Pharmacokinetics Flashcards
pharmacodynamics
what the DRUG does to the body
Pharmacokinetics
what the BODY does to the drug
absorption, metabolism, excretion, etc.
parenteral administration
intravenous, subcutaneous, or intramuscular administration of a drug
Questions to ask when anticipating drug interactions
- Wide therapeutic serum [ ] range?
(then may not alter efficacy/toxicity) - Elimination primarily by metabolism or excretion?
– What P450 subtype used? (is it the same for both drugs?)
major types of active renal transporters (for drugs)
in distal tubule of nephron, transport specific molecs into renal lumen (–> excretion in urine).
- Organic cat/anion transporters
- p-glycoprotein transporters
Major and minor sites of drug excretion
Major: liver and kidney (most drugs, often combination)
Minor:
lungs (volatile gases and EtOH)
breast milk (rarely enough to affect nursing infant)
hair (not enough to detect cmpds on individual basis)
toxicity occurs when…
- failure of endogenous mechanisms to prevent toxicity
- exposure to overwhelming dose of toxin
- exposure to a novel toxin (no pre-existing elim/detox mech)
types of toxicity
- reversible binding
- covalent binding
- heavy metals
- mixtures
- drug allergies
- idiosyncracies
reversible binding toxicity
when an agonist binds to a receptor, but binding can be undone to end response symptoms.
* the antidote = antagonist for the same receptor
ie:
opiates (antidote: naloxone)
benzodiazepines (antidote: flumazenil), CO (antidote: 2.5 atm O2)
Types of receptor-mediated toxicity of medications
- exaggeration of therapeutic effects (dose-related)
2. toxicity unrelated to therapeutic effect (bind to unintended R)
arsenic toxicity
sources: #1 ground water, industrial, rice
effects: periph. neuropathy, anemia, arrhythmia, GI Sx, keratosis
- chronic: cancer (of lung, skin)
treatment: chelating agents
(limited success, best for acute exposure)
Lead exposure
sources: air, drinking water, soil, glazed dishes, etc.
effects: cognitive impairment in kids, chronic Dx in adults (DM, etc.)
treatment: chelating agents (for dangerous/acute levels)
Bioavailability
the fraction of drug absorbed by body (from administration to circulation)
* highest = IV, lowest = oral (but wide range)
usually depends on rate of 1st pass metabolism
1st pass metabolism
absorption of drugs (usually from oral administration) through gut wall and liver into circulation, via transporters;
usually ).
* stomach controls rate of absorption (regulates timing into intestines), amt absorption depends on small intestine*
types of active transporters for 1st pass metabolism
- ABC (ATP Binding Cassette) transporters
2. SLC (Solute Carrier) transporters –> for organic ions
general function/characteristics of active transporters
broad specificity, can inhibit other molecs at same transporter;
F(x): 1) protect against xenobiotics
2) shuffle/remove endogenous toxins
a) increase elimination (esp. intestine, kidney, liver)
b) decrease serum levels (esp. brain, placenta, testis, stem cells, cancer cells)
subsequent metabolism
amount of drug removed from body,
= rate of elimination from body (aka: clearance) x [ ]plasma.
* removal time-course patterns:
- zero order metabolism - first order metabolism
clearance
rate of removal (of a drug) for a given system
zero order metabolism
pattern of elimination, = fixed amount drug elimination/unit time.
- usually high drug affinity, high dose &/or high [ ]plasma
- metabolic capacity = rate-limiting step
- do NOT calculate half-life
first order metabolism
pattern of elimination for most drugs,
= constant fraction of drug removed/unit time.
* describe trend w/ elimination half-life
* high clearance –> low elimination half-life
2 compartment model
model of distribution (of drug from circulation to tissues),
where distribution rate = to ALL tissues.
= simplistic model, bc not constant (gets slower near equilibrium)
* limited by the Blood-Brain Barrier
factors for duration of action (of drug)
- elimination rate
- distribution rate (esp. for anesthetics)
* drug effect ~= [ ]tissue ~= [ ] plasma *
pros/cons of oral administration of drugs
+: convenient, inexpensive
-: delayed absorption –> slow effect, wide bioavailability range
pros/cons of IV drug administration
+: 100% bioavailability, precise dose control
- : expensive, unpleasant to patient
- esp. used in emergencies
pros/cons of Subcutaneous and intramuscular drug administration
+: fast onset, good bioavailability
* used for drugs which are UNstable in GI tract*
benefits of dermal drug administration
+: sustained release –> lower/fewer peaks, longer duration
benefits of sublingual drug administration
+: rapid absorption, no GI exposure/skips first pass.
ie: nitroglycerine used for angina
benefits of intranasal drug administration
+: rapid onset (bc highly vascular mucosa), may travel to brain via olfactory neurons
* can be used for stem cells…(?)
general mechs for detoxification of xenobiotics
(xenobiotic = exogenous compound)
- convert to less active form
- convert to mor easily excreted form
sites of drug metabolism
major: Liver, GI tract
minor: kidney, lungs, brain, skin
phase I metabolism
modification of the functional group(s) of the compound
phase II metabolism
aka: conjugation;
- -> addition of molecule(s) to increase the polarity of the compound, therefore facilitate excretion.
* esp. useful for detox. (for xenobiotics and endogenous toxins)
Cytochrome P450
(aka: CYP450), w/ many subtypes.
a mixed function oxidase that serves as the microsomal oxidation system in all life forms.
- located in sER, mostly in liver
- most responsible for drug metabolism
–> induction/inhibition of P450 alters drug metabolism
Types of drug-drug interactions
- -> involve CYP450, can alter drug absorption (1st pass metabolism) or excretion
1. Competitive (inhibit each other’s metabolism)
2. non-competitive (reduce P450 activity)
competitive drug-drug interactions
when two drugs metabolized by P450 inhibit each other’s metabolism
(through P450 activity)
non-competitive drug-drug interactions
when metabolism of a drug is reduced because other non-substrate drugs bind to P450 and reduce it’s activity
(only metabolism of 1 drug is affected, all else = normal)
influence of liver diseases on drug metabolism
- hepatocellular liver disease (ie: portal HTN, coagulopathy, hepatic encephalopathy): reduces amt of P450
- -> reduced drug clearance - cirrhosis: shunts blood around the liver, so reduces delivery of drug to hepatocytes
- -> reduced drug clearance.
CYP450 induction
Amount/activity of P450 = increased by drugs that induce it’s synthesis or decrease it’s degradation
–> by binding to nuclear response element.
compounds that induce P450 synthesis
drugs: Rifampin, phenobarbitol, carbemazepine, St. John’s wort
foods/environment: Dioxin, charred meat, EtOH, tobacco smoke
Fast/slow metabolizers
variations in patients of drug metabolism rates,
due to genetic variants which drug metabolizing isoenzymes with more or less activity than typical.
* may require different dosing*
CYP2D6 polymorphism
genetic variation causing slow metabolism of drugs,
in 5% of caucasians,
–> get NO relief from codeine
[ codeine –(CYP2D6)–> morphine ]
plasma cholinesterase polymorphism
very rare, but 0.01% of US population are deficient in plasma cholinesterase
–> prolonged paralysis after neuromuscular blockade w/ succinylcholine
aldehyde dehydrogenase polymorphism
in many ppl of asian descent,
reduced aldehyde dehydrogenase activity
–> unpleasant effects after drinking EtOH (nausea, vomiting, etc.)
** lower rate of alcoholism in this population! **
types of metabolic activation
- inactive –> active
- active –> active
- active –> toxic (ie: acetaminophen, esp. w/ overdose)
liposomal formulations
encapsulation of water-soluble drug or embedding of drug/targeting Ab in lipid membrane for parenteral administration,
–> reduce toxicity, prolong duration, and target specific tissues (for certain drugs).
active renal transport of drugs
active transporters (organic anion/cation, P-gp) used in kidney to excrete drugs.
- drugs may compete for excretion –> inhibit other’s excretion
ie: amoxicillin –> methotrexate toxicity
effect of renal insufficiency on drug excretion
drug excretion impaired if renal clearance = #1 route, and renal f(x) = impaired;
% reduction GFR ~= % reduction drug excretion
* use: Css = dose/CL to calculate appropriate dose *
steps of drug “processing” in body
“ADME” (acronym)
- absorption (#1 factor)
- distribution (#3 factor)
- metabolism (#2 factor)
- excretion (#4 factor)
on time (x) vs drug concentration (y) graph, AUC = __?
AUC (“Area Under Curve”) = total exposure to the drug
- curve also has:
- peak concentration
- minimum concentration
