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Clinical Pharmacology, Therapeutics & Principles of Prescribing > Pharmacokinetics & Pharmacodynamics > Flashcards

Pharmacokinetics & Pharmacodynamics Flashcards

1
Q

What is the difference between pharmacokinetics and pharmacodynamics?

A

PKs are the effects of the drug on the body

PDs are the effects of the body on the drug

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2
Q

What are the 4 broad ways in which drugs work?

A

Depression

Stimulation

Destruction

Replacement

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3
Q

Name some unconventional mechanisms of action.

A

Disruption of structural proteins

Enzymes

Covant linkage

Chemical reactions

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4
Q

What is the difference between an agonist and a partial agonist?

draw a dose response curve to show the difference?

A

An agonist will bind to a receptor fully whereas a partial agonist will only partially bind to a receptor to ellict a smaller response.

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5
Q

What is a competitive antagonist?

Draw the dose-response curve from competitive antagonists

A

Competitive antagonists bind to receptors at the same binding site as the endogenous ligand or agonist, but without activating the receptor.

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6
Q

What is the definition of bioavailabilty?

A

The fraction of a dose which finds its way into a body compartment, usuaully the circulation

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7
Q

What is the bioavaliability of an IV bolus?

A

100%

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8
Q

How would you measure bioavaliabilty for all routes apart from IV bolus?

A

Bioavaliability = Area under curve for route
Area under curve for IV

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9
Q

What does the area of the curve (AUC) represent?

A

The total drug exposure

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10
Q

Which factors effect bioavaliability?

A
  • *A**bsorption of drug
  • First pass metabolism
  • *D**istribution
  • Protein binding
  • Volume of distribution (Vd)

Metabolism

Excretion

“ADME”

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11
Q

Give examples of some things that may effect absorption of a specific drug?

A

Drug formulation - intermediate vs modified release

Age of patient

Food intake

Vomiting, malabsorption

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12
Q

What is meant by the term “first pass metabolism”?

At what sites might this occur?

A

Metabolism occuring before the drug enters the systemic circulation

The gut lumen

The gut wall

The liver

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13
Q

Give some examples of drugs that are metabolised before they enter the systemic circulation i.e. at first pass metabolism

A

Insulin

Ciclosporin

Propanolol

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14
Q

The distribution of a drug refers to its ability to ________ in the body

A

‘dissolve’

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15
Q

Drug distribution can be divided into which two categories?

A

Protein binding

&

Volume of distribution (Vd)

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16
Q

In order to have a pharmalogical effect, most drugs must be bound or unbound?

A

Unbound (free)

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17
Q

Give some examples of circulating proteins that drugs might be bound to?

A

Albumin

Globulins

Lipoproteins

Acid glycoproteins

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18
Q

The amount of ______ drug determines its action at receptor

A

free

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19
Q

What does displacement of drugs from binding sites cause?

A

Protein Binding Drug Interactions

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20
Q

Changes in protein binding that cause changes in drug distribution are only important if which 3 criteria are met?

A
  1. high protein binding
  2. low Vd
  3. has narrow therapeutic ratio
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21
Q

Which factors may affect protein binding?

A

Hypoalbuminaemia

Pregnancy

Renal failure

Displacement by other drugs

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22
Q

Why does the risk of toxic effects of protein bound drug “A” increase when adding a highly protein bound drug?

A

The highly protein bound drug is going to take up the binding sites on protein and mean that amount of free drug A increases- the risk of toxic effects from drug A also increases

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23
Q

How do you work out volume of distribution?

A

Dose
Concentration of drug at time 0

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24
Q

The half life of a drug is ________ to Vd (and clearance)

A

Proportional

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25
Q

What are the amounts (in litres) of fluids in the major body compartments of a 70kg man?

A

Intracellular: 23l

Interstitial space: 14l

Intravascular space: 5l

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26
Q

What are the differences between phase I and phase II liver enzymes in relation to drug metabolism?

A

Phase I- oxidation & reduction by CYP enzymes

Phase II- conjugating enzymes: facilitate the addition of endogenous molecules such as glucuronic acid and glutathione

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27
Q

The end products of conjugation are ________ enabling rapid elimination from the body

A

water-soluble

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28
Q

True of Flase: The end products of conjugation are usually pharmacologically active

A

FALSE

They are usually inactive

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29
Q

CYP450 isoenzymes are present mainly where?

Where else can they be found?

A

Liver

Gut and lung

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30
Q

Give some examples of the major isoforms of cytochrome P450

A

CYP2D6

CYP3A4

CYP2C9

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31
Q

Give an example of a drug interaction that causes changes in plasma levels of the drug due to enzyme inhibition

State what the clinical consequence of such could be

A

Warfarin

+Cimetidine

Increase in plasma concentration of warfarin

Patient becomes increasingly anti-coagulated

Increased risk of bleeding for that patient

32
Q

List some important factors that should be considered when prescribing drugs, in relation to their metalbolism

A

OTC drugs
Drug-drug interactions
Food-drug interactions
Race
Age

Sex
Species (drug development)
Clinical/physiological condition

33
Q

The main route of drug elimination is via what?

Give examples of some other, less common, routes.

A

The kidneys

Lungs, breast milk, sweat, tears, genital secretions, bile, saliva

34
Q

Which 3 processes determine the renal excretion of drugs

A
  • Glomerular filtration
  • Passive tubular reabsorption
  • Active tubular secretion
35
Q

What is drug clearance?

A

The ability of the body to excrete drug

36
Q

Clearance mostly = _______

If _______ is reduced, then clearance is reduced

A

GFR

37
Q

______ is inversely proportional to clearance

A

Drug half-life

38
Q

A reduction in clearance (GFR) increases ________

A

drug half-life

39
Q

What is meant by 1st order kinetics in relation to drug elimination?

What is another term for this kind of drug elimination?

A

The rate of elimination is proportional to drug level

Linear drug elimination

40
Q

What is the meaning of the term “Zero order kinetics”?

How else can this be described?

A

The rate of elimination is constant- it is FIXED per unit time

Non-linear kinetics

41
Q

What can we obtain from drugs displaying 1st order kinetics compared to those with 0 order kinetics?

A

Can determine the HALF-LIFE of the drug and predict the dose increment with 1st order

Cannot do these with 0 order

42
Q

Why are zero order drugs more likely to result in toxicity?

A

The half life is not calculable

Dose increments not predictable

Small dose changes may produce:

  • Large increments in plasma concentration
  • Therefore lead to toxicity
43
Q

Because of the unpredictability of drugs showing zero order kinetics, what must we do to ensure they are safe to use?

A

Drug monitoring

44
Q

Apart from zero order kinetics, why else might we use drug monitoring?

A

Long half-life

Narrow therapeutic window

Greater risk of drug-drug interactions

Known toxic effects

Monitoring of therapeutic effect

45
Q

During repeated drug administration, a new steady state is achieved in ________ half-lives, irrespective of _________

A

3-5

Dose or frequency of administration

46
Q

Once the steady state (CpSS) is reached, how may half lives does it usually take to eliminate the drug?

A

Same as to reach steady state from initial dose

(3-5)

47
Q

Due to the number of half-lives required to get to steady state, what can we do clinically to ensure the patient is benefitting from the drug from the initial dose and not having to wait for therapeutic levels to be reached?

A

Give a loading dose (much higher dose than maintenance dose) to get to therapeutic levels

48
Q

Give an example of a drug that requires a loading dose, and explain why

A

Digoxin

It has a high volume of distribution due to its long half-life

It would take over a week to reach a steady state but patient needs the benefit of the drug asap- therefore we use loading dose to get to this therapeutic level

49
Q

How does renal failure effect the ability to use a loading dose?

A

It doesn’t usually, unless the patient has very severe renal failure

But the maintenance dose should be reduced if the renal failure leads to reduced clearance of the drug

50
Q

In a patient with renal failure it is going to take ________ to eliminate the drug

A

Longer

51
Q

How do we work out the loading dose of a drug?

A

Loading dose = Vd x [Drug]target

52
Q

Work out the loading dose for this patient:

100kg man

Phenytoin Vd= 0.7L per kg body weight

CpSS Phenytoin= 20mg/L

Phenytoin is administered as salt w. 92% Phenytoin

A

Phenytoin Vd= 100 x 0.7 = 70L

LD= 70 x 20 = 1400 mg

True LD= 1.4g ÷ 0.92 = 1.5g

53
Q

How do we calculate the half-life of a drug?

A

Drug half-life = Vd ÷ Clearance

54
Q

Example of working out half life ??????

A

?????

55
Q

Explain what is meant by the multi compartment model of the rate drug elimination

A

Takes into account that most drugs do not remain solely in the plasma

Distribution occurs in multiple compartments and equilibrium between these is not equal

Therefore rate of elimination varies

56
Q

How does the addition of a competitive antagonist to agonist change Emax and EC50 in a dose-response curve?

What does this mean in terms of the dose of agonist required?

A

Emax = not changed

EC50= increased

Higher dose of agonist needed to eliicit the same response

57
Q

How does the addition of a non-competitive antagonist to agonist change Emax and EC50 in a dose-response curve?

What does this mean in terms of the dose of agonist required?

A

Emax is reduced

EC50 stays the same

No matter how the dose of agonist is changed, the response stays the same and will be less than it would have been with agonist alone

58
Q

Describe the term “drug selectivity” and how this relates to side effects in patients.

A

The more “selective” a drug is for its target, the less chance that it will interact with different targets and have less undesirable side effects

59
Q

Describe the term “drug specificity” and give some examples

A

How well targeted drugs are against a specific receptot subtypes which enables them to be targeted against a specific organ

Less actions on non-target organs

e.g. heart beta1 adrenergic receptors

lungs beta2 adrenergic receptors

60
Q

What is “affinity”?

A

The tendency of a drug to bind to a specific receptor type

61
Q

What is “efficacy”?

A

The ability of a drug to produce a response as a result of the receptors being occupied

The maxmum effect of a drug

62
Q

What is “potency”?

A

The dose required to produce the desired biologic response

63
Q

What is the therapeutic index?

A

The relationship between concentrations causing adverse effects and concentrations causing desirable effects

= EC50(adverse effect)
EC50(disired effect)

64
Q

What is a therapeutic window?

A

A range of dosages that can effectively treat a condition whilst still remaining safe

65
Q

give some examples of drugs with narrow therapeutic windows

A

Warfarin

Digoxin

66
Q

How does altered P-glycoprotein activity change the absorption of a drug?

A

It changes the active transporter

67
Q

Large amount of free drug leads to increased rate of ____________

A

Excretion

68
Q

Protein binding interactions are important for what kinds of drugs?

A

IV drugs

Drugs with hort-half life

Drugs with narrow therapeutic index

69
Q

Give some examples of drug-renal disease interactions and the consequences that make these important to bear in mind when prescribing

A

Falling GFR - either chronic or acute:

(digoxin, aminoglycoside abx)

  • Reduced clearance of renally excreted drugs
  • Disturbances of electrolytes may lead to toxicity
  • Nephrotoxins may cause further kidney damage
70
Q

Give some examples of drug-hepatic disease interactions and the consequences that make these important to bear in mind when prescribing

A

Reduced clearance of drugs metabolised by the liver

Reduced CYP450 activity

= Longer half lives = Increased toxicity

e.g. Opiates in cirrhosis–> accumulation–> coma

71
Q

Give some examples of drug-cardiac disease interactions and the consequences that make these important to bear in mind when prescribing

A

Falling cardiac output:

-Excessive response to hypotensives

-Reduced organ perfusion
reduced hepatic blood flow & clearance, reduced renal blood flow & clearance

72
Q

Give some examples of drug-food interactions and the consequences that make these important to bear in mind when prescribing

A

Grapefruit juice
Inhibits several CYP450 isoenzymes, reduced clearance of simvastatin, amiodarone, terfenadine = increased exposure of drug

Cranberry juice
Inhibits CYP2C9 isoform, reduced clearance of warfarin= enhanced anticoagulant effect, increased risk of haemorrhage

73
Q

What is an adverse drug reaction?

A

An unwanted or harmful reaction which occurs after administration of a drug(s) and is suspected or known to be due to the drug(s)

74
Q

Explain the differences between major, moderate and mild ADRs

A

Major: permanent/life threatening

Moderate: requires additional treatment

Mild: trivial/unnoticable

75
Q

Give some examples of situations that would be high risk for ADRs

A
  • Ignorant, inappropriate and reckless prescribing (salty+++)
  • Polypharmacy
  • Patients at the extremes of age
  • Multipple medical problems
  • Use of drugs with narrow therapeutic windows

Clinical Pharmacology, Therapeutics & Principles of Prescribing (22 decks)

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