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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 ®) |
| 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 |
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 |
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. Many antimalarial drugs such as primaquine, chloroquine, quinine, quinidine, sulfa drugs, chloramphenicol (a rarely used antibiotic), 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. |
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 (blocks transmission on the muscle side of the NMJ) |
| Pharmacokinetics: Succinylcholine’s action is terminated following its metabolism by cholinesterase & pseudo-cholinesterase. |
Atypical Pseudocholinesterase:Succinylcholine should be used carefully in patients with reduced plasma cholinesterase (pseudo-cholinesterase) 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. |
| Side Effects: 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. |
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. |
| NOTE: Malignant Hyperthermia (a topic to be discussed later on during this course): 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). |
Reference: www.rxlist.com |
Anti-Cancer Drugs & Pharmacogenomics
| Drug: Imatinib ( Gleevac ®) |
| Drug Class: Antineoplastic "designer drug" |
| Mechanism of Action: an inhibitor of the tyrosine kinase domain of the Bcr-Abl oncoprotein. Imatinib prevents the phosphorylation of the kinase substrate by ATP. (see Notes below & lecture handout). |
| Indications: treatment of chronic myelogenous leukemia (CML). |
| Side Effects: hepatotoxicity, edema, fluid retention. tyrosine kinases associated with the platelet-derived growth factor receptor, stem cell factor and c-kit are also inhibited by Imatinib |
| Pharmacokinetics: metabolized by cyt P450 (CYP3A4). |
| Major drug interactions: inhibitors or inducers of the CYP3A4 family. |
| Notes: CML is caused by an abnormal chromosomal translocation that results in the formation of the Bcr-Abl fusion protein. This fusion protein is present in up to 95% of patients with this disease. Hence it is a selective target for drug action against this form of cancer. |
| Drug: 5-Fluorouracil ( Adrucil, Efudex, Fluoroplex ®) |
| Drug Class: Commonly used cancer drug against solid tumors |
| Mechanism of Action: a prodrug with active metabolites that inhibit both DNA synthesis and RNA processing. Its cytotoxicity is therefore due to effects on both DNA- and RNA-mediated events. |
| Indications: the most widely used agent for colorectal cancer. In addition, it has activity against a wide variety of solid tumors, including those in breast, stomach, pancreas, esophagus, liver, head, neck & anus. |
| Side Effects: primarily bone marrow suppression & GI toxicity (nausea, diarrhea) due to its effects to inhibit rapidly dividing cells in those organ systems; occasional neurotoxicity |
| Pharmacokinetics: given i.v. In most individuals it has a short metabolic half-life of ~13-15 mins (but see Notes below). |
| Notes: a genetic mutation or SNP (single nucleotide polymorphism) present in 1-3% of cancer patients increases its half-life from 13-15 mins to 160 mins (2.6 hrs). This results in elevated blood levels and increased toxicity in these patients. Genotyping a patient before treatment can help identify a patient who is at risk for toxic side effects for toxic side effects upon undergoing chemotherapy using 5-FU & facilitate the individualization in treatment of patients. |
Other Examples of Genetic Mutations Affecting Drug Responses (not covered):
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 |
PBL
- drug metabolism
| 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. |