threshold preipherally, and antipyresis through action on the hypothalamic heat regulating center. |
| Indications: mild to moderate pain such as headache, myalgia, postpartum pain, and other circumstances in which aspirin is also an effective analgesic. It is a prefered drug for the treatment of pain & fever in patients allergic to aspirin, when salicylates are poorly tolerated, in patients with bleeding disorders, history of peptic ulcers, and patients in whom bronchospasm is precipitated by aspirin. Acetaminophen is prefered to aspirin for the treatment of pain/fever in children with viral infections. |
| Pharmacokinetics: Well absorbed orally, with absorption being related to the rate of gastric emptying. Peak blood levels are usually reached in 30-60 mins. Acetaminophen is partially metabolized by hepatic microsomal enzymes and converted to acetaminophen sulfate and glucuronide, which are inactive. Less than 5% is excreted unchanged. A minor but highly active metabolite (N-acetyl-p-benzoquinone) is important in large doses because of its toxicity to both liver and kidney. The half life of acetaminophen is 2-3 hrs. With toxic doses or liver disease, the half-life may be increased two-fold or more. |
| Side Effects: In therapeutic doses, a mild reversible increase in hepatic enzymes may occasionally occure in the absence of jaundice. With larger doses, dizziness, excitement, and disorientation are seen. Ingestion of 15 g of acetaminophen may be fatal, death being caused by severe hepatotoxicity with centrilobular necrosis, sometimes associated with acute renal tubular necrosis. Early symptoms of hepatic damage include: nausea, vomiting, diarrhea & abdominal pain. Toxicity is treated with supportive therapy and N-acetylcysteine to neutralize the toxic metabolites. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. |
| Notes: Acetaminophen is equal to aspirin in analgesic and antipyretic effectiveness, but differs by lacking anti-inflammatory properties. It also does not affect uric acid levels and lacks platelet-inhibitiing properties. Note that acetaminophen is not a NSAID. |
Reference: www.rxlist.com & Katzung's text |
| Drug: Beclomethasone (QVAR, Vanceril ®) |
| Drug Class: Glucocorticoid (Aerosol) |
| Mechanism of Action: Binds to intracellular glucocorticoid receptors and modulates gene expression. Between 10 to 20% of expressed genes in a cell are regulated by glucocorticoids. Glucocorticoids have multiple anti-inflammatory effects, inhibiting both inflammatory cells and release of inflammatory mediators. Important contributors to the anti-inflammatory effects of glucocorticoids result from inhibition of phospholipase A2 and reduced expression of COX-2. Inhaled beclomethasone probably acts topically at the site of deposition in the bronchial tree after inhalation. Improvement in asthma control following inhalation can occur within 24 hours of beginning treatment in some patients, although maximum benefit may not be achieved for 1 to 2 weeks, or longer. This is associated with the inhibition of lung infiltration by eosinophils. |
| Indications: 1) the maintenance treatment of asthma as prophylactic therapy. 2) indicated for asthma patients who require systemic corticosteroid administration, where adding beclomethasone aerosol may reduce or eliminate the need for the systemic corticosteroids. Beclomethasone is NOT indicated for the relief of acute bronchospasm. |
Reference: www.rxlist.com & Katzung's text |
| Drug: Dexamethasone (generic, Decadron-LA ®) |
| Drug Class: Glucocorticoid, Anti-Inflammatory |
| Mechanism of Action: (see above). Glucocorticoids dramatically reduce the manifestations of inflammation due to their profound effects on the concentration, distribution, and function of peripheral leukocytes and to their suppressive effects on the inflammatory cytokines and chemokines and on other lipid and glucolipid mediators of inflammation. |
| Indications: used for its potent anti-inflammatory effects in disorders of many organ systems. Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli. At equipotent anti-inflammatory doses, dexamethasone almost completely lacks the sodium-retaining property of hydrocortisone and closely related derivatives of hydrocortisone. Some specific examples of indications include: rheumatic disorders, arthritis, lupus erythrematosus, bronchial asthma & ulcerative colitis. |
| Contraindications: Systemic fungal infections. Hypersensitivity to this drug. |
| Pharmacokinetics: Available in oral, aerosol and topical forms. Topical corticosteroids can be absorbed from normal intact skin. Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. |
| Side Effects: Sodium retention, fluid retention, steroid myopathy, loss of muscle mass; osteoporosis, aseptic necrosis of femoral and humeral heads, peptic ulcer with possible perforation and hemorrhage, Impaired wound healing. |
| Major drug interactions: |
Reference: www.rxlist.com & Katzung's text |
| Drug: Alprostadil (Caverject, Edex, Muse, Prostin VR Pediatric ®) |
| Drug Class: PGE-1 Prostaglandin |
| Mechanism of Action: Prostaglandin E1 is one of a family of naturally occurring acidic lipids with various pharmacologic effects. Prostaglandins bind to receptors on the cell surface, and pharmacologic specificity is determined by receptor density and receptor type in different tissues. Vasodilation, inhibition of platelet aggregation, and stimulation of intestinal and uterine smooth muscle are among the most notable effects produced by PGE-1. The smooth muscle of the ductus arteriosus is especially sensitive to alprostadil, and alprostadil increases penile cavernous arterial blood flow in vivo. Smooth muscle relaxing effects are mediated by the generation of cAMP. |
| Indications: 1) Prostin VR is indicated for palliative, notdefinitive, therapy to temporarily maintain the patency of the ductus arteriosus until corrective or palliative surgery can be performed in neonates who have congenital heart defects and who depend upon the patent ductus for survival. Such congenital heart defects include pulmonary atresia, pulmonary stenosis, tricuspid atresia, tetralogy of Fallot, interruption of the aortic arch, coarctation of the aorta, or transposition of the great vessels with or without other defects. 2) Caverject is indicated for the treatment of erectile dysfunction due to neurogenic, vasculogenic, psychogenic, or mixed etiology. Intracavernosal Caverject may be a useful adjunct to other diagnostic tests in the diagnosis of erectile dysfunction. |
| Contraindications: Alprostadil should not be used in patients who have a known hypersensitivity to the drug, in patients who have conditions that might predispose them to priapism, such as sickle cell anemia or trait, multiple myeloma, or leukemia, or in patients with anatomical deformation of the penis, such as angulation, cavernosal fibrosis, or Peyronie's disease. |
| Pharmacokinetics: For maintaining the patency of the ductus arteriosus, Alprostadil is given by continuous i.v. infusion. The drug has a rapid pulmonary clearance, requiring continuous infusion. For treatment of erectile dysfunction, alprostadil is administered by injection into the corpora cavernosa. Alprostadil is rapidly metabolized |
| Side Effects: Apnea is experienced by about 10 to 12% of neonates with congenital heart defects treated with Prostin VR Pediatric Sterile Solution. Other side effects include fever (14%) and seizures (4%). A common side effect associaated with Caverject is penile pain after intracavernosal administration (37%). Prolonged erection and priapism are less frequent side effects (<4%). |
Reference: www.rxlist.com & Katzung's text |
| Drug: Dinoprostone (Prostin E2, Prepidil, Cervidil ®) |
| Drug Class: PGE-2 Prostaglandin |
| Mechanism of Action: when administered endocervically it can stimulate the myometrium of the gravid uterus to contract in a manner similar to contractions seen in the term uterus during labor. Dinoprostone also directly affects the collagenase of the cervix, resulting in softening. |
| Indications: for oxytocic use. In the USA, it is approved for inducing abortion in the 2nd trimester of pregnancy, for missed abortion, for benign hydatidiform mole, and for ripening an unfavorable cervix in pregnant women at or near term with a medical or obstetrical need for labor induction. |
| Contraindications: Patients in whom oxytocic drugs are generally contraindicated or where prolonged contractions of the uterus are considered inappropriate (e.g. history of cesarean section, active herpes genitalia, etc.) |
| Pharmacokinetics: PGE2 is completely metabolized in humans. PGE2 is extensively metabolized in the lungs (~95% in first pass), and the resulting metabolites are further metabolized in the liver and kidney. The major route of elimination of the products of PGE2 metabolism is the kidneys. Plasma half life is 2-5 minutes. |
| Major drug interactions: PREPIDIL Gel may augment the activity of other oxytocic agents and their concomitant use is not recommended. For the sequential use of oxytocin following PREPIDIL Gel administration, a dosing interval of 6-12hours is recommended. |
Reference: www.rxlist.com & Katzung's text |
| Drug: Misoprostol (Cytotec ®) |
| Drug Class: PGE-1 synthetic analog |
| Mechanism of Action: Misoprostol has both cytoprotective (low dose) and antisecretory (higher doses inhibit gastric acid secretion) properties. |
| Indications: for the prevention of NSAID-induced gastric (peptic) ulcers in patients at high risk of complications from gastric ulcer |
| Contraindications: contraindicated, because of its abortifacient property, in women who are pregnant. |
| Pharmacokinetics: Misoprostol is extensively and rapidly absorbed after oral administration, and undergoes rapid de-esterification to its free acid, which is responsible for its clinical activity and unlike the parent compound, is detectable in plasma. Half life of 20-40 minutes. |
| Side Effects: diarrhea and abdominal pain. Cytotec has been shown to produce uterine contractions that may endanger pregnancy. |
Reference: www.rxlist.com and Katzung's text |
| Drug: Montelukast (Singulair ®) |
| Drug Class: Leukotriene receptor antagonist |
| Mechanism of Action: a selective and orally active leukotriene receptor antagonist that inhibits the effects of LTD4 at the cysteinyl leukotriene CysLT1 receptor. |
| Indications: prophylaxis and chronic treatment of asthma in adults and pediatric patients 6 years of age and older. |
| Contraindications: history of hypersensitivity |
| Pharmacokinetics:rapidly absorbed following oral administration. Cytochromes P450 3A4 and 2C9 are involved in the metabolism of montelukast. Montelukast and its metabolites are excreted almost exclusively via the bile. Plasma half life is 3-6 hrs. |
| Notes: Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. Sulfido-peptide leukotrienes (LTC4, LTD4, LTE4, also known as the slow-releasing substances of anaphylaxis) and LTB4, a chemoattractant for neutrophils and eosinophils, can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF) from asthmatic patients. |
Reference: www.rxllist.com & Katzung's text |
| Drug: Zafirlukast (Accolate ®) |
| Drug Class: Leukotriene receptor antagonist |
| Mechanism of Action: Synthetic, selective peptide leukotriene receptor antagonist of D4 and E4 (LTD4 and LTE4), components of slow-reacting substance of anaphylaxis (SRSA). |
| Indications: prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older |
| Contraindications: history of hypersensitivity |
| Pharmacokinetics: rapidly absorbed when taken orally. Metabolized by the the cytochrome (CYP2C9) pathway. Mean terminal half life is ~10 hrs. |
| Major drug interactions: increases the plasma concentration & half life of warfarin; concurrent administration of erythromycin decreases zafirlukast plasma levels due to decreased bioavailability |
Reference: www.rxlist.com |
| Drug: Zileuton (Zyflo ®) |
| Drug Class: 5-lipoxygenase Antagonist |
| Mechanism of Action: an orally active and inhibitor of 5-lipoxygenase, the enzyme that catalyzes the formation of leukotrienes (LTB4, LTC4, LTD4, and LTE4) from arachidonic acid. |
| Indications: prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older |
| Contraindications: Active liver disease or transaminase elevations greater than or equal to three times the upper limit of normal, or history of hypersensitivity |
| Pharmacokinetics: Administered orally. Elimination of zileuton is predominantly via metabolism with a mean terminal half-life of 2.5 hours. Metabolized by the cytochrome P450 isoenzymes 1A2, 2C9 and 3A4 (CYP1A2, CYP2C9 and CYP3A4). |
| Side Effects: Dyspepsia |
| Major drug interactions: will increase the plasma levels of theophylline and propranolol and increases their half life if taken concomitantly. (Note: theophylline has a low TI.) |
Reference: www.rxlist.com |
| Drug: Cimetidine (generic, Tagamet ®) |
| Drug Class: Histamine type-2 receptor blocker |
| Mechanism of Action: competitive receptor antagonist at H2 receptors. |
| Indications: Acid-peptic diseases (gastroesphageal reflux, peptic ulcer, stress-related mucosal injury |
| Pharmacokinetics: rapidly absorbed from the intestine & undergoes 1st pass metabolism with a bioavailability of ~50%. |
| Major drug interactions: cimetidine inhibits several hepatic cytochrome P450 enzymes including: CYP isoforms 1A2, 2C9, 2D6 & 3A4. The half-lives of drugs metabolized by these pathways may be prolonged. Such drugs include: warfarin, theophylline, phenytoin, lidocaine, quinidine, propranolol, labetalol, metoprolol, tricyclic antidepressants, several benzodiazepines, calcium channel blockers, sulfonylureas, metronidazole and ethanol. It is best to avoid cimetidine in patients using these drugs. |
| Drug: Warfarin (generic, Coumadin ®) |
| Drug Class: anticoagulant |
| Mechanism of Action: blocks the carboxylation of several glutamate residues in prothrombin & factors VII, IX and X as well as the endogenous anticoagulant proteins C and S. The blockade results in incomplete molecules that are biologically inactive in coagulation. The protein carboxylation is physiologically coupled with the oxidative deactivation of vitamin K. Warfarin prevents the reductive metabolism of the inactive form of vitamin K back to its active form by vitamin K epoxide reductase. Mutational change of this enzyme results in genetic resistance to warfarin in a subset of the human population. |
| Indications: 1) prophylaxis and/or treatment of venous thrombosis and its extension, and pulmonary embolism. 2) prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement. 3) to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction |
| Contraindications: pregnancy (warfarin can cross the placenta & cause a hemorrhagic disorder in the fetus). |
| Side Effects: fatal or non-fatal bleeding from any tissue or organ, necrosis of skin & other tissues. Hemorrhagic complications may present as paralysis; paresthesia; headache, chest, abdomen, joint, muscule, or other pain; dizziness, shortness of breath, difficult breathing or swallowing; unexplained swelling; weakness; hypotension; or unexplained shock. |
| Pharmacokinetics: has 100% bioavailability & 99% becomes bound to plasma albumin, resulting in a small apparent volume of distribution (the albumin space). It's half-life is 36 hrs. There is an 8-12 hour delay in the action of warfarin due to the time it takes for degredation of clotting factors within the circulation. |
| Major drug interactions: there are significant interactions between warfarin and other drugs and disease states. These can be divided into pharmacodynamic & pharmacokinetic effects. Pharmacokinetic interactions can occur from enzyme induction, enzyme inhibition or reduced plasma protein binding. Pharmacodynamic mechanisms for interactions are synergism (reduced clotting factor synthesis - as in hepatic disease), competitive antagonism (vitamin K), and altered physiologic control loop for vitamin K (hereditary resistance to warfarin). The most serious interactions are those that increase warfarins anticoagulant effect & risk of bleeding. Drugs that do this (increase prothrombin time) by pharmacokinetic interactions include amiodarone, cimetidine & numerous other drugs. In contrast, barbiturates & rifampin produce a marked decrease of the anticoagulant effect of warfarin by induction of cytochrome P450 enzymes that metabolize warfarin. |
| Drug: Rifampin (generic, Rifadin ®, Rimactane ®) |
| Drug Class: antimycobacterial agent |
| Mechanism of Action: Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. Rifampin at therapeutic levels has demonstrated bactericidal activity against both intracellular and extracellular Mycobacterium tuberculosis organisms. |
| Indications: 1) indicated in the treatment of all forms of tuberculosis. 2) the treatment of asymptomatic carriers of Neisseria meningitidis to eliminate meningococci from the nasopharynx. |
| Pharmacokinetics: oral or iv administration. |
| Major drug interactions: Rifampin strongly induces most cytochrome P450 isoforms (CYP 1A2, 2C9, 2C19, 2D6 & 3A4) which increases the elimination of numerous other drugs including warfarin, some anticonvulsants, protease inhibitors and contraceptives. |
Notes: rifampin is a large MW 823 complex semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. |
| Drug: Histamine |
| Drug Class: Autacoid (Greek "self-remedy") |
Mechanism of Action: Histamine stimulates H1-H4 receptors. Nervous system: H1 & presynaptic H3 receptors. Cardiovascular: H1 & H2 receptors. Bronchioles: H1. Gastric mucosa: H2 receptors. Triple response of Lewis: mostly H1, some H2 and H3. Postreceptor mechanisms: H1: increased IP3 & DAG (Gq) |
Biological Function: Important mediator of immediate allergic and inflammatory reactions; has an imporant role in gastric acid secretion; and functions as a neurotransmitter and neuromodulator. It may also play a role in chemotaxis of white blood cells. Most tissue histamine is bound in granules (vesicles) in mast cells or basophils. Mast cells have a high density at sites of potential tissue injury - nose, mouth, feet, internal body surfaces, blood vessels. Non-mast cell histamine is found in the brain, where it functions as a neurotransmitter. Histamine is a powerful stimulant of sensory nerve endings, especially those mediating pain & itching (H1 mediated). An additional important site of histamine storage & release is in enterochromaffin-like cells of the fundus of the stomach which release histamine as a secretagogue (H2) to activate acid-producing parietal cells of the mucosa. Histamine, released by mast cells in response to injury, inflammation and allergic responses, causes arteriolar vasodilation, venous constriction in some vascular beds, and increased capillary permeability (by causing endothelial cell contraction). Both H1 and H2 receptors may be involved in the vascular effects of histamine |
Reference: Katzung's text |
| Drug: Betazole |
| Drug Class: H2 agonist |
| Mechanism of Action: A histamine H2 agonist used clinically as a diagnostic aid to test gastric secretory function (e.g. in patients who may have achlorhydria). |
| Drug: Bromopheniramine (Brovex, Dimetane ®) |
| Drug Class: H1 Antagonist (alkylamine subtype) |
| Mechanism of Action: Competitive H1 receptor antagonist |
| Indications: treatment of allergic reactions such as allergic rhinitis, hay fever and urticaria, control of itching related to angioedema |
| Side Effects: slight sedation & anticholinergic side effects |
| Notes: In bronchial asthma, which involves several mediators, H1 antagonists are largely ineffective. |
Reference: Katzung's text |
| Drug: Chlorpheniramine (generic, Chlor-Trimeton ®) |
| Drug Class: H1 Antagonist (alkylamine subtype) |
| Mechanism of Action: Competitive H1 receptor antagonist |
| Indications: (same as bromopheniramine) Provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. |
| Side Effects: slight sedation & anticholinergic side effects |
| Notes: a common component of OTC "cold" medication |
Reference: www.rxlist.com |
| Drug: Diphenhydramine (generic, Benadryl ®) |
| Drug Class: H1 Antagonist (ethanolamine subtype) |
| Mechanism of Action: Competitive H1 receptor antagonist |
| Indications: 1) Antihistaminic: For allergic conjunctivitis due to foods; mild, uncomplicated allergic skin manifestations of urticaria and angioedema; adjunctive to epinephrine and other standard measures in treatment of anaphylactic reactions - after the acute manifestations have been controlled. 2) Motion sickness: For active and prophylactic treatment of motion sickness. 3) Antiparkinsonism: For parkinsonism (including drug-induced) in the elderly unable to tolerate more potent agents. 4) Local anesthesia: in patients allergic to conventional local anesthetics. |
| Contraindications: should not be used in nursing mothers, newborn or premature infants, or patients with history of drug hypersensitivity to similar antihistamines. |
| Pharmacokinetics: A single oral dose of diphenhydramine HCl is quickly absorbed with maximum activity occurring in approximately one hour. The duration of activity following an average dose of diphenhydramine HCl is from four to six hours. Little, if any, is excreted unchanged in the urine; most appears as the degradation products of metabolic transformation in the liver, which are almost completely excreted within 24 hours. |
| Side Effects: marked sedation; disturbed coordination. Antihistamine overdosage reactions may vary from central nervous system depression to stimulation. Stimulation is particularly likely in children. Atropine-like signs and symptoms, dry mouth; fixed, dilated pupils; flushing, and gastrointestinal symptoms may also occur. |
| Major drug interactions: has additive effects with alcohol and other CNS depressants (hypnotics, sedatives, tranquilizers, etc). MAO inhibitors prolong and intensify the anticholinergic (drying) effects of antihistamines. |
| Note: the salt of diphenhydramine is dimenhydrinate (Dramamine ®), which is commonly used to treat motion sickness. Diphenhydramine is more potent than procaine as a local anesthetic. |
Reference: www.rxlist.com & Katzung's text |
| Drug: Hydroxyzine (generic, Atarax, Vistaril ®) |
| Drug Class: H1 Antagonist (piperazine subtype) |
| Mechanism of Action: 1) H1 competitive receptor antagonist. 2) Bronchodilator activity, and analgesic effects have been demonstrated experimentally and confirmed clinically. 3) An antiemetic effect, both by the apomorphine test and the veriloid test, has been demonstrated. |
| Indications: 1) management of pruritus due to allergic conditions such as chronic urticaria and atopic and contact dermatoses, and in histamine-mediated pruritus. 2) for symptomatic relief of anxiety and tension associated with psychoneurosis and as an adjunct in organic disease states in which anxiety is manifested. |
| Contraindications: contraindicated in early pregnancy (it has been shown to cause fetal abnormalities in rats and mice at doses substantially above the human therapeutic range.) |
| Pharmacokinetics:rapidly absorbed from the gastrointestinal tract and Vistaril's clinical effects are usually noted within 15 to 30 minutes after oral administration. |
| Side Effects: marked sedation, dry mouth |
| Major drug interactions: As a sedative when used as premedication and following general anesthesia, Hydroxyzine may potentiate meperidine (Demerol®) and barbiturates, so their use in pre-anesthetic adjunctive therapy should be modified on an individual basis. |
Reference: www.rxlist.com |
Second Generation H1 Blockers
| Drug: Fexofenadine (Allegra ®) |
| Drug Class: H1 Antagonist (piperidine subtype) |
| Mechanism of Action: antihistamine with selective peripheral H1-receptor antagonist activity. |
| Indications: 1) relief of symptoms associated with seasonal allergic rhinitis in adults and children 6 years of age and older. Symptoms treated effectively include sneezing, rhinorrhea, itchy nose/palate/throat, itchy/watery/red eyes. 2) fexofenadine is indicated for treatment of uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 years of age and older. It significantly reduces pruritus and the number of wheals. |