Pathophysiology and Drug Action Exam 3 Flashcards
What is ADME?
-how the drug enters the body (absorption)
-where it goes once it enters (distribution)
-how it is broken down within the body (metabolism)
-how it is removed from the body (excretion)
What are the three primary means to quantify drug effect?
Onset: how quickly the drug exhibits its pharmacologic effect
Duration: how long it exhibits its effect
Intensity: magnitude of the pharmacologic effect
What are some barriers associated with ADME?
-membranes that limit the movement of drug into certain tissues
-enzymes within membranes that metabolize the parent drug
! can reduce amount of drug that reaches receptor as well as speed it reaches site
What will a reduction in the extent of absorption result in?
-reduces peak drug concentration and time the drug remains above the MEC
-reduce intensity and duration
What will a reduction in speed of entry into systemic circulation result in?
-effects onset
What happens if a parent drug is active and a metabolite is inactive and they get co-administrated?
co-administration of the inhibitor of the metabolism of the parent drug will prolong the pharmacologic effect
What happens if a parent drug is inactive and a metabolite is active and they get co-administered?
-giving an inhibitor of the metabolism of the parent drug will decrease the pharmacologic effect
What are the factors that determine movement of a drug across membranes?
- Characteristics of the membrane
- Mechanisms of passage across membrane
- Dwell time of drug-membrane interface
- Physiochemical characteristics of the drug
- pH of the microenvironment
- Surface area of absorptive surface
What is the site in the GI tract that involves the most absorption?
-Small Intestine
is covered by folds of Kerckring (villi and microvilli) increases surface area
What are the mechanisms by which Drugs cross Biological Membranes?
-Paracellular, Transcellular (passive), Facilitated Diffusion (carrier-mediated), Active transport (carrier-mediated)
What are the effects of carrier-mediated transport?
facilitated diffusion and active transport are saturable and susceptible to competitive inhibition;
facilitated diffusion only moves molecules with a concentration gradient; passive
active transport requires energy (ATP); can go against the concentration gradient
How do efflux transporters affect the absorption of a drug in the small intestine?
-Transport proteins that facilitate movement of solutes out of the cell are efflux transporters
1. Limited drug absorption
2. Enhanced drug elimination
3. Limited distribution
How do nanoparticles cross biological membranes?
-Endocytosis
-usually for large molecules and nanoparticle drug delivery
How is transcellular permeability increased?
- Removing charged (ionized) groups
- Increasing lipophilicity
- Reducing size
consequence: more lipoplhilic(cross membranes)—> less soluble(less absorbed)—–>poor bioavailability
What is the effect of drug distribution on the concentration versus time curve?
-distributes into perfuse tissues first; then concentration increases in other tissues
-after equilibrium is reached; tissue and plasma are parallel in decline even though concentrations are not the same in each tissues the decline is
what are the differences between perfusion rate limited and permeability rate limited distribution of drug tissues?
-Permeability rate limited will show slower perfusion rate because the solute can only get across the membrane so fast
-Perfusion rate limited is going across the membrane NOT going to the organ
Differentiate between transvascular movement and via convection versus diffusion
-Convection is driven by pressure; used by large molecules
-Diffusion is driven by concentration gradient from high concentration to low concentration
How does drug “trapping” occur?
-uses the pH partition phenomenon
-ionizes certain drugs so it can excreted in the urine
-results in differences in drug concentration compared to blood
How does plasma protein binding effect distribution and pharmacologic effect?
-free drug is the pharmacologically active species and therefore when drug is bound it is inactive and can change distribution of a drug
What are 4 mechanisms that allows drug access to the CNS?
-appropriate physiochemical properties
-utilize an existing transporter
-disruption of the blood brain barrier (osmotic load chased by drug; risk of toxicity)
-direct administration into the CNS (cerebrospinal fluid)
What type of drug molecule is best to used with a pregnant woman?
-highly polar charged drugs
-can’t cross the placenta
What are the main routes drugs are excreted from the body?
-Renal and biliary (hepatic)
-other routes: salivary, pulmonary, mammary
What are the main processes and location involved in renal excretion?
-filtration -Glomerulus
-active tubular secretion -proximal tubule
-tubular reabsorption -proximal tubule
-biotransformation -proximal tubule
How does physiochemical properties of a drug influence its filtration?
-molecular size
-protein binding
What is the relationship between molecular weight and renal clearance?
if molecular size is too big (MW<500) it will not get filtered through renal clearance
-smaller the molecule, the more the renal clearance will occur
What is the relationship between dose and urinary excretion rate for a drug that only goes through filtration vs one eliminated through renal secretion?
-renal clearance increases as creatinine clearance increases
-drugs that go through renal secretion are susceptible to competitive binding (exhibits saturation at high concentration) and can be stereoselective
What is the relationship between molecular weight and percent of drug excreted in the bile?
-the larger the molecular weight (~500-600 optimal) larger the percent excreted in the bile; conjugated drugs also excreted in bile
-less than 300-400 MW will be reabsorbed by kidneys and not excreted in the bile
-also whether polar or not (polar gets eliminated in bile)
What is the impact of enterohepatic recirculation regarding drug half-life in the body?
-increases half life
-conjugated drugs can be hydrolyzed in GI tract and reabsorbed
-reduces elimination of xenobiotics
what are the CYP3A4 substrates, inhibitors, and inducers?
substrates: midazolam, indinavir
inhibitors: ritonavir, ketoconazole
inducers: rifampin, St. John’s Wort
What are CYP2D6 substrates, inhibitors, and inducers?
substrates: fluoxetine, codeine
inhibitors: fluoxetine, quinidine
inducers: no clinical relevance
What are CYP2C9 substrates, inhibitors, and inducers?
substrates: S-warfarin, ibuprofen
inhibitors: fluconazole, amiodarone
inducers: rifampin, secobarbital
What is the primary organ involved in drug metabolism?
-Liver
What are some differences between Phase I and Phase II metabolism?
-Phase I involves biotransformation (chemical modification; oxidation) which introduces new functional groups for Phase II reactions
-Phase II involves conjugation of a polar group with drug
When given a specific CYP450, name the family, subfamily, individual gene, and allelic variant component
CYP(2-family)(D-subfamily)(6-Individual gene) *1A(allele)
What are the differences between the mechanism of reversible and irreversible CYP450 inhibition?
-reversible CYP450 inhibition compete with substrates for occupancy of active site of same CYP enzyme
-irreversible CYP450 inhibition is mechanism-based (suicide inhibition); most potent and longest-acting type of inhibitor
Why does an enzyme inducer increase the metabolism of drugs metabolized by different CYP450’s?
-the drugs bind to/induce transcription factor proteins which induce transcription of CYP genes which in turn increases CYP450’s which increases overall metabolism
-lots of cross-talk
What are the Phase II metabolic processes?
UGT (glucuronidation) involved in conjugation of many functional groups
SULT (sulfotransferases) for steroid hormones, catecholamine neurotransmitters, phenolic drugs
NAT (N-acetyltranferases)
Why is genetic variation not the most important factor in determining variation in drug concentration and clinical response?
-there is a huge source of variation in responses because there are so many factors that affect metabolism and differences in each person in all these factors
