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Pharmacokinetics and Pharmacodynamics Flashcards

(64 cards)

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1
Q

Large molecules

A
  • recombinant engineering techniques
  • Parenteral administration with slow tissue distribution- multi-compartment kinetics
  • Variable 1/2 lifes
  • Mabs have long elimination half lives
  • Unique adv effects
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2
Q

Pharmacokinetics phases

A
  • Absorption
  • Distribution
  • Metabolism
  • Excretion
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3
Q

Bioavailability

A

How much of drug gets into circulation
-100% when IV
=AUCoral/AUCiv x 100
-AUC represents total amt of drug available over time

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4
Q

What must be equal for two drugs to be bioequivalent

A

Cmax, Tmax, AUC

-

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5
Q

Cholestyramine

A

resin that goes through GI tract and binds bile acids and other lipids
-Lowers bioavailability of other drugs (like digoxin)

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6
Q

Distribution

A 
Volume of distribution=amt of drug (IV)/C0
(C0- theoretical concentration) 
-Plasma= .045 L/kg
-ECW= .20 
-TBW= .6
-Tissue concentration= >.7 (high Vd)
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7
Q

What effects distribution?

A
  • Blood flow to organ, solubility of drug, level of binding to substances in blood vs to substances in tissues
  • transporters (active transport system that brings it into certain cell types)
  • ion trapping
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8
Q

CYP450

A

-CYP1, 2, 3 encode enzymes for most drug biotransformations

-

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9
Q

Main enzyme for metabolism

A

CYP3A4

Extensively expressed in GI cells and liver, and often responsible for poor oral bioavailability (first pass)

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10
Q

Enzyme induction

A
  • increase in enzyme activity due to activating nuclear receptors and upregulation of enzymes and drug transporters
  • major cause of drug drug interactions
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11
Q

CYP2C9 induced by

A

Phenobarbital, phenytoin, carbamazepine, rifampin

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12
Q

CYP2C19 induced by

A

barbiturates, carbamazepine, phenytoin, rifampin

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13
Q

CYP2E1 induced by

A
  • isoniazid, chronic alcohol

- imp for acetaminophen liver toxicity

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14
Q

CYP3A4 induced by

A

glucocorticoids, anticonvulsants (barbiturates, phenytoin, carbamazepine, primidone), rifampin, st. john’s wort

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15
Q

Polymorphism leads to decreased activity in which CYP enhances toxicity of warfarin when used in 60 yo chronic alcoholic man

A

CYP2C9

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16
Q

Key inducers of metabolism

A

Phenobarbital, primidone, phenytoin, carbamazepine, rifampin, polycyclic chemicals, glucocorticoids, chronic alcohol, st. john’s wort

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17
Q

Key inhibitors of metabolism

A

cimetidine, erythromycin, ketoconazole, chloramphenicol, disulfiram, acute alcohol, grapefruit juice
(slow down metabolism)

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18
Q

Deficiency of CYP2C9

A

increases biological effect of warfarin

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19
Q

Mutation of VKORC1

A

decreases biological effect of warfarin

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20
Q

Isoniazid ADR due to polymorphism

A

Causes hepatotoxicity and nuerotoxicity in N-acetyltransferase (NAT2) polymorphism

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21
Q

Mercaptopurine ADR

A

hematological toxicity when TPMT polymorphism (thiopurine s- methyltransferase)

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22
Q

Irinotecan ADR

A

Diarrhea or neutropenia when UDP-glucuronosyltransferase (UGT1A1) is polymorphic

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23
Q

Codeine ADR

A

-lack of analgesic effect because polymorphic CYP2D6 won’t be able to convert to active form morphine

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24
Q

Phase 1 metabolism

A
  • changes structure
  • CYP enzymes
  • oxidation, reduction, hydrolysis
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25
Phase 2 metabolism
-conjugation, adding group
26
Phase 2 metabolism making drugs more water soluble
-glucuronidation, sulfate conj, glycine conj
27
phase 2 metabolism making drugs more lipid soluble
-acetylation, methylation
28
phase 2 metabolism detoxifying reactive chemicals and ROS
-glutathione conjugation
29
Phase 0 and phase 3 disposition
- transporters (influx and efflux) | - moves drugs and metabolites in and out of cells
30
Kidney excretion
- Filtration (small MW drugs bound to albumin cannot be filtered) - Secretion (anions- blocked by probenecid, cationics- blocked by n-methyl nicotinamide) - Reabsorption- diffuse across lipid membranes IF uncharged (trap acidic cpds in basic urine)
31
Liver excretion
secretion: -MW >350, anions, cations, neutral cpds enterohepatic circulation (recycling drug)
32
First order kinetics
- most drugs - everything is proportional to drug concentration - elimination, metabolism, everything is higher with higher concentrations
33
Zero order kinetics
- constant rate of elimination in drug concentration/time | - aspirin and phenytoin work at zero order at high therapeutic doses
34
Clearance eq
Cl=Vd x Kel
35
t1/2
=.693/Kel
36
Css=
input/Cl =(Fx(D/t))/Cl t= interval between doses
37
Xb
Xb=Vd x Cp | drug in body
38
Loading dose=
LD= Cp x Vd/F
39
Maintenance dose=
MD=Cp X Cl/F Input=Clearance of drug
40
How many 1/2 lives to reach steady state
4-5 1/2 lives
41
receptor
molecule to which drug binds to to bring about response
42
agonist
drug that activates its receptor upon binding
43
graded dose- response curve
graph of increasing response of an individual to increasing dose
44
quantal dose response curve
graph of fraction of a population that shows a specified response at progressively increasing doses
45
pharmacological antagonist
drug that binds w/o activating its receptor and thus, prevents activation by agonist
46
comp antagonist
pharma antagonist that can be overcome by increasing agonist concentration
47
irreversible antagonist
pharm antagonist that cannot be overcome by inc agonist concentration -lower maximal response- Emax decreases -number of fxnal receptors is decereased -
48
partial agonist
drug that binds to its receptor but produces smaller effect at full dosage than a full agonist
49
efficacy
% response
50
potency of affinity
concentration | -low concentration, high affinity
51
Kd (1/2 maximal binding) and EC50 not matching?
Due to spare receptors - Effects occur at lower concentrations of ligand because intracellular processes are response limiting (not drug receptor binding) - Max effect is when intracellular process is saturated, not receptor - EC50>Kd and EC100 is lower than drug concentration for receptor saturation
52
Spare receptors + noncompetitive antagonist
- Noncompetitive antagonist will decrease # of fxnal receptors - Decrease number of spare receptors-- EC50 and Kd move closer, and the curve is shifted to the right - After more receptors are occupied by noncomp antagonist, curve will show typical downward shift
53
Signal coupling mechanisms
Steroids- take hours to translocate to nucleus, activate transcription, etc. Insulin, growth factors (Via tyrosine kinase)- min Cytokines, growth factors (via tyrosine kinase)- min Ion gated channels- msec G protein coupled (a, b adrenergic, muscarinic)- secs
54
G proteins affect Gs by
Adenylyl cyclase system Increase cAMP -ACTH, thyrotropin, FSH, b-agonists (isoproterenol), dopamine D1 agonists, glucagon, PGE2, PGI2
55
Ginhibitory
Inhibits adenylyl cyclase | -a2 agonists (clonidine), muscarinic M2 agonists, dopamine D2, D3, D4 agonists, serotonin agonists, opioid Mu agonists
56
Gq
``` -polyphosphoinositide signaling system Affects phospholipase C -inc DAG and IP3 both of which are 2nd messengers DAG activates PKC IP3 releases intracellular Ca ```
57
Gq causing vasoconstriction
a1 adrenoreceptors (phenylephrine), vasopressin recceptors, Thrombonxane A2 (TXA2), angiotensin receptors, endothelin
58
Gq causing vasorelaxation
muscarinic receptors (m1, M3- pilocarpine), histamine, bradykinin
59
cytoplasmic guanylyl cyclase
Arginine and NOS makes NO and reacts with metals, superoxide, or activation of guanylyl cyclase, which produce cGMP which activates protein kinase G-- > vasorelaxation
60
EDRF
substances that cause vasodilation via a nitric oxide dependent endothelial pathway (activating protein kinase g via cGMP) -acetylcholine, histamine, bradykinin, VEGF
61
ligand responsive transcription factors (nuclear receptors) examples
- signal via gene expression | - glucocorticoids, mineralocorticoids, sex steroid hormones, vit D, thyroid hormone, retinoid acid
62
adverse effects of drugs
-toxicities, hypersensitvities, idiosyncrasies (genetics), perceived responses (placebo)
63
All or non (quantal response)
distributions (variance) of effect and overlap of desired and undesired effect and the doses for those -look at margin of safety
64
AE of biologics
-proteins, which can cause hypersensitivities, innate immune reactions

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