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Exam 1 Pharm (NURS615) Study Guide

Terms in this set (60)

ANS: Reduced drug dosages may be indicated in these cases.
In a pt with hypoalbuminemia drugs especially antibiotics are unable to bind as needed with albumin which means there is more of the drug free in the plasma then there would be in a pt with a normal albumin level.Drug-plasma protein binding forms a "reservoir" of drug, but only the free (unbound) drug is available to the tissues to exert a therapeutic effect.

This condition appears to be associated with alterations in the degree of protein binding of many highly protein-bound antibacterials, which lead to altered pharmacokinetics and pharmacodynamics, although this topic is infrequently considered in daily clinical practice. The effects of hypoalbuminaemia on pharmacokinetics are driven by the decrease in the extent of antibacterial bound to albumin, which increases the unbound fraction of the drug. Unlike the fraction bound to plasma proteins, the unbound fraction is the only fraction available for distribution and clearance from the plasma (central compartment). Hence, hypoalbuminaemia is likely to increase the apparent total volume of distribution (V(d)) and clearance (CL) of a drug, which would translate to lower antibacterial exposures that might compromise the attainment of pharmacodynamic targets, especially for time-dependent antibacterials. The effect of hypoalbuminaemia on unbound concentrations is also likely to have an important impact on pharmacodynamics, but there is very little information available on this area.

More Background on hypoalbuminemia:
Albumin comprises 75-80% of normal plasma colloid oncotic pressure and 50% of protein content. When plasma proteins, especially albumin, no longer sustain sufficient colloid osmotic pressure to counterbalance hydrostatic pressure, edema develops.
Albumin transports various substances, including bilirubin, fatty acids, metals, ions, hormones, and exogenous drugs. One consequence of hypoalbuminemia is that drugs that are usually protein bound are free in the plasma, allowing for higher drug levels, more rapid hepatic metabolism, or both.
The Cytochrome P450 isoenzymes (CYPs) are superfamily of haemoprotein enzymes found on the membrane of endoplasmic reticulum. They are responsible for catalyzing the metabolism of large number of endogenous and exogenous compounds. CYPs are also known as mixed function oxidases and mono-oxygenases as metabolism of a substrate by a CYP consumes one molecule of molecular oxygen and produces an oxidized substrate and another molecule of oxygen appears in water as byproduct.[1] CYPs are also called polysubstrate mono-oxygenases as one isoenzyme can have multiple substrates.[1],[2] These enzymes are responsible for biotransformation of drugs and are body's defense against xenobiotics along with P-glycoprotein. P-glycoprotein is efflux pump or transporter present in brain capillary endothelial cells, intestinal mucosal, renal and tubular cells, hepatic canalicular cells etc and are responsible for extrusion or efflux of drugs thereby enhancing drug elimination.

Cytochrome P450 isoenzymes are predominantly present in liver but are also found in intestine, lungs, kidneys, brain etc. Biotransformation of drugs by these enzymes render them ionic and more water soluble so that they can be excreted, drawback of this process is limited bioavailability of drugs

Drug-drug interactions have become an important issue in health care. It is now realized that many drug-drug interactions can be explained by alterations in the metabolic enzymes that are present in the liver and other extra-hepatic tissues. Many of the major pharmacokinetic interactions between drugs are due to hepatic cytochrome P450 (P450 or CYP) enzymes being affected by previous administration of other drugs. After coadministration, some drugs act as potent enzyme inducers, whereas others are inhibitors. However, reports of enzyme inhibition are very much more common. Understanding these mechanisms of enzyme inhibition or induction is extremely important in order to give appropriate multiple-drug therapies. In future, it may help to identify individuals at greatest risk of drug interactions and adverse events.
The cytochrome P450 (P450 or CYP) isoenzymes are a group of heme-containing enzymes embedded primarily in the lipid bilayer of the endoplasmic reticulum of hepatocytes, it takes part in the metabolism of many drugs, steroids and carcinogens [1].
...The metabolism and excretion of many drugs and their pharmacologically active metabolites depend on normal renal function. Accumulation and toxicity can develop rapidly if dosages are not adjusted in patients with impaired renal function. In addition, many drugs that are not dependent on the kidneys for elimination may exert untoward effects in the uremic milieu of advanced renal disease. A familiarity with basic pharmacologic principles and a systematic approach are necessary when adjusting drug dosages in patients with abnormal kidney function. The distinct steps involve calculating the patient's glomerular filtration rate, choosing and administering a loading dose, determining a maintenance dose, and a decision regarding monitoring of drug concentrations. If done properly, therapy in renal patients should achieve the desired pharmacologic effects while avoiding drug toxicity. Physicians must not oversimplify the pharmacologic complexities presented by patients with renal failure by relying excessively on nomograms and "cookbook" equations. In addition to a reduced glomerular filtration rate, patients with renal disease often have alterations in pharmacokinetics such as bioavailability, protein binding, hepatic biotransformation, and volume of distribution. An awareness of biologically active or toxic metabolites of parent compounds that accumulate when the glomerular filtration rate is reduced is also necessary to avoid toxicity. The effects of dialysis on drug elimination and the need for supplemental dosing are additional considerations in patients undergoing renal replacement therapy.
St. John's Wort interacts with MAO inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors, OTC cold and flu medications, narcotics, and sympathomimetics. (p. 112)

UGT (Uridine 5'-diphospho-glucuronosyltransferase) substrates: St. John's wort modulates UGT enzymes in vitro and may increase the side effects of drugs such as acetaminophen (31).

P-gp substrates: St. John's wort induces intestinal P-gp, resulting in decreased absorption and lowered plasma concentrations of certain drugs including digoxin (54), talinolol (55), and fexofenadine (56). It may also produce severe adverse effects in conjunction with pegylated interferon α (48).

CYP450 3A4 (57) and CYP 2C9 (58) substrates: St. John's wort induces these isoenzymes, affecting the metabolism of certain medications and reducing serum concentrations (59). Drugs metabolized by these enzymes include:
HIV protease inhibitors: Blood levels of indinavir and ritonavir can be significantly reduced, resulting in increased HIV viral load and development of viral resistance (60) (61).
HIV non-nucleoside reverse transcriptase inhibitors: Increased oral clearance and lowered plasma concentrations of nevirapine possibly resulting in antiretroviral resistance and treatment failure (62).
Cyclosporin / Tacrolimus: Blood levels of cyclosporin (45) (46) or tacrolimus (63) (64) can be significantly reduced, resulting in decreased efficacy or acute transplant rejection.
Diltiazem / Nifedipine: Blood levels of diltiazem or nifedipine can be reduced, resulting in decreased efficacy (36).
Irinotecan: Due to changes in hepatic metabolism caused by St. John's wort, levels of irinotecan metabolite SN-38 may be lowered by as much as 40% for up to 3 weeks following discontinuation of St. John's wort (37).
Imatinib: Increased clearance (38) (39).
Docetaxel: Subtherapeutic docetaxel concentrations may result when docetaxel is administered to patients who regularly use St. John's wort (65).
Warfarin: May increase or decrease activity when administered concomitantly. Internal normalization ratio should be monitored routinely (66).
Clopidogrel: May enhance clopidogrel-induced platelet inhibition (17).
Triptans: Increased serotonergic effect and possible serotonin syndrome when combined with sumatriptan, naratriptan, rizatriptan, or zolmitriptan (36).
SSRIs: Increased serotonergic effect and possible serotonin syndrome when combined with citalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline (49).
Tricyclic Antidepressants: Increased serotonergic effect and possible serotonin syndrome when combined with nefazodone, amitriptyline, or imipramine. Possible reduction in efficacy of antidepressants due to changes in metabolism (36).
Zolpidem: decreased plasma concentration (67).
Oral Contraceptives: May reduce blood levels resulting in decreased efficacy (i.e., breakthrough bleeding or pregnancy) (43).
Alcohol: May result in increased sedation (36).
Alprazolam: May reduce blood levels, resulting in decreased efficacy (57).
Dextromethorphan: May reduce blood levels, resulting in decreased efficacy (57).
Simvastatin: Increased clearance, resulting in elevated LDL cholesterol (68).
Atorvastatin: Increased clearance, resulting in elevated LDL cholesterol (69).
Rosuvastatin: Reduces efficacy via increased clearance (70).
Oxycodone: Reduces oxycodone plasma concentrations, significantly reducing its effectiveness (71).
Gliclazide: Increased clearance (58).
Clozapine: Reduces plasma level of clozapine (73).
Methotrexate: Increases exposure and toxicity of Methotrexate in rats(74)
Attenuation or reversal of antihypertensive effect and potentially life-threatening increases in BP may occur. Because of a potential for additive effects, such as bradycardia and AV block, caution is warranted in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction (eg, beta-blockers). If clonidine therapy is discontinued in patients receiving a beta-blocker, withdraw the beta-blocker several days before gradual discontinuation of clonidine.
Agitation, apnea, bradycardia, CNS depression, coma, constricted pupils, decreased or absent reflexes, drowsiness, hypotension, hypothermia, irritability, lethargy, respiratory depression, reversible cardiac conduction defects or dysrhythmias, seizures, vomiting, weakness.
Patient Information
ER tablets may be taken with or without food and should be swallowed whole and never crushed, cut, or chewed.
Inform patients that if the total daily dose of clonidine does not result in equal doses in the morning and at bedtime, the higher of the 2 doses should be taken at bedtime.
Instruct patients not to discontinue therapy without consulting their health care provider. Sudden cessation of clonidine treatment has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor.
Caution patients who wear contact lenses that treatment with clonidine may cause dryness of the eyes.
Advise patients who engage in potentially hazardous activities, such as operating machinery or driving, of a possible sedative effect of clonidine. Also inform them that this sedative effect may be increased by concomitant use of alcohol, barbiturates, or other sedating drugs.
Advise breast-feeding women taking modified-release tablets not to breast-feed.