| Background for Roland's Equation |
| Liver metabolism is the major route for elimination for a wide variety of drugs & it can be affected by a variety of parameters. Hepatic drug clearance can be defined as the volume of blood perfusing the liver that is cleared of the drug per unit of time. There are three major parameters that determine drug elimination by the liver: 1) blood flow through the liver (Q), which reflects drug delivery to the liver; 2) the fraction of drug in the blood that is free or not bound to plasma proteins and capable of interacting with hepatic enzymes (f); and 3) the intrinsic ability of hepatic enzymes to metabolize the drug, which is commonly refered to as "intrinsic clearance" (Clint). Intrinsic clearance is the ability of the liver to remove drug in the absence of flow limitations and binding to cells or proteins in the blood. The ratio of the hepatic clearance of a drug to the hepatic blood flow is called the extraction ratio of the drug. Extraction ratio can be generally classified as high (>0.7), intermediate (0.3-0.7) or low (<0.3) according to the fraction of drug removed during one pass through the liver. |
| Rowland's Equation |
Hepatic Clearance: Cl(h) = Q [(f x Clint)/(Q+ f x Clint)] Q = hepatic blood flow f = fraction of free drug (not bound) Clint = intrinsic capacity of the hepatocytes to metabolize a drug |
Drug categories:
|
| Drugs with "Flow Dependent" or "Non-Restrictive" hepatic clearance (high hepatic extraction) |
|
Pharmacokinetics: This class of drugs will: 1) undergo extensive "first pass" metabolism when given orally. 2) have a hepatic drug clearance that is sensitive to changes in liver blood flow & less sensitive to alterations in binding to plasma proteins or "intrinsic clearance" (changes in hepatic metabolism or biliary excretion). 3) conditions that reduce hepatic blood flow (CHF, hypotension) will reduce hepatic clearance. |
| Reference: Lertora's handout |
| Drugs with "Restrictive" or "Capacity-Limited" hepatic clearance (low hepatic extraction) |
|
Pharmacokinetics: This class of drugs will: 1) have a hepatic clearance that is sensitive to changes in binding to plasma proteins or changes in drug metabolism/excretion. 2) have a clearance that is insensitive to changes in liver blood flow. 3) No first "pass metabolism" when given orally. |
| Reference: Lertora's handout |
| Drugs with intermediate hepatic extraction |
|
Pharmacokinetics: This class of drugs will: 1) have a hepatic clearance that is sensitive to changes in both hepatic blood flow, binding to plasma proteins or changes in drug metabolism/excretion. |
| Reference: Lertora's handout |
Example: Lidocaine - Pharmacokinetics & Changes in CHF
| Drug: Lidocaine (Xylocaine ®) |
| Drug Class: Antiarrhythmic (Class Ib), Local anesthetic |
Pharmacokinetics:
|
| Side Effects: (related to overdose) lightheadedness, tinnitus, metalic taste, blured vision, numbness, twitching, convulsions, hypotension |
| References: Lertora's handout |
Antimicrobial agents
| Drugs: Bismuth, plus either Metronidazole + Tetracycline or Amoxacillin + Clarithromycin |
| Drug Class: Antimicrobial Drugs |
| Mechanism of Action: bacteriocidal against H. pylori |
| Indications: patients infected with H. pylori |
| Pharmacokinetics: 2 week course of triple therapy (sometimes a proton pump inhibitor may be used instead of bismuth) |
Reference: Katzung's text |
H2 Antihistamines (drugs ending in "tidine")
| Drug: Cimetidine (generic, Tagamet, Tagamet HB ®) |
| Drug Class: First Generation H2 Antihistamine |
| Mechanism of Action: Selective blocker of parietal cell H2 histamine receptors, thereby suppressing both basal & meal-stimulated acid secretion. The volume of gastric secretion and concentration of pepsin are also reduced. H2 blockers reduce acid secretion stimulated by both histamine, gastrin & cholinomimetic agents through two mechanisms: 1) histamine released from ECL cells by gastrin or vagal stimulation is blocked from binding to the parietal H2 receptor; and 2) direct stimulation of the parietal cell by gastrin or ACh results in diminished acid secretion in the presence of an H2 blocker. This may be due to the ability of H2 blockers to reduce parietal cell cAMP levels, which in turn reduces the intracellular activation of protein kinases by gastrin or ACh. |
| Indications: ulcers (peptic, acute stress related), Gastroesophageal Reflux Disease (GERD). Therapeutic doses of H2 blockers reduce 60-70% of the total 24-hr acid secretion. They are especially effective (90%) at inhibiting nocturnal acid secretion (which is largely dependent on histamine), but have a modest impact (60-80%) on meal-stimulated acid secretion (which is stimulated by gastrin & ACh as well as histamine). These agents usually promote healing of ulcers among 90% of patients within 3-7 weeks. |
| Contraindications: pregnancy (can cross into the placenta & into breast milk). |
| Pharmacokinetics: Commonly given orally twice a day. The duration of acid inhibition is less than 6 hrs. H2 blockers are cleared by a combination of hepatic metabolism, glomerular filtration & renal tubular secretion. Dose reduction is required in patients with moderate to severe renal (& possibly hepatic) insufficiency. In the elderly there is a decline of up to 50% in drug clearance & a significant reduction in Vd. |
| Side Effects: headaches, diarrhea, muscular pain, hallucinations & confusion in elderly patients. Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits the metabolism of estradiol & increases serum prolactin levels. Chronic use may cause gynecomastia or impotence in men & galactorrhea in women. |
| Major drug interactions: cimetidine has multiple interactions due to inhibition of cyt P450 & P-glycoprotein. The other H2 blockers have fewer drug interactions. |
Notes: |
| References: www.rxlist.com & Katzung's text |
Newer H2 Blockers
Drugs: |
| :Drug Interactions much less than cimetidine due primarily to a much lower affinity for Cyt P450. All will compete for renal tubular secretion (P-GP mechanism). |
| References: Katzung's text & www.rxlist.com (ranitidine, famotidine, nizatidine) |
Prostaglandins
| Drug: Misoprostol (Cytotec ®) |
| Drug Class: Prostaglandin analog (synthetic) |
| Mechanism of Action: a methyl analog of PGE1. It is believed to stimulate mucus & bicarbonate secretion & enhance mucosal blood flow, thereby helping protect the stomach by forming a protective barrier against acid. It also binds to prostaglandin receptors on parietal cells, reducing histamine-stimulated cAMP production & causing modest inhibition of acid secretion. |
| Indications: prevention of NSAID (including aspirin)-induced gastric ulcers in patients at high risk of complications from gastric ulcer, e.g., the elderly and patients with concomitant debilitating disease, as well as patients at high risk of developing gastric ulceration, such as patients with history of ulcer. |
| Contraindications: contraindicated, because of its abortifacient property, in women who are pregnant. Women of childbearing potential should be told that they must not be pregnant when misoprostol therapy is initiated, and that they must use an effective contraception method while taking misoprostol. |
| Side Effects: diarrhea, increased uterine contractions |
References: www.rxlist & Katzung's text |
Proton Pump Inhibitors (drugs ending in "prazole")
| Drug: Omeprazole (Prilosec ®), Esomeprazole (Nexium ®) & others |
| Drug Class: Proton pump inhibitors (prodrug) |
| Mechanism of Action: Proton pump inhibitors are administered as inactive pro-drugs & are given as acid-resistant enteric-coated formulations. They form covalent disulfide bonds with the H/K ATPase, which causes irreversible inactivation. |
| Indications: Gastroesophageal Reflux Disease (GERD), peptic ulcer disease, nonulcer dyspepsia (a pain in the upper middle part of your stomach), stress induced gastritis, gastrin-secreting tumors (Zollinger-Ellison syndrome). |
| Pharmacokinetics: administer on an empty stomach 1 hr before a meal to achieve maximal effective concentrations when proton pump secretion will be maximal. Not all pumps are inactivated with the first dose & up to 3-4 days of treatment are needed to reach the maximal acid-inhibiting potential. |
| Side Effects: minor |
| Major drug interactions: they inhibit the metabolism of warfarin, diazepam & phenytoin (via competitive P-450 metabolism) |
Notes: Esomeprazole (the purple pill) is the S-isomer of omeprazole |
| Reference: Katzung's text |
Antimuscarinics
| Drug: Pirenzepine |
| Drug Class: Antimuscarinic (M-1 selective) |
| Indications: adjunct to H2 blockers when patients are refractory |
Reference: Beckman's handout |
Mucosal Protective Agents
| Drug: Sucralfate (generic, Carafate ®) |
| Drug Class: Mucosal Protective Agent |
| Mechanism of Action: Sucralfate is a salt of sucrose complexed to sulfated aluminum hydroxide. In acidic solutions it forms a viscous, tenacious paste that binds selectively to ulcers or erosions for up to 6 hrs. It is believed that the negatively charged sucrose sulfate binds to positively charged proteins in the base of ulcers or erosions, forming a physical barrier that restricts further caustic damage. |
| Indications: treatment of duodenal ulcer. |
| Pharmacokinetics: Less than 3% of intact drug gets absorbed into the body. The remainder gets excreted in the feces. |
| Side Effects: constipation, black stool |
| Major drug interactions: don't take with H2 blockers or antacids, which reduce the acidic environment required for activation of sucralfate. |
References: www.rxlist.com & Katzung's text |
| Drug: Bismuth subsalicylate (Pepto-Bismol, others ®) |
| Drug Class: Colloidal Bismuth Compound |
| Mechanism of Action: like sucralfate, bismuth coats ulcers and erosions, creating a protective layer against acid and pepsin. It may also stimulate prostaglandin, mucus & bicarbonate secretion. It also has direct antimicrobial effects (e.g. against H. pylori) and binds enterotoxins (useful in treating traveler's diarrhea). It also reduces stool frequency and liquidity in acute infectious diarrhea, due to salicylate inhibition of intestinal prostaglandin & chloride secretion. |
| Indications: treatment of dyspepsia & acute diarrhea, prevention of traveler's diarrhea |
| References: Katzung's text |
Antacids
| Drug: Calcium carbonate (Tums ®) , magnesium hydroxide, sodium bicarbonate (Alka Seltzer ®), aluminum hydroxide (Amphojel ®) |
| Drug Class: Antacids |
| Mechanism of Action: weak bases that react with gastric HCl to form water & a salt, thereby lowering the acidity in the stomach. |
| Indications: dyspepsia & acid-peptic disroders |
| Pharmacokinetics: effective for a few hours after administration. |
| Side Effects: Al & Mg are often combined because when used alone Al containing formulations can cause constipation, and Mg containing formulation can cause an osmotic diarrhea. |
| Major drug interactions: may affect the absorption of other medications by binding the drug, or by altering a drug's pH-dependent solubility. Examples: tetracyclines, flouroquinolone, itraconazole, iron. |
Reference: Katzung's text |
| Drug: Dronabinol (Marinol ®) |
| Drug Class: Cannabinoid / Antiemetic |
| Mechanism of Action: stimulation of cannabinoid receptors in the CNS |
| Indications: 1. anorexia associated with weight loss in patients with AIDS (dronabinol is an appetite stimulant); and 2. nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. |
| Side Effects: cannabinoid dose-related "high" (easy laughing, elation and heightened awareness) |
| Notes: hide the brownies |
| References: www.rxlist.com |
5-HT3 Antagonists
(drugs ending in "setron")
| Drug: Ondansetron (Zofran ®) & Granisetron (Kytril ®) |
| Drug Class: Antiemetic |
| Mechanism of Action: selective 5-HT3 (serotonin) receptor antagonist. Serotonin receptors of the 5-HT3 type are present both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. It is not certain whether ondansetron's antiemetic action in chemotherapy-induced emesis is mediated centrally, peripherally, or in both sites. |
| Indications: treatment of nausea related to cancer chemotherapy & prevention of postoperative nausea/vomiting. |
Notes: ondansetron & granisetron
are NOT dopamine antagonists. |
| References: www.rxlist.com (ondansetron & granisetron ) |
Antihistamines & Anticholinergics
| Drug: Scopolamine & Dimenhydrinate |
| Drug Class: Antiemetic |
| Mechanism of Action: block muscarinic receptors |
| Indications: motion sickness |
| Pharmacokinetics: scopolamine is better tolerated when administered by a transdermal patch |
| Side Effects: sedation, dry mouth, urinary retention, etc. |
Reference: Katzung's text |
| Drug: Metoclopramide (generic, Reglan ®) |
| Drug Class: Prokinetic drug |
| Mechanism of Action: The primary prokinetic mechanism is by acting as a cholinergic agonist. In addition, it is a D2 dopamine receptor antagonist, which may potentiate cholinergic smooth muscle stimulation in the GI tract. D2 receptor blockade in the chemoreceptor trigger zone of the medulla (area postrema) produces a potent antinausea & antiemetic action. The GI effects incease esophageal peristaltic amplitude, increase lower esophageal sphincter pressure & enhance gastric emptying. |
| Indications: Gastroesophageal reflux disease, impaired gastric emptying without obstruction (gastroparesis), reflux esophagitis, prevention of vomiting |
| Side Effects: CNS side effects include restlessness, drowsiness, dystonias, parkinsonian features. |
Notes: used in combination with
antihistamines to reduce extrapyramidal side effects, or with corticosteroids,
to counter metoclopramide-induced diarrhea. Cisapride is a similar drug that was removed from the market due to its potential
to cause serious cardiac arrhythmias (torsade de pointes). It will not
be covered on exams. |
Antimotility Drugs
| Drug: Diphenoxylate (generic, Lomotil ®) |
| Drug Class: Opioid Agonist |
| Mechanism of Action: activate presynaptic opioid receptors in the enteric nervous system to block ACh release & decrease peristalsis. Results in prolongation of gastrointestinal transit time. |
| Indications: mild to moderate diarrhea |
| Side Effects: no analgesic effects in standard doses. Higher doses have CNS effects & prolonged use can lead to opioid dependence. |
Notes: commercial preparations
commonly contain small amounts of atropine to discourage overdosage. The
anticholinergic effects of atropine may contribute to the antidiarrheal
action. Less expensive than loperamide. |
| References: Katzung's text |
| Drug: Loperamide (generic, Imodium ®) |
| Drug Class: Opioid Agonist (OTC, non-prescription) |
| Mechanism of Action: same as diphenoxylate |
| Indications: mild to moderate diarrhea |
| Pharmacokinetics: does not cross the BBB |
| Side Effects: has no analgesic effects & no potential for addiction. |
| References: Katzung's text |
Absorbants
| Drug: Kaolin/pectin (generic, Kaopectate ®), methycellulose |
| Drug Class: Absorbant |
| Mechanism of Action: absorb bacteria, toxins & fluid, thereby decreasing stool liquidity and number. |
| Indications: treatment of acute diarrhea (seldom used on a chronic basis) |
| Major drug interactions: they may bind other medications & should not be taken within 2 hrs of each other. |
| References: Katzung's text |
| Drug: Agar, Methylcellulose, Psyllium seeds, Bran |
| Drug Class: Bulk laxatives - hydrophillic colloids & fibers |
| Mechanism of Action: they are indigestible food biproducts that absorb water, foming a bulky substance that distends the intestine & stimulates peristaltic movement. |
| Indications: constipation. (Constipation can typically be better treated or prevented with a high fiber diet, adequate fluid intake & exercise.) |
| Side Effects: bacterial digestion of plant products can cause bloating & flatus. |
| References: Katzung's text |
| Drug: Castor Oil, Cascara, Senna, Aloe, Bisacodyl |
| Drug Class: GI Irritants & Stimulants (Cathartics) |
| Mechanism of Action: castor oil is broken down to ricinoleic acid in the small intestine, which causes GI irritation & increased GI motility. Cascara, senna & aloe contain emodin, which stimulates colonic activity. Bisacodyl is also a GI stimulant |
| Indications: constipation |
| References: Katzung's text |
| Drug: Docusate sodium, Mineral oil |
| Drug Class: Stool Softeners (Surfactants) |
| Mechanism of Action: softens & lubricates the stool |
| Indications: To minimize straining |
| References: Katzung's text |
| Introduction: Herbal medications are available without a prescription & are legally considered dietary supplements rather than drugs. As such they are not as tightly regulated by the FDA. They are governed by the Current Good Manufacturing Practice in Manufacturing (CGMP) regulations that are administered by the FDA. However these regulations are often inadequate for ensuring product purity & potency. For example, in the past, doses for several Ma-huang preparations contained 3-5 X the medically recommended daily dose of ephedrine. Adverse effects can be caused by either the active ingredient, or an adulterant. |
| Reference: Katzung's text |
| Herb: Melatonin |
| Intended Use: Prevent jet lag & to induce sleep (reduce insomnia) |
| Mechanism of Action: A serotonin derivative that is released by the pineal gland & is believed to be inolved in regulating sleep-wake cycles. Melatonin release coincides with darkness & is suppressed by daylight. |
| Clinical Trials: Results for reducing jet lag are unclear due to flaws in trial design. It may or may not help one return to a normal sleep pattern. Maximizing exposure to daylight on arrival at a new destination may also aid in resetting one's circadian clock.Trials results for melatonin's ability to reduce insomnia are also unclear due to study limitations. However it seems to increase REM sleep & improve sleep onset & duration in healthy volunteers. |
| Contraindications: pregnancy or desire to conceive (see below) |
| Side Effects: Partial inhibition of ovulation in women (by supressing LH secretion), decreased sperm quality (by aromatase inhibition in the testes). Next-day drowsiness, tachycardia, depression. |
| Reference: Katzung's text |
| Herb: Ma-huang (ephedra) |
| Intended Use: diet suppressant, bronchodialator, stimulant |
| Mechanism of Action: contains ephedrine & ephedrine-like alkaloids. Ephedrine has both direct (alpha and beta) agonist effects and indirect (amphetamine or tyramine - like) sympathomimetic effects. |
| Clinical Trials: In Dec 2003, the FDA issued a consumer alert to alert consumers to immediately stop buying and using ephedra products. The alert was based mainly upon a review of recent adverse event reports that indicated an increased risk of stroke, myocardial infarction and sudden death in those using ephedra containing dietary supplements. The FDA also announced a plan to ban the sale of all food supplements containing ephedrine in the near future. |
| Contraindications: cardiovascular disease |
| Side Effects: higher than normal incidence of myocardial infarction, stroke and sudden death. Hypertension, insomnia. |
| Pharmacokinetics: tachyphylaxis develops with repeated dosing. |
| Notes: There is considerable variability in the amount of ephedrine & it's isomers from "batch to batch". |
| Reference: Katzung's text |
| Herb: St. John's wort (Hypericum perforatum) |
| Intended Use: Antidepressant |
| Mechanism of Action: A variety of compounds (e.g. hyperforin & hypericin) are believed to be involved in producing its antidepressant effect. Research suggests that they may inhibit the reuptake of serotonin, norepinephrine & dopamine, down-regulate the experssion of cortical beta receptors and up-regulate the experssion of serotonin receptors. Other mechanisms have also been proposed. |
| Clinical Trials: Clinical trials suggest that St. John's wort may have a similar efficacy as some prescribed antidepressants for mild to moderate depression. However, clinical trials indicate that it is not effective against major or severe depression. |
| Contraindications: Drugs metabolized by cyt-P450 or transported by P-glycoprotein |
| Side Effects: photosensitization |
| Pharmacokinetics: Onset of effect takes 2-4 weeks. |
| Major drug Interactions: use cautiously with other antidepressants, stimulants & MAO inhibitors due to the risk of producing a serotonin syndrome. St. John's wort can induce hepatic cyt- P450 enzymes and the P-glycoprotein drug transporter. This has led to case reports of subtherapeutic levels of digoxin, birth control drugs (& subsequent pregnancy), cyclosporin, HIV protease inhibitors (e.g. indinavir), warfarin, anticonvulsants, etc. |
| Notes: St. John's wort is a plant/bush that grows 1-3 feet tall. Found in Europe, US, Australia & other countries. The name Wort is thought to be derived from the Old English word for plant. The origins of the designator "St. John" might be attributable to it’s medicinal usage by the Knights of St. John in Jerusalem to heal the wounds of Crusaders or that it blooms around the Christian Feast of St. John. |
| Reference: www.rxlist.com & Katzung's text. |
| Herb: Ginkgo (Ginkgo Biloba) |
| Intended Use: treatment of cerebrial insufficiency & Alzheimer dementia |
| Mechanism of Action: has antioxidant and free-radical scavenging properties that may reduce ischemic injury and oxidative stress. Ginkgo has been shown to increase blood flow and reduce blood viscosity (antiplatelet effect). Enhancment of nitric oxide may be involved. |
| Clinical Trials: Trials have suggested that ginkgo is more effective than placebo, and possibly comparible to pentoxifylline in relieving the symptoms of intermittent claudication (a leg pain that develops after walking & is associated with peripheral artery disease). Analysis of ginkgo's effectiveness on cerebral insufficiency & dementia so far suggest either questionable or small improvements (e.g. a 3% increase in cognition) at best. Ginkgo is currently under investigation as a prophylactic agent for dementia of the Alzheimer type. |
| Side Effects: antiplatelet properties |
| Major drug Interactions: Ginkgo has antiplatelet properties & should not be used in combination with other anticoagulant medications. |
| Notes: an extract from the leaves of the ginkgo tree |
| Reference: Katzung's text & http://www.herbs.org/ |
| Herb:Ginseng |
| Intended Use: to improve physical and mental performance, enhancement of immune function |
| Mechanism of Action: active principles appear to be a dozen or more triterpenoid saponin glycosides called ginsenosides or panaxosides. |
| Clinical Trials: Previous clinical trials have had small sample size & report either an improvement in mental function & physical performance, or no effect.Some randomized trials evaluating "quality of life" and enhancement of immune function have claimed significant effects. Others have indicated a decrease in postpradial glucose indices & a lower epidemiological incidence of cancer. To quote Katzung's text: "Until better clinical trials are published, no recommendation can be made regarding the use of ginseng." |
| Side Effects: weak estrogenic effects (vaginal bleeding & mastalgia), insomnia, nervousness, hypertension |
| Major drug Interactions: use cautiously when taking any other psychiatric, estrogenic or hypoglycemic medication. Should not be used in combination with warfarin (ginseng has antiplatelet properties). |
| Notes: derived from several plants belonging to the species Panax |
| Reference: Katzung's text |
| Herb: Saw Palmetto |
| Intended Use: Treatment of benign prostatic hyperplasia |
| Mechanism of Action: inhibits the 5-alpha reductase enzyme responsible for breakdown of testosterone to dihydrotestosterone. Active ingredients are unclear. The effect is similar to that produced by finasteride, which is also used for the same disorder. In vitro palmetto also inhibits the binding of dihydrotestosterone to androgen receptors, inhibits prostatic growth factors, blocks alpha-1 adrenergic receptors & inhibits inflammatory mediators produced by the 5-lipoxygenase pathway. |
| Clinical Trials: Clinical trials suggest it may be more effective than placebo in reducing nocturnal urinary frequency, daytime urinary frequency and increasing peak urinary flow. Another clinical trial found it to be less effective than finasteride at reducing prostate volume (6% vs 18%, respectively). Small comparitive trials of saw palmetto vs. alpha-blockers showed greater improvement with alpha-blockers. |
| Side Effects: 1-3% hypertension, decreased libido. |
| Notes: derived from saw palmetto berries. |
| Reference: Katzung's text |
| Herb: Dehydroepiandrosterone (DHEA) |
| Intended Use: Relief of age-related disorders, weight loss, reduced risk of heart disease, prevention of cancer, boosting the immune system |
| Mechanism of Action: a precursor hormone (to as many as 50 different hormones) that is secreted by the adrenal cortex & CNS. It is converted to androstenedione, testosterone & androsterone. In peripheral tissues aromatase converts DHEA to estradiol. In the plasma, DHEA is converted to DHEA sulfate (DHEAS). |
| Clinical Trials: Studies (often with small sample size) have shown unclear beneficial effects on weight loss, cholesterol levels, Alzheimer's dx. etc. |
| Side Effects: Adrongenic side effects are common. Women complain of masculinizing effects, men may experience gynecomastia & breast tenderness. May worsen prostrate cancer & other hormone-dependent cancers due to elevation of hormone levels. Euphoria, mania & cardiac arrhythmias may occur. |
| Reference: Katzung's text |