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Pharmacology > Introduction to Pharmacokinetics > Flashcards

Introduction to Pharmacokinetics Flashcards

1
Q

What is the bioavailability of a drug?

A

Fraction of unchanged drug that reaches the systemic circulation.

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2
Q

What is the bioavailability of IV injected drugs?

A

100%

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3
Q

What is the journey of an oral drug?

A
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4
Q

What are the oral routes of a drug?

A
  • Buccal / sublingual mucosa
  • Smal intestine
  • Large intestine / colon
  • Rectal mucosa
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5
Q

Describe the buccal / sublingual mucosa absorption of an oral drug.

A
  • Direct absorption into the blood stream
  • Avoids first pass metabolism
  • Not an ideal surface for absorption
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6
Q

Describe the small intestine absorption of an oral drug.

A
  • Main site of drug absorption
  • Large surface area, more neutral pH
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7
Q

Describe the large intestine absorption of an oral drug.

A

Poor absorption, long transit times.

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8
Q

Describe the rectal mucosa absorption of an oral drug.

A

Direct to systemic circulation

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9
Q

What are the ways which small molecules cross cell membranes?

A
  • Diffusion through lipid (bilayer)
  • Diffusion through aqueous channel
  • By way of a carrier
  • Potentially pinocytosis (mostly macromolecules, not drugs)
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10
Q

Describe the lipid diffusion of hydrophilic and lipophylic drugs.

A
  • Hydrophilic drugs are soluble in aqueous, polar media.
  • Lipophylic drugs are soluble in fats and non-polar solutions.
    • Highly lipophilic drugs may accumulate in the phospholipi bilayer.
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11
Q

Give examples of aqueous polar media.

A
  • Blood plasma
  • Cytosol
  • Interstitial fluid
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12
Q

Give examples of non-polar solutions.

A
  • Interior of the lipid bilayer
  • Fat
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13
Q

Describe the ionisation of drugs post-administration.

A
  • Many drugs are weak acids or bases
  • Ionised : unionised ratio depends on pH
  • Ionised drugs have low lipid solubility.
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14
Q

What is the pH of gastric acid?

A

pH 1.0-3.0

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15
Q

What is the pH of the large intestine?

A

pH 8.0

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16
Q

What is the pH of the small intestine?

A

pH 5.0-6.0

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17
Q

What is the pH of the plasma?

A

pH 7.4

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18
Q

Describe the properties involved in drug absorption.

A
  • The route of administration is affected by both drug and by patient factors.
  • Unless the drug is injected directly to the systemic circulation, there are barriers to absorption.
  • The main drug properties that affect absorption are lipophilicity and ionisation.
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19
Q

What are the factors which affect distribution of a drug?

A
  • Degree of drug ionisation
  • Lipid solubility
  • pH of compartments
  • Cardiac output and blood flow
  • Capillary permeability
  • Plasma protein binding
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20
Q

What are the different types of capillary diffusion?

A
  • Continuous
  • Fenestrated
  • Discontinuous
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21
Q

Describe fenestrated capillary diffusion.

A

Small lipophobic molecules pass through the fenestrated capillary.

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22
Q

Describe continuous capillary diffusion.

A
  • Very fast diffusion of:
    • Gases
    • Lipophilic molecules
  • Slow diffusion of:
    • Small lipophoobic molecules
  • Very slow diffusion of:
    • Large lipophobic molecules
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23
Q

Describe sinusoid / discontinuous capillary diffusion.

A
  • Route taken by:
    • Red blood cells
    • Large lipophobic molecules - these can pass across the plasma membrane as long as it is not charged.
24
Q

Describe the blood-brain barrier.

A

Highly selective barrier formed by endothelial cells, astrocytes and pericytes. Astrocytes make a seal to protect the very tightly controlled blood-brain barrier.

25
Q

Describe the placenta.

A
  • Tight endothelial cell junctions in maternal and fetal capillaries.
  • Partially protective, except with:
    • Lipid soluble drugs and unionised forms of weak acids / bases.
26
Q

Give examples of drugs which bind to plasma proteins.

A
  • Albumin
  • α-1 acid glycoprotein
  • Lipoproteins
  • Globulins
  • The fraction of unbound drug can be as low as 1%.
  • Note:
    • Very difficult to tell how safe warfarin is.
    • About 99% of warfarin is bound to plasma proteins so there is only 1% of warfarin which can do what it is supposed to do.
27
Q

What are the factors which control the distribution of drugs between body fluid compartments?

A
  • Permeability across tissue barriers
  • Binding within compartments
  • pH partition
  • Fat : water partition
28
Q

Describe the factors which control the distribution of a drug in the body.

A
  • Body water is distributed in to 4 main compartments - specialist compartments exist and factors such as perfusion influence distribution.
  • The degree of distribution between these compartments depends on tissue- and drug- dependent factors.
  • Side-effects of some drugs can be minimised by limiting their distribution via the route of administration.
29
Q

List the sites of drug metabolism.

A
  • Gut lumen
  • Gut wall
  • Plasma
  • Lungs
  • Kidneys
  • Nerves
  • Liver
30
Q

List the potential results of metabolism of a drug.

A
  • Deactivation
  • Activation
    • In the case of prodrugs. They rely on a biological transformation to produce the effect it was intended to produce.
  • Type of pharmacological response
  • No change in activity
    • Metabolsim can alter the chemical structure of the drug and therefore affect the effect it has.
  • Change in uptake
  • Change in distribution
31
Q

Describe phase 1 metabolism of a drug.

A
  • Introduce / reveal a reactive chamical group.
  • ‘Functionalisation’
    • Generally oxidation, reduction or hydrolysis.
  • Products often more reactive.
  • Generally makes the drug more hydrophilic so it can be passed out in the urine. Or it can be made big and clumpy and cannot be absorbed, so is excreted in the faeces.
  • Phase 1 metabolism is the biggest site of variation between patients.
32
Q

Describe phase 2 metabolism of a drug.

A
  • Synthetic, conjugative reactions
  • Hydrophilic, inactive compounds generated (usually)
33
Q

What are cytochrome P450 enzymes?

A
  • Mixed function monooxygenases
  • Found throughout the body, and extensively in the liver.
  • There are 57 human genes coding for CYP450 enzymes.
    • There is huge potential here for individual variation. There is also huge potential here for some of these genes to be switched on or off.
34
Q

What are the functions of cytochrome P450 enzymes?

A
  • Biosynthesis of steroids, fatty acids and bile acids.
  • Metabolism of endogenous and exogenous substrates.
35
Q

Describe the metabolism of paracetamol.

A
36
Q

What happens in the event that the toxic metabolite of paracetamol occurs in the presence of depleted glutathione levels?

A

In the presence of depleted glutathione levels, the toxic metabolite of paracetamol combines with hepatic proteins (instead of with glutathione) and this results in paracetamol toxicity.

37
Q

What are the factors which can affect drug metabolism?

A
  • Disease
  • Other medications
  • Genetic variation
  • Age
38
Q

Describe how disease can affect drug metabolism.

A
  • Drug metabolism is dependent on proper liver function. This can be disrupted by:
    • Cirrhosis
    • Hepatitis
    • Cancer
  • Drug metabolism also depends on adequate essential amino acid supply. This can be disrupted by:
    • Starvation
    • Cancer
  • Other disease / conditions affect drug metabolism:
    • Kidney disease
    • Severe burns
39
Q

How does age affect drug metabolism?

A
  • Fetus:
    • Maternal protection
  • Children:
    • Low level of metabolic activity
  • Elderly:
    • Metabolic activity starts to decline
40
Q

How does genetic variaton affect drug metabolism?

A
  • Wide range of CYP phenotypes
    • Rapid, slow, unusual metabolisers
  • Race
    • Inherent generalisable variability
41
Q

How to other medications affect drug metabolism?

A
  • Induction of metabolic enzymes
    • Reduced effectiveness of drugs
  • Inhibition of metabolic enzymes
    • Dietary constituents or drugs
42
Q

Describe drug metabolism.

A
  • The aim is to produce metabolites that can be excreted.
  • Mainly occurs in the liver, metabolites can be active or toxic.
  • Genetic variability in metabolic enzymes occurs, and expression of metabolic enzymes can be induced and / or inhibited.
  • Competition for metabolic enzymes occurs and metabolic pathways can be saturated.
  • Metabolism can affect the bioavailability of drugs.
43
Q

How are drugs eliminated from the body?

A
  • Drugs are eliminated either unchanged or as metabolites.
  • Hydrophilic drugs are eliminated more readily than lipophilic drugs.
    • Except in the the lungs
  • Possible sources of excretion include:
    • Breath
    • Urine
    • Saliva
    • Perspiration
    • Faeces
    • Milk
    • Bile
    • Hair
  • The kidneys are the most important organs involved in the elimination of drugs and their metabolites.
44
Q

Describe the plasma concentration graph following a single oral dose of a drug.

A
45
Q

Describe the plasma concentration graph following repeated doses of a drug.

A
46
Q

Describe the graph of plasma concentration against time if a drug is infused at a constant rate and no drug is removed from the body.

A
47
Q

Describe the amount of drug eliminated per unit time.

A
  • Drug is eliminated from the body as soon as it is in the circulation (eg. via the kidneys).
  • For most drugs, the amount of drug eliminated per unit time is related to the concentration of drug in the plasma (first-order kinetics):
    • Higher concentrations, more drug if removed per unit of time.
    • Lower concentrations, less drug is removed per unit of time.
  • THEREFORE, the graph of plasma concentration against time for most infusions will bend towards a plateau when the rate in of drug equals the rate out.
48
Q

Describe the plasma drug concentration during IV infusion.

A
  • Plasma concentration increases during infusion until rate of input equals rate of output.
  • “Steady state”
49
Q

Describe how to calculate plasma steady state concentration (Css).

A
50
Q

What does the time taken to reach Css depend on?

A
51
Q

What does t1/2 depend on?

A
  • t1/2 directly depends on the volume of distribution (Vd) and inversely on the clearance (CL) of a drug from the body:
52
Q

Describe clearance of drugs.

A

Clearance (CL) is defined as the volume of blood or plasma cleared of drug in a unit time - eg. 10ml/min.

53
Q

What happens to clearance of a drug in first order kinetics?

A

In first order kinetics, whilst amount of drug eliminated per unit time varied, clearance is a constant:

54
Q

Describe how to calculate the apparent volume of distribution (Vd).

A
  • Vd is the theoretical volume required to account for the amount of drug in the body.
  • Units are in litres (L) or sometimes L/kg of body weight.
55
Q

What is the clinical relevance of the apparent volume of distribution (Vd) of a drug?

A
  • Vd can be used to determine a loading dose to achieve a desired plasma concentration of drug.
  • Vd varies with:
    • Height
    • Weight
    • Age
    • Fluid accumulation
      • Ascites
      • Oedema
      • Pleural effusion
    • Accumulation of fat

Pharmacology (7 decks)

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