Pharm basics (PD,PK,etc)

*Rxn Type* *Typical drug substrates* Hydroxylation---Amphetamines, barbs, phenytoin, warfarin N-dealkylation---Caffeine, morphine, theophylline O-dealkylation---Codeine N-oxidation---Acetaminophen, Nicotine S-oxidation---Chlorpromazine, cimetidine, thioridazine Deamination---Amphetamine, Diazepam

*Oxidants, P450 independent* Amine oxidation Epinephrine Dehydrogenation Chloral hydrate, Ethanol *Reductions* Chrloramphenicol, clonazepam, dantrolene, naloxone *Hydrolyses* Esters - Aspirin, clofibrate, procaine, Succinylcholine Amides - Indomethacin, Lidocaine, Procainamide

The PK process that distinguishes elimination of EtOH and high doses of Phenytoin & Aspirin from elimination of most other drugs is called?

0-order elimination for these conditions (while most other drugs follow 1st-order kinetics)

Select the statement that BEST explains the effect of increasing urinary pH on the urinary excretion of indobufen, (it's an acid with COOH groups)

1. Raising the pH shifts the ionization equilibrium towards the CB form, which facilitates excretion. 2. Raising the pH shifts the ionization equilibrium towards the CB form, which facilitates reabsorption. Correct answer: 1. At higher pHs (lower [H+]) the ionized CB form of the acid predominates. Ionized forms are more water soluble and can be excreted in the urine.

Ampicillin is eliminated 1st order kinetics. which statement describes process by which the Cp of this drug declines ? - Theres only 1 metabolic path for drug elimination - t1/2 is the same regardless of Cp - Drug is largely metabolized in liver after oral admin and has low bioavailability - Re is proportional to Ra at all times - Drug is distributed to only 1 compartment outside the vascular system

1st order means the elimination rate is proportional to the concentration perfusing the organ of elimination. The t-1/2 is constant, Re is proportional to the Ra only at steady state. The order of elimination is independent of the number of compartments into which a drug distributes *t-1/2 is the same regardless of Cp*

A new drug was administered intravenously, and its plasma level measured for several hours. A graph shown below with plasma levels (log scale) plotted vs time (linear abscissa). It was concluded that the drug has 1st order kinetics, what is the best estimate of t-1/2 0.5, 1, 3, 4, 7 (hours)

3 hours Drugs w/ 1st order kinetics have constant half-lives, and when log conc in a body compartment is plotted vs time, a straight line results. the half-life is defined as the time required for conc to decrease by 50%.

Common p450 inhibitors and the drugs whose metabolism is inhibited are listed: CYP1A2 inhibitors- benzo(a)pyrene from tobacco smoke, carbamazapine, phenobarbital, rifampin, omeprazole induces metabolism of acetaminophen, clozapine, haloperidol, theophylline, TCAs, (R)-warfarin 2D6 inhibitors - Amiodarone, Cimetidine, quinidine, SSRIs -- induce metabolism of antiarrhythmics, antidepressants, beta-blockers, clozapine, flecainide, lidocaine, mexilitine, opioids

3A4 inhibitors - amiodarone, azoles, cimetidine, clarithromycin, cyclosporine, diltiazem, erythromycin, FQs, grapefruit juice, HIV protease inhibitors, Metronidazole, quinine, SSRIs, tacrolimus induce metabolism of antiarrhythmics, antidepressants, azoles, benzos, CCBs, cyclosporine, delaviridine, doxorubicin, efavirenz, erythromycin, estrogens, HIV protease inhibitors, nefazadone, paclitaxel, PPIs, HMG-CoA reductase inhibitors, rifabutin, rifampin, sildenafil, SSRIs, tamoxifen, Trazodone, vinca alkaloids

if therapy with multiple drugs causes induction of drug metabolism in your asthma patient it will A) be assoc w/ inc SER B) be assoc w/ inc RER C) be assoc w/ inc enz in soluble cyto fraction D) require 3-4 mo to reach completion E) be reversible

A SERs mixed-function oxidase drug metabolizing enzymes are selectively increased by inducers

P-Glycoprotein MDR-1

ATP-dependent transport molecule found in many epithelial and cancer cells. The transporter expels drugs from cyto into EC-space. In epithelial cells, expels to surface/lumen

animal testing of potential new theraputic agents - may be abbreviated in the case of some very toxic agents used in cancer

Ames test is a method that detects mutagenesis in bacteria

which drug may inhibit hepatic microsomal p450 responsible for warfarin metabolism A) amiodarone B) EtOH C) phenobarbital D) procainamide E) rifampin

Amiodarone is well documented to inhibit hepatic metabolism of many drugs answer is A

3y.o. OD's on diphenhydramine, a WB w/pKa 8.8 it's capable of entering most tissues, including brain. PE - HR 100, BP 90/50, RR 20, Urinary excretion would be accelerated by administration of NH4CL, an acidifying agent

At higher pHs (lower [H+]) the ionized CB form of the acid predominates. Ionized forms are more water soluble and can be excreted in the urine.

which drug is genetically assoc w/ slower metab in eruo-americans & AAs than in most asians A) cmetidine B) hydralazine C) propanolol D) rifampin E) succinylcholine

B hydralazine like procainamide and INH is metabolized by n-acetylation -- this process is slow in 20% of asians and 50% of euro-americans and AAs

CYP isoenzymes

Cyt-P-450 enzyme species (i.e. 2D, 3A4 which do 75% of the P450 rxns) that are responsible for much of the drug metabolism. CYP450 aka mixed-function-oxidases

which statement about the distribution of drugs to specific tissues is most correct ? - distribution to organ is independent of blood flow - distribution is independent of the solubility of drug in that tissue - distribution depends on unbound drug concentration gradient between blood and tissue - distribution is increased for drugs that are strongly bound to plasma proteins - distribution has no effect on half-life of drug

Distribution depends on the unbound drug concentration gradient between blood and the tissue

60 yo pt with severe cancer pain is given 10mg morphine (po). The Cp is found to be only 30% of that found after IV-10mg. Which of the following describes the process by which the amount of active drug in the body is reduced after administration but before entering the systemic circulation? Excretion 1st order elimination 1st pass-effect metabolism pharmacokinetics

Emphasis is on PK-principles (1st pass-effect) in this vignette, which is the term given to elimination of a drug after admin but before reaching systemic circulation (i.e. on it's 1st pass through portal circ and liver). 1st pass effect is d/t metabolism in the gut, portal blood, or liver usually.

Botulinum toxin is a large protein. It's action on cholinergic transmission depends on an intracellular action within nerve endings. which of following processes is best suited for permeation of very large protein molecules into cells? Aq diffusion Aq hydrolysis Endocytosis Lipid diffusion Special carrier transport

Endocytosis - an important mechanism for large molecules to move across membrane. Aq diffusion isn't involved in moving lipids across membrane, Lipid diff/special carriers move small molecules, hydrolysis has nothing to do with permeation (its a mechanism of metabolism)

which following drugs has higher 1st pass metab in men than in women A) cimetidine B) EtOH C) ketoconazole D) procainamide E) quinidine F)ritonavir G) SCH H)Verapamil

EtOH has metabolism in stomach and liver. Independent of body weight etc men have grater gastric metab of EtOH and thus lower EtOH bioavail than women answer is B

Log (a)*(b) = Log a + Log b Log (a)/(b) = log a - log b pKa = pH + log [CA] - log [CB] CA = acidic, protonated, ionized form (if drug is a base that acquired a proton, BH+) CA = acidic, protonated, ionized form (if drug is an acid that has not yet donated its proton, HA) CB = basic, deprotonated, ionized form (drug is acid that donated its proton, A-) CB = basic, deprotonated, unionized form (if drug is a base that has not yet accepted a proton, B)

For Acids and bases pKa = pH + log [protonated form]/[deprotonated form] for Acids pKa = pH + log [unionized form]/[ionized form] for bases pKa = pH + log [ionized form]/[unionized form] Renal excretion of a weak base is enhanced by acidifying the urine. Renal excretion of a weak acid is enhanced by basifying the urine.

Which of the following is most correct regarding termination of drug action? - Drugs must be excreted to terminate their action - Metabolism of drugs always increases their H2Osolubility - Metabolism of drugs always abolishes pharma activity - Hepatic metab &renal excrete = 2 most imp mech involved - Distrib of drug out of Bloodstream terminated drugs Fx

Hepatic metabolism and renal excretion are the 2 most important mechanisms involved in termination of a drugs actions

Smoking - enzyme induction in liver and lung may increase metabolism of some drugs Biotransformation rate is a primary determinant of CLEARANCE, thus variations in drug metabolism must be considered carefully when designing or modifying dosing regimens

Hydrolysis of esters - Succinylcholine (ester) metabolized in Phase 1 rxn by plasma cholinesterase (pseudocholinesterase or butyrylcholinesterase). In most this occurs rapidly within 5 min, but 1/2500 peeps has an abnormal enzyme and metabolizes it much much slower, along with similar esters. I.e. a pt with 1 dose of SCH getting NM blockade and paralysis for hours.

important inhibitors amiodarone, cimetidine, furanocoumarins in grapefruit juice, azoles, ritonavir (protease inhibitor) Suicide inhibitors - drugs metabolized to products that irreversibly inhibit metabolizing enzyme, (ethinyl estradiol, norethindrone, spironolactone, secobarbital, sllopurinol, fluroxene, PTU Metabolism may also be decreased by pharmacodynamic factors like reduction in blood flow to metabolizing organ (propanolol reduces hepatic blood flow)

Inhibitors of P-glycoprotein (intestinal)-MDR-1, in intestinal cells (spitting drugs back into lumen), also BBB and cancer cells. P-Gp inhibitors mimic drug metabolism inhibitors, by increasing bioavailability, co admin of P-Gp inhibitors may result in toxic Cp of drugs that are normally nontoxic doses exampes: Verapamil, furanocoumarin components of grapefruit juice, drugs normally expelled by p-gp (and therefore potentially more toxic when given with P-Gp inhibiotr) include digoxin, cyclosporine, saquinavir

FDA drug safety pregnancy IND - investigational new drug exemption app, submitted by manufacturer to FDA - includes all preclinical data collected up to submission, and detailed proposal for clinicla trials. Major clinical testing process is usually divided into 3 phases that are carried out to provide info for a NDA (new drug app) which has all the results of preclinical and clinical testing and costitutes the request for FDA approval of general marketing of new agent for Rx use. a 4th phase is surveillance and follows NDA approval.

Phase 1 - careful eval of D/R relationship and PK of new drug in a small # of normal human volunteers (20-100). Except chemodrugs which are given to pt volunteers with target disease. Acute effects of agent studied over broad range of dosages Phase 2 eval of drug in moderate # of pt's (100-200) w/ target disease. A placebo or + control is included in single or double blind design. Study carried out under carefully controlled conditions, pt's monitored usually in research hospital. Goal is to determine whether agent has desired efficacy at doses that are tolerated by sick pt's. Phase 3 - 1000+ pt's and many clinicals who are using the drug in manner proposed for unltimate general use (outpt's) usually include placebo/+ controls in double blind crossover design. Goals are to explore further, under the conditions of proposed clinical use, the spectrum of beneficial actions of the new drug, compare it w/ older Tx, discover toxicieties, (very expensive) NDA Phase 4 surveillance

Which of the following is liekly to increase DOA of drug metabolized by 3A4 in liver A) chronic admin of phenobarb before & during therapy with drug in ? B) chronic therapy w/cimetidine C)displacement from tissue-binding sites by another drug D) increased CO E) chronic admin of rifampin

Phenobarb and rifampin can induce drug-metabolizing enzymes and thus may reduce duratio of drug action. Displacement of drug from tissue may transiently increase the intensity of the effect but decreases the Vd. Cimetidine is recognized as a p450 inhibitor and may also decreased hepatic blood flow answer = B

which would probably be included in an optimal p3 clinical trial - A negative control (placebo), Positive control (current standard Tx), double blind protocol, group of 1000-5000 subjects requiring analgesia

Remember**** Theraputic index is ratio of median toxic dose (TD50) or medial lethal dose (LD50) to the effective dose in half the population (ED50) determined in a population of subjects. Thus, the quantal dose-response experiments are needed to ascertain theraputic index. The min eff dose and max efficacy of a drug are dtermined by gradually increasing the dose and noting the responses produced. Graded DR experiments are needed fro these measurements

which when used in combo w/ other anti-HIV drugs permised dose reductions? A) cimetidine B) EtOH C) ketoconazole D) procainamide E) quinidine F)ritonavir G) SCH H)Verapamil

Ritonavir inhibits hepatic drug metabolism and its use at low doses in combo regimens has permitted dose reduction of other HIV protease inhibitors (i.e. indinavir) the answer is F

A 3-year-old is brought to the emergency department having just ingested a large overdose of diphenhydramine, an antihistaminic drug. Diphenhydramine is a weak base with a pK

Since absorption involves permeation acros lipid membranes, we can in theory treat an OD by decreasing it's absorption from the gut and reabsorption from tubular urine by MAKING DRUG LESS LIPID SOLUBLE. Ionization attracts water molecules & decreases lipid solubility. Diphenhydramine is a WB, which means that it is more ionized when protonated . i.e. at acid pH

Enzyme induction

Stimulation of drug-metabolizing-capacity; usually manifested in the liver by increased synthesis of Smooth ER (which contains hich concentrations of phase 1 enzymes)

reports of arrhytmias caused by unusually high blood levels of 2 antihistamines (terfenadine and astemizole) led to their removal from markey, which explains these effects A) concomitant tx w/ phenobarb B) use of them by smokers C) genetic predisp to metabolize SCH slow D) tx of these pt's w/ ketoconazole

Tx w/ phenobarbital and smoking are assoc w/ increased drug metabolism and lower blood levels. keto/itra conazoles, erythromycin and grapefruit juice slow metabolism of older nonsedating antihistamines answer D

which drug is established inhibitor of P-gp (p-glycoprotein) drug transporters A) cimetidine B) Efavirenz C) ketoconazole D) procainamide E) quinidine F)ritonavir G) SCH H)Verapamil

Verapamil is an inhib of P-GP and has been shown to enhance cytotoxic actions of methotrexate in cancer chemo, answer is H

which drug if used chronically is most likely to increase acetaminophen toxicity? A) cimetidine B) EtOH C) ketoconazole D) procainamide E) quinidine F)ritonavir G) SCH H)Verapamil

acetaminophen normally elim by P2 conjugation rxns - the drugs tox is caused by an oxidized reactive metabolize produced by p1 oxidizing p450 enymes. EtOH and other drugs induce p450 and thus reduce the hepatotoxic dose. Alcoholic cirrhosis reduces hepatotoxic dose even more answer is B

12 yo w/ pharyngitis and is to receive oral ABX. Ampicillin is WA (organic) w/ pKa 2.5. What %age of a given dose will be in lipid-soluble form in duodenum at pH 4.5? 1% 10% 50% 90% 99%

ampicillin is an acid, =more ionized at alkaline pH & less ionized at acidic pH HH eqn predicts the ratio changes from 50/50 at pH=pKa to 1/10 (protonated/deprotonated) at 1 pH unit more alkaline than the pKa, and 1/100 at 2 pH units more alkaline For acids, the protonated form is the non-ionized, more lipid soluble form. Answer = 1%

ur planning to treat asthma pt (19) with recurrent, episodic bronchospasm w/wheezing. Concerned about interxns caused by changes in drug metabolism in this patient. Drug metab in humans usually results in a product that is A) less lipid soluble than original drug B) more likely to distribute intracellularly C) more likely to be reabsorbed by kidney tubules D) more lipid soluble than the original drug E) less water soluble than the original drug

biotransformation usually results in product thats less lipid soluble, this facilitates elimination of drugs that would otherwise be reabsorbed from the renal tubule A

teratogenesis - induction of developental defects in somatic tissues of fetus (by exposure of fetus to a chemical, infxn, radiation) Mutagenesis - inducing changes in genetic material of animals of any age and therefore induction of heritable abnormalities

i.e. thalidomide, isotretinoin, valproate, EtOH, glucocorticoids, warfarin, Lithium, androgens. Ames test - standard in vitro test for mutagenicity uses special strain of salmonella that naturally depends on specific nutrients in culture medium. Loss of this dependence as a result of exposure to the test drug signals a mutation. Carcinogens i.e. aflatoxin, chemoTx, an others that bind to DNA have mutagenic effects and test + for Ames test. Dominant lethal test in vivo mutagenicity test given to male mice before mating -- if loss of embryo/deformed fetus that's + dom lethl in vivo test and it signals mut male germ cells.

A weak base like pyrimethamine (pKa = 7.0) is trapped in the urine because at a pH of 6 (lower than its pKa) the protonated, ionized form predominates, and the total concentration of both species is higher in the urine (11.0 µM) than in the blood (1.4 µM). Therefore, if the goal is to enhance the excretion of pyrimethamine, one would administer an urine acidifier, since lowering the pH in the urine will shift even further the equilibrium towards the ionized, water soluble form of the drug.

pKa = 6 + log[protonated form]/[deprotonated form] = 7.0 log[protonated form]/[deprotonated form] = 1.0 [protonated form]/[deprotonated form] = 10 = [ionized form]/[unionized form] This result tells us that for every 1 unionized pyrimethamine species in the urine, there are 10 ionized species. A similar process for the equilibrium in the blood compartment yields the following: pKa = 7.4 + log[protonated form]/[deprotonated form] = 7.0 log[protonated form]/[deprotonated form] = 7.0 - 7.4 = -0.4 [protonated form]/[deprotonated form] = 10^-0.4 = 0.398 = [ionized form]/[unionized form] This result tells us that for every 1 unionized pyrimethamine species in the urine, there are 0.4 ionized species.

Properties that characterize the effects of a drug on the body is called

pharmacodynamics (Drug's effects on the body)

Phase 1 reactions

rxns that convert parent drug to a more polar (water-soluble) or more reactive product by unmasking or inserting a polar functional group such as OH, SH, NH2

Phase 2 reactions Glucouronidation (acetaminophen, diazepam, digoxin, morphine, sulfamethoxazole) Acetylation (clonazepam, dapsone, INH, Mescaline, sulfonamides) Glutathione conj (Ethacrynic acid, reactive p1 metabolite of acetaminophen) Glycine conj (deoxycholic acid, nicotinic acid (niacin), salicylic) Sulfation (acetaminophen, methyldopa) Methylation (DA, Epi, Hist, NE, Thiouracil)

rxns that increase water solubility (decrease lipid solubility) by conjugation of the drug with a polar moiety (glucouronate, acetate, sulfate, methyl, glycine, glutathione) Most of these like P1 enzymes, are not very selective. Those undergoing both may undergo P2 before or after P1