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Pharm Y3S2 > Drug Disposition > Flashcards

Drug Disposition Flashcards

Galetin teaching

1
Q

Define pharmacokinetics.

A

How the body responds to drugs

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2
Q

Define pharmacodynamics.

A

The impacts the drug has on the body.

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3
Q

What is the main aim of metabolism?

A

To make the molecule more hydrophilic in preparation for elimination.

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4
Q

Define bioavailability.

A

A measure of the extent of absorption of unchanged administered compound.

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5
Q

What is distribution?

A

Reversible transfer of a substance between site of administration and site of measurement.

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6
Q

What is metabolism?

A

Irreversible loss of unchanged substance by chemical conversion.

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7
Q

What is elimination?

A

Irreversible loss of unchanged substance from site of measurement.

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8
Q

Name 6 factors that influence pharmacokinetics?

A 
Genetics
Age
Size of molecule
Disease state
Concomitant drugs
Environment
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9
Q

What are the names of two pharmacokinetic models?

A

Single equation, integrated

Kinetic compartmental

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10
Q

Define rate of change in an equation.

A

Rate of change = rate of absorption - (rate of excretion + rate of metabolism)

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11
Q

What is the main reason that the effectiveness of a drug molecule will eventually plateau?

A

Receptor saturation

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12
Q

Name 6 physiological parameters affecting drug action.

A 
Tissue volume
Blood flow
Tissue composition
Intestinal pH
Gut transit time
Enzyme/transporter abundance
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13
Q

What is absolute bioavailability?

A

Bioavailability assessed with reference to an IV dose

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14
Q

What is relative bioavailability?

A

Comparison of different formulations of the same drug

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15
Q

Define bioequivalence.

A

Formulations containing the same dose intended to be interchangeable.

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16
Q

What impact does a fasted state have on delivery in the GIT?

A

Rapid delivery to the upper small intestine

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17
Q

What impact does a fed state have on delivery in the GIT?

A

Can delay gastric emptying by up to 10 hours

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18
Q

When should enteric coating be given? Why?

A

Given on a fasted stomach to ensure it reaches the small intestine as quickly as possible.

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19
Q

What impact does gastric bypass surgery have on absorption?

A

Reduces surface area of the stomach and bypasses approximately 75cm on the intestine, main area of drug absorption.

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20
Q

What impact does coeliac disease have on drug delivery?

A

Expression of intestinal CYP3A reduced to 15%.

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21
Q

What impact does chronic kidney disease have on drug delivery?

A

Increased gastric pH and emptying time

Can alter CYP450 expressio

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22
Q

What is transcellular movement?

A

Passive diffusion often via facilitated transport
Continues until equilibrium reached
Increased molecule size reduces permeability

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23
Q

What is paracellular movement?

A

Transport between epithelial cells mainly via passive diffusion
Important for polar, hydrophilic drugs

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24
Q

What is P-glycoprotein?

A

Efflux transporter found on the apical membrane of enterocytes and biliary canicular membrane of hepatocytes
Active efflux of drugs into intestinal lumen

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25
Q

What is first pass metabolism?

A

Metabolism of molecules before reaching systemic circulation. Can occur in the intestine, liver or kidney
F= FaFgFh

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26
Q

What are the pharmacokinetic parameters affecting IM/SC absorption?

A

Muscle capillary membrane is more porous than the gut, allowing paracellular absorption
Perfusion rate is limited by blood flow

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27
Q

What are the pharmacokinetic parameters affecting transdermal absorption?

A

Permeability rate is limited, even for lipophilic drugs

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28
Q

What are the pharmacokinetic parameters affecting pulmonary absorption?

A

Rapid access too systemic circulation due to surface area

Only 2-10% of aerosol actually deposits in the lungs

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29
Q

Name two drugs affecting absorption of paracetamol. Explain why.

A

Metoclopramide- increases gastric emptying therefore paracetamol reaches SI faster, increasing Cmax and reducing Tmax
Anticholinergics- reduce Cmax of paracetamol and increase Tmax however the AUC remains the same

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30
Q

When does perfusion limited distribution occur?

A

When the tissue/cell membrane does not represent a barrier to drug distribution

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31
Q

Give 4 examples of highly perfused tissues.

A

Brain
Lungs
Liver
Kidney

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32
Q

Which tissue do lipophilic drugs have particularly high affinity for?

A

Adipose

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33
Q

When is permeability limited distribution most likely to occur?

A

Polar molecules

Relatively impermeable membranes

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34
Q

What are the features of the blood brain barrier relevant for molecule distribution?

A

Very small pores

Barrier at capillary level

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35
Q

What are the features of the muscle/kidney cells relevant for molecule distribution?

A

Capillaries porous to small molecules

Barrier at cellular level

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36
Q

What are the 3 key water volumes within the body?

A

Plasma water 3L
Extracellular water 12L
Total body water 40L

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37
Q

At equilibrium what is the amount of drug in the body defined by?

A

A= V x C

Where V= volume of distribution and C= concentration

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38
Q

What do acidic drugs show strong affinity to? Give an example.

A

Plasma proteins

I.e. warfarin

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39
Q

What do basic drugs show strong affinity to? How does this impact the volume of distribution? Give an example.

A

Acidic phospholipids in tissues, thus have a higher volume of distribution.
I.e. fluoxetine

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40
Q

How do lysosomes affect volume of distribution? Give examples of drugs affected by this.

A

Sequester cationic amphiphilic drugs
Molecule (logP >2, pH 6.5-11) can accumulate and not reach receptor target
Reduces activity and off target effects of drugs.
I.e. azithromycin, vinblastine

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41
Q

Name the three plasma proteins largely responsible for drug binding. What drugs are likely to bind?

A

Albumin- acidic and neutral drugs such as cyclosporine
Alpha-1 acid glycoprotein- basic drugs
Globulins- steroids

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42
Q

What is Fu?

A

Fraction unbound

Fu= Cu/C

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43
Q

What circumstances may alter fraction of drug unbound?

A

Pregnancy
Liver cirrhosis
Renal impairment

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44
Q

What is Kp?

A

Tissue to plasma partition coefficient

VpC= KpVtCt

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45
Q

What are the most common drug-drug interactions?

A

Metabolic DDIs, inhibition or induction of CYP enzymes

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46
Q

Describe the effects of an inhibition DDI.

A

Reduced metabolising rate, increased drug concentration potentiating drug effect.

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47
Q

Describe the effects of an induction DDI.

A

Increased metabolising rate, decreased drug concentration and drug effect.

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48
Q

What is Ki?

A

The inhibitor-enzyme dissociation constant, analogous to Km

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49
Q

What are the 3 classifications of CYP inhibition?

A

Strong 5 fold increase in AUC
Moderate 2-5 fold increase
Weak 1.25-2 fold increase
AUC ratio= AUC(inh)/AUC

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50
Q

What impact does grapefruit have on drug metabolism?

A

Irreversible inhibition of intestinal CYP3A4 by furanocoumarins
No effect seen when given IV so minimal effects on hepatic CYP

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51
Q

What is auto-induction? Give a drug example.

A

A drug increases its own metabolism at an enzyme

I.e. Carbamazepine

52
Q

What is the common mechanism of enzyme induction?

A

Requires complement of cellular processes

Increased transcription and translation, reduced degradation

53
Q

What occurs physiologically upon enzyme induction?

A

Increased Vmax
Altered Km at enzyme level
Increased CYP synthesis
Pronounced proliferation of endoplasmic reticulum
Increased liver size, weight and blood and bile flow

54
Q

Describe the clinical consequences of concomitant administration of ketoconazole and terfenadine.

A

Ketoconazole is a CYP3A4 inhibitor
Terfenadine must be broken down to fexofenadine for action but CYP3A4
Increased levels of terfenadine can cause QT prolongation and severe arrhythmia

55
Q

What are the two major subfamilies of transporters?

A

ATP-binding cassette

Solute carriers

56
Q

Where are the most clinically relevant transporters expressed?

A

Epithelia of intestine, liver and kidney

Endothelium of BBB

57
Q

What is OATP?

A

Organic anion transporting peptide
Located on sinusoidal membrane of hepatocytes
Mediates uptake of drugs and endogenous compounds

58
Q

Describe the clinical consequences of concomitant administration of cyclosporine and rosuvastatin.

A

Cyclosporine inhibits OATP1B1
Rosuvastatin is transported into the liver for metabolism via OATP1B1
Inhibition of this increases Cmax and AUC of rosuvastatin leading to rhabdomyolysis

59
Q

Which drug is responsible for the most relevant P-gp DDIs?

A

Digoxin

60
Q

What is the role of BCRP in drug uptake?

A

Attenuates intestinal absorption of poorly permeable drugs and contributes to biliary elimination

61
Q

What drug does turmeric most commonly interact with?

A

Inhibits intestinal efflux of sulphasalazine.

62
Q

What effect does apple juice have on drug absorption?

A

Inhibits intestinal uptake of aliskiren and fexofenadine via OPAT2B1

63
Q

Define renal clearance.

A

CLr= rate of urinary excretion/concentration in plasma

64
Q

What percentage of cardiac output do kidneys receive?

A

20%

65
Q

What is the average urine flow rate and GFR?

A

Urine flow= 1-2mL/min

GFR= 120mL/min

66
Q

What is the rate of renal excretion?

A

Rate of excretion= (rate of filtration + rate of secretion) x (1-fraction resorbed)

67
Q

What is active tubular secretion?

A

Active uptake of compounds via OAT/OCT paired with efflux transporters

68
Q

Give 4 examples of OAT1 substrates.

A

Adefovir, oseltamivir, methotrexate, penicillin G

69
Q

Give 2 examples of OCT2 substrates.

A

Metformin, pindolol

70
Q

What two major factors affect reabsorption in kidneys?

A

Lipophilicity and ionisation

71
Q

How does urine pH affect renal clearance?

A

Ranges from 4.5-7.6
Weak acids- CLr is urine pH sensitive, pKa 3-7.5 drug is non-ionised and lipophilic
Strong acids- pKa<3 mostly ionised thus minimal absorption
Weak bases- CLr is urine pH sensitive at pKa 6-12, drug is non-ionised

72
Q

How does urine flow affect renal clearance?

A

Flow dependent on CLr occurs when drug is resorbed

If equilibrium is achieved, higher urine volume means higher CLr

73
Q

What occurs when renal resorption rate = secretion rate?

A

CLr = fu x GFR

74
Q

Which CYP enzymes are present in the kidneys?

A

CYP3A5 in cortex and medulla

CYP2D6 in PT and loop of Henle

75
Q

Where are carboxylesterases present in the kidneys?

A

PT and bowman’s capsule

76
Q

What affect does CKD have on metabolism and elimination?

A 
Reduced CLr and GFR
Reduced kidney weight
Reduced tubular secretion and transporter expression
Reduced CLh
Increased gastric emptying time and pH
Downregulation of CYP enzymes
77
Q

What is clearance?

A

CL= rate of elimination/concentration in plasma

Remains constant irrespective of dose if drug PK is linear

78
Q

What are the two major sites of metabolism?

A

Liver and intestine

79
Q

What is the elimination rate constant (k)?

A

The fractional rate of drug loss

k= Cl/V

80
Q

What is flow rate (Q)?

A

CL= Q(Ca-Cv)/Ca

81
Q

What is Fh?

A

Fraction escaping hepatic metabolism

Fh= 1-Eh

82
Q

What are the three classes of hepatic extraction? Give examples.

A 
Low extraction (<0.3) diazepam, warfarin, phenytoin
Medium extraction (0.3-0.7) quinidine, codeine, cyclosporine
High extraction (>0.7) propranolol, verapamil, lidocaine
83
Q

What is the typically blood flow through the liver?

A

1300-1500mL/min

84
Q

What is the additivity of clearance?

A

The total clearance is the addition of the individual organ CL values.

85
Q

What is unique about the hepatic blood supply?

A 
It has a dual supply:
Portal vein (1.1L/min)
Hepatic artery (0.4L/min)
86
Q

What can affect the hepatic flow rate?

A

Increase- bed rest, thyrotoxicosis, isoprenaline

Decrease- exercise, heart failure, propranolol

87
Q

What can affect plasma protein binding?

A

Increase- burns, neonate, nephrosis, heart failure

Decrease- stress, cancer, arthritis, crohn’s, myalgia

88
Q

What physiological effects does liver cirrhosis have?

A 
Decreased liver volume
Portal hypertension
Renal impairment
CLh reduced
Impaired albumin synthesis and protein binding
89
Q

What parameters are affected by hepatic extraction?

A

Hepatic clearance only affects drugs with high Eh

Plasma protein binding is important for low Eh drugs

90
Q

What are the structural requirements for biliary excreted molecules?

A

Active facilitated transport
Polar
MW >350 Da

91
Q

What is the average bile flow?

A

0.5-0.8mL/min

92
Q

What is bile clearance?

A

CLb = (bile flow x drug concentration)/drug concentration in plasma

93
Q

Describe enterohepatic recirculation. Give examples of drugs.

A

Liver-> common bile duct-> small intestine-> superior mesenteric vein-> portal vein-> liver
Occurs with bile salts, rosuvastatin, mycophenolic acid

94
Q

Briefly describe how CYP enzymes are classified.

A

12 families total, 1-4 important in drug metabolism

>60% homology in subfamilies

95
Q

Which letter/number denotes the family, subfamily and gene?

CYP2D6

A

Family- 2
Subfamily- D
Gene- 6

96
Q

Describe the activity of CYP enzymes in disease.

A

Reduced activity of CYP2D6 and CYP3A4 in cancer and HIV

Downregulation of CYPs mediated by pro-inflammatory mediators

97
Q

What are the major roles of CYP450?

A

Membrane bound haem containing proteins

Activation of oxidation and oxidation of drug

98
Q

What are the binding properties of CYP450 enzymes?

A

Substrate binding at protein active site
Haem ligand for oxygen and CO binding
CO binding has absorption spectrum max at 450nm

99
Q

Describe the 6 stages of the CYP cycle?

A

1- substrate binds to active site, enzyme conformation changes
2- transfer of electron (NADPH-> NADP+) via flavoprotein-1
3- binding of oxygen to harm
4- transfer of second electron, reducing dioxygen to negatively charged peroxy group (NADPH-> NADP+)
5- peroxy group protonated twice forming highly reactive Fe
6- substrate reacts with Fe species, releases hydroxylated product, water molecule returns to distal haem position

100
Q

Describe the preference for substrates of CYP2D6? Give an example.

A

Arylalkylamines (basic) with a site of oxidation 5-7 atoms from protonated nitrogen.
i.e. ecstasy

101
Q

Describe the preference for substrates of CYP2C9? Give an example.

A

Neutral or acidic molecules with oxidation site 5-8A from H-bond donor heteroatom
Generally amphipathic with lipophilic region at site of hydroxylation
Hydrophilic area around H-bond forming region
i.e. tolbutamide

102
Q

Describe the preference for substrates of CYP3A4? Give an example.

A

Neutral or basic molecules
Lipophilic and bulky
Site of oxidation often basic nitrogen
i.e. testosterone or midazolam

103
Q

Describe the multimodal distribution of CYP2D6.

A

7% of caucasians are poor metabolisers, lacking CYP2D6 gene

2% of Swedish, 10% of Spanish and 8% of Italians are ultra-metabolisers, have gene duplication

104
Q

What is the role of phase I metabolism?

A

Expose functional groups via oxidation at C, N or S atom

105
Q

What is phase 1 hydroxylation?

A

Aromatic oxidation to form phenols i.e. lignocaine

Aliphatic oxidation to form alcohols i.e. pentobarbitone or tolbutamide

106
Q

What is phase 1 cleavage?

A

O-dealkylation to form phenols i.e. codeine

N-dealkylation to form amines i.e. theophylline

107
Q

What is phase 1 reduction?

A

Nitro-reduction i.e. chloramphenicol, nitrazepam

Azo-reduction i.e. prontosil

108
Q

What is phase 1 hydrolysis?

A

Catalysed by carboxylesterases
Ester hydrolysis i.e. oseltamivir
Amine hydrolysis i.e. procainamide

109
Q

What is phase II metabolism?

A

Conjugation of phase I metabolites for renal and biliary excretion via efflux transporters

110
Q

What is glucuronidation?

A

Occurs via UDO-glucuronosyltransferases on luminal side of the endoplasmic reticulum
Glycoproteins (UGT) catalyse addition of glucuronic acid

111
Q

What are the two key paediatric clinical differences in glucuronidation?

A 
Morphine glucuronidation (UGT2B1) is deficient in young adults
UGT1A1 reaches adult levels at 3-6 months, congenital jaundice due increased bilirubin
112
Q

What is Gilbert’s syndrome?

A

Unconjugated hyperbilirubinaemia in adults due to deficiency of UGT1A1

113
Q

What are the three most abundant glucuronidation enzymes in healthy kidneys and tumour tissues?

A

UGT1A9
UGT2B7
UGT1A6

114
Q

How does CKD affect glucuronidation?

A

Inhibition of UGT enzymes by uremic toxins

115
Q

What is phase II sulphation?

A

Occurs mainly via cytosolic enzymes, activated by ATP cofactor PAPs
SULT enzymes present in liver and small intestine
Metabolism of drugs such as paracetamol and salbutamol

116
Q

What is glycine conjugation?

A

Phase II reaction limited to acids

Drug becomes activated as acyl coenzyme A intermediate

117
Q

What is acetylation?

A

Phase II reaction limited to amines

Formation of N-acetyl conjugates via acetyl CoA

118
Q

What is phase III metabolism?

A

Prolongs drug effect via action of glucuronidase of sulphates enzymes reversing phase II metabolism

119
Q

Describe the 3 major metabolites of diazepam.

A

Temazepam and oxazepam are rapidly metabolised and barely detectable in the plasma but marketed as short acting
Nordazepam has a longer half life and can cause local toxicity at site of formation i.e. liver injury

120
Q

What is benzopyrene?

A

A major polycyclic aromatic hydrocarbon in cigarette smoke

Forms a reactive metabolite in the lung causing irritation

121
Q

What is glutathione conjugation?

A

Protective mechanism

Electrophilic phase I metabolic interacts with nucleophilic glutathione tripeptide

122
Q

What occurs in paracetamol overdose?

A

Electrophilic metabolite forms (NAPQI) which leads to liver cell death
N-acetylcystiene is a well tolerated nucleophile that can be given as an antidote.

123
Q

What is a type A adverse drug reaction?

A

Reversible reaction that is dose related

Causes 80% of ADRs

124
Q

What is a type B adverse drug reaction?

A

Irreversible, idiosyncratic ADR with a genetic basis, often associated with the liver

125
Q

What is a type C adverse drug reaction?

A

Irreversible chemical reaction with tissue macromolecule often leading to necrosis

126
Q

What is a type D adverse drug reaction?

A

Irreversible ADR that is chronic, response is often delayed

127
Q

Under what circumstances, according to the FDA, should a drug metabolite be evaluated as an enzyme inhibitor?

A

Less polar and present at >25% of parent systemic exposure

More polar and present at >100%

Pharm Y3S2 (29 decks)

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