Pharmacokinetics Flashcards
(135 cards)
1
Q
Drug effects, whether therapeutic or toxic, are directly correlated to what ?
A
Plasma concentration
2
Q
What processes are pharmacokinetics concerned with?
A
Absorption, distribution, elimination (metabolism and excretion)
3
Q
LD
A
Loading dose
4
Q
MD
A
Maintenance dose
5
Q
What determines the bioavailability of a drug?
A
Route of administration
6
Q
What determines the speed of onset of a clinical effect due to a drug?
A
Route of administration
7
Q
What does bioavailability describe?
A
Extent of absorption of drug from non-IV site of administration
8
Q
What is bioavailability?
A
The fraction of unchanged drug reaching the systemic circulation
9
Q
Bioavailability (F)= ?
A
F=AUC (non IV)/AUC(IV)
10
Q
What does volume of distribution describe?
A
Extent of movement of drug throughout body
11
Q
Volume of distribution (Vd)=?
A
Vd=Dose/Plasma concentration
12
Q
What factors influence a drugs ability to cross a lipid membrane?
A
Molecular size, lipid solubility, ionization, concentration gradient
13
Q
Regarding oral administration of drugs, what factors influence the drugs bioavailability?
A
GI environment, ability to cross GI membranes, first pass metabolism
14
Q
How can the rate of absorption for a drug (po) be increased?
A
Liquid preparations, rapidly disintegrating tables
15
Q
How can the rate of absorption for a drug (po) be decreased?
A
Enteric coating, sustained release preparations
16
Q
What is the major equivalency test required by the FDA for generics?
A
Bioequivalency
17
Q
What parameters must be met for a generic drug to be considered bioequivalent to a brand name drug?
A
Rate of absorption, extent of absorption
18
Q
What determines if a drug product is a therapeutic equivalent?
A
If it is bioequivalent
19
Q
Describe the amphipathic properties of a drug formulation that influence its absorption.
A
Formulation must have hydrophilicity to dissolve, drug must be lipophilic to cross membranes
20
Q
Regarding inhalation, what type of formulation results in systemic drug effects/local drug effects?
A
Systemic= volatile gases, Local = aerosolized particles
21
Q
What impact does food have on drug absorption?
A
Slows absorption by delaying gastric emptying
22
Q
What are advantages of controlled release oral drug preparations?
A
Decrease number of daily doses, maintain drug effects overnight, eliminate toxic peaks or subtherapeutic troughs
23
Q
What is the most direct route of drug administration?
A
IV
24
Q
What is the most hazardous route of drug administration? Why?
A
IV, it is easy to reach toxic levels quickly and difficult to reverse effect
25
Why is there an increased risk for infection when administrating a drug via the IV route?
Absorption barriers are bypassed
26
What determines of aersolized drug particles will have an effect?
Particle size, cannot be too large (side effects) or too small (exhaled w/ no effect)
27
IM drug administration may be rapidly absorbed or slowly absorbed. What determines this?
Aqueous solutions are absorbed fast. Depot forms exhibit sustained absorption.
28
What is a common characteristic of subcutaenous and transdermal drug absorption?
Slower, sustained drug release
29
What are characteristics of the dermal route of drug administration regarding location of action and systemic circulation?
Act locally, minimal systemic absorption
30
Order the routes of administration from greatest bioavailability to smallest bioavailability.
IV=inhalation>IM>sc>po
31
What routes of administration exhibit the most rapid onset of drug effects?
IV, inhalation
32
What routes of administration exhibit intermediate onset of drug effects?
Sublingual, IM, sc
33
What routes of administration exhibit slow onset of drug effects?
Oral
34
What routes of administration exhibit the slowest onset of drug effects?
Transdermal, oral (enteric coated / sustained release), IM and sc (depot forms)
35
What determines the duration of drug action?
Route of administration and drug formulation
36
What does a small volume of distribution mean?
More of a drug remains in the plasma
37
A drug with a Vd of 3-5L is distributed in what body compartment(s)?
Plasma
38
A drug with a Vd of 12-15L is distributed in what body compartment(s)?
ECF
39
A drug with a Vd of 42L is distributed in what body compartment(s)?
Total body water
40
A drug with a Vd of >50L is distributed in what body compartment(s)?
Other compartments
41
What factors influence drug distribution?
Anatomy (tight junctions), pH, drug-plasma protein binding, lipid solubility
42
Is a drug bound to a plasma protein diffusible?
No
43
What tissues have tight junctions, what is the implication for drug absorption?
GI mucosa, BBB, placenta, renal tubules. Requires drugs to pass through membranes.
44
Regarding, ionized and non-ionized species, which species is more readily absorbed?
Nonionized (protonated acid and nonprotonated base)
45
When pH
Protonated
46
When pH>pKa what drug form predominates?
Deprotonated
47
Regarding a 2 compartment system with different pH in each compartment, the total concentration of a drug is greater on what side?
Where ionization is greater (ion trapping)
48
Describe the concentration of non-ionized drug at equilibrium in a 2 compartment system.
Concentration is the same
49
What types of drugs have a greater potential to concentrate in breast milk? Why?
Basic drugs, breast milk is acidic
50
What effect does drug-protein binding in plasma have on drug metabolism?
Hinders degradation and reduces excretion
51
What effect does drug-protein binding in plasma have on Vd?
Decreases Vd
52
What effect does drug-protein binding in plasma have on a drugs ability to enter the CNS?
Decreases its ability
53
What effect does drug-protein binding in plasma have on drug action?
Can prolong drug action (reservoir for drug)
54
Administration of a drug may displace a previously administered drug from a drug-protein interaction. This is unlikely to be of clinical consequence, but when might it be?
Displaced drug has narrow therapeutic index, high doses of 2nd drug, Vd of displaced drug is small, response to drug occurs more rapidly than redistribution
55
What cancer drug do salicylates displace?
Methotrexate
56
What do acidic drugs bind in plasma?
Albumin
57
What do basic drugs bind in plasma?
α-1 acid glycoprotein
58
What is the general mechanism of drug metabolism?
Lipid soluble compounds are converted to more water soluble (polar) compounds to be excreted
59
What is the primary organ of drug metabolism?
Liver
60
Besides the liver, what other organs are involved in drug metabolism?
Lung, kidney, intestine, placenta, skin
61
What is the most common outcome of drug metabolism?
Inactivation/detoxification of compound
62
What are 3, less common (than inactivation/detoxification), outcomes of drug metabolism?
Inactive drug > active drug, active drug > more active compound, drug > toxin
63
What are the reaction types of Phase 1 metabolism?
Oxidation, hydrolysis, reductions
64
What enzymes are typical of Phase 1 metabolism?
CYP450, esterases-amidases, reductases
65
What does the Amplichip CYP450 test detect?
Polymorphisms in CYP2D6 and CYP2C19 (account for 25% of drug metabolism)
66
Is Phase 1 or Phase 2 metabolism more easily induced/inhibited?
Phase 1
67
Does Phase 1 or Phase 2 metabolism decrease more substantially with age?
Phase 1
68
Is Phase 1 or Phase 2 metabolism more saturable?
Phase 2
69
What is the general mechanism of Phase 1 biotransformation metabolism?
Inserts/unmasks functional group that renders the compound more water soluble.
70
Does a drug have to undergo Phase 1 metabolism to undergo Phase 2 metabolism?
No
71
What types of reactions are involved in Phase 2 metabolism?
Conjugations: glucuronidation, acetylation, glutathione / glycine / sulfate conjugation
72
What types of enzymes are involved in Phase 2 metabolism?
Transferases
73
What are the components of the CYP450 oxidation system?
CYP450, NADPH, P450 reductase, oxygen
74
What are the classification extremes of drug metabolizers?
Ultra rapid (UM) or poor metabolizers (PM)
75
What is the consequence to patients who are CYP2D6 PMs taking antipsychotic drugs?
Increased drug toxicity (inactivating enzyme)
76
What is the consequence to patients who are CYP2D6 PMs taking codeine?
Insufficient analgesia (activating enzyme)
77
What is the consequence to patients who are CYP2D6 UMs taking codeine?
Codeine intoxication (activating enzyme)
78
What is the consequence to patients who are CYP2D6 UMs taking antipsychotic drugs?
No response to antidepressants (inactivating enzyme)
79
What is the consequence to patients who are CYP2C19 PMs taking PPIs?
Decreased efficacy (activating enzyme)
80
What is the metabolizing enzyme that acts on warfarin?
CYP2C9 (inactivating)
81
What is the target enzyme of warfarin, what is its action?
Inhibits VKORC1
82
What is the consequence to patients who are CYP2C9 PMs taking warfarin?
Bleeding
83
What types of Phase 1 oxidations are CYP450 dependent?
Aromatic hydroxylations, aliphatic hydroxylations, oxidative dealkylation
84
What types of Phase 1 oxidations are CYP450 independent?
Amine oxidases, dehydrogenations
85
What are the types of Phase 1 reductions?
Azo, nitor, carbonly
86
What enzymes are involved in Phase 1 hydrolysis reactions?
Esterases, amidases
87
What type of Phase 1 metabolism enzyme is commonly used in design of pro drugs?
Esterases
88
What is the mechanism of action of esterases?
Hydrolyze esterases to corresponding alcohol and acid
89
What is the mechanism of action of amidases?
Hydrolyze amides to corresponding amine and acid
90
Where are esterases typically found?
Plasma, liver
91
Where are amidases typically found?
Liver, gut flora
92
Why are Phase 2 conjugations more easily saturable?
Limited supply of reactants
93
What process is glutathione-S-transferases extremely important in?
Detoxification of carcinogens, pollutants, toxic metabolites
94
What is the main mechanism of enzyme induction?
Increases synthesis of enzyme protein
95
How long does it take to see the onset effect of enzyme induction? Maximal effect?
2-3 days, max effect seen in 7-10 days
96
What mechanisms can lead to enzyme inhibition?
Inhibit enzyme synthesis, competitive inhibition, allosteric inhibitor, destroy enzyme
97
What is enterohepatic recirculation? What are the clinical consequences of this?
A drug is secreted by liver to bile > reabsorbed via GI tract. Reduces elimination of drug and prolongs half life
98
What are the possible clinical implications of induced drug metabolism?
Reduced therapeutic effect, increased toxicity (drug metabolite or activation of drug)
99
What is the implication of taking Rifampin while on an oral contraceptive?
Rifampin induces drug metabolism, this decreases the plasma concentration of OC, and can lead to unplanned pregnancy
100
How long does it take to see the onset effect of enzyme inhibition?
Hours
101
What is the effect of inhibiting an activating metabolic reaction?
Reduced therapeutic effect
102
What is the effect of inhibiting drug (A) by another drug (B)?
Decreased clearance of drug A, higher plasma concentration, increased toxicity
103
Regarding inhibition of drug metabolism, the time to effect on steady state plasma concentration depends on what?
Inhibited drugs half life
104
If a patient on Lipitor is given erythromycin, what is the effect on Lipitor clearance?
Lipitor clearance is decreased, its plasma concentration, increased risk of myopathy
105
What is the primary action of P-glycoproteins?
Move drugs out of the cell
106
P-glycoproteins located in the GI tract have what effect on drug absorption?
Decrease
107
P-glycoproteins located in the liver/kidney have what effect on drug excretion?
Enhance
108
P-glycoproteins located in the BBB have what effect on drug distribution?
Limit
109
P-glycoproteins are responsible for multidrug resistance in what type of cells?
Cancer
110
What is the most important organ for drug excretion?
Kidney
111
What are the sites of elimination in the kidney?
Glomerular filtration, active tubular secretion
112
What is the rate of drug clearance for glomerular filtration?
120 ml/min
113
What is the rate of drug clearance for active tubular secretion?
120-600 ml/min
114
Due to tubular reabsorption drugs that are lipid-soluble and uncharged are cleared at what rate?
1 ml/min
115
What is the effect of antibiotics on enterohepatic recycling?
Stops the cycle, bacteria do not produce the enzyme that converts the metabolized drug to its active form
116
Do many drugs cross into breast milk?
No
117
What is first order kinetics?
Rate of elimination (mg/hr) is proportional to the concentration of the drug in plasma (mg/L)
118
What is half life?
The time required to eliminate 1/2 of the drug in the plasma
119
How many half lives does it take for a drug to be eliminated?
4-5
120
How many half lives does it take to reach steady state when drugs are administered continuously?
4-5
121
ln(C2/C1)=?
-k*half life
122
Half life=?
0.693/k
123
What does k equal?
Rate of drug elimination
124
What is clearance?
Volume of plasma (Vd) completely cleared of drug in a given period of time
125
CL = ?
Vd*k or ([MD]/tau)/Cpss
126
For a low extraction drug, what effect will increased blood flow to liver have?
No significant influence
127
For a high extraction drug, what effect will increased blood flow to liver have?
Major influence
128
Aside from blood flow to liver,what other factors affect drug clearance?
Protein-drug binding, intrinsic hepatic metabolic activity
129
What is the time to reach steady state related to? What is the time to steady state independent of?
Drugs half life, drug dosage
130
If you increase the maintenance dose of a drug, will steady state be reached sooner?
No, Cpss will be higher when reached though
131
How can you obtain a desired state state plasma level sooner?
Give a loading dose, then follow with normal maintenance dose
132
Fold fluctuation in Cp = ?
2^n where n= number of half lives in dosing interview
133
What is the effect on fluctuation when half lives in a dosage interval are increased?
More fluctuated
134
What is zero order kinetics?
Amount of drug eliminated per unit time is constant
135
Regarding hepatic metabolism, what may cause a drug to be eliminated by zero order kinetics?
Saturation of hepatic metabolic processes
