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ICPP > ICPP S10/11 Pharmacokinetics > Flashcards

ICPP S10/11 Pharmacokinetics Flashcards

1
Q

What is pharmacokinetics?

A

Branch of pharmacology concerned with how the body acts on a drug and how the drug moves around the body.

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2
Q

What are the four phases of Pharmacokinetics?

A

Absorption
Distribution
Metabolism
Elimination

ADME

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3
Q

What is meant by absorption?

A

How the drug is absorbed into the body from the site of administration.

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4
Q

What is meant by distribution?

A

How the drug is distributed/ spread out through out the body and it’s many compartments.

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5
Q

What is meant by metabolism?

A

The chemical changes that occur to a drug as it travels through the body.

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6
Q

What is meant by excretion?

A

The way in which the drug is removed from the body.

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7
Q

What are 2 types of route a drug can be administered through?

A

Enteral - absorbed through GI tract

Parentral - absorbed through other route than GI tract - GI tract is bypassed.

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8
Q

What are the 3 enteral routes?

A

Oral
Sublingual
Rectal

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9
Q

What are some parentral routes and which 3 are the main ones?

A

Subcutaneous
Intramuscular
Intravenous

Transdermal
Intra-arterial
Intravitreal
Intrathecal

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10
Q

Why is oral administration the most common form of drug administration?

A

No training required
Easily stored
Non-invasive and therefore reduces risk of infection

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11
Q

What are some cons of oral admin?

A

Limited bioavailability
Dependant on patient taking it
Exposed to first pass metabolism
Exposes drug to GI tract - broken down in stomach, react with other drugs/ nutrients.

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12
Q

What are some factors which affect GI absorption?

A
  • Other chemicals in the gut altering pH.
  • Interaction of drug with other chemicals in the gut.
  • Lipophilicity/ pKa
  • GI length and SA
  • GI motility
  • Density of SLC expression
  • First pass metabolism in gut lumen, gut wall/ liver.
  • Blood flow to GI - increased after meal - reduced during shock/ anxiety/ exercise.
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13
Q

Lower pH values encourage absorption of weakly acidic drugs.

True or false?

A

True

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14
Q

How do molecules with a net ionic charge get carried across GI epithelia?

A

SLC transport

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15
Q

In which epithelia are SLCs highly expressed?

A

GI, hepatic and renal.

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16
Q

What two types of transport can be carried out by SLCs?

A

Facilitated diffusion

Secondary active transport

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17
Q

Give 2 examples of secondary active transport across GI epithelia?

A

Fluoxetine - cotransported with N+

Penicillin - cotransported with H+

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18
Q

Define first pass metabolism.

A

Process of drugs becoming rendered inactive before reaching systemic circulation.

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19
Q

Where does FPM occur?

A

Gut lumen
Gut wall
Liver

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20
Q

What occurs in the gut wall in terms of FPM?

A

Gut and bacterial enzymes may denature some drugs,

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21
Q

Where are Phase I/II Enzymes present?Where are the more expressed?

A

Gut wall and liver

In the liver

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22
Q

Are phase I reactions catabolic or anabolic?

A

Catabolic.

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23
Q

Name 4 phase I reactions.

A

Oxidation, reduction, dealkylation and hydrolysis.

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24
Q

Describe, in general, a phase II reaction.

A

Involve the addition of other groups through conjugation reactions, to make the drug more water soluble, make it more readily excreted.

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25
Q

Give some examples of Phase II reactions.

A

Glucuronidation, methylation, sulphation, N-acetylation and gluthionine conjugation.

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26
Q

What is glucuronidation?

A

Conjugation of glucoronic acids by action of UDP glucuronyl transferases.

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27
Q

How can phase I reaction change drugs in terms of their physiological activity?

A

Can turn a physiologically inactive drug into an active drug. I-dopa - dopamine.

Can convert the original drug into a different drug. Eg codeine to morphine

Can turn a pharmacologically active drug into an inactive drug.

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28
Q

What can be said about the ionic charge of metabolised drugs?

A

Increased.

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29
Q

Phase I drugs always go onto Phase II.
True or false?

Explain answer.

A

False, they may be directly eliminated here.

If Mr of over 300 - gall bladder - bile

If Mr under 300 - kidney - urine

30
Q

What is the type of enzyme that catalysed phase I reactions?

A

Cytochrome P450s

31
Q

Name the CYP450 class that metabolises about 50% of current drugs.

A

CYP3A

32
Q

What CYP450 metabolises alcohol and paracetamol?

A

CYP2E

33
Q

CYPs can be unregulated or down regulated to meet demands.

True or false?

A

True

34
Q

What is meant by induction of a CYP?

A

Increased expression - transcription and translation of CYP

Decreased/ slower degradation of CYP

35
Q

If induction of a CYP occurs of a specific CYP which metabolises a drug that is already present in the body, what will happen to that drug?

A

It’s rate of elimination from systemic circulation will increase resulting in low plasma levels.

36
Q

What does CBZ stand for and what does it do?

A

Carbamezepine

Anti-epileptic

37
Q

What CYP metabolises CBZ?

A

CYP3A4

38
Q

CBZ induces CYP3A4.

What are the therapeutic consequences of this?

A

Lowers its own levels and will therefore affect the control of epilepsy.

39
Q

Give a clinical example of the consequences of concurrent drug administration in terms of inhibition of CYP450s.

A

Verapimil - drug used to lower BP.

Grapefruit (or could be an actual drug that) inhibits CYP3A4, which is the CYP450 which metabolises Verapimil.

Means reduced rate of elimination from plasma and therefore increased concentrations.

Overly reduced BP and fainting can result.

40
Q

What drugs often undergo phase II reactions and why?

A

Lipophillic drugs due to their poor ability to be excreted.

41
Q

What will be conjugated onto a lipophillic drug to allow for enhancement of renal elimination?

A

Hydrophilic sub groups to further increase the ionic charge of the drug.

42
Q

What are some factors that affect FPM?

A 
Age 
Sex
Health - diet / disease state
Induction
Inhibition
43
Q

What is meant by genetic polymorphism?

A

DNA sequence variation that is common within a population.

44
Q

Give example of genetic polymorphism in relationship to codeine and its relevant CYP450.

A

Codeine is broken down by CYP2D6 to morphine.

Highly polymorphic gene which’s variants within a population can be catogerised into normal, high and ultra-rapid metabolisers of codeine.

Poor variant - insufficient conversion of codeine to morphine and inadequate pain relief.

Ultra rapid variant - leads to morphine intoxication and ADRs.

45
Q

Define bioavailability (F).

A

The proportion of a given dose of a drug that ends up in in a specific body compartmen (usually systemic circulation).

46
Q

How can bioavailability be calculated?

A

Integral of [Drug in Plasma] - time post dose for the route of interest.

Divided by

Integral of [Drug in Plasma] - time post dose for IV route.

47
Q

What is bioavailability of IV route at t=0 and why is this the case?

A

1 or 100%

Because GI tract is bypassed and as a result first pass metabolism.

48
Q

Drinking fluid with orally administered drug gives increased bioavailability due to more absorption, true or false?

A

True

49
Q

Name some body fluid compartments.

A 
Intracellular
Interstitial 
Plasma
Lymph
Transcellular: 
- CBF
- Ocular
- Synovial
50
Q

What are different types of capillary?

A

Continuous
Fenestrated
Sinusoid

51
Q

What is the differences in structure between the 3 different capillary types?

A

Continuous and fenestrated capillaries have continuous basement membranes whereas sinusoidal basement membrane is incomplete.

Fenestrated capillaries have gaps in the endothelium called fenestration, whereas sinusoids have intracellular gaps between the endothelial cells.

52
Q

Once the drug is in the body, how does it get to its specific compartment.

A

Initially enters systemic circulation where it will travel by bulk flow through arteries and capillaries, diffusing across the relevant membranes to enter the relevant compartments.

53
Q

What does differing levels of capillary permeability allow for, in terms of drug distribution?

A

Enables variation in entry of charged drugs into ISF.

54
Q

What are factors affect rate of drug distribution?

A

Membrane permeability - more permeable the membrane between 2 compartments the faster the distribution.

Blood perfusion - more blood flow - more perfusion and more distribution.

55
Q

What factors affect the extent of drug distribution?

A

Lipophilicity

Tissue binding - lipid-based drugs - stored in adipose - larger doses for people with more adipose

Plasma protein binding.

56
Q

What effect doesn’t plasma protein binding have on clearance and drug action?

A

Slows drug action and clearance.

57
Q

How can plasma protein binding be beneficial therapeutically

A

If the effect of drug needs to be prolonged.

58
Q

What is clearance?

A

The amount of drug removed from the plasma through metabolism and excretion per unit time.

59
Q

Explain clearance in terms of equilibrium.

A

As drug becomes eliminated - plasma concentration decreases and as a result drug from other departments will diffuse into the plasma.

This cycle continues until all drug has been eliminated.

60
Q

What is the volume of distribution?

A

The theoretical volume of fluid needed to contain the total amount of drug in the body at the same concentration as that of the blood plasma.

Unit = L

61
Q

What does a high Vd mean?

A

Drug is more distributed into tissues.

62
Q

Name some routes of drugs and their metabolites.

A

Kidneys

Hepatobilliary system - drug stored with bile then secreted into GI tract and excreted as faeces.

Lungs

Glandular secretion

Lacrimation - tears

63
Q

What are the 3 steps involved in renal elimination?

A

Glomerular filtration

Tubular secretion

Tubular reabsorption

64
Q

What occurs in glomerular filtration?

A

Drugs with Mr less than 65000 are filtered out into glomerular filtrate.

PP binding drugs or large drugs ie heparin remain in pertitubular capillaries.

65
Q

What happens in tubular secretion?

A

Active ionic drug transport from peritubular fluid into tubular lumen by OATs and OCTs.

66
Q

Why is tubular secretion independant of plasma-protein binding?

A

PP bound drugs from an equilibrium

As free drug is secreted actively this causes more dissociation of the PP-drug complex until all free drug is secreted into the tubular fluid.

67
Q

What occurs in tubular reabsorption?

A

Involves transfer of drug passive from nephron lumen into peritubular capillaries.

Water is reabsorbed along the tubule for filtrate will be at high concentration and therefore lipophillic and unionised drug will passively diffuse back into peritubular fluid.

68
Q

What are some examples of OAT secretion and OCT secretion?

A

OAT

  • Urate
  • Penicillin

OCT

  • Morphine
  • Histamine
69
Q

What is meant buy drug half life?

A

The amount of time over which the concentration of a drug in plasma decreased to half its concentration at t=0.

70
Q

How is elimination half life calculated?

A

(0.693 x Vd) / CL

71
Q

If clearance increases how does this affect half life?

A

Decreases.

72
Q

If Vd increases how does it affect half life?

A

Increases.

ICPP (17 decks)

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