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FRACP > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

4 drugs were found in a CRIB and noted to induce p450 enzyme, what are they?

A

Carbamazepine
Rifampicin (classic inducer)
Isoniazid
Barbituates

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2
Q

What do the drug categories A-E for pregnancy mean?

A 
A no harm
B no harm in human/animal studies
C harm in animals but NOT human studies
D some risk
E high risk (contraindicated)
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3
Q

What are 2 pharmacodynamic drug considerations in pregnancy that implicate the foetus?

A
  1. All drugs enter the placenta
  2. All drugs enter breast milk
    NB: to some extent
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4
Q

Give one example of pharmacokinetic and pharmacodynamic drug interaction in the elderly.

A

Pharmacokinetic: warfarin and antibiotics leading to deranged LFTs and high INR due to common pathway for metabolism.

Pharmacodynamic: warfarin and aspirin causing a GI-bleed.

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5
Q

Describe 3 pharmacokinetic changes that come with the biology of aging?

A

Reduce, reduce, reduce!!!

  1. Clearance reduced - reduced hepatic and renal clearance
  2. Vd reduced - reduced volume of distribution as lean body mass and water is replaced with fat
  3. Protein binding reduced - due to hypoalbuminaemia
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6
Q

For the 4 phases of clinical trials, describe the clinical question asked in each. Give approximate sizes for such trials.

A

I - safety and dose finding (n=20)
II - safety and preliminary efficacy (n=100)
III - safety and mostly efficacy (n=500)
IV - post-marketing surveillance

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7
Q

What are type A and B drug reactions? Give an example of each.

A

Type A: related to drug action and therefore dose dependent e.g. warfarin causing bleeding.

Type B: unrelated to drug reaction and therefore NOT dose-dependent i.e. idiosyncratic and often immune mediated drug reactions e.g. penicillin rash.

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8
Q

Is the therapeutic index for warfarin high or low?

A

Low as therapeutic dose may cause adverse effect of bleeding.

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9
Q

Describe the following in terms of ability to attain maximal effect given a sufficiently high dose:

  1. Agonist
  2. Partial agonist
  3. Agonist with competitive antagonist
  4. Agonist with non-competitive antagonist
A

Agonist - maximal effect given high dose)
Partial agonist - submaximal effect despite high dose
Agonist with competitive (non-selfish) antagonist - maximal effect given high dose of agonist
Agoinst with non-competitive (selfish) antagonist - submaximal dose despite high dose of agonist

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10
Q

With what dosing regimen might steady-state plasma concentration (Cpss) be rapidly attained?

A

Double the normal dosing regimen and administer drug at t1/2 dosing intervals.

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11
Q

What are the considerations given the following t1/2 for a drug:

  1. t1/2 8-24h
  2. Short t1/2
  3. Long t1/2
A
  1. If t1/2 = 8-24h then in dosing interval should be t1/2
  2. Short t1/2 requires use slow-release preparations
  3. Long t1/2 requires daily dosing
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12
Q

If a drug dose is changed, how long will it take to attain the new Cpss (steady-state concentration) assuming first-order kinetics?

A

4-5 t1/2 assuming first order kinetics (i.e. non-saturable elimination)

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13
Q

When is drug equilibrium attained?

A

Drug accumulation = Drug elimination

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14
Q

How is drug bioavailability calculated?

A

B (%) = AUC (PO) / AUC (IV)

Always adjust for the same dose of drug.

AUC = area under the curve

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15
Q

Describe the difference between first-order (linear) and zero-order drug kinetics.

A

First-order kinetics (linear kinetics) = constant PROPORTION of drug eliminated per unit time, non-saturable, most drugs have first-order kinetics.

Zero-order kinetics = constant AMOUNT of drug eliminated per unit time, saturable.

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16
Q

True/False: hepatic drug clearance is dependent upon renal clearance.

A

False: hepatic and renal clearance is mutually independent.

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17
Q

What is the formula for Clearance?

What is the formula for t1/2?

A

IMPORTANT:

Cl (L/min) = Vd x 0.693 / t1/2

t1/2 = Vd x 0.693 / CL

(Where 0.693 = ln2)

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18
Q

What percentage of Asians have alcohol dehydrogenase deficiency? What does it do?

A

50% of Asians have alcohol dehydrogenase deficiency, enzyme usually acts to remove acetyleadehydes (toxic) from the body.

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19
Q

In terms of drug metabolism, explain the different SEs of isoniazid.

A

Phase II metabolism (acetylation) dictates isoniazid SEs:

Slow acetylators = peripheral neuropathy

Fast acetylators = hepatitis

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20
Q

What percentage of caucasions are slow acetylators? Which is the consequence of this?

A

50% of causasians are slow acetylators with phase II metabolism, these inidividuals are at risk of drug-induced SLE e.g. hydralazine and proacainamide.

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21
Q

What is the clinical significance of the following p450 enzymes:

  1. CYP2D6
  2. CYP2C9
  3. CYP2C19
A
  1. CYP2D6 (codeine): poor metabolisers unable to metabolise codeine (no analgesia), timolol (systemic beta blockade) and perhexeline (neuropathy and liver toxicity) - 10% of caucasians
  2. CYP2C9 (warfarin): poor metabolisers require only a small dose of warfarin - 2% of general population
  3. CYP2C19: poor metabolisers have reduced clearance of omeprazole.
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22
Q

What are the few drugs that lower INR (SCCRaP INR)?

A 
St Jon't Wort
Carbmazepine (competitive substrate)
Cholestyramine
Rifampicin (common CYP inducer)
Phenytoin
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23
Q

How is CYP2D6 implicated in analgesia?

A

CYP2D6 metabolises codeine to morphine.

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24
Q

Quinidine is a substrate and inhibitor of different CYP enzymes - which ones?

A

Quinidine:

Substrate of CYP3A4 Inhibitor of CYP2D6.

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25
Q

List a few common cytochrome p450 enzymes, which is the most common/dominant.

A

CYP3A4 is the most common and dominant cytochrome p450, others include CYP2D6, CYP2C9 and CYP2C19.

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26
Q

What are 4 inhibitors of the most common cytochrome p450 enzyme - CYP3A4?

(DAVE is tough and stops CYP3A4)

A 
Diltiazem
-Azoles
Verapamil
Erythromycin
(2CCBs, 2 antimicrobial)
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27
Q

What is a common p450 inhibitor? What is the effect on drug levels?

A

Cimetidine is a common cytochrome p450 inhibitor, this causes an increase in drug levels as drugs fail to metabolise.

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28
Q

What is a common p450 inducer? What is the effect on drug levels?

A

Rifampicin is a common cytochrome p450 inducer, this leads to reduced drug levels as drugs metabolised more.

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29
Q

Regarding drug levels comment on the following in terms of free/unbound and bound drugs:

  1. Binding to receptors
  2. Metabolised and renally excreted
  3. Measured drug levels
A
  1. Only free/unbound drug is available for binding to receptors.
  2. Only free/unbound drugs are metabolised and renally excreted.
  3. Drug levels measure free and bound drug.
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30
Q

Protein-binding properties of a drug are rarely clinically significant. When might protein-binding me relevant?

A

For protein-binding to be clinically significant a drug needs to be highly protein bound and large changes to protein levels need to occur (uncommon)

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31
Q

Describe phase I and II metabolism.

A

Phase I metabolism (RHO) = reduction, hydrolysis, oxidation

Phase II metabolism (conjugation) = glucuronidation and acetylation

32
Q

It is rare for drugs to have saturable protein binding, give 2 examples, what need to be considered for such drugs?

A

2 drugs with saturable protein binding include aspirin and disopyramide, increasing the dose of these medications increases the free drug levels disproportionately.

33
Q

What dose of drug will attain a plasma concentration (Cp) of 20mg/L with a given Vd of 1.5L? How might the dose be adjusted to achieve CPss (steady-state plasma concentration)?

A

Cp = Ab / Vd → Ab = Cp x Vd = 20mg/L x 1.5L = 30mg, steady state attained if Cp = Cpss

34
Q

What are 3 HIP causes of drug-induced lupus?

A

Hydralazine
Isoniazid
Phenytoin

35
Q

Given fu (fraction excreted unchanged), a patients estimated eGFR (PeGFR), normal eGFR (NeGFR) and a given dose (D), how does one calculate an adjusted dose (Dadj) in accordance with the patients eGFR?

A

Dadj = D[(1-fu) + fu(PaEGFR/NeGFR)]

i.e. adjustment of the the renally excreted dose only.

36
Q

Calculate the dose (D) required to achieve a plasma steady-state of Cpss given bioavailability (B) and clearance (CL).

A

B x D = CL x Cpss,

therefore D = (CL x Cpss) / B

B = bioavailability (%)
D = dose (mg/h)
CL = clearance (L/h)
Cpss = steady state plasma concentration (mg/L)
37
Q

Compare drugs of the same class in terms of efficacy and potency.

A

Drugs of the same class have the same efficacy but different potency

38
Q

Describe 3 pharmacokinetic changes in pregnancy.

A

3 pharmacokinetic changes in pregnancy:

  1. Increased Vd (increased by 20%)
  2. Increased CL (increase hepatic and renal clearance)
  3. Decreased PB (hypoalbuminaemia)
39
Q

What are the definitions of the following drug nomenclature:

  1. Medical incidents
  2. Advere drug events
  3. Adverse drug reactions
A
  1. Medical incidents: not harm to patient
  2. Adverse drug events: harm to patient but not related to action of drug
  3. Adverse drug reactions: harm to patient and related to drug action
40
Q

How is therapeutic index calculated? Is a high or low therapeutic index prefarable?

A

Therapeutic index = min dose toxic / min dose efficacious = LD50 / ED50

High therapeutic index is preferable.

41
Q

What are on the y-axis and x-axis of a efficacy/potency graph? How is ED50 defined on this graph?

A

Graph with %Emax (y-axis) and ln(Cp) (x-axis) describes efficacy (y-axis) and potency (x-axis). ED50 is defined as dose required to attain 50% efficacy.

42
Q

Give an example of an antagonist and describe the difference between a competitive and non-competitive antagonist.

A

Propanolol is a beta receptor antagonist.

Competitive antagonist (unselfish) antagonist that binds reversible to a receptor, high dose of agonist can achieve maximal effect.

Non-competitive antagonist (selfish) antagonist that binds irreversibly to a receptor, even at high doses an agonist only attains submaximal effect.

43
Q

Give an example of an agonist and describe the difference between full and partial agonist.

A

Salbutamol is a beta receptor agonist.

Full agonist = achieves maximal effect at high doses

Partial agonist = achieves submaximal effect even at high doses

44
Q

For saturable drug metabolism comment on 2 aspects of pharmacokinetics and give a few examples of such drugs.

A

Saturable metabolism (e.g. phenytoin):

Drug levels will increase exponentially with increase dosing i.e. the amount of free drug increases with increased dose.

Changes to dosing need to be small and close monitoring with either drug levels or biomarker is required.

Examples (APE) = aspirin, phenytoin and EtOH

45
Q

In words, describe the difference between the graphs of first-order and zero-order kinetics.

A

Graphic of %Cmax (y-axis) and time (x-axis):

First-order kinetics (non-saturable) – linear kinetics but depicted as a curve (semantic dissonance), same PROPORTION of drug eliminated per unit time.

Zero-order kinetic (saturable), same AMOUNT of drug eliminated per unit time.

46
Q

Define therapeutic index with respect to adverse effects.

A

Therapeutic index determines the doses outside of which AEs occur, hence the larger the therapeutic index the better.

47
Q

What is the arbitrary definition of Cpss?

A

Cpss > or = 95% of Cmax

48
Q

Give 3 inhibitors of CYP2D6.

A

QNF: quinidine, neuroleptics, fluoexetine

49
Q

Give 5 substrates for CYP3A4.

A

MCCWQ: methylprednisolone, cyclosporin, carbamazepine, warfarin, quinidine.

50
Q

Give 4 sites of drug metabolism in the body, which of these is the most common?

A

Sites of metabolism: liver (most common), renal, lung, adrenals.

51
Q

True/False: for most drugs protein binding is saturated.

A

For most drugs protein binding is NOT saturated, this means that there is a constant PROPORTION on drug eliminated (i.e. clearance is constant). The % bound also remains constant. Dose increases lead proportional increases to Cp.

52
Q

Outline common aspects of:

  1. Pharmacokinetics
  2. Pharmacodynamics
A
  1. Pharmacokinetics: Vd, CL, PB, metabolism

2. Pharmacodynamics: efficacy, toxicity, AEs

53
Q

What is the unit for eGFR?

A

eGFR unit = mL/min/1.73m^2

54
Q

What is the effect of of lipid-solubility upon a drugs volume of distribution (Vd)?

A

Lipid-soluble drugs have larger Vd than water-soluble drugs.

55
Q

Given a Vd of 4L and desired plasma concentration of 125mg/L, calculate the required STAT dose of digoxin requires.

A

Cp (mg/L) = drug dose (mg) / Vd (L)

drug dose = Cp x Vd = 125 x 4 = 500mg

56
Q

What is P-glycoprotein and what is it’s effect on drug absorption?

A

P-glycoprotein is an EFFLUX protein that lies in the gastrointestinal lumen, it causes decrease in drug absorption.

57
Q

For P-glycoprotein give:

  1. Substrate
  2. Inhibitor
  3. Inducer
A
  1. Substrate = digoxin
  2. Inhibitor = amiodarone
  3. Inducer = phenytoin
58
Q

For OATP give:

  1. Substrates (2)
  2. Inhibitors (2)
A
  1. OATP substrate = digoxin / hydrocortisone

2. OATP inhibitor = fruit juice / erythromycin

59
Q

What is OATP and what is it’s effect upon drug absorption?

A

INFLUX protein that is found in different locations (effect depends upon location):

GIT (between intestinal lumen and intestinal wall): INCREASES drug absorption into blood plasma

Liver (between sinusoidal membrane and portal circulation): DECREASES drug levels by allowing excretion into bile (hepatic filtration)

60
Q

What effect does water-solubility and lipid-solubility have upon volume of distribution?

A

Effect of type of solubility upon volume of distribution:

  1. Lipid-soluble = increased Vd
  2. H20-soluble = decreased Vd
61
Q

What does the term ‘fraction excreted ‘ (fu) mean?

A

Fraction excreted unchanged (fu) is the proportion of a drug excreted by the kidney is a healthy individual

62
Q

What is the simplified definitions of pharmacokinetics and pharmacodynamics?

A

Pharmacokinetics = body on drug

PharmacoDynamics = Drug on body

63
Q

2 drug preparations of the same drug: Drug A has a Cp of 10mg/L with a 90% protein binding and drug B has Cp 5mg/L with 80% protein binding. Compare the pharmacodynamics of the two drug preparations?

A

Cp 10mg/L with 90% PB = 1mg/L active drug

Cp 5mg/L with 80% PB = 1mg/L active drug

Therefore these two drug preparations are ‘pharmacodynamically’ identical.

64
Q

Very few medication are not affected by warfarin, list 4.

A

SAAB drivers are NOT affected by warfarin:

Statins
ACEi
ARBs
Benzodiazepines

65
Q

In more detail list the aspects of pharmacokinetics?

  1. Drug going in
  2. Drug inside
  3. Drug going out
A

Pharmacokinetics = effect of body on drug

Inward: Administration / Absorption / Bioavailability

Inside: Distribution / Protein-binding / steady-state (accumulation = limination)

Outward: Metabolism / Excretion / Half-life / Clearance

66
Q

How does one calculate clearance (CL)?

A

CL = Vd x 0.693 / t1/2

F x D = CL x Cpss
CL = F.D/Cpss

Vd = vol. of distribution
F = bioavailability
D = dose
Cpss = steady-state plasma concentration.
67
Q

Summarise the less common CYP enzymes in 3 points (i.e. non CYP3A4).

A
  1. CYP2D6 poor metabolisers in CAUCASIANS: codeine (ineffective),
    timilol (systemic beta blockade), perhexeline (liver toxicity and neuropathy)
  2. CYP2D9 poor metabolisers e.g. warfarin (only low dose required).
  3. CYP2C19 poor metabolisers in 20% of mongoloids with reduced clearance of omeprazole
68
Q

Define type A and type B adverse drug reactions.

A

Types of adverse drug reaction:

Type A = dependent upon drug action e.g. warfarin and bleeding
Type B = independent of drug action and immunological e.g. pencillin drug reaction

69
Q

True/False: In first-order kinetics drug elimination ‘mirrors’ drug accumulation

A

True.

70
Q

Give 2 examples of drugs affected by first-pass metabolism?

A

Drugs with decreased PO absorption due to 1st pass metabolism (i.e. drug aren’t given PO):

  1. Morphine (SC)
  2. GTN (topical)
71
Q

Describe aspects of pharmacodynamics?

A

Pharmacodynamics is effect of drug on body and includes:

  1. Efficacy / Potency / AEs
  2. Monitoring
  3. Agonists / Antagonists
72
Q

For Digoxin, how many hours after administration should blood be taken to measure a level? Why is this?

A

6 hours - to ensure adequate distribution.

73
Q

If a dose of Digoxin is changed, after what period of time will the new steady-state plasma concentration be attained (assuming normal renal function)?

A

Assuming 4 half-lives - 6 days.

74
Q

Foe 100mg hydrocortisone, give the approximate equivalents for:

Cortisone
Prednisone/Prednisolone
Methylprednisolone
Dexamethasone

A

100mg hydrocortisone equals:

125mg cortisone

25mg prednisone/prednisolone/methylprednisolone

4mg Dexamethasone (actually 3.75mg)

75
Q

True/False: In zero-order kinetics ELIMINATION is constant.

A

True

76
Q

Compare the Cpss of zero-order and first-order kinetic drugs.

A

Zero-order kinetics = Cpss independent of t1/2 (arguable no half-life)

First order kinetics = Cpss dependent upon t1/2 (confers predictability in drug elimination)

77
Q

How total clearance of a drug calculated?

A

Cl (total) = Cl (hepatic) + Cl (renal) + Cl (other)

NB: hepatic and renal clearance are independent of one another.

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