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A Quantitative Pharmacology > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

What does ADME stand for

A

Absorption, Distribution, Metabolism, Excretion

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2
Q

What is absorption

A

The process by which a drug enters the blood stream from site of administration

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3
Q

What is distribution

A

The process by which a drug leaves the circulation and enters the tissues perfused by blood. Blood independent distribution can occur in tissues by diffusion

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4
Q

What is metabolism

A

The process by which tissue enzymes catalyse the chemical conversion of a drug to a more polar form that is more easily excreted

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5
Q

What is excretion

A

The processes that remove the drug from the body

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6
Q

Where does metabolism usually happen

A

Liver - Hepatic metabolism

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7
Q

Where does excretion usually happen

A

Kidneys - Renal Excretion

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8
Q

What are the physiochemical factors controlling drug absorption

A

Solubility
Chemical stability
Lipid to water partition coefficient
Degree of ionisation

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9
Q

How does drug solubility affect absorption

A

The drug must be dissolved to be absorbed

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10
Q

How does the chemical stability of a drug affect absorption

A

Some drugs can be destroyed by acid in the stomach or enzymes in the GI tract. Must be stable to avoid this

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11
Q

How do drugs get from the stomach/intestines to the liver

A

Through portal circulation

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12
Q

What is the lipid to water partition coefficient

A

~LogP

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13
Q

What effect does the lipid to water partition coefficient on drug absorption

A

Greater lipid solubility (LogP) = higher rate of diffusion across a membrane

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14
Q

Which ionisation form does a drug need to be to cross the lipid bilayer

A

Unionised.

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15
Q

What is the pKa

A

The pH at which 50% of the drug is ionised, and 50% is unionised

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16
Q

How can the proportions of [un]ionised drug be calculated

A

Henderson-Hasselbalch equation: pKa - pH = log (HA/A-) or log(BH+/B)

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17
Q

How does the degree of drug ionisation affect drug absorption

A

Must be in unionised state to cross membrane. Acid drug = less ionised in acid environment. Basic drug = less ionised in basic environment.

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18
Q

Where is a slightly acidic drug likely to be absorbed

A

Stomach (and small intestine because >surface area)

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19
Q

Where is a slightly basic drug likely to be absorbed

A

Small intestine

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20
Q

Which factors affect GI absorption

A 
Motility (rate of movement)
pH at absorption site
Blood flow to GI tract
Drug formulation 
Physicochemical interaction
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21
Q

Define oral availability

A

The fraction of drug that reaches the systemic circulation after oral ingestion
(amount in circulation / amount administered)

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22
Q

Define systemic availability

A

The fraction of drug that reaches the systemic circulation after absorption.
(amount in circulation / amount absorbed)

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23
Q

What is the enteral route of administration

A

Drug administration that involves the intestines / GI tract

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24
Q

What is the parenteral route of administration

A

Drug administration that does NOT involve the intestines / GI tract

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25
Q

What are the advantages of oral administration

A

Convenient
Non-sterile route
Generally good absorption

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26
Q

What are the disadvantages of oral administration

A

Some drugs inactivated by acid/enzymes
Variable absorption
Must deal with 1st pass metabolism
Can cause GI irritation

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27
Q

What are the advantages of sublingual administration

A

Bypasses portal system
Avoids 1st pass metabolism
Avoids gastric acid

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28
Q

What are the disadvantages of sublingual administration

A

Infrequent route

Few preparations available

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29
Q

What are the advantages of rectal administration

A

Bypasses portal system, 1st pass metabolism and gastric acid

Used for nocturnal administration of some drugs

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30
Q

What are the disadvantages of rectal administration

A

Infrequent route
Variable absorption
Aesthetically unacceptable (in UK… french love it!)

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31
Q

Name some enteral routes of drug administration

A

Oral, sublingual, rectal

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32
Q

Name some parenteral routes of drug administration

A

Intravenous, Intramuscular, subcutaneous, inhalation, topical, nasal, vaginal, ocular, intrathecal, intracerebral

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33
Q

What are the advantages of intravenous administration

A

Rapid onset
Continuous infusion
Complete availability
Allows administration of drugs that might have caused tissue damage

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34
Q

What are the disadvantages of intravenous administration

A

Sterile prep required
Risk of sepsis/embolism
High drug levels at heart

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35
Q

What are the advantages of intramuscular/subcutaneous administration

A

Rapid onset of lipid soluble drugs

depot injection for slow release possible

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36
Q

What are the disadvantages of intramuscular/subcutaneous administration

A

Painful
Tissue damage can be caused
Variable absorption

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37
Q

What are the advantages of inhalational administration

A

Lungs = high surface area
Good for volatile agents
Good for local effect

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38
Q

What are the advantages of topical administration

A

Ideal for local effect

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39
Q

What are the disadvantages of inhalational/topical administration

A

There are ‘few’

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40
Q

Name the fluid compartments found in the body

A

Plasma water
Interstitial water
Intracellular water
Transcellular water

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41
Q

Where can ionised drugs move in the body

A

Between the plasma and interstitial water

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42
Q

Where can unionised drugs move in the body

A

Fat/cells Interstitial water (start point) Intracellular water transcellular water

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43
Q

What is the volume of distribution (Vd)

A

The volume into which a drug ‘appears’ to be distributed with a concentration equal to that of plasma.

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44
Q

What is the Vd for an i/v administered drug

A

Vd = dose / plasma concentration

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45
Q

What does a Vd <5L show

A

Drug retained in vasular compartment (v. protein bound or too big to cross wall)

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46
Q

What does a Vd <15 L show

A

Drug restricted to extracellular water (like perma charged compounds)

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47
Q

What does a Vd >15 L show

A

Drug is distributed throughout total body water (or ^ conc in specific tissues)

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48
Q

What does MEC stand for

A

Minimum Effective Concentration

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49
Q

What does MTC stand for

A

Maximum tolerated dose

50
Q

What is the therapeutic ratio (/index)

A

TR = MTC / MEC

51
Q

What is the desired therapeutic ratio

A

Higher = safer drugs; lower = unsafe drugs

52
Q

Define pharmacokinetics

A

The mathematical analysis of all drug disposition factors (ADME)

53
Q

What is first order kinetics (in drug context)

A

When the rate of elimination is directly proportional to drug concentration

54
Q

What type of graph is given by a drug that shows 1st order kinetics

A

Exponential. 50% decrease per standard half life.

55
Q

Define half life (t1/2)

A

The time taken for concentration of drug in plasma to halve. Inversely related to Kel.

56
Q

What is the equation for working out a half-life

A

T1/2 = 0.69 / Kel (rate of elimination)

57
Q

How does the dose-response curve change for a 1st order drug when the dose conc administered changes

A

Cp (plasma concentration) changed in direct proportion. Kel and T1/2 are unchanged.

58
Q

Define Clearance (Cl)

A

The volume of plasma cleared of drug in unit time.

A constant relating the rate of elimination to plasma concentration

59
Q

Which type of drug does Clearance (Cl) apply to

A

First order drugs ONLY

60
Q

How is Clearance (Cl) determined

A

Rate of elimination = Cl (clearance) x Cp (plasma concentration)

61
Q

Why is Clearance (Cl) important?

A

Determines the maintenance dose rate needed to maintain a given plasma concentration (need to match rate of administration to rate of removal)

62
Q

What is the rate of elimination/administration at steady state

A

Cl (clearance) x Cp[ss] (plasma concentration at steady state)

63
Q

Approx how many half lives does it take for a drug to reach Css (steady-state conc)

A

5

64
Q

Approx how many half lives does it take for a drug to be eliminated from the body

A

5

65
Q

Define oral bioavailability

A

The fraction of the drug administered that enters the systemic circulation

66
Q

What does volume of distribution (Vd) relate

A 
Plasma concentration (Cp) and amount of drug in the body (Ab):
Ab = Vd x Cp
67
Q

Define loading dose

A

An initial higher dose of a drug given at the beginning of a course of treatment before stepping down to a lower maintenance dose.

68
Q

How is a loading dose calculated for i/v administration

A

LD = Vd x target Cp

69
Q

How is a loading dose calculated for oral administration

A

LD = (Vd x target Cp) / F (oral bioavailability)

70
Q

What can half-life determine

A

The time course of drug accumulation and drug elimination. The choice of dose interval.

71
Q

What is the dose response curve for zero order drugs

A

Linear. Drug eliminated at a constant rate

72
Q

Give an example of how a drug can be zero order

A

Plasma concentration of drug is greater than Km of an enzyme that metabolises it

73
Q

How are drugs usually removed by the body

A

In urine and occasionally the bile.

Rarely by sweat, milk etc

74
Q

What form is a drug usually in when removed from the body

A

Commonly a more polar compound, occasionally unchanged (if highly charged)

75
Q

Which organs are involved in drug metabolism

A

Mainly liver. Also GI tract, lungs and plasma

76
Q

What does drug metabolism do

A

Convert parent drugs to more polar metabolites that are not easily absorbed by the kidney
Usually convert drugs to less pharmacologically active metabolites

77
Q

What occurs in phase 1 metabolism

A

Oxidation, reduction, hydrolysis.

Makes a drug more polar and adds stuff that can allow conjugation

78
Q

What occurs in phase 2 metabolism

A

Conjugation.

Adds a compound to add polarity. Often glucuronyl, also: sulphate, methyl, acetyl, glycyl, glutathione

79
Q

How is aspirin metabolised

A

Aspirin –[1]-> Salicylic acid –[2]-> Glucuronide

80
Q

Which enzymes are mainly involved in phase 1 metabolism

A

Cytochrome P450 monooxygenases.

81
Q

What are CYP450 enzymes involved in

A

Phase 1 metabolism

82
Q

Which is the most common type of CYP450 enzyme

A

CYP3A4

83
Q

Which are the most common CYP450 gene families in the human liver

A

CYP1, CYP2, CYP3

84
Q

Describe the monooxygenase P450 cycle

A

Drug enters as drug substrate ‘RH’
O2 provides two oxygen atoms
One oxygen atom is added, drug becomes ROH , which leaves the cycle.
Second oxygen combines with protons to form water.

85
Q

Where does phase 2 metabolism mainly occur

A

Liver

86
Q

What happens in a Glucuronidation reaction

A

Glucuronic acid is transferred to electron-rich atoms of the substrate (N/O/S).

87
Q

Which enzyme mainly catalyses a Glucuronidation reaction

A

UDP-glucuronyl transferase

88
Q

Which three process are involved in renal excretion of drugs

A

Glomerular filtration
Active tubular secretion
Passive reabsorption by diffusion across the tubular epithelium

89
Q

When can/cannot a drug be filtered by the glomerular

A

Large plasma proteins are not filtered. If a drug is unbound, it can be filtered. If it is bound to a protein, it cannot.
Charge has no importance.

90
Q

How can Clearance by filtration (CLfil) be calculated

A 
CLfil = GFR x fraction of drug unbound in plasma (fup)
GFR = Glomerular filtration rate; usually 120 ml/min
91
Q

How can Clearance by filtration (CLfil) be calculated

A 
CLfil = GFR x fraction of drug unbound in plasma (fup)
GFR = Glomerular filtration rate; usually 120 ml/min
92
Q

How much of the renal flow is filtered through the glomerulus

A

Up to 20%

93
Q

How much of the renal flow is delivered to the peritubular capillaries of the proximal tubule

A

Around 80%

94
Q

Which two transporters are involved in active secretion of drugs into the lumen of the nephron

A

Organic anion transporter (OAT)

Organic cation transporter (OCT)

95
Q

What is the specific role of the Organic anion transporter (OAT)

A

Transports acidic drugs.

Also endogenous acids (e.g. uric acid) and the marker for renal plasma flow (para-aminohippuric acid PAH)

96
Q

What is the specific role of the Organic cation transporter (OCT)

A

Transports basic drugs

97
Q

Give examples of acidic drugs

A

Penicillins, probenecid, thiazides

98
Q

Give examples of basic drugs

A

Morphine, neostigmine, amiloride, triamterene

99
Q

How does tubular secretion differ from glomerular filtration

A

Tubular secretion is able to secrete drugs that are highly protein-bound (filtration cannot)

100
Q

How much water filtered at the glomerulus is reabsorbed by the tubules

A

~99%

101
Q

List factors influencing reabsorption rate

A 
Lipid solubility (Higher LogP = v. reabsorbed and slowly excreted)
Polarity (v. polar = excretion, no reabsorption)
Urinary flow rate (diuresis decreases reabsorption)
Urinary pH (alkaline = acids excreted more. Acidic = bases excreted more)
102
Q

What does a quantal dose response relationship curve show

A

The fraction of the population that responds to a given dose of drug VS drug dose

103
Q

What is the purpose of a quantal dose response curve

A

Generalises effect of a drug to a population, as opposed to an individual. Can work out ED50, LD50 etc for the population

104
Q

Describe two types of Drug-drug interactions

A

Pharmacodynamic - modifies pharmacological effect, not change in tissue concentration
Pharmacokinetic - modifies the concentration that reaches the site of action

105
Q

Describe pharmacokinetic DDIs that can affect absorption

A

Metoclopramide - increases rate of stomach emptying
Atropine - decreases rate of stomach emptying
Antibiotics can reduce effectiveness of gut bacteria, which can decrease reabsorption rate (e.g. of oral contraceptives)

106
Q

Describe pharmacokinetic DDIs that can affect distribution

A

Plasma protein bound drugs might be displaces by a second drug. Free concentration increased. Only important when drug is highly protein bound or have a low TR (therapeutic ratio)

107
Q

Describe pharmacokinetic DDIs that can affect metabolism

A

Some drugs can inhibit or induct specific CYP450 enzymes, which reduce or increase activity.
Phenytoin (induction of CYP3A4), decrease warfarin effect
Cimetidie (inhibition of CYP2C9), increase warfarin effect

108
Q

Describe pharmacokinetic DDIs that can affect excretion

A

Drug can share a transporter (e.g. in proximal tubule of nephron).
Probenecid competitively reduces penicillin excretion

109
Q

List population variation factors that can cause an increased plasma concentration of a drug

A 
Saturable metabolism
Genetic enzyme deficiency
Renal/liver failure
Old/v.young age
Enzyme inhibition
110
Q

List population variation factors that can cause a decreased plasma concentration of a drug

A 
Poor absorption
High 1st pass metabolism
Genetic hypermetabolism
Enzyme induction
Non-compiance
111
Q

What is the result of competitive enzyme inhibition

A

Higher Km, same Vmax

112
Q

What is the result of non-competitive enzyme inhibition

A

Same Km, lower Vmax

113
Q

What is the result of enzyme induction

A

Same Km, higher Vmax

114
Q

How does prescribing change in patients with hepatic impairment

A

Most important in drugs that are extensively metabolised with a low TR.
Dose adjusted for:
High Cl drugs (affected by blood flow and enzyme capacity)
Low CI drugs (affected by enzyme capacity only)

115
Q

Describe specific altered drug responses in liver disease

A

Reduced synthesis of plasma proteins (causes toxicity of PPB drug with low TR)
Reduced synthesis of clotting factors (enhanced sensitivity to oral anti-coagulants)
Impaired excretion of drugs eliminated by the bile (occurs in chloestasis)
Pharmacodynamics:
Hepatic encephalophathy (deterioration of brain function, made worse by many drug classes)
Ascities (fluid build up in peritoneal cavity ass. with liver disease)

116
Q

How is renal impairment measured

A

Creatinine clearance (CrCl)

117
Q

How is drug dosage adjusted in renal imparirment

A

Drug dosage determined by:
Rate of CrCL (Creatinine clearance)
The fraction of drug that is excreted by the kidney in unchanged form (fu)
If fu = 1 ; adjust dose in direct proportion to degree of CrCl impairment
If fu = 0.5 ; adjust dose for fraction cleared by the kidney
If fu = 0 ; no adjustment needed

118
Q

What do different CrCl (creatinine clearance) values mean in terms of renal impairment

A

20-50 ml/min = mild
10-20 ml/min = moderate
< 10 ml/min = severe

119
Q

How does dosing for children differ to dosing for adults

A

Often dose by body weight or surface area.
Pharmacokinetics/dynamics are altered in neonates (<30 days old) - poor renal filtration, enzyme deficiencies, poor detoxifying systems, delayed excretion
Many medicines unlicensed for children

120
Q

How does dosing for the elderly differ to dosing for adults

A

Often poor rate of excretion.
Clearance is important consideration.
Metabolised or renally eliminated drugs usually have impaired clearance.

121
Q

How does dosing in pregnancy differ to dosing for adults

A

Main issue is teratogenicity.
If drug is orally absorbed, assume it can cross the placenta.
Most drugs not recommended, but may not be known to be dangerous.
Benefits need to outweigh risks.

A Quantitative Pharmacology (4 decks)

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