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Pharmacology (Semester 6) > 1.1 Pharmacokinetics > Flashcards

1.1 Pharmacokinetics Flashcards

1
Q
A
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2
Q

Define the following terms:

  • Pharmaceutical Process
  • Pharmacokinetic Process
  • Pharmacodynamic Process
  • Therapeutic Process
A

Pharmaceutical Process: getting the drug into patient

Pharmacokinetic Process: getting drug to the site of action

Pharmacodynamic Process: producing required pharmacological effect

Therapeutic Process: Pharm effect translated to a therapeutic effect

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3
Q

Define the following terms:

  • Pharmacokinetics
  • Pharmacodynamics
  • Pharmacogenetics
A

Pharmacokinetics: what the body does to the drug

Pharmacodynamics: what the drug does to the body,

Pharmacogenetics: effect of genetic variability on PK and PD

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4
Q

Give 2 importances of Pharmacokinetics

A

1) essential part of drug regulation: MHRA / FDA
2) elucidates the mechanisms of drug interactions

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5
Q

Give the 5 key factors of Pharmacokinetics (HI DEB)

A
  1. Half-life
  2. Intra-subject variability
  3. Drug-Drug interactions
  4. Drug Elimination
  5. Bioavailability
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6
Q

Give 4 factors affecting drug pharmacokinetics in an individual

A
  1. Infection
  2. Disease
  3. Stress
  4. Renal function
  5. Liver function
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7
Q

Pharmacokinetics is the study of the ________ of drugs and their _____ through the body

A

movement, metabolites

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8
Q

What 4 general processes determine pharmacokinetics of a drug? (ADME)

A

Absorption, Distribution, Metabolism, Elimination

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9
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10
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11
Q

How do we calculate Therapeutic index (or ratio)?

A

Therapeutic index = TD50 / ED50

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12
Q

Define the following:

  • TD50
  • Therapeutic window
  • ED50
A

TD50: the dose at which toxicity occurs in 50% of cases

Therapeutic window: the range of blood level where the drug is producing the desired effect

ED50: the dose that produces a specific effect in 50% of the population

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13
Q

What is meant by the Therapeutic index and what can be said about a larger TI?

A

A ratio that compares the blood conc at which a drug becomes toxic and the conc at which the drug is effective

The larger the therapeutic index (TI), the safer the drug is

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14
Q

Define bioavailability?

A

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

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15
Q

Compare the bioavailability of an intravenous bolus vs other routes

A

Intravenous bolus: bioavailability is 100%

Other routes: compare amount reaching the body compartment by that route with intravenous bioavailability

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16
Q

What is meant by AUC and what can be said about IV AUC?

How do we therefore calculate oral bioavailability (F)?

A

AUC = area under the Curve

IV AUC = Total drug Exposure

oral bioavailability: F = AUC oral / AUC IV

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17
Q

Give 4 factors affecting bioavailability

A

Absorption:

  • drug formulation
  • age
  • food ie. lipid-soluble > water-soluble
  • vomiting / malabsorption

First pass metabolism (extraction ratio)

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18
Q

Compare long (extended release) vs short (immeadiate release) oral drugs in terms of the graph below

Incl which has a higher bioavailability

A

Extended release: only one dose is required which is delayed being released into the plasma, but results in a sustained ongoing release and therfore a higher conc in plasma (higher bioavailability)

Immediate release: graph shows 4 doses are required in order to maintain drug within theraputic window (lower bioavailability)

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19
Q

Describe the structue of an extended release oral tabel

A

Extended release drugs have a capsule surrounding them. Within this is the tablet. The capsule consists of a range of beads of different sizes, all containing the SAME conc of drug. The difference in sizes accounts for the sustained plasma conc of the drug due to smaller beads releasing faster than larger ones

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20
Q

What is meant by first pass metabolism?

A

Metabolism occurring before the drug enters the systemic circulation, the ‘first-pass’ effect

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21
Q

Give 3 locations where first pass metabolism may occur and how

A

1) Gut Lumen by gastric acid and proteolytic enzymes (+ grapefruit juice)
2) Gut Wall by P-glycoprotein efflux pumps, which pump drugs out of the intestinal enterocytes back into the lumen
3) The Liver

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22
Q

Give 3 examples of drugs in which first pass metabolism occurs in the gut lumen

A

Benzylpenicillin, insulin, cyclosporin

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23
Q

Give an example of a drug in which first pass metabolism occurs in the gut wall

A

cyclosporin

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24
Q

Give an example of a drug in which first pass metabolism occurs in the liver

A

Propranolol (extensively metabolised in the liver)

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25
Q

How do drugs abosrbed in the gut wall enter the liver?

A

Via the portal vein

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26
Q

What is meant by Drug Distribution?

A

Its ability to ‘dissolve’ in the body

27
Q

What 2 key factors influence Drug Distribution?

A

1) Protein binding
2) Volume of Distribution (Vd) (Theoretical Constant)

28
Q

In the systemic circulation many drugs are bound to circulating proteins, give 4 examples and which type of drugs bind each

(GALA)

A

1) Albumin (acidic drugs)
2) Globulins (hormones)
3) Lipoproteins (basic drugs)
4) Acid glycoproteins (basic drugs)

29
Q

What MUST a drug be in order to have a pharmacological effect and why?

A

Unbound (free)

Only the fraction of the drug that is not protein-bound can bind to cellular receptors, pass across tissue membranes, gain access to cellular enzymes etc..

30
Q

What determines a drugs action at a receptor?

Displacement of drugs from binding sites causes what?

A

Free drug determines its action at receptor

Displacement of drugs from binding sites causes protein binding drug interactions

31
Q

A drug must be in its free form in order to __1__ or __2__

A

1) bind to target receptor
2) be eliminated

32
Q

Changes in protein binding can occur, causing changes in drug distribution

These are only important if 3 criteria are met, list these

A

1) High protein binding
2) Low Vd
3) Has a narrow therapeutic ratio

33
Q

Give 4 factors affecting protein binding

A
  1. Hypoalbuminaemia
  2. Pregnancy
  3. Renal failure
  4. Displacement by other drug
34
Q

Drug that is not bound to plasma proteins is available for distribution to ____

Some are distributed only to the body _____, while others are bound extensively in body _____.

A

tissues, fluids, tissues

35
Q

How can we measure the distibution of drugs in the tissues?

A

Volume of distribution (Vd)

36
Q

What is Vd, how is it calculated and when may it be useful

A

Volume of Distribution is how widely drug is distributed in body tissues

Vd ~ Dose / [Drug] t0

It is a hypothetical measure, but is useful in understanding dosing regimens

  • e.g. 100mg gentamicin dose, peak plasma concentration 5mg/l, then the Vd will be 20 litres.
37
Q

What is t1/2 and what is it’s relationship to Vd and clearance?

A

t1/2 ➞ Half life of a drug: the time required for plasma concentration to decrease by half

t1/2 is proportional to Vd BUT inversely proportional to clearance

38
Q

Describe the 2 phases of drug metabolism in the liver

A

1) Modification of drug to more reactive or polar metabolite by phase I enzymes via oxidation, reduction, hydrolysis etc.. This exposes the reactive groups
2) Conjugation ➞ phase II enzymes conjugates drug with endogenous molecules ie. glucoronide, sulphate and glutathione. This makes drug water solube

39
Q

Oxidation and reduction of phase I metabolism are in part dependent on what family of enzymes?

What is their other role?

A

Cytochrome P450 (CYPs)

Also metabolise toxins such as carcinogens and pesticides

40
Q

What are the 2 outcomes of a drug following phase II metabolism is the liver?

A

1) kidney ➞ urine
2) gallbladder ➞ bile

41
Q

What is the purpose of phase II metabolism in the liver?

A

The end products of conjugation are water-soluble enabling rapid elimination from the body. They are also usually pharmacologically inactive

42
Q

What are Pro-drugs and give 2 examples

A

Pharmacologically inactive compound metabolised to an active one

Eg.

  • Inactive enalapril to active enalaprilat
  • L-Dopa metabolised to a more active metabolite to improve distribution (crosses blood-brain barrier)
43
Q

Codine is a prodrug, how does it differ from prevously mentioned prodrugs?

Give one other drug that is also metabolised this way

A

Codine is a pharmacologically active compound which is metabolised to another active compound morphine

Other drug: Losartan to EXP3174

44
Q

Give 4 ways in which P450 enzymes can be influenced

A

1) by enzyme- inducing and enzyme-inhibiting drugs
2) age
3) liver disease
4) hepatic blood flow
5) cigarette and alcohol consumption

45
Q

What do enzyme- inducing and enzyme-inhibiting drugs do?

A

Alter the rate of metabolism of other drugs by influencing activity of P450 enzymes

46
Q

Where are CYP450 located and how do they differ

Give 4 major examples

A

Present mainly in the liver (some gut and lung). They have genetic differences in metabolism

Major examples: CYP2D6, 2C9, 2C19, 3A4

47
Q

Give 5 factors that may influence drug metabolism and why

A

Race: development of pharmacogenetics

Age: metabolism reduced in aged patients and children

Sex: women are slower ethanol metabilisers

Species: drug development

Clinical or physiological condition

48
Q

What else MUST we consider when prescribing drugs?

A

Consider OTC and food as drug-drug interactions

Eg. charcoal grill 1A+; grapefruit juice 3A- ????

49
Q

What is the MAIN route of drug elimination plus 4 other routes?

A

Main route is the kidney.

Other routes include the lungs, breast milk, sweat, tears, genital secretions, bile, saliva

50
Q

What 3 processes determine the renal excretion of drugs?

A

1) Glomerular Filtration
2) Passive tubular reabsorption
3) Active tubular secretion

51
Q

Explain how drug elimination occur in the nephron?

A
52
Q

What is Clearance?

A

Ability of body to excrete drug (mostly = GFR)

53
Q

1) If the GFR is reduced then clearance is ______
2) t1/2 is __________ to clearance
3) A reduction in clearance (or GFR) ______ t1/2

A

reduced, inversely proportional, increases

54
Q

Drug elimination may either be first order kinetics or zero order kinetics, define each

A

1st Order kinetics - Linear
Rate of elimination is proportional to drug level. Constant fraction of drug eliminated in unit time. Half life can be defined.

Zero Order kinetics – Non-linear

Rate of elimination is a constant.

55
Q

What does each of the graphs show?

A

Both demostrate 1st order kinetics

First graph shows how concentration of the drug decreases by half every 15 mins

Second graph is linear when ln[drug] is plotted against time

(ln[drug] = natural logarithim of plasma conc of drug)

56
Q

The graph below shows 1st order kinetics, what does the gradient of this line give us and how is it calculated?

A

k = Elimination Rate Constant = Cl / Vd

(ERC is itself equal to Cl/Vd)

Allows us to calculate the half life of the drug

57
Q

Zero order kinetics is ______ to predict than linear order kinetics. This means ______ is easier with 1st order kinetics

A

Harder, dosing

58
Q

A drug showing first order kinetics is _____ likley to hit the theraputic window. Whereas, ______ levels are more likely to be reached with a drug showing zero order kinetics

A

More, toxic

59
Q

What would a graph of Zero order kinetics show and how does this differ from one showing first order kinetics?

A

Zero: straight line when linear y axis scale plotted against time

First: linear when ln[drug] plotted against time

Zero order shown on image below

60
Q

Most drugs exhibit _____ order kinetics at high doses. However, drugs within their theraputic window exhibit _____ order kinetics

Explain why

A

Zero, First

At high doses, the receptors/enzymes become saturated

61
Q

Give 4 main pharmacokinetic reasons why we would do drug monitoring + 2 others

A

If the drug has:

  1. zero order kinetics
  2. long half-life
  3. narrow therapeutic window
  4. at greater risk of drug-drug interactions

Others include:

  1. know toxic effects (e.g. bone marrow suppression or alteration in U+Es)
  2. monitoring therapeutic effect (e.g. BP, glucose etc)
62
Q

Most drugs are given as prescriptions for longer cources of time, what are we trying to achieve?

A

CpSS ➞ Steady State Concentration in Plasma

63
Q

During repeated drug administration, a new steady state is achieved in ___ half lives.

Generally this is irrespective of ____ or _____ of administration.

From CpSS, it also takes ___ half live to ______ most of the drug

A

5, dose, frequency, 5, eliminate

64
Q

Compare the black vs red line below and state what the red box indicates

A

Black line: we see the concentration is slowly reaching the theraputic window

Red line: Alternative, where we may administer a loading dose (red box) which is an initial higher dose that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose

Pharmacology (Semester 6) (17 decks)

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