Pharmacokinetics

Question 0

pharmacodynamics

Answer 0

what the DRUG does to the body

Question 1

Pharmacokinetics

Answer 1

what the BODY does to the drug

absorption, metabolism, excretion, etc.

Question 2

parenteral administration

Answer 2

intravenous, subcutaneous, or intramuscular administration of a drug

Question 3

Questions to ask when anticipating drug interactions

Answer 3

1. Wide therapeutic serum [ ] range?
   (then may not alter efficacy/toxicity)
2. Elimination primarily by metabolism or excretion?
   – What P450 subtype used? (is it the same for both drugs?)

Question 4

major types of active renal transporters (for drugs)

Answer 4

in distal tubule of nephron, transport specific molecs into renal lumen (–> excretion in urine).

• Organic cat/anion transporters
• p-glycoprotein transporters

Question 5

Major and minor sites of drug excretion

Answer 5

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)

Question 6

toxicity occurs when…

Answer 6

• failure of endogenous mechanisms to prevent toxicity
• exposure to overwhelming dose of toxin
• exposure to a novel toxin (no pre-existing elim/detox mech)

Question 7

types of toxicity

Answer 7

1. reversible binding
2. covalent binding
3. heavy metals
4. mixtures
5. drug allergies
6. idiosyncracies

Question 8

reversible binding toxicity

Answer 8

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)

Question 9

Types of receptor-mediated toxicity of medications

Answer 9

1. exaggeration of therapeutic effects (dose-related)

2. toxicity unrelated to therapeutic effect (bind to unintended R)

Question 10

arsenic toxicity

Answer 10

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)

Question 11

Lead exposure

Answer 11

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)

Question 12

Bioavailability

Answer 12

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

Question 13

1st pass metabolism

Answer 13

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*

Question 14

types of active transporters for 1st pass metabolism

Answer 14

1. ABC (ATP Binding Cassette) transporters

2. SLC (Solute Carrier) transporters –> for organic ions

Question 15

general function/characteristics of active transporters

Answer 15

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)

Question 16

subsequent metabolism

Answer 16

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

Question 17

clearance

Answer 17

rate of removal (of a drug) for a given system

Question 18

zero order metabolism

Answer 18

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

Question 19

first order metabolism

Answer 19

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

Question 20

2 compartment model

Answer 20

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

Question 21

factors for duration of action (of drug)

Answer 21

1. elimination rate
2. distribution rate (esp. for anesthetics)
   * drug effect ~= [ ]tissue ~= [ ] plasma *

Question 22

pros/cons of oral administration of drugs

Answer 22

+: convenient, inexpensive

-: delayed absorption –> slow effect, wide bioavailability range

Question 23

pros/cons of IV drug administration

Answer 23

+: 100% bioavailability, precise dose control

• : expensive, unpleasant to patient
• esp. used in emergencies

Question 24

pros/cons of Subcutaneous and intramuscular drug administration

Answer 24

+: fast onset, good bioavailability

* used for drugs which are UNstable in GI tract*

Question 25

benefits of dermal drug administration

Answer 25

+: sustained release –> lower/fewer peaks, longer duration

Question 26

benefits of sublingual drug administration

Answer 26

+: rapid absorption, no GI exposure/skips first pass.

ie: nitroglycerine used for angina

Question 27

benefits of intranasal drug administration

Answer 27

+: rapid onset (bc highly vascular mucosa), may travel to brain via olfactory neurons
* can be used for stem cells…(?)

Question 28

general mechs for detoxification of xenobiotics

Answer 28

(xenobiotic = exogenous compound)

1. convert to less active form
2. convert to mor easily excreted form

Question 29

sites of drug metabolism

Answer 29

major: Liver, GI tract
minor: kidney, lungs, brain, skin

Question 30

phase I metabolism

Answer 30

modification of the functional group(s) of the compound

Question 31

phase II metabolism

Answer 31

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)

Question 32

Cytochrome P450

Answer 32

(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

Question 33

Types of drug-drug interactions

Answer 33

• -> involve CYP450, can alter drug absorption (1st pass metabolism) or excretion
  1. Competitive (inhibit each other’s metabolism)
  2. non-competitive (reduce P450 activity)

Question 34

competitive drug-drug interactions

Answer 34

when two drugs metabolized by P450 inhibit each other’s metabolism
(through P450 activity)

Question 35

non-competitive drug-drug interactions

Answer 35

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)

Question 36

influence of liver diseases on drug metabolism

Answer 36

1. hepatocellular liver disease (ie: portal HTN, coagulopathy, hepatic encephalopathy): reduces amt of P450
   - -> reduced drug clearance
2. cirrhosis: shunts blood around the liver, so reduces delivery of drug to hepatocytes
   - -> reduced drug clearance.

Question 37

CYP450 induction

Answer 37

Amount/activity of P450 = increased by drugs that induce it’s synthesis or decrease it’s degradation
–> by binding to nuclear response element.

Question 38

compounds that induce P450 synthesis

Answer 38

drugs: Rifampin, phenobarbitol, carbemazepine, St. John’s wort
foods/environment: Dioxin, charred meat, EtOH, tobacco smoke

Question 39

Fast/slow metabolizers

Answer 39

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*

Question 40

CYP2D6 polymorphism

Answer 40

genetic variation causing slow metabolism of drugs,
in 5% of caucasians,
–> get NO relief from codeine
[ codeine –(CYP2D6)–> morphine ]

Question 41

plasma cholinesterase polymorphism

Answer 41

very rare, but 0.01% of US population are deficient in plasma cholinesterase
–> prolonged paralysis after neuromuscular blockade w/ succinylcholine

Question 42

aldehyde dehydrogenase polymorphism

Answer 42

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! **

Question 43

types of metabolic activation

Answer 43

1. inactive –> active
2. active –> active
3. active –> toxic (ie: acetaminophen, esp. w/ overdose)

Question 44

liposomal formulations

Answer 44

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).

Question 45

active renal transport of drugs

Answer 45

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

Question 46

effect of renal insufficiency on drug excretion

Answer 46

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 *

Question 47

steps of drug “processing” in body

Answer 47

“ADME” (acronym)

1. absorption (#1 factor)
2. distribution (#3 factor)
3. metabolism (#2 factor)
4. excretion (#4 factor)

Question 48

on time (x) vs drug concentration (y) graph, AUC = __?

Answer 48

AUC (“Area Under Curve”) = total exposure to the drug

• curve also has:
• peak concentration
• minimum concentration