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IC > Pharmacokinetics and Pharmacodynamics > Flashcards

Pharmacokinetics and Pharmacodynamics Flashcards

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
Q

Phase 2 metabolism

A

-conjugation, adding group

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26
Q

Phase 2 metabolism making drugs more water soluble

A

-glucuronidation, sulfate conj, glycine conj

27
Q

phase 2 metabolism making drugs more lipid soluble

A

-acetylation, methylation

28
Q

phase 2 metabolism detoxifying reactive chemicals and ROS

A

-glutathione conjugation

29
Q

Phase 0 and phase 3 disposition

A
  • transporters (influx and efflux)

- moves drugs and metabolites in and out of cells

30
Q

Kidney excretion

A
  • 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
Q

Liver excretion

A

secretion:
-MW >350, anions, cations, neutral cpds

enterohepatic circulation (recycling drug)

32
Q

First order kinetics

A
  • most drugs
  • everything is proportional to drug concentration
  • elimination, metabolism, everything is higher with higher concentrations
33
Q

Zero order kinetics

A
  • constant rate of elimination in drug concentration/time

- aspirin and phenytoin work at zero order at high therapeutic doses

34
Q

Clearance eq

A

Cl=Vd x Kel

35
Q

t1/2

A

=.693/Kel

36
Q

Css=

A

input/Cl
=(Fx(D/t))/Cl

t= interval between doses

37
Q

Xb

A

Xb=Vd x Cp

drug in body

38
Q

Loading dose=

A

LD= Cp x Vd/F

39
Q

Maintenance dose=

A

MD=Cp X Cl/F

Input=Clearance of drug

40
Q

How many 1/2 lives to reach steady state

A

4-5 1/2 lives

41
Q

receptor

A

molecule to which drug binds to to bring about response

42
Q

agonist

A

drug that activates its receptor upon binding

43
Q

graded dose- response curve

A

graph of increasing response of an individual to increasing dose

44
Q

quantal dose response curve

A

graph of fraction of a population that shows a specified response at progressively increasing doses

45
Q

pharmacological antagonist

A

drug that binds w/o activating its receptor and thus, prevents activation by agonist

46
Q

comp antagonist

A

pharma antagonist that can be overcome by increasing agonist concentration

47
Q

irreversible antagonist

A

pharm antagonist that cannot be overcome by inc agonist concentration

-lower maximal response- Emax decreases
-number of fxnal receptors is decereased
-

48
Q

partial agonist

A

drug that binds to its receptor but produces smaller effect at full dosage than a full agonist

49
Q

efficacy

A

% response

50
Q

potency of affinity

A

concentration

-low concentration, high affinity

51
Q

Kd (1/2 maximal binding) and EC50 not matching?

A

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
Q

Spare receptors + noncompetitive antagonist

A
  • 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
Q

Signal coupling mechanisms

A

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
Q

G proteins affect Gs by

A

Adenylyl cyclase system
Increase cAMP

-ACTH, thyrotropin, FSH, b-agonists (isoproterenol), dopamine D1 agonists, glucagon, PGE2, PGI2

55
Q

Ginhibitory

A

Inhibits adenylyl cyclase

-a2 agonists (clonidine), muscarinic M2 agonists, dopamine D2, D3, D4 agonists, serotonin agonists, opioid Mu agonists

56
Q

Gq

A 
-polyphosphoinositide signaling system
Affects phospholipase C
-inc DAG and IP3  both of which are 2nd messengers
DAG activates PKC
IP3 releases intracellular Ca
57
Q

Gq causing vasoconstriction

A

a1 adrenoreceptors (phenylephrine), vasopressin recceptors, Thrombonxane A2 (TXA2), angiotensin receptors, endothelin

58
Q

Gq causing vasorelaxation

A

muscarinic receptors (m1, M3- pilocarpine), histamine, bradykinin

59
Q

cytoplasmic guanylyl cyclase

A

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
Q

EDRF

A

substances that cause vasodilation via a nitric oxide dependent endothelial pathway (activating protein kinase g via cGMP)
-acetylcholine, histamine, bradykinin, VEGF

61
Q

ligand responsive transcription factors (nuclear receptors) examples

A
  • signal via gene expression

- glucocorticoids, mineralocorticoids, sex steroid hormones, vit D, thyroid hormone, retinoid acid

62
Q

adverse effects of drugs

A

-toxicities, hypersensitvities, idiosyncrasies (genetics), perceived responses (placebo)

63
Q

All or non (quantal response)

A

distributions (variance) of effect
and overlap of desired and undesired effect and the doses for those
-look at margin of safety

64
Q

AE of biologics

A

-proteins, which can cause hypersensitivities, innate immune reactions

IC (31 decks)

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