Session 7 (Pharmacokinetics) Flashcards by Milly Abbott

What are the four main stages of pharmacokinetics?

absorption, distribution, metabolism and excretion

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What are the two types of drug administration? Describe them

Enteral (via GI tract-oral, rectal, sublingual)

Parenteral (via other routes- intravenous, subcutaneous, intramuscular)

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During oral administration, when does most absorption occur?

Small intestine

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What is the transit time of the small intestine?

Normally 3-5hrs (but can range form 1-10)

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What is the pH of the small intestine?

6-7 (weakly acidic)

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How are lipiphilic drugs moved across membranes?

Passive diffusion

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What molecules carry out facilitated diffusion?

Solute carriers (SLC)

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Name the two types of solute carriers

OAT (organic anions transporter) and OCT (organic cation transporter)

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What is secondary active transport?

When a molecule is moved using the energy derived from the transport of another molecule (using a pre-existing electrochemical gradient)

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Name the physiochemical factors that are important in drug administration (3)

GI length/SA
Drug lipiphilicity/pka
Density of SLC

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Name the Gastrointestinal physiology factors that are important in drug administration (3)

Blood flow
GI motility
Food/pH

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What 2 enzyme groups affect first pass metabolism?

Phase 1 (cytochrome P450s)
Phase 2 (conjugating)

(These break down drug before it enter systemic circulation therefore these enzymes affect therapeutic potential)

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What is bioavailability?

The amount of the drug that actually reached the greater systemic circulation (CVS)

(Intravenous drugs=100% because it has no barrier to overcome to reach CVS)

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How is oral bioavailability calculated?

F=AUCo/AUCiv

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What does the first stage of distribution involve? (3)

Bulk flow (arteries), diffusion (interstitial fluid and tissue form capillaries), barriers to diffusion (leaky capillaries)

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What is ‘overall rate of delivery’ dependent on?

Density of capillary supply

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Name the 3 types of capillary wall

Continuous, fenestrated (holes) and sinusoid (gaps)

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What are the 4 main factors affecting distribution?

Lipophilicity/hydrphilicity
Degree to which it binds to plasma proteins
Degree to which it binds to tissue proteins
Mass/vol. of tissue + density of binding sites within tissue

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‘Degree to which it binds to plasma proteins’ is a factor affecting distribution. Explain what it means

Regardless of concentration, a fixed % will always bind to plasma proteins (ie albumin, this affects how much drug is free to move into tissue. In this way it affects distribution

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What type of molecule experiences problems when crossing the membrane?

Hydrophilic (need to rely on capillary permeability, local pH, prescience of OAT/OCT)

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What are the main body fluid compartments?

Total=42L –>extracellular=14L, intracellular=28L

Extracellular–>plasma=3L, interstitial fluid=11L

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What is Vd?

Volume of distribution (in L or L/Kg- when dealing with an individual with a specific weight)

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How would you express Vd? (Looking for an example)

If the drug remained in the plasma Vd=3L,

Vd refers to the vol of fluid that the drug has penetrated

What does elimination include?

Metabolism and excretion

What is responsible for metabolism?

Phase 1 (Cytochrome P450) + phase 2 (conjugating) enzymes

What do phase 1 (CYP450) enzymes do?

Perform redox reactions (add/take away polar groups -NH2/-OH)

What do phase 2 (conjugating) enzymes do?

Add molecules to drugs (ie glycine)

Why might a drug pass straight to phase 2 enzymes?

Because they already posses polar groups

Why are drugs metabolised?

To make renal excretion easier (the idea is to enhance ionic charges to prevent reabsorption in nephrons)

Where are phase 1 (CYP450) enzymes found in cells?

External face of ER in cells

How many super families of CYP450 enzymes are there?

3 (CYP1/2/3)

What sort of drug do CYP450 enzymes target?

None, they're generalists

What happens to 'pro-drugs'?

They are activated by phase 1 metabolism

How is the [CYP450] increased?

Some drugs induce production of it (therefore metabolism is faster, some drugs induce their own metabolism)

On what time scale would the [CYP50] be increased by a drug?

1-2 weeks

How is the [CYP450] decreased?

Some drugs inhibit the enzymes

Why is it bad to reduce [CYP450]?

Can result in toxic build up

What types of inhibition are there?

Competitive and non-competitive

What time scale to inhibiting drugs work on?

Few days

How is the increase of [CYP450 enzyme] done? (3)

Transcription increases Translation increases Slower degradation

What factors effect metabolism? (5)

``` Genetic factors (lacking enzymes) Sex Age Genetic variation Polymorphism ```

What are the 3 stages of renal excretion?

Glomerular filtration, proximal tubular secretion, distal tubular reabsorption

When are drugs/metabolites moved out of the blood?

During proximal tubular secretion and glomerular filtration (-only those not bound to proteins)

What type of molecules are actively moved during proximal tubular secretion?

Charged/ polar metabolites

What performs the active movement of polar molecules in proximal tubular secretion?

OATs and OCTs

What do OATs and OCTs move? (Acids and bases, (de)protonated?)

OAT- deprotonated acids (weak) | OCT- protonated bases (weak)

What is clearance?

Rate of elimination

Aside from hepatic and renal, how else might a drug be secreted?

Sweating and exhalation

What is 'total body clearance'?

Hepatic + renal (clearance) Or Vol of plasma that is completely cleared of the drug per unit time (ml/min)

What can CL (clearance) and Vd estimate?

Drug half life (t1/2)

What happens to the t1/2 if Vd increases?

It increases (drug has penetrated further)

What happens to t1/2 if CL increases?

It decreases (because the body is effectively getting rid of the drug at a faster rate)

If the [drug] is low, is the rate of elimination and metabolism increased or decreased?

Decreased (whole process is slower because there are fewer molecule to be metabolised and excreted, the chance of metabolising the drug is reduced if the enzyme rarely comes into contact with it)

Why is it necessary to make the 'plasma drug concentration/time' graph logarithmic?

It makes it easier to see half life

Why are linear elimination kinetics linear?

The rate of metabolism/excretion is proportional to conc of drug

What makes a drug obey linear elimination kinetic rules?

If there are plenty of phase 1 and 2 enzymes and OAT/OCT

What happens if there are not plenty of enzymes and OAT/OCT? (In terms of linear elimination kinetics)

The plot becomes a straight line on a linear scale (zero order kinetics), usually occurs at higher doses (when everything is saturated)