L8, L11- Pharmacokinetics Flashcards Preview

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Flashcards in L8, L11- Pharmacokinetics Deck (51):

list the mechanisms of drug permeation

-aqueous diffusion (paracellular)
-lipid diffusion (transcellular)
-special carriers (facilitative diffusion, active transport)
-endo-/exo-cytosis (transcytosis)


list the three main parts of pharmacokinetics

-absorption (drug --> systemic circulation)
-distribution (drug --> tissue)
-elimination (drug --> excreted)


list the enteral routes of administration of drugs

-oral: through gut, has first pass effect
-sublingual: under tongue, into systemic circulation, by-passes first pass effect
-rectal: into systemic circulation, by-passes first pass effect


(T/F) only IV administration has 100% absorption/bioavailability

T- every other route has partial absorption (lower bioavailability)


describe first pass-effect

drug absorbed in the gut goes into portal system which directs blood to liver and drug will undergo metabolism before reaching systemic circulation (GI tract also contributes)


list the paraenteral routes of administration of drugs

IM (muscles are very well perfused --> gradual absorption of drug via muscle), SQ, ID


list the other routes (non-enteral or non-paraenteral routes) of administration of drugs

-oral inhalant
-nasal inhalent


list the 5 factors that effect drug absorption

-available SA
-blood flow to absorption site
-contact time at absorption site
-P-Glycoprotein (MDR1 / multi-drug resistance 1)


describe pH's effect on absorption

(most drugs are weak acids or weak bases)
-Weak Acid: HA H+ + A-; HA (protonated form at low pH) crosses membrane, A- (at high pH) will not

-Weak Base: BH+ B + H+; B (unprotonated form at high pH) crosses membrane, BH+ (at low pH) will not


Weak Acids in the (un-/protonated) form can cross the plasma membrane at (high/low) pHs

Weak Bases in the (un-/protonated) form can cross the plasma membrane at (high/low) pHs

1- protonated (HA)
2- low pH

3- unprotonated (B)
4- high pH


Henderson-Hasselbalch Equation

pH - pKa = log([unprotonated form]/[protonated form])


describe pH's effect on RE-absorption

-in the kidney, drugs enter lumen and the more lipophilic forms of the drug will be reabsorbed back into the blood and avoid excretion
-weak acids are excreted faster in more alkaline urine (unprotonated, A- form)
-weak bases are excreted faster in more acidic urine (protonated, BH+ form)


Weak Acids are excreted faster in (acidic/alkaline) urine, in the (un-/protonated) form

Weak Bases are excreted faster in (acidic/alkaline) urine, in the (un-/protonated) form

1- alkaline urine
2- unprotonated form (A-)

3- acidic urine
4- protonated form (BH+)


how does SA affect drug absorption

most drugs are absorbed in the small intestine (rather than stomach) b/c of a much, much larger SA for drugs to cross


how does blood flow affect drug absorption

most drugs are absorbed in the small intestine (rather than stomach) b/c there is much blood flow to SI than stomach


how does contact time affect drug absorption

most drugs are absorbed in the small intestine (rather than stomach) b/c drugs move slower in SI than in stomach and therefore have more time to cross


why are most drugs absorbed in the small intestine rather than the stomach

-more SA
-more blood flow
-more contact time (slower movement thru SI than stomach)


how does P-glycoprotein affect drug absorption

P-Glycoprotein = MDR1 (multi-drug resistance 1_
-transporter (active, requires ATP) that removes drugs within the cell and puts it back into the gut lumen (or from BBB into cerebral circulation)
-inc MDR1 => dec absorption
-dec MDR1 => inc absorption


explain the Bioavailability (F) equation

F = (AUC oral) / (AUC IV) x 100

-using a graph with plasma [drug] (y) v time (x), plot the [drug] given IV and orally
-Area Under the Curve (AUC) of each are taken and plugged into the above equation


list the factors that influence Bioavailability (F)

-drug formulation
-chemical instability
-food / drug interactions
-first-pass effect
-drug solubility


define bioequivalence

-two pharmaceutically equivalent drug products have nearly superimposable concentration-time plots
-one can safely replace the other


define drug distribution and the factors that effect it

-process of drug leaving blood and entering ECF/ICF

-blood flow
-drug binding to plasma proteins
-tissue binding
-drug liposolubility


how does blood flow affect drug distribution

-initially liver, kidney, brain (+ other well perfused organs) receive most of the drug

-delivery to muscle, vicera, skin, fat is much slower (dec perfusion)


how does binding to plasma proteins affect drug distribution

-acidic drugs bind plasma albumin
-basic drugs bind α1-acid glycoprotein

-this reversible binding slows distribution


how does tissue binding affect drug distribution

-many drugs accumulate in tissues: liposoluble ones in fat
-accumulated drugs can serve as a reservoir to prolong drug action


how does drug liposolbility affect drug distribution

-polar molecules can't cross Blood-Brain barrier (via paracellular entry)
-nonpolar molecules can penetrate BBB (via transcellular entry)


The BBB is made up of (1), (2), (3). Therefore only drugs that are (4) or (5) can cross BBB.

(BBB- blood-brain barrier)
1- endothelial tight junctions (+ endothelial basal lamina)
2- astrocytic 'end feet' surrounding capillary endothelium
3- P-glycoprotein (many)

4- lipophilic drugs
5- have active transporter


list the 4 ways drug metabolism alters the drug

-active drug --> inactive drug
-unexcretable drug --> excretable metabolite
-active drug --> active/toxic metabolite
-inactive prodrug --> active drug


most drugs are absorbed in the (1) form, then are metabolized into the (2) form for easier excretion

1- lipophilic
2- polar/charged inactive metabolite


describe phase I reactions of drug metabolism

-oxidations/reductions, decarboxylations, deaminations, hydrolytic rxns
-usually Parent Drug --> Polar Metabolite, inactive
-sometimes activity is modified or enhanced
-mostly mediated by cytochrome P450


prodrugs are usually converted to active metabolites by....

hydrolysis of an ester or amide linkage


describe phase II reactions of drug metabolism

-conjugation reactions
-covalent bond between drug and: glucuronate, acetate, glutathione, AAs, sulfate
-allows for easier elimination


drug metabolism predominately happens in (1), but can also occur in (2)

1- liver
2- GI tract, kidney, lungs, skin


phase I reactions primarily occur in (1) of the cell and phase II in (2)

1- ER membrane
2- cytosol (conjugation)


(1) isoform accounts for 30% of all CYP450 enzymes in liver and metabolizes about (2)% of all drugs

1- CYP3A4
2- 50%


phenobarbital, rifampin, carbamazepine will (inc/dec) synthesis of multiple P450 isoforms

INCREASE synthesis of one or more forms


for drugs to enter hepatocytes, they must bind (1), which then is activated and allows (2) to occur

1- xenobiotic receptors
2- translocate to nucleus --> bind promoters of various enzymes


describe the effect of St. John's wort

-herb plant, has natural antidepressant properties
-induces CYP3A4 production => inc drug metabolism of various drugs
-this can lead to subtherapeutic levels of drug and or toxic levels of drug metabolite (causing tissue damage)


list some inhibitors of cytochrome P450

amiodarone, cimetidine, ketoconazole, erythromycin, chloramphenicol, grapefruit juice


drugs that induce P450 enzymes will also induce....

P-glycoprotein (pumps drugs out of cells- usually into gut lumen or cerebral circulation as apart of BBB)


macrolide antibiotics (activate/inhibit) P-glycoprotein

(ex. clarithromycin)


Acetominophen is usually metabolized by conjugation with (1) or (2). At high levels, (3) will convert it to (4). (4) will be attached with (5) for excretion, but at toxic levels (5) stores are depleted and (6) occurs.

1- glucuronate
2- sulfate
3- CYP2E1
4- NAPQI (N-acetyl-P benzoquinoneimine), a toxic intermediate
5- glutathione (into mercaptopuric acid, excreted thru kidneys)
6- cell death


acetaminophen overdose is treated with (1) with (2) as its mechanism

Acetadote / N-acetylcysteine: supplies Cys for glutathione production to react directly with NAPQI


grapefruit juice (activates/inhibits) (2) in the liver and (3) in the (4)

1- inhibits
2- CYP3A4
3- P-glycoprotein
4- small intestine


list the three ways genetic variation can influence pharmacotherapy (indicate most common factor)

-variation in proteins involved in drug metabolism or transport (enzymes that catalyze drug metabolism are most common)
-variation in drug targets or associated pathways
-variation associated with idiosyncratic drug effects (unpredictable effects)


(1) present in cigarette smoke cause (2)-mediated P450 enxyme (induction/inhibition)

1- aromatic hydrocarbons
2- AhR (aryl hydrocarbon receptor)
3- induction


charcoal-broiled food and cruciferous (broccoli, cauliflower, brussel sprouts, kale, ect) vegetables induce....

CYP1A enzymes


(T/F) only the elderly have a decrease in many reactions of biotransformation (drug metabolism)

F- biotransformation is slowed in the elderly and young children


the most common mechanism of drug excretion is (1), and a small number are excreted through (2)

1- kidneys / urine
2- bile // feces or metabolites reabsorbed --> excreted in urine


list the three processes involved in renal excretion of drugs

1) glomerular filtration- MW <20000 Da (lipid solubility and pH have no influence)
2) active tubular secretion- into urine, via PCT, cation and anion transporters
3) passive diffusion across tubular epithelium- reabsorption of lipophilic drugs


describe biliary excretion

-many drug metabolites are secreted from liver into bile
-some excreted in feces
-most are reabsorbed into blood and ultimately excreted in urine