Flashcards in ADME Deck (102):
The therapeutic window lies between what 2 values?
Minimum toxic concentration and minimum effective concentration
What is the difference between pharmacodynamics and pharmacokinetics?
pharmacodynamics describes the effect of a drug on a specific receptor in the body
pharmacokinetics describes the effect that the body has on a drug
What are the 4 features of drug dynamics that determine pharmacokinetics?
Pharmacokinetics govern what 3 features of drug action?
What are the methods clinicians use to effect a drug's concentration v. time profile?
frequencies of administration
What is the therapeutic index?
What types of drugs are allowed to pass through cellular membranes?
low molecular weight (100-200 Da)
Non polar/Non ionized compounds
What are the two major process by which drugs cross biological membranes?
1) Passive diffusion** MAJOR
2) Carrier-Mediated Transport
What law governs rate of diffusion?
What is Fick's Law?
Diffusion rate= -DAK(Cout-Cin)/deltaX
What does D stand for in Fick's law?
Diffusion coefficient is related to what feature of drugs?
INVERSELY related to size
What does K stand for in Fick's law?
Partition coefficient is related to what feature of drugs?
Lipid solubility (oil:water)
Ionization (dictated by pH)
An ionized drug has higher or lower partition coefficient?
LOWER, diffusion rate is therefore slower
What does A stand for in Fick's law?
surface area (larger means more diffusion
True or false: thinner membranes promote higher rates of diffusion.
Name 2 types of carrier mediated transportation.
True or false: carrier mediated transportation are saturable.
What is the name of the major transporter of chemotherapeutic agents?
What assumption does the pH-partition theory make?
Drugs are absorbed only when they are non-ionized and therefore have a higher lipid solubility
What is the Henderson-Hasselbalch equation?
log(protonated form/unprotonated form)=pKa-pH
Acidic drugs accumulate on what side of a membrane?
the basic side (where they will dissociate into their unprotonated, ionized form)
Basic drugs accumulate on what side of a membrane?
the acidic side (because the protonated form is ionized)
Acidic drugs are absorbed best where?
Basic drugs are absorbed best where?
How do you promote excretion of an acidic dug?
alkalinize the urine (by giving bicarbonate so drug dissociates into its ionized form and cannot be absorbed back into the blood from the renal tubule)
What term describes the rate at which a drug leaves its side of administration and the extent to which that occurs?
What term describes the fractional extent to which a given dose of a drug reaches either its site of action or a biological compartment from which the drug has free access to its site of action?
What has a bioavailability of 1?
First pass metabolism has what affect on bioavailability?
severely limits it
What is the most common form of drug administration?
List the enteral routes of administration.
oral, sublingual, rectal
What must occur before drugs taken via the enteral rate are absorbed?
How can absorption be modified?
-Delayed/sustained release tablets
-Rapid release formulations
Why is the small intestine a generally better place for drug absorption?
larger surface area (A)
What greatly increases drug absorption in the small intestine?
increasing gastric emptying
What factors SLOW gastric emptying?
-Eating large volumes or bulky food
-Lying on left side
-Drugs (narcotics, anticholinergics, analgesics)
List the 6 forms of parenteral routes of administration.
What is the maximum dose that can be given subcutaneously?
What is the maximum does that can be given IM?
Where is the best place to give an IM injection?
Name the 3 major factors that affect the rate of distribution of a drug?
1) Blood Perfusion Rate (CO and regional blood flow)
2) Tissue Volume
3) Capillary permeability
Which organs receive the highest total blood flow/highest perfusion rates?
Drugs larger than 25 kD are transported via what mechanism?
Describe the permeability of renal capillaries.
Renal capillaries have increased permeability due to large spaces between endothelial cells. Good at filtering drugs.
Describe the permeability of brain capillaries.
tight junctions between cells make the brain capillaries relatively impermeable and restrict the transfer of molecules from blood to brain tissue
List the 2 major factors affecting the extent of distribution.
Plasma protein binding (most common)
Plasma protein binding causes drug to stay in what compartment?
central blood compartment
What plasma protein binds to acidic drugs?
What plasma protein is in highest concentration?
What plasma protein binds to basic drugs?
What factors influence the total fraction of drug bound at any given time?
-Drug's affinity for binding sites (esp. at low conc.)
-Number of binding sites (esp. at high conc.)
What can lead to drug reservoirs? What is the effect of having a reservoir of drug?
trapping of free, nonionized forms of a drug (ex. basic drugs trapped in stomach)
-This leads to a prolonged duration of response
Describe volume of distribution.
Vd indicates the apparent body volume that a given drug is located within and is generally indicative of the compartment to which it distributes
What is the equation for volume of distribution?
Vd= amount of drug administered/plasma drug concentration
What is the volume of extracellular fluid?
around 14 L
What is the volume of plasma?
What is the volume to total body water?
What does it mean if a drug has a Vd much higher than total body water?
it is concentrating in organs! (this lowers the plasma concentration and makes the Vd look HUGE
What two processes determine elimination of drug from the body?
metabolism and excretion
What term describes chemical modifications of xenobiotics by endogenous enzymes?
What term describes the chemical transformation of both endogenous and exogenous agents?
True or False: inactivation of a drug converts it to a less lipid soluble, more polar form.
TRUE! this form favors drug excretion
Where do biotransformation reactions usually take place?
Where do phase I reactions typically take place in the cell?
ER which fragments into mirosomes
Describe what a phase I reaction is.
Reaction that converts a parent drug to an inactive metabolite/or activates a prodrug by introducing or unmasking a functional group
Products of phase I reactions often have what characteristics?
highly reactive free radicals that are potentially toxic
Name 3 examples of phase I reactions.
1) oxidation (add oxygen, remove hydrogen)
2) reduction (add hydrogen, remove oxygen)
3) hydrolysis (add water and break-down molecule)
Where do phase II reactions typically take place in the cell?
Describe what a phase II reaction is.
covalent addition of a functional group onto a parent compound or reactive product of phase I reaction
Products of phase II reactions often have what characteristics?
more water soluble and less lipid soluble (less drug is reabsorbed, inactive drug is readily excreted)
What is the major conjugation (phase II) reaction in the body?
What catalyzes glucuronidation?
List other phase II reactions.
Name an example of when a phase II reaction produces a product that is more reactive than the reactant.
morphine metabolite is a more potent analgesic than morphine
What is the major catalyst for phase I reactions?
Where are CYP450 enzymes located?
smooth ER of numerous tissues (highest concentration in the liver)
What is the major CYP involved in metabolization of drugs absorbed from the GI tract?
(3A4 and 3A5 can metabolize around 50% of drugs)
What makes up the CYP450 enzyme complex?
CYP450 enzyme and CYP450 reductase
True or false: drugs bind to the reduced form of the CYP450 enzyme complex?
FALSE: they bind to the oxidized form of the complex and the complex gets reduced by CYP450 reductase
What returns CYP450 reductase to its original reduced form after molecular oxygen oxidizes the drug bound to the CYP450 complex?
What is the term for the genetic basis for differences among the population in drug responses?
What is the term for application of genomic information towards the discovery/development of novel specific drugs?
What is a genetic polymorphism?
a variation in DNA sequence between individuals that can be propogated to the protein sequence
What type of phenotypic variation has two or three discrete distributions?
What type of phenotypic variation hasone broad population distribution?
What is the major organ for excretion of drugs?
What is the glomerular filtration rate?
around 20% of blood which enters the glomeruli of the nephron is filtered. GFR is usually 110-130 mL/min
How to you measure GFR?
renal clearance of creatinine
What prevents drugs from being filtered at the glomerulus?
if they are bound to plasma proteins or RBCs
How much of filtrate is reabsorbed typically?
Where does tubular secretion occur? By what method?
proximal tubule by active secretion
What is the transporter involved in tubular secretion?
MDR2 and energy supply work to secrete weak electrolytes (removes organic anions and cations--as well as most drugs from blood)
Where does tubular reabsorption occur? By what method?
distal tubules by passive diffusion
What types of things can be reabsorbed in the distal tubule?
nonionized forms of weak acids and bases
What is a major factor in what gets reabsorbed in the distal tubule?
pH of urine
What value quantifies the renal excretion of a drug?
renal clearance value
What does a renal clearance value of 120 mL/min tell you?
drug is neither secreted or reabsorbed
What does a renal clearance value of less than 120 mL/min tell you?
drug shows NET reabsorption
What does a renal clearance value of greater than 120 mL/min tell you?
drug must be having tubular secretion contributing to elimination process