Pharmacokinetics Flashcards

0
Q

pharmacodynamics

A

what the DRUG does to the body

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1
Q

Pharmacokinetics

A

what the BODY does to the drug

absorption, metabolism, excretion, etc.

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2
Q

parenteral administration

A

intravenous, subcutaneous, or intramuscular administration of a drug

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3
Q

Questions to ask when anticipating drug interactions

A
  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?)
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4
Q

major types of active renal transporters (for drugs)

A

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

  • Organic cat/anion transporters
  • p-glycoprotein transporters
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5
Q

Major and minor sites of drug excretion

A

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)

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6
Q

toxicity occurs when…

A
  • failure of endogenous mechanisms to prevent toxicity
  • exposure to overwhelming dose of toxin
  • exposure to a novel toxin (no pre-existing elim/detox mech)
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7
Q

types of toxicity

A
  1. reversible binding
  2. covalent binding
  3. heavy metals
  4. mixtures
  5. drug allergies
  6. idiosyncracies
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8
Q

reversible binding toxicity

A

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)

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9
Q

Types of receptor-mediated toxicity of medications

A
  1. exaggeration of therapeutic effects (dose-related)

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

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10
Q

arsenic toxicity

A

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)

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11
Q

Lead exposure

A

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)

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12
Q

Bioavailability

A

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

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13
Q

1st pass metabolism

A

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*

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14
Q

types of active transporters for 1st pass metabolism

A
  1. ABC (ATP Binding Cassette) transporters

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

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15
Q

general function/characteristics of active transporters

A

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)

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16
Q

subsequent metabolism

A

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

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17
Q

clearance

A

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

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18
Q

zero order metabolism

A

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
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19
Q

first order metabolism

A

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

20
Q

2 compartment model

A

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

21
Q

factors for duration of action (of drug)

A
  1. elimination rate
  2. distribution rate (esp. for anesthetics)
    * drug effect ~= [ ]tissue ~= [ ] plasma *
22
Q

pros/cons of oral administration of drugs

A

+: convenient, inexpensive

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

23
Q

pros/cons of IV drug administration

A

+: 100% bioavailability, precise dose control

  • : expensive, unpleasant to patient
  • esp. used in emergencies
24
pros/cons of Subcutaneous and intramuscular drug administration
+: fast onset, good bioavailability | * used for drugs which are UNstable in GI tract*
25
benefits of dermal drug administration
+: sustained release --> lower/fewer peaks, longer duration
26
benefits of sublingual drug administration
+: rapid absorption, no GI exposure/skips first pass. | ie: nitroglycerine used for angina
27
benefits of intranasal drug administration
+: rapid onset (bc highly vascular mucosa), may travel to brain via olfactory neurons * can be used for stem cells...(?)
28
general mechs for detoxification of xenobiotics
(xenobiotic = exogenous compound) 1. convert to less active form 2. convert to mor easily excreted form
29
sites of drug metabolism
major: Liver, GI tract minor: kidney, lungs, brain, skin
30
phase I metabolism
modification of the functional group(s) of the compound
31
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)
32
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
33
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)
34
competitive drug-drug interactions
when two drugs metabolized by P450 inhibit each other's metabolism (through P450 activity)
35
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)
36
influence of liver diseases on drug metabolism
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.
37
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.
38
compounds that induce P450 synthesis
drugs: Rifampin, phenobarbitol, carbemazepine, St. John's wort foods/environment: Dioxin, charred meat, EtOH, tobacco smoke
39
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*
40
CYP2D6 polymorphism
genetic variation causing slow metabolism of drugs, in 5% of caucasians, --> get NO relief from codeine [ codeine --(CYP2D6)--> morphine ]
41
plasma cholinesterase polymorphism
very rare, but 0.01% of US population are deficient in plasma cholinesterase --> prolonged paralysis after neuromuscular blockade w/ succinylcholine
42
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! **
43
types of metabolic activation
1. inactive --> active 2. active --> active 3. active --> toxic (ie: acetaminophen, esp. w/ overdose)
44
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).
45
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
46
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 *
47
steps of drug "processing" in body
"ADME" (acronym) 1. absorption (#1 factor) 2. distribution (#3 factor) 3. metabolism (#2 factor) 4. excretion (#4 factor)
48
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