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Pharmacy Year 3 > Drug Disposition > Flashcards

Drug Disposition Flashcards

1
Q

How does Coeliac Disease affect drug absorption and first-pass?

A

Reduced intestinal CYP3A expression

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2
Q

How does Liver Cirrhosis affect drug absorption and first-pass?

A

Reduced activity of a number of metabolic enzymes
Extent depends on severity of cirrhosis
GFR often impaired

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3
Q

How does CKD affect drug absorption and first-pass?

A

Increased gastric emptying time
Increased pH
Altered expression of some CYP450 enzymes

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4
Q

How do P-gp and CYP3A4 lower bioavailability?

A

Drug metabolised by CYP3A4 in enterocyte
Remaining drug and metabolite effluxed by P-gp
Drug then into enterocyte and undergoes further metabolism
Cycle reduces amount of drug entering bloodstream unchanged

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5
Q

When is absorption perfusion rate limited?

A

Small lipophilic molecules
Very small hydrophilic molecules
Membrane doesn’t provide barrier to drug

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6
Q

When is absorption permeability rate limited?

A

Large, polar, hydrophilic molecules
Ionised WA/WB
Membrane is barrier for absorption

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7
Q

Give an example of an irreversible inhibition food-drug interaction

A

Furanocoumarins (grapefruit juice) are irreversible inhibitors of intestinal CYP3A4
Prevents metabolism of statin, leading to increased plasma conc.

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8
Q

What factors affect the rate of drug distribution?

A 
Tissue perfusion
Permeability of tissue membranes
Physicochemical properties of the drug
Binding to plasma proteins
(Binding to acidic phospholipids in tissue membranes)
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9
Q

How does perfusion affect distribution equilibrium?

A

Equilibrium achieved fasted in more highly perfused tissues

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10
Q

What tissues are considered highly perfused?

A

Lungs
Kidneys
Liver
Brain

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11
Q

What tissues are considered poorly perfused?

A

Muscle
Skin
Adipose

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12
Q

At what level is the distribution barrier in muscles and the brain and why?

A

Brain - Capillary level, very small pores

Muscle - Cellular level, more porous capillaries

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13
Q

What affects drug distribution at equilibrium?

A

Binding to plasma proteins and tissue components

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14
Q

What is the volume of plasma in the body?

A

3L

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15
Q

What is the volume outside the plasma in the body? What does this include?

A

39L

Extracellular space + cellular space

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16
Q

Define the amount of the body as an equation

A

V.C

Vp.C + Vtw.Ct (amount in plasma + amount outside plasma

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17
Q

Define the fraction unbound in plasma and tissues (equation)

A 
fu = Cu/C
fu(t) = Cu(t)/C(t)
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18
Q

What determines the volume of distribution?

A

Relative balance of drug binding in plasma compared to tissues

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19
Q

What parameters result in high volume of distribution?

A

High fu or low fu(t)

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20
Q

What are the roles of hepatic uptake and efflux transporters?

A

Uptake - Active uptake of drugs into hepatocytes

Efflux - Excretion of drug into bile

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21
Q

What is the relevance of Cu=Cu(t)?

A

Distribution equilibrium reached, no active processes (passive diffusion)

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22
Q

Why may Cu be more than Cu(t)?

A

Metabolism in tissues

Efflux transporters

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23
Q

Why may Cu be less than Cu(t)?

A

Uptake transporters

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24
Q

What can cause different V values from measuring different reference fluids?

A

Drug binding to proteins or cell components

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25
Q

Why is V clinically relevant?

A

To find an appropriate loading dose for a drug

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26
Q

Define the fraction of drug in the body in plasma and outside plasma

A

In plasma, V(p)/V

Outside of plasma, 1-V(p)/V

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27
Q

Why is unbound concentration important?

A

Only unbound drug can diffuse into tissues for pharmacological effect or to be eliminated

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28
Q

What is the most common cause of DDIs?

A

Inhibition of metabolic enzymes in liver and intestine

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29
Q

Why is metabolism important?

A

Dominant elimination route

Prevents drug accumulation

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30
Q

Give two examples of pharmacologically active metabolites

A

Ezetimibe Glucuronide

Morphine-6-Glucuronide

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31
Q

Give to examples of inhibiting metabolites

A

Gemfibrozil glucuronide

Itraconazole metabolites

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32
Q

What is the role of the liver in drug metabolism/elimination?

A

Most important metabolising organ due to size, blood flow and high enzyme concentrations
First-pass metabolism

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33
Q

What are classed as phase 1 reactions?

A

Oxidation
Reduction
Hydrolysis

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34
Q

What is classes as a phase 2 reaction?

A

Conjugation

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35
Q

Which family of enzymes catalyses oxidation reactions?

A

Cytochrome P450s

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36
Q

What is the purpose of phase 1 reactions?

A

Introduce or expose functional groups

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37
Q

What happens in oxidation of C atoms?

A

Hydroxylation of aromatic or aliphatic carbons

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38
Q

What happens in oxidation to N or S atoms?

A

Cleavage of alkyl group

Oxidation of N and S

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39
Q

What functional groups are susceptible to reduction?

A

Nitro and keto groups

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40
Q

What functional groups are susceptible to hydrolysis?

A

Ester and amide groups

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41
Q

Where can sequential oxidation occur?

A

On the same C or on a different C

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42
Q

Describe the properties of metabolites and how they are excreted

A

More polar and hydrophilic than the parent drug, really excreted

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43
Q

What are the routes of excretion?

A

Renal
Hepatic (biliary)
Pulmonary

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44
Q

What is clearance?

A

Relates rate of drug elimination to concentration (units L/hr)
Volume of plasma cleared of drug per unit of time

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45
Q

When is clearance independent of dose?

A

When drug pharmacokinetics are linear

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46
Q

What is the elimination half life?

A

The time taken for the plasma concentration to fall by half once the distribution equilibrium has been achieved

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47
Q

Why do clearance values vary between drugs?

A

Degree of extraction through elimination organ

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48
Q

What are the typical blood flow values?

A

Liver: 1300-1500ml/min
Kidney: 1100ml/min
Cardiac Output: 6000ml/min

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49
Q

What are the values for low, medium and high hepatic extraction ratio?

A

Low: <0.3
Medium: 0.3-0.7
High: >0.7

50
Q

What is additivity of clearance?

A

Rate of elimination is equal to the combined rates of excretion and hepatic metabolism

51
Q

What is hepatic clearance determined by?

A

Hepatic blood flow and hepatic extraction ratio

52
Q

What factors can influence hepatic clearance?

A 
Hepatic blood flow
Plasma protein binding
Enzyme activity
Disease status
Transporter activity
53
Q

When does blood flow have a significant effect on hepatic clearance?

A

Drugs with an extraction ratio >70%

54
Q

What are the structural requirements for biliary excretion?

A

Polar molecules

MW >350

55
Q

Describe the process of enterohepatic circulation

A

Small intestine to superior mesenteric vein to portal vein to liver
Excreted in bile duct and re enters small intestine

56
Q

How does enterohepatic circulation impact plasma-concentration profile?

A

Plasma concentration increases after dropping as drug is reabsorbed from bile in small intestine (peaks and troughs)

57
Q

What are the components of a CYP system?

A

Haemoproteins - Cytochrome P450, Cytochrome b5
Flavoproteins - FP1 (NADPH-cytochrome P450 reductase), FP2 (NADH-cytochrome b5 reductase)
Phospholipid membrane

58
Q

What are the two binding sites on CYPs?

A

Substrate binds to active site

O2 binds to haem ligand

59
Q

Give an example of a substrate metabolised by CYP2D6

60
Q

Give an example of a substrate metabolised by CYP2C9

A

Tolbutamide

61
Q

Give two examples of substrates metabolised by CYP3A4

A

Midazolam

Testosterone

62
Q

What is a common cause of DDIs?

A

2 or more drugs metabolised by the same CYP

63
Q

Describe the three types of CYP2D6 metabolisers and how drug regimens should be altered

A

Poor Metaboliser - Lacks gene, higher plasma conc, increased side effects. Reduce dose
Extensive Metaboliser - Normal activity. Normal dosing
Ultra-Rapid Metaboliser - Gene duplication, lower plasma concentrations, therapeutic failure. Consider increasing dose

64
Q

Give an example of a drug that is metabolised by CYP2D6 to produce a pharmacologically active metabolite

65
Q

What are the types of metabolic DDIs?

A

Induction - Increased synthesis or activity of metabolic enzymes
Reversible Inhibition - Enzyme-Inhibitor complex formed but enzyme activity recovered after removal of inhibitor
Irreversible Inhibition - Covalent binding to enzyme inactivates it, activity restored when new enzymes synthesised

66
Q

What are the classifications of drugs as CYP inhibitors?

A

Weak: 1.25-2-fold increase in AUC
Moderate: 2-5-fold increase in AUC
Strong: >5-fold increase in AUC

67
Q

Give an example of a reversible inhibition DDI

A

Ketoconazole inhibits CYP3A4
Terfenadine metabolism to fexofenadine inhibited
Terfenadine cardiotoxic at higher concentrations (QT prolongation, severe cardiac arrhythmia)

68
Q

How does Ritonavir act as a booster for HIV protease inhibitors?

A

Ritonavir is an irreversible inhibitor of CYP3A4, increasing plasma concentrations and effect of HIV protease inhibitors
HIV protease inhibitors can be given at a lower dose to avoid side effects

69
Q

Give an example of a drug that increase its own metabolism

What is this known as?

A

Carbamazepine

Autoinduction

70
Q

Which CYP enzymes are induced by Phenobarbital, Rifampicin, Phenytoin, Carbamazepine?

A

CYP3A4, 3A5, 2C9, 2B6

71
Q

What CYP enzyme is induced by cigarette smoke?

72
Q

Which non-CYP enzymes are induced by Rifampicin and Phenobarbital?

73
Q

Which non-CYP enzyme is induced by carbamazepine?

74
Q

Describe the mechanism of induction

A

Increased transcription of DNA to mRNA
Increased Translation of mRNA to enzymes
Decreased degradation of enzymes

75
Q

What are the roles of OATP1B1 and OAT1B3?

A

1B1 - Mediates uptake of therapeutic drugs in hepatocytes and endogenous compounds
1B3 - Substrate overlap, uptake of glutathione

76
Q

What is the clinical effect of inhibiting OATP transporters?

A

Increased plasma concentrations and risk of adverse effects

77
Q

Give some examples of OATP1B1 inhibition DDIs

A

Cyclosporin inhibits, increases plasma conc. of statins
Single dose of Rifampicin inhibits uptake of Glibenclamide
Lopinavir and Ritonavir inhibits uptake of Rosuvastatin

78
Q

Which P-gp DDIs are most relevant and why?

A

Digoxin as a substrate

Narrow therapeutic index

79
Q

Give some examples of transporter food-drug interactions

A

Turmeric inhibits BCRP, efflux of sulfasalazine is inhibited so increased effect/side effects
Apple juice inhibits OAT2B1, reduced plasma conc. of aliskiren and fexofenadine

80
Q

Give an example where changes in systemic exposure may not reflect an effect on tissue distribution

A

Metformin DDIs (OCT/MATE)

81
Q

What is the purpose of endogenous biomarkers?

A

Many are transporter substrates

Monitoring change in biomarker AUC to predict drug AUC change

82
Q

What is the purpose of PET imaging in DDIs? What are the ideal properties?

A

Investigate changes in tissue pharmacokinetics

Transporter specific, metabolically stable, amenable to radiolabelling

83
Q

Give two examples of inhibiting metabolites and what they inhibit

A

N-desmethyl diltiazem - Metabolic enzymes

Cyclosporine AM1 - Uptake transporters

84
Q

What are the mechanisms of renal drug excretion?

A

Filtration
Reabsorption
Active Secretion

85
Q

What is the average flow and pH of urine?

A

1-2ml/min

pH 4.5-7.6

86
Q

Define the rate of renal excretion (equation)

A

CLr.C plasma

rate of filtration + rate of secretion)x(1 - fraction reabsorbed

87
Q

What is glomerular filtration and how is renal clearance by filtration worked out?

A

Passive process filtering unbound drug in plasma water

CLr = fu.GFR

88
Q

What are the average GFR values for men and women?

A

120ml/min - Men

110ml/min - Women

89
Q

How is GFR determined?

A

Inulin or creatinine as fu=1 and they are not secreted or reabsorbed

90
Q

What is the purpose of active secretion?

A

Adds drug to tubular to facilitate excretion

Saturable process

91
Q

What is the mechanism of active secretion?

A

Active uptake via transporters, efflux transporters move drugs into tubule

92
Q

What is the DDI between Penicillin G and Probenecid?

A

Probenecid inhibits organic anion transporters in kidney tubule preventing active secretion of penicillin, results in higher plasma concentrations of penicillin

93
Q

When does reabsorption from the kidney tubule occur?

A

Unbound and non-ionised drug can be reabsorbed (needs to be lipophilic enough)

94
Q

When are weak acids susceptible to reabsorption?

A

pKa 3-7.5 as they will be mostly unionised over urine pH range

95
Q

When are weak bases susceptible to reabsorption?

A

pKa 6-12 as they will be mostly unionised over urine pH range

96
Q

When is renal clearance dependent on urine flow?

A

When reabsorption equilibrium has been reached - higher volume of urine increases renal clearance

97
Q

What is the purpose of forced diuresis?

A

Altered urine pH in drug overdose can be used to increase elimination
Only effective if renal excretion is significant

98
Q

How are the mechanisms of renal elimination identified?

A

CLr = fu.GFR, filtration
CLr > fu.GFR, secretion
CLr < fu.GFR, reabsorption

99
Q

What metabolising enzymes are present in the kidney tubule?

A

CYP3A5, 2D6, UGT1A9, 2B7, carboxylesterases

100
Q

When should dose adjustments be made in renal impairment?

A

fe is >50%
Narrow therapeutic window
Produces active metabolites
Metabolism is impaired

101
Q

Describe the properties of conjugates

A

Extremely polar
pKa <3
Terminal metabolites

102
Q

How are conjugates excreted?

A

Biliary excretion
Renal excretion

Via efflux transporters (MRP2/4)

103
Q

What are the phase 2 reactions for OH, COOH and NH2 functional groups?

A

OH - Glucuronidation or Sulphation
COOH - Glucuronidation or Glycine conjugation
NH2 - Glucuronidation or Acetylation

104
Q

Give two examples of direct conjugation and the enzymes involved

A

Midazolam -> Midazolam N-glucuronide (UGT1A4)

Naloxone -> Naloxone Glucuronide (UGT2B7)

105
Q

What are the enzymes and cofactors required for glucuronidation?

A

Enzyme - UDP-glucuronosyltransferases (UGT)

Cofactor - UDP glucuronic acid (UDPGA)

106
Q

Give an example of a toxic glucuronide

A

Acyl glucuronide of NSAIDs cause renal toxicity

107
Q

Give an example of a glucuronide DDI

A

Gemfibrozil glucuronide inhibits OATP1B1 and CYP2C8 - prevents metabolism of Cerivastatin

108
Q

What is Gilbert’s Syndrome?

A

Deficiency of UGT1A1, results in unconjugated hyperbilirubinaemia

109
Q

What are the enzymes and cofactors required for sulphation?

A

SULT1A1 enzyme

Cofactor - PAPS

110
Q

What is required for glycine conjugation?

A

Drug activated as acyl coenzyme A intermediate

Glutathione conjugation

111
Q

What is required for acetylation?

A

Coenzyme - Acetyl CoA
Amines - N-acetyl conjugates formed
N-acetyl transferase enzyme

112
Q

What are phase 3 reactions and what are their purpose?

A

Hydrolysis of biliary metabolites by glucuronidase or sulphatase in small intestine
Prolongs drug effect

113
Q

What are the types of non-inert metabolites?

A

Pharmacologically active metabolites (mainly phase 1 metabolites)
Reactive metabolites (N-OH metabolite in paracetamol overdose, ADRs)
Metabolites contributing to DDIs (inhibition of metabolic enzymes and transporters)

114
Q

What affects action of pharmacologically active metabolites?

A

Balance of formation rate and elimination rate (plasma concentration)
Receptor affinity

115
Q

Give an example of pharmacologically active metabolites

A

Diazepam Metabolites:
Nordiazepam is pharmacologically active
Temazepam and Oxazepam are rapidly metabolised although pharmacologically active, marketed as short-acting alternatives

116
Q

Give two examples of chemically-reactive metabolites

A 
Benzopyrene (polycyclic aromatic hydrocarbon in cigarette smoke) forms reactive metabolites in lung
Paracetamol metabolites (NAPQI) cause liver failure in cases of overdose
117
Q

How are reactive metabolites protected?

A

Conjugation to glutathione

N-acetyl cysteine

118
Q

What are type A ADRs?

A

Reversible, usually dose related
A1 - Effect linked to pharmacological action
A2 - Effect unrelated to drug action

119
Q

What are type B ADRs?

A

Often have a genetic basis, immune mediated toxicity
Metabolite binds to protein and is recognised as an antigen, creating an immune response
Commonly associated with liver

120
Q

What are type C ADRs?

A

Often lead to cell death and tissue necrosis - necrotic toxicity
Chemical reaction between drug/metabolite with tissue macromolecules
Commonly associated with liver

121
Q

What are type D ADRs?

A

Similar to type B and C but delayed response - chronic toxicity
Teratogenic
Mutagenic
Carcinogenic

122
Q

Give an example of a weakly acidic drug where the elimination is urine pH dependent

A

Sulphamethoxazole

Pharmacy Year 3 (15 decks)

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