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HHD 2 > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

What is Pharmacokinetics?

A

This is what the body does to the drug

The processes which determine the changes in concentration of a drug in the body over time

The knowledge of the fate of a drug, its disposition (drug disposition)

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2
Q

What is pharmacodynamics?

A

This is what the drug does to the body

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3
Q

What is the pneumonic that describes the disposition of a drug?

A

ADME

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4
Q

What does ADME stand for?

A

Absorption- drugs enters the blood plasma following administration
Distribution- drug distributed throughout body tissues and fluids
Metabolism- tissue enzymes convert the drug to different form (hepatic metabolism)
Excretion- removal of the drug from the body (renal excretion)

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5
Q

What is the meaning of absorption? (pharmacologically)

A

Drug absorption is the movement of drug molecules across biological membranes

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6
Q

The gastrointestinal tract is a biological membrane for oral drugs. The GI tract is a barrier to what kind of drugs?

A

Barrier to more water soluble drugs

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7
Q

The GI tract is a biological membrane for oral drugs. The GI tract is permeable to what kind of drugs?

A

Lipid- soluble drugs

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8
Q

What are the 4 ways by which small molecules are able to cross cell membranes?

A

Diffusion (through lipid membrane)
Membrane transporter
Aquaporins (pores formed by aquaporin proteins)
Pincocytosis (cells engulf molecules into special membrane bound vesicles)

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9
Q

What factors related to drugs affect absorption

A
  1. lipid (can it cross membrane) or water solubility(will it dissolve)
  2. particle size- smaller?
  3. degree of ionisation- unionised form can cross bilayer much easier
  4. physical form- suspension is easier than a coated tablet
  5. chemical stability- broken down by gastric acid, enzymes, bacteria
  6. drug concentration- higher concentration, better diffusion
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10
Q

What factors related to the body can affect absorption?

A
  1. area of absorption (intestines with villi are better than stomach)
  2. vascularity (more blood vessels to carry the drug)
  3. Effect of pH- ion trapping, pH of environment (most drugs are weak acids?)
  4. Gut motility (diarrhoea will result in poor absorption)
  5. Diseases- integrity of absorptive surface
  6. pre-systemic (first pass metabolism)
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11
Q

Where does first pass metabolism (pre-systemic metabolism) occur?

A

Gut wall and liver

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12
Q

Many drugs are weak acids or weak bases and this they exist in equilibrium of what forms ?

A

Ionised and unionised forms

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13
Q

What is pH?

A

how many free H+ ions are available in a solution

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14
Q

What is pKa?

A

Dissociation constant
how a molecule (drug) will react in a solution at a specific pH at which the acid/base exists as ionised (50%) and unionised (50%) form in equal amount (equilibrium)

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15
Q

Give an example of a drug that is a weak acid

A

Aspirin

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16
Q

How will aspirin behave in the stomach?

A

It is able to cross the membrane into the plasma
This is because the stomach is acidic therefore there will be more of the unionised form of the drug (HA).

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17
Q

How will aspirin behave once it has entered the blood plasma

A

More of the active ionised form (A-) is formed due to the fact that the plasma is more neutral and hence will encourage formation of H+ ions

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18
Q

How will aspirin behave in the urine?

A

Urine has a more basic pH (8). This will encourage formation of H+ ions and therefore also the ionised (A-) active form.
The ionised form is not able to cross the lipid membrane to the plasma and hence it is trapped in the urine and excreted

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19
Q

Give an example of a drug that is a weak base

A

Pethidine

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20
Q

How will a drug such as Pethidine behave in the stomach?

A

Pethidine is trapped in the stomach and does not reach the plasma. This is because the stomach is an acidic environment hence the reaction will shift to making the ionised form which cannot cross the lipid membrane

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21
Q

How does Pethidine behave in the urine?

A

Urine has a pH of 8. This will encourage the formation of H+ ions and thus the formation of the unionised (B) form which is able to cross the lipid membrane. Pethidine as such is not excreted in the urine as it can be absorbed back into the plasma

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22
Q

What is bioavailability (F)?

A

The proportion of the drug does that reached the systemic circulation.

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23
Q

Unless drugs are administered ___________, most drugs are absorbed incompletely.

A

Intravenously

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24
Q

An F value of 0% indicates that …

A

none of the drug dose have entered the systemic circulation

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25
Q

An F value of 100% indicated that…

A

All of the drug dose has been absorbed into systemic circulation

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26
Q

What is the bioavailability value of intravenously administered drugs?

A

100%

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27
Q

What is the bioavailability of drugs administered intramuscularly?

A

75 to =<100

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28
Q

What is the bioavailability of drugs administered subcutaneously?

A

75 to =<100

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29
Q

What is the bioavailability of drugs administered rectally?

A

30 to <100

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30
Q

What is the bioavailability of drugs administered orally?

A

5 to <100

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31
Q

What is the bioavailability of drugs that are inhaled?

A

5 to <100

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32
Q

What is the bioavailability of drugs that are administered transdermally?

A

80 to <= 100

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33
Q

What is the drug nicarpidine used to treat?

A

High blood pressure
A calcium channel blocker

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34
Q

What is the effect of grapefruit on orally administered Nicardipine?

A

It increases the bioavailability of nicardipine.
It inhibits the action of CYP450 enzymes
This reduces pre-systemic clearance that drugs administered orally have to undergo

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35
Q

How is bioavailability (F) calculated?

A

F= AUCoral/AUCiv X Div/Doral

AUC- area under the curve
D- dose

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36
Q

Where is the main site of metabolism for orally administered drugs?

A

Liver

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37
Q

What other site metabolises orally administered drugs?

A

Intestinal wall

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38
Q

What is first pass metabolism?

A

This is when drugs pass from GI tract to the liver via the hepatic portal vein before entering main circulation

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39
Q

Following metabolism, drugs are prepared for ________

A

elimination

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40
Q

Briefly describe the bioavailability of orally administered drugs

A

Reduced drug bioavailability

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41
Q

What is a prodrug?

A

This is a pharmacologically inactive compound that is converted into a pharmacologically active compound after metabolism.

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42
Q

What is the active compound of Enalapril and what is it used to treat?

A

Enalaprilat
Hypertension

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43
Q

The prodrug of aciclovir is _______

A

Valaciclovir
Antiviral drug

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44
Q

What is the active compound for the aspirin prodrug and what is its use?

A

Salicylic acid
Pain relief

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45
Q

Describe, briefly, the absorptive quality of prodrugs

A

Prodrugs have good absorption

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46
Q

The concentration (amount) of a drug can be calculated by…

A

Mass(bioavailability)/volume (plasma volume)

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47
Q

Systemic circulation refers to …

A

Blood plasma

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48
Q

How do drug molecules exist?

A

Bound or free form

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49
Q

In what form are drugs able to move through body fluid compartments?

A

Free drug

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50
Q

What does the volume of distribution take into consideration?

A

Other body compartments outside of the blood plasma

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51
Q

What is the equation for drug concentration when taking into account other body compartments?

A

C=M(mass/bioavailability)/Vd (volume of distribution- body compartments)

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52
Q

What is the definition of the volume of distribution?

A

It is the apparent volume the drug is dissolved in

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53
Q

Calculate the volume of distribution for a patient who was given 10mg IV bolus

A

Blood= 5L
Plasma= blood- cells= 2.5L
C= 10mg/2.5L= 4mg/L

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54
Q

Calculate the volume of distribution after an hour of administering 10mg IV bolus to a patient

A

At time 0= 4mg/L ( calculated in another Q card)
After an hour
10mg/(2.5L+7.5L)= 1mg/L

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55
Q

What happens to the volume of distribution for a drug that cannot cross the vascular endothelium?

A

Volume of distribution decreases and the concentration of the drug in the plasma increase

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56
Q

What happens to the volume of distribution for a drug that can cross the vascular endothelium easily?

A

An apparent large volume of distribution
Volume of distribution increases
Concentration in plasma decreases

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57
Q

Suggest some reasons as to why a drug might be confined to the plasma

A

Drug too large to cross vascular endothelium
Drug strongly bound to plasma proteins

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58
Q

Suggest some reasons as to why a drug might be confined to the extracellular space

A

Polar drugs cannot enter the cells
Large macromolecules which access cell membrane receptors

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59
Q

What kinds of drugs are difficult to remove during overdose?

A

Drugs restricted to total body water (readily crosses cell membranes inside and outside cells)
Drugs that extensively dissolve in far or bound to a proteing

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60
Q

What does the phrase “apparent volume of distribution mean”?

A

this refers to the fact that all of the body equilibrated with the drug do not have equal concentrations

It is defined as the volume in which the amount of drug would be uniformly distributed to produce the observed blood concentration

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61
Q

List some reasons why the volume of distribution would not necessarily correspond to any physical compartment

A
  1. binding to tissues
  2. binding to plasma proteins
  3. partitioning into fat
  4. adsorption onto bone
  5. blood flow
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62
Q

Na+ K+ ATPase enzyme is essential for all cells. What tissues contain large quantities of the enzyme?

A

Muscle
Nervous Tissue
Kidneys

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63
Q

What is the MOA of digoxin, a medication used to treat heart failure.

A

It inhibits the Na+/K+ ATPase enzyme.
This increases intracellular Na+ and therefore causes an influx of Ca2+ ions in the heart
This leads to increased contractility

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64
Q

The amount of a drug that is bound to a protein is dependent on what 3 factors?

A
  1. concentration of the free drug
  2. its affinity for the protein binding sites
  3. the concentration of the protein
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65
Q

Albumin mainly binds to what kinds of drugs?

A

Weak acids such as warfarin

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66
Q

Weak bases such as Lignocaine bind to what plasma protein?

A

alpha 1/2 acidic glycoproteins

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67
Q

The unbound form of a drug is described to be …

A

Pharmacologically active

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68
Q

As a first approximation, the binding reaction can be regarded as a _____________ of the drug molecules with a finite population of binding sites.

A

simple association

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69
Q

What fraction of a drug undergoes metabolism in the liver and other tissues?

A

the unbound fraction

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70
Q

The fraction of unbound drug can be altered by a number of variables such as… (list them)

A
  1. concentration of drug in the body
  2. the amount and quality of plasma protein
  3. other drugs that bind to the plasma protein
71
Q

When drugs accumulate in certain tissues, these tissues act as _____ of extra drug. What do these tissues do?

A

reservoirs
They slowly release the drug into the bloodstream

72
Q

Briefly describe the fat:water partition coefficient of most drugs

A

Relatively low

73
Q

What is the lipid: water coefficient of morphine? What is the consequence of this?

A

0.4
Sequestration into tissues is very little

74
Q

What is the lipid: water coefficient of thiopental, an ultrashort acting depressant on the CNS?

A

10

75
Q

There is a _______ correlation between blood flow in tissue and distribution of drugs

A

Positive

76
Q

What effect does low blood supply have on the accumulation of drugs in fat and bone

A

Low blood supply will limit accumulation of the drug in fat and bone

77
Q

What is the effect of high blood supply on drugs?

A

This increases metabolism and clearance in liver and kidneys

78
Q

What is the effect of enzymatic activity on the pharmacological activity of many drugs?

A

Pharmacological activity is reduced or abolished by enzyme activity

79
Q

What is the main site of drug metabolism?

A

Liver hepatocytes- smooth endoplasmic reticulum

80
Q

Drugs administered ______ and _______ enter the liver to undergo “first pass metabolism” before reaching systemic circulation.

A

Orally
Rectally
(enter GI tract and travel to liver via portal vein)

81
Q

Why do we metabolise drugs?

A

this is to decrease lipid solubility of the drug (increase water solubility) and therefore increase renal elimination of drug in the urine

82
Q

What does the smooth endoplasmic reticulum of the hepatocytes contain that is relevant to pharmacokinetics?

A

They contain the cytochrome P450 enzyme superfamily

83
Q

How many different CYPs have been found in humans?

A

more than 50

84
Q

What is the function of CYP enzymes?

A

metabolise foreign substances (xenobiotics- including drugs)

85
Q

What are the 2 sets of chemical reactions utilised by CYP enzymes for metabolism to occur?

A
  1. Phase I metabolism- CYP450 enzymes
  2. Phase II metabolism- conjugation reactions
86
Q

Phase I reactions are often catabolic (breaks down). Give examples of phase I reactions.

A

Oxidation
Reduction
Hydrolysis

87
Q

How do phase I reactions make use of CYP450 enzymes?

A

These enzymes are oxidases and they are used to unmask or introduce polar groups (-OH’s/-Os) on the drug

88
Q

What is the overall effect of phase I metabolism on drugs?

A

Decrease lipid solubility and therefore increase renal elimination (due to making them more polar)

89
Q

In phase I reactions, reactive groups (functionalisation) are introduced for _________

A

Conjugation

90
Q

What is an isoenzyme?

A

an enzyme that differs in amino acid sequence but catalyses the same chemical reaction

91
Q

Elucidate the nomenclature of CYP 3A4

A

3- family
A- subfamily
4- isoenzyme

92
Q

What is the most common P450 isoenzyme?

A

accounts for 50% of isoenzyme
CYP3A4

93
Q

What is the second most common P450 enzyme?

A

CYP2D6
accounts for 20% of P450 isoenzymes

94
Q

Polymorphisms of CYP2D6 lead to either ______ or _______ metabolism

A

fast
slow

95
Q

CYP1A2 metabolises which drugs?

A

Caffeine
paracetamol (NAPQI)
tacrine
theophylline

96
Q

CYP2B6 metabolises which drugs?

A

cyclophosphamide
methadone

97
Q

CYP2C8 metabolises which drugs?

A

paclitaxel
repaglinide

98
Q

CYP2C19 metabolises which drugs?

A

omeprazole
phenytoin

99
Q

CYP2C9 is used to metabolise which drugs?

A

warfarin
ibuprofen
tolbutamide

100
Q

CYP2D6 is used to metabolise which drugs?

A

codeine
debrisoquine
S- metoprolol

101
Q

CYP2E1 metabolises…

A

alcohol
paracetamol

102
Q

CYP3A4, 5, 7 metabolise which drugs

A

Nifedipine (calcium channel blocker)
simvastatin
ciclosporin (immunosuppresant)
Indinavir

103
Q

An example of a substrate (drug) for CYP3A4 enzyme is …

A

Midazolam (sedative)

104
Q

Give an example of an inhibitor of CYP3A4

A

fluconazole (anti-fungal)

105
Q

Carbamazepine (anti-convulsant) acts as an ________ of CYP3A4 enzyme

A

Inducer

106
Q

What is the effect of an inhibitor of a CYP450 enzyme?

A

decreases metabolism of the target drug (increase in t1/2-half-life); increases the plasma drug concentration
This increases the effect of the drug as well as drug toxicity

107
Q

What is the meaning of t1/2 (half-life)?

A

the amount of time required to reduce drug level to half of its initial value (plasma concentration)

108
Q

What is the effect of an inducer on CYP450 enzymes?

A

Increases synthesis or decreases degradation of CYP450 enzymes
Increases metabolism of the drug (reduces its half-life)
There is a decrease in plasma concentration of the drug
The effect of the drug is decreased

109
Q

Inducer activity is ______ whilst inhibitor activity is _________. How long does inducer activity take?

A

Slow
Rapid
inducer activity takes 1-2 weeks

110
Q

Drugs such as suzamethonium are metabolised by …

A

Plasma cholinesterases

111
Q

Salbutamol is metabolised by enzymes in the ______ system

A

GI
Short acting B-adrenoceptor (SABA)

112
Q

Ethanol is metabolised by which enzymes? Where are these enzymes located

A

Alcohol dehydrogenase
these are often cytoplasmic enzymes

113
Q

Prostanoids in the lungs have a role in the metabolism of drugs. True or false

A

True

114
Q

Give examples of other oxidases (outside of CYPs) that can metabolise drugs

A

Noradrenaline
Tyramine
5-HT- monoamine oxidases

115
Q

Phase II reactions are _______

A

Anabolic (build up)

116
Q

What is the function of phase II reactions

A

use enzymes (transferases) to attach small endogenous polar molecules to the drug
this makes them more likely to undergo renal elimination in the urine

117
Q

Phase II reactions are also known as …

A

Conjugation reactions

118
Q

Where do conjugation reactions take place

A

Mainly liver
other tissues such as lungs and kidneys are involved

119
Q

Give examples of chemical groups inserted in conjugation reactions

A

glucuronyl
sulfate
methyl
acetyl

120
Q

What is the most common enzyme that catalyses the conjugation (phase 2) reactions?

A

UDP-glucoronosyltransferase

121
Q

What is the function of UDP-glucoronosyltransferase

A

Glucoronic acid binds making the drugs very water soluble (hydrophilic)

122
Q

Briefly describe how phase I and phase II metabolism work in tandem

A

during phase I, CYP isoenzyme (oxidase) introduces or unmasks a polar group
A larger molecule can attach to polar group such as -OH or -O; for instance, UDP-glucoronosyltransferase can add glucuronyl group making it very polar.
The water soluble drug is now more easily filtered and excreted through kidneys.

123
Q

Drugs undergoing extensive first- pass metabolism exhibit pronounced inter-individual variability in drug disposition. List some reasons for this.

A
  1. genetic variation- polymorphism in enzymes- CYP2D6 fast and slow metabolisers of codeine
  2. induction and inhibition of drug metabolising enzymes
  3. food can increase hepatic flow, increasing bioavailability of drug (propanolol)
  4. drugs can increase or decrease hepatic flow, increase of decrease bioavailability of drugs (hydralazine increases propanolol)
  5. liver disease increases bioavailability of drug (morphine)
  6. Age
124
Q

Describe the CYP450 activity in the elderly and in newborns

A

Elderly- livers capacity for CYP450 metabolism is reduced >30%, higher levels of drug and prolonged half-life can lead to increased toxicity
Newborns- have partially developed CYP450 enzyme systems and hence can also have difficulty metabolising many drugs and can lead to toxicity

125
Q

What is the primary metabolic pathway for paracetamol

A

90% glucoronidation

126
Q

What enzymes metabolise paracetamol into NAPQI metabolite

A

CYP3A4 and CYP2E1

127
Q

NAPQI metabolite build up can cause …

A

liver damage

128
Q

In an adult, how much of the therapeutic paracetamol dose produced NAPQI

A

10%

129
Q

How is NAPQI inactivated?

A

by conjugation with glutathione

130
Q

Briefly describe what happens in a paracetamol overdose

A

glutathione runs out
NAPQI cannot be inactivated
build up of NAPQI can lead to liver toxicity

131
Q

When is there a good prognosis for paracetamol overdose?

A

If treatment is within 8 hours with the antidote acetylcysteine

132
Q

What is the function of acetylcysteine in a paracetamol overdose?

A

replenishes livers gluthathione
Allows NAPQI to be metabolised safely

133
Q

Give examples of tranferase reactions that can occur in phase II metabolism

A

methylation
acetylation
glucuronidation
sulphation
mercaptopuric acid formation
gluthathione conjugation

134
Q

Elimination is a combination of …

A

Metabolism by liver
Excretion by kidneys , hepatobiliary system, lungs

135
Q

___% of drugs undergo metabolic degradation whilsyt ___% are renally excreted as their unchanged active form in the urine

A

66%
33%

136
Q

Of the 66% of drugs metabolically degraded, ___% undergo renal elimination of the inactive drug and ___% undergo hepatobiliary elimination of the inactive drug

A

33%
33%

137
Q

Metabolic degradation of the drug leads to the elimination of what form of the drug?

A

The inactive form

138
Q

What is the definition of elimination?

A

process that removes drugs from the body- clearance

139
Q

What is clearance?

A

Volume of plasma that is cleared of drug per unit time (volume: CL=mL/min)

140
Q

What is the rate of elimination?

A

the is the mass of drug eliminated per unit time (AMOUNT: rate of elimination; ug/min)

141
Q

What is used to determine the rate of elimination?

A

Clearance
Rate of elimination= clearance x [Drug]plasma (ug/min=mL/min x ug/mL)

142
Q

Clearance occurs through any organ that has access to the outside world. Give examples of this

A

Kidney can excrete drugs into the urine
Liver can excrete drugs into the bile
Lungs can excrete drugs into the air

143
Q

How would you calculate total clearance CLtotal?

A

CLtotal= CLrenal + CLliver + CLlungs

144
Q

What organ is involved in the elimination of virtually every drug or drug metabolite?

A

Kidney

145
Q

How is the kidney involved in the elimination of drugs or drug metabolites?

A
  • glomerular filtration- free drug enters the glomerular filtrate
  • proximal tubular active secretion
  • passive distal tubular reabsorption (lipid soluble, unionized drug)

Ionised, lipid insoluble drug enters into the urine

146
Q

What part of the kidney is the main site for interactions?

A

Proximal tubular active secretion

147
Q

What is the first step in making urine?

A

Glomerular filtration

148
Q

What is glomerular filtration?

A

The process that your kidneys use to filter excess fluid/ waste/ DRUGS out of the blood and into the urine via the collecting ducts of the kidney

149
Q

What kinds of drugs are cleared by filtration?

A

Free water soluble drugs (low molecular weight)

150
Q

In the case that a drug is bound to a plasma protein that has a high molecular weight, what happens?

A

Protein bound drug remains in circulation

151
Q

What is the glomerular filtration rate?

A

This is the flow rate of filtered fluid through the kidney

152
Q

Why is creatinine clearance a useful measure for approximating GFR

A

Creatinine is a by product of muscle metabolism that is excreted unchanged by the kidney

153
Q

How does active secretion in the proximal tubules take place?

A

Active secretion of drugs from blood into the urine against its concentration gradient
It requires transporter proteins on the plasma membrane of the proximal convoluted tubule

154
Q

Give an example of a drug that is secreted via active secretion in the proximal tubules

A

Penicillin

155
Q

The secretion of free-drug perturbs the equilibrium of free and protein-bound drugs. What is the consequence of this?

A

This allows some protein-bound drug to become available which is then later secreted

156
Q

Different drugs may compete for the same transporters. True or false

A

True

157
Q

Transporters involved in active secretion at proximal tubules can not become saturated. True or false

A

False
They can

158
Q

List some drugs that inhibit proximal tubular secretion of penicillin, azidothymidine and indometacin by competing for the same transporter proteins

A

Probenecid
Sulfinpyrazone
Phenylbutazone
Sulfonamides
Aspirin
Thiazide diuretics
Indometacin?

159
Q

List some drugs that inhibit proximal tubular secretion of dioxin by competing for the same transporter proteins

A

Verapamil
Amiodarone
Quinidine

160
Q

List some drugs that inhibit proximal tubular secretion of furosemide (frusemide) by competing for the same transporter proteins

A

Indometacin

161
Q

List some drugs that inhibit proximal tubular secretion of methotrexate by competing for the same transporter proteins

A

Aspirin
NSAIDs

162
Q

Passive reabsorption occurs in the _______ of the kidney

A

Distal tubule

163
Q

The renal tubule behaves like a lipid barrier. What does it seperate?

A

High drug concentration in the tubular lumen
Low drug concentration in the blood plasma

164
Q

If a drug is lipid soluble (unionised), what occurs in the distal tubule of the kidney

A

It will go down its concentration gradient and back into the plasma

165
Q

What affects tubular reabsorption?

A

Urine flow rate

166
Q

A low urine flow rate causes a _______ in reabsorption of the drug back into the plasma

A

low urine flow rate will cause an increase in reabsorption

167
Q

A high urine flow rate causes a _______ in reabsorption of the drug back into the plasma

A

a decrease in reabsorption

168
Q

For a weak base drug, how is reabsorption through the distal tubule affected by an increasing/high pH

A

high pH- less H+ ions present
unionised (B) form is produced
more of the drug is reabsorbed back into the blood plasma

169
Q

For a weak acid drug, how is reabsorption through the distal tubule affected by a decreasing/low pH

A

low pH- more H+ ions
unionised (AH) form is produced
More AH is reabsorbed back into the blood plasma

170
Q

For a weak base drug, how is reabsorption through the distal tubule affected by an decreasing/ low pH

A

low pH- more H+ ions
less of unionised (B) is formed and more BH+ ionised form is produced
less B is reabsorbed back into the plasma

171
Q

If elimination is entirely renal (not metabolic) and the drug is filtered but not reabsorbed or secreted, what is the clearance of that drug roughly

A

125ml/min
GFR

172
Q

If elimination is entirely renal and drug is filtered and secreted but not reabsorbed, what is the rough clearance of that drug?

A

625ml/min
renal plasma flow

173
Q

If elimination of a drug is both via renal and hepatic mechanisms the clearance value …

A

exceeds 625ml/min

HHD 2 (37 decks)

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