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91 Cards in this Set

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Define pharmacokinetics (PK)
Field of study that deals with time required for drug absorption, distribution in the body, metabolism, and method of excretion
Define Volume of distribution (Vd)
A proportionality constant that relates the amount of drug in the body to the plasma concentration; apparent fluid volume in which a drug appears to be dissolved; Vd = (dose)/ (plasma drug concentration)
Define clearance (Cl)
Volume of blood cleared of the drug per unit time; Cl = (rate of elimination of drug)/ (plasma drug concentration); total body Cl = Cl hepatic + Cl renal + Cl pulmonary + Cl other
Define Half-life (t½ )
Time required for plasma concentration of drug to decrease by one-half after absorption and distribution are complete; t ½ = (0.693 x Vd)/ (Cl)
Define Bioavailability (F)
The fraction of drug absorbed into the systemic circulation after extravascular administration; F= (AUC0)/(AUCiv), where AUC0 and AUCiv are the extravascular and intravenous areas under the plasma concentration vs. time curves, respectively
None
Define Steady state (Css)
Steady state is reached when the rate of drug into the body = the rate of drug out of the body; Css = plasma concentration of drug at steady state
None
How many half-lives does it take for a drug to reach (clinical) steady state
5 half lives
How much drug is left after 1 half life
50%
How much drug is left after 2 half-lives
25%
How much drug is left after 3 half lives
12.5%
During constant infusion, what percent of steady state is reached after 1 half life
50%
During constant infusion, what percent of steady state is reached after 2 half lives
75%
During constant infusion, what percent of steady state is reached after 3 half lives
87.5%
What is the equation for infusion rate (k0)
k0 = Cl x Css
What is the equation for loading dose (LD)
LD = (Vd x Css)/ F; for examination purposes, F is usually 1
What is the equation for maintenance dose (MD)
(Cl x Css x tau)/ (F); where tau is the dosing interval
What is the equation for clearance (Cl)
Cl = K x Vd, where K is the elimination constant
What is the equation for volume of distribution
Vd = (LD)/(Css)
What is the equation for Half-life (t ½)
(T ½) = (0.693)/(K) or (0.693 x Vd)/ (Cl)
What happens to the steady state concentration of a drug if the infusion rate is doubled
Steady state concentration is also doubled; remember that dose and concentration are directly proportional (linear kinetics); Css = k0/ Cl
If there is no active secretion or reabsorption, then renal clearance (Cl renal) is equal to what
Glomerular filtration rate (GFR)
If a drug is protein bound, then Cl renal is equal to what?
GFR x free fraction (of drug)
What happens to the LD in patients with impaired renal or hepatic function
Stays the same
What happens to the MD in patients with impaired renal or hepatic function
Decreased
What type of elimination refers to a rate of elimination that is constant regardless of concentration
Zero-order elimination
What type of elimination refers to a plasma concentration that decreases exponentially with time
First-order elimination
What type of elimination refers to a rate of elimination that is proportional to the drug concentration
First-order elimination
What type of elimination refers to a plasma concentration that decreases linearly with time
Zero-order elimination
What type of elimination refers to a rate of elimination that is independent of concentration
Zero-order elimination
What type of elimination refers to a rate of elimination that is dependent on concentration
First-order elimination
What are some examples of drugs/ substances that undergo zero-order elimination
Aspirin (ASA) at high/ toxic concentration
Phenytoin
Ethanol
None
Describe phase I metabolism
Metabolism that generally yields more polar, water-soluble metabolites (may still be active); enzyme activity decreases with age
Describe phase II metabolism
Metabolism that generally yields very polar, inactive metabolites (renally excreted); enzyme activity does not decrease with age
Phase I (microsomal) metabolism involves what types of reactions
Oxidation; reduction; hydrolysis (carried out by cytochrome P-450 enzymes)
Phase II (nonmicrosomal) metabolism involves what types of reactions
Acetylation
Amidation
Glucuronidation
Glutathione conjugation
Sulfation
None
Give examples of drugs that undergo phase II metabolism
Minoxidil; procainamide; hydralazine; isoniazid (INH); morphine; lorazepam; oxazepam; temazepam; 6-mercaptopurine; chloral hydrate; zaleplon; acetaminophen
Where are cytochrome P-450 enzymes found
Smooth endoplasmic reticulum of cells in mainly the liver, but also found in the GI tract, kidney, and lungs
Explain what phase 1 in drug development is trying to accomplish
Safety in healthy individuals; PK
Explain what phase 2 in drug development is trying to accomplish
Efficacy in diseased individuals (small scale trials, single or double blind)
Explain what phase 3 in drug development is trying to accomplish
Efficacy in diseased individuals (large scale trials, mainly double blind)
Explain what phase 4 in drug development is trying to accomplish
Postmarketing surveillance (monitored release)
At what point during drug development is an investigational new drug application filed
Before phase 1
At what point during drug development is a new drug application filed
After phase 3 (and before phase 4)
What does the term bioequivalence mean
When comparing two formulations of the same compound, they are said to be bioequivalent to each other if they have the same bioavailability and the same rate of absorption
What is the first-pass effect
After oral administration, many drugs are absorbed intact from the small intestine and transported first via the portal system to the liver, where they undergo extensive metabolism
None
How many liters are found in blood
5L
How many liters are found in plasma
3L
How many liters are found in total body water
42L
What is the most common plasma protein that drugs bind to
Albumin
Displacing a drug that is bound to plasma albumin will increase its what
Free fraction (therefore may possibly increase the risk of toxicity because the concentration of active drug has been increased, yet depending on the drug, may actually increase its metabolism because more drug is available to metabolizing enzymes)
For passive diffusion, state the direction of flow, if energy is required, if a carrier is required, and if the system is saturable
Downhill; no energy required; no carrier; not saturable (proportional to concentration gradient)
For facilitated diffusion, state the direction of flow, if energy is required, if a carrier is required, and if the system is saturable
Downhill; no energy required; carrier required; saturable
For active transport, state the direction of flow, if energy is required, if a carrier is required, and if the system is saturable
Uphill (against concentration; electrical gradient); energy required; carrier required; saturable
The permeation of drugs across cellular membranes is dependent on what
Solubility; concentration gradient; ionization; surface area; vascularity
Acidification of urine will increase renal elimination of what types of drugs
Weak bases (ionized form of drug will be trapped in the renal tubules and thus excreted in the urine)
Acidification of urine will decrease renal elimination of what types of drugs
Weak acids (nonionized form of drug can cross membranes)
Alkalinization of urine will increase renal elimination of what types of drugs
Weak acids (ionized form of a drug will be trapped in the renal tubules and thus excreted in the urine)
Alkalinization of urine will decrease renal elimination of what types of drugs
Weak bases (nonionized form of drug can cross membranes)
What agents are used to acidify urine
NH4Cl; high dose vitamin C
What agents are used to alkalinize urine
NaHCO3; acetazolamide
Give an example of two weakly acidic drugs
ASA; barbiturates
None
Give an example of a weakly basic drug
Amphetamines
Give examples of drugs that the cytochrome P-450 enzyme CYP 1A2 metabolizes
Caffeine
Acetaminophin
Ciprofloxacin; theophylline; R-warfarin
None
Give examples of drugs that the cytochrome P-450 enzyme CYP 2C9 metabolizes
S-warfarin
Hexobarbital
Ibuprofen
Phenytoin
Naproxen
None
Give examples of drugs that the cytochrome P-450 enzyme 2C19 metabolizes
Propranolol
Omeprazole
Diazepam
None
Give examples of drugs that the cytochrome P-450 enzyme CYP 2D6 metabolizes
Codeine
β-blockers
TCAs
Dextromethorphan
None
Give examples of drugs that the cytochrome P-450 enzyme CYP 2E1 metabolizes
Ethanol
INH
Acetaminophen (at high doses)
None
Give examples of drugs that the cytochrome P-450 enzyme CYP 3A4 metabolizes (50-60% of all therapeutically used drugs are metabolized via CYP 3A4)
Alprazolam; carbamazepine; cyclosporine; diltiazem; erythromycin; fluconazole; itraconazole; ketoconazole; lidocaine; lovastatin; midazolam; nifedipine; quinidine; simvastatin; tacrolimus; verapamil
None
Give examples of drugs that generally induce cytochrome P-450 enzymes
Rifampin (2C9, 3A4)
Nicotine (1A2)
Chronic alcohol use (2E1)
Phenobarbital
Phenytoin
Carbamazepine
St. John’s wort
None
Give examples of drugs that generally inhibit cytochrome P-450 enzymes
Cimetidine, Ketoconazole
Omeprazole
Ritonavir
Fluoxetine
Erythromycin; ciprofloxacin; quinidine; chloramphenicol; acute alcohol intoxication
None
Which antiepileptic medication is said to be able to autoinduce its own metabolism
Carbamazepine
Intracellular volume (ICV) makes up what fraction of TBW
2/3 (ICV = 2/3 TBW)
Extracellular volume (ECV) makes up what fraction of TBW
1/3 (ECV = 1/3 TBW)
Interstitial volume makes up what fraction of ECV
2/3 (interstitial volume = 2/3 ECV)
Plasma volume makes up what fraction of ECV
1/3 (plasma volume = 1/3 ECV)
What type of elimination involves a constant fraction of drug eliminated per unit time
First-order elimination
What type of elimination involves a constant amount of drug eliminated per unit time
Zero-order elimination
What is the equation for half life
T1/2= 0.693/k
This formula allows you to go back and forth between elimination half-life and the rate constant of elimination
What is the equation for volume of distribution
Vd= X0/C0
The volume of distribution can be well estimated from the dose given at zero time, X0, and the drug concentration, C, is extrapolated back to time zero (C0) for all cases when absorption is "instantaneous" (e.g. i.v. administration)
What are the two equations for Clearance
Cl=keVd or Cl=(0.693Vd)/(t1/2)

Clearance is given in L/hr, volume of distribution is L, and the rate constant is in fraction per hr
What is the equation for dosing rate
Dosing rate = Cl x Css
Clearance x desired steady state concentration of drug
What is the equation for maintenance dose
Maintenance dose = dosing rate x dosing interval
What is the equation for loading dose
Loading dose = Vd x TC
TC= Target concentration (usually the same as desired Css)
What is the equation for steady state concentration
Css= Dosing/Clearance
What are some compounds acetylated by NAT-2 (phase II reaction)
Isoniazid (INH)
Procainamide
Sulfonamides
Histamine, Caffeine, Dapsone, Hydralazine
What are two Thiopurine methyl transferase substrates (TPMT)
6-mercaptopurine (6-MP)
Azathioprine
Polymorphism in the glucuronyl transferase UGT1A1 may impair the metabolism of what anti-cancer drug
Irinotecan
Those with variant forms of Catechol O-methyltransferase (COMT) show reduced metabolism of what drug
Levodopa, giving enhanced drug effect and possible toxicity
The 2677 T genotype of the multidrug resistance gene 1 (MDR-1) has been associated with lower plasma levels of what drug
Fexofenadine
What will be the effect of isoproterenol in a patient with Arg/Arg at codon 16 of β2 receptors
Rapid desensitization of the venodilation response, but increased bronchodilator response
What will be the result of warfarin treatment in a patient with polymorphisms in VKORC1
They will be insensitive to Warfarin