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Session 7 - pharmacokinetics Flashcards

1
Q
  • Understand the importance of Pharmacokinetics applied to clinical practice
  • Used the Interactive Clinical Pharmacology website icp.nz
  • Recognise main routes of drug administration into the body
  • Understand factors affecting drug Absorption and Distribution
  • Recognise Equations used for Bioavailability and Volume of Distribution
  • Understand factors affecting drug Metabolism and Excretion
  • Recognise equations used for Clearance and drug Half Life
  • Understand difference between Linear and Non-Linear Kinetics
A
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2
Q

What is Pharmacokinetics

A

What the body does to drugs:

  • Absorption (drug in)
  • Distribution (drug in)
  • Metabolism (drug out)
  • Elimination (drug out)
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3
Q

Recognise main routes of drug administration into the body LO

A

Enteral: Delivery into internal environment of body - GI Tract

Parenteral: Delivery via all other routes that are not the GI

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4
Q

Understand factors affecting drug Absorption and Distribution LO

Drug Absorption

  • Oral route - majority of formulations most convenient
  • Normally little absorption in stomach - SA = 0.75 - 1m2
  • Drug mixes with chyme enters small intestine
  • Small intestine = 6-7 m in length x 2.5 cm diameter
  • Total SA for absorption = 30-35 m2
  • Constant GI movement - mixing - presenting drug molecules to GI epithelia
A
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5
Q

Drug Absorption Small Intestine

Typical Transit Time = ?

Varying motility = ?

Weakly acidic pH = ?

A

3-5 hrs

1-10 hrs

6 -7 pH

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6
Q
  1. Molecular Level how do drugs pass the plasma membrane in the SI
A
    • Passive Diffusion
      - Facilitated Diffusion
      - Primary / Secondary Active Transport
      - Pinocytosis
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7
Q

Passive Diffusion 1

  • Common mechanism for lipophilic drugs weak acids/ bases
  • Lipophilic drugs e.g. steroids diffuse directly down concentration gradient into GI capillaries

Passive Diffusion 2

  • Weak acids/bases protonated /deprotonated species can diffuse
  • * E.g. Valproate : Anti -Epileptic Drug weak acid pKa = 5
  • In gut at pH 6 - 10 % Valproate protonated - Lipophilic
  • Lipophilic species crosses GI epithelia
  • Over transit time 4-5 hrs and very large GI SA valproate diffuses into GI capillary bed
A
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8
Q

Drug Absorption: Facilitated Diffusion: Solute Carrier (SLC) Transport

  • Molecules (or Solutes) with nett ionic + or - charge within GI pH range can be carried across GI epithelia
  • Passive process based on electrochemical gradient for that (solute) molecule SLCs are either OATs and OCTs
  • Large family – expressed in all body tissue
  • Pharmacokinetically important for drug absorption and elimination
  • Highly expressed in GI, Hepatic and Renal Epithelia
A
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9
Q

Secondary Active: Solute Carrier (SLC) Transport

  • SLCs can also enable drug transport in GI by Secondary Active Transport
  • Not utilise ATP - Transport driven by pre-existing electrochemical gradient across GI epithelial membrane e.g. Renal OATs and OCTs

Example

  • Fluoxetine/Prozac - SSRI antidepressant co-transported with Na+ ion
  • B-lactam antibiotics/Penicillin - co-transported with H+ ion
A
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10
Q

Understand factors affecting drug Absorption and Distribution LO

  1. Physicochemical Factors:
  2. GI Physiology:
  3. First Pass Metabolism by GI and Liver:
A
  1. • GI length /SA
  • Drug lipophilicity / pKa
  • Density of SLC expression in GI
  1. • Blood Flow: Increase post meal – drastically reduce shock/anxiety exercise
  • GI Motility: Slow post meal - rapid with severe diarrhoea
  • Food /pH: Food can reduce/increase uptake. Low pH destroy some drugs
  1. • Gut Lumen: Gut/Bacterial Enzymes - can denature some drugs

• Gut Wall/Liver (larger expression) : Some drugs metabolised by two major enzyme groups Cytochrome P450s:

  • Phase I Enzymes Conjugating
  • Phase II Enzymes
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11
Q

‘First Pass’ metabolism:

A

Reduces availability of drug reaching systemic circulation - therefore affects therapeutic potential

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12
Q

Recognise Equations used for Bioavailability and Volume of Distribution LO

Drug Absorption: Bioavailability

  1. Bioavailability Definition:
  2. What is most common reference compartment
  3. How do you work out bioavailability?
A
  1. Fraction of a defined dose which reaches its way into a specific body compartment
  2. Cvs/circulatory
  3. IV bolus = 100%
    - No physical/metabolic barriers to overcome
  • For other routes - compare amount reaching CVS by other route referenced to intravenous bioavailability
  • Most common comparison oral or (O)/(IV)
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13
Q

How do you work out Oral Bioavailability (F)?

A
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14
Q

What is the first stage of drug distrubution?

A

First stage

  • Bulk flow - Large distance via arteries to capillaries
  • Diffusion - Capillaries to interstitial fluid to cell membranes to targets
  • Barriers to Diffusion - Interactions /local permeability/non- target binding
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15
Q

Understand factors affecting drug Absorption and Distribution LO

  1. Major factors affecting drug distribution:
A

Drug Molecule Lipophilicity/Hydrophilicity

  • If drug is largely lipophilic can freely move across membrane barriers
  • If drug is largely hydrophilic journey across membrane barriers dependent on factors described for Absorption
  • Capillary permeability
  • Drug pKa & Local pH
  • Presence of OATs/OCTs

Degree of drug binding to plasma and/or tissue proteins

• In circulation many drugs bind to proteins e.g.

  • Albumin Globulins
  • Lipoproteins Acid glycoproteins
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16
Q

What are the differing levels of capillary permeability?

A
  • Enables variation in entry by charged drugs into tissue interstitial fluid
  • Then on to target site (s)
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17
Q

Elaborate on why Degree of drug binding to plasma and/or tissue proteins affects distrubution of the drug

A
  • Only free drug molecule can bind to target site(s)
  • Binding in plasma/tissue decreases free drug available for binding
  • Plasma/Tissue protein bound drug acts as ‘reservoir’
  • Binding forces not strong – bound/unbound in equilibrium
  • Binding can be up to = 100%

(Aspirin = 50%)

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18
Q

Simplify body fluid compartments in to model with three main compartments

A
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19
Q
A
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20
Q

Increasing Penetration by Drug into Interstitial and Intracellular Fluid Compartments Leads to?

A
  • Decreasing Plasma Drug Concentration
  • Increasing Vd
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21
Q

Recognise Equations used for Bioavailability and Volume of Distribution LO

  1. What is Vd?
  2. Smaller Vd values - ?
  3. Larger Vd values - ?
  4. What is the equation for volume of distrubution?
  5. What is the units for Vd ?
A
  1. Summarises movement out of Plasma -> Interstitial -> Intracellular Compartment
  2. less penetration of Interstitial/Intracellular Fluid Compartment
  3. less penetration of Interstitial/Intracellular Fluid Compartment
  4. Look at the image
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22
Q

When can Vd be affected?

23
Q

Drug Elimination
Elimination

  • Term used to cover both Metabolic and Excretory Processes
  • Both ‘flow’ processes closely integrated to optimise drug removal
  • Elimination removes both exogenous and endogenous molecular species
  • Evolutionary advantage in recognising xenobiotics – potential toxins
  • Protective and Homeostatic function
24
Q

Understand factors affecting drug Metabolism and Excretion LO

  1. Hepatic Drug Metabolism: Phase 1 and II
  • Drug Metabolism largely takes place in Liver via ?
  • Enzymes expressed ?
  • Very large hepatic reserve – also ‘first port of call’ after GI absorption
  1. Phase I and II Enzymes function and why?
A
  1. Phase 1 and II enzymes

throughout body tissues

  1. • Metabolise drugs - increase ionic charge enhance renal elimination
  • Lipophilic drugs diffuse out renal tubules back into plasma
  • Once metabolised - drugs usually inactivated *
25
Q

Drug Metabolism: Phase 1

  1. Phase 1 Metabolism is carried out by Cytochrome ?
  2. Phase 1 enzymes collectively refer to as ?
  3. Large group of > 50 isozymes located on ?
  4. Catalyse: ?
  5. CYP450s are versatile generalists, what does that mean?
  6. What do the CYP450s do?
  7. What happens to the drugs CYP450s have ?
  8. * Some ‘pro-drugs’ activated by Phase I metabolism to active species
A
  1. P450 Enzymes
  2. CYP450s
  3. external face of ER
  4. redox; dealkylation; hydroxylation reactions
  5. metabolise very wide range of molecules
  6. Metabolised drugs have increased ionic charge
  7. Metabolised drug eliminated directly or go onto Phase II
26
Q

Drug Metabolism: Phase 1

Phase 1 Metabolism can activate prodrugs

Some ‘pro-drugs’ activated by Phase I metabolism to active species

  1. Example: ?
A
  1. Codeine to Morphine

In metabolisers = 0-15% Codeine metabolised by CYP2D6 to Morphine

Morphine x 200 Codeine affinity for Opioid µ-Receptor

CYP2D6 exhibits genetic polymorphism

27
Q

Drug Metabolism Phase II

  1. Phase II Metabolism is carried out by ? Enzymes
  2. Phase II enzymes - mainly (location) enzymes
  3. Phase II still generalists but ?
  4. Enhance hydrophilicity by ?
  5. Catalyse:
  6. Phase II metabolised drugs further increased ?
  7. Phase II metabolism enhances?
A
  1. Hepatic
  2. cytosolic
  3. exhibit more rapid kinetics than CYP450s
  4. Further inc ionic charge - add to Phase I
  5. Sulphation - Glucorinadation - Glutathione conjugation -
    Methylation N-acetylation
  6. ionic charge
  7. renal elimination
29
Q

Cytochrome P450 Enzymes

Cytochrome P450 enzymes include three superfamilies

  1. Three superfamilies:
  2. Isozyme members in each family coded by suffix: e.g. CYP3A4
  3. Six isozymes metabolise = 90% prescription drugs
  4. Other isozymes exhibit very variable hepatic expression
  5. Each isozyme optimally metabolise specific drugs but do show overlap
A
  1. CYP 1, 2 and 3

2.

30
Q

Understand factors affecting drug Metabolism and Excretion LO

  1. Many Factors of Direct Clinical Relevance:
  2. CYP450s: Induction and Inhibition and Genetic Factors:
A
  1. • Age (Variable patterns in paediatric groups reduced in elderly)
  • Sex (gender differences drugs e.g. alcohol metabolism slower in women)
  • General Health/Dietary/Disease - especially Hepatic Renal CVS
  1. • Other drugs (Rx/OTC) can induce or inhibit CYP450s

• Genetic variability/polymorphism/ non-expression affects CYP450s

31
Q

Phase I Metabolism: CYP450 Induction

  1. Concurrent administration of certain drugs (including just the one drug) can
    induce specific CYP450 isozymes. Induction mechanism via: ?
  2. If another drug in body metabolised by induced CYP450 isozyme then its rate of elimination will be ? Plasma levels of drug will ?
  3. For patient can have serious therapeutic consequences if levels drop significantly. Induction process typically occurs over ?
A
  1. Inc transcription; inc translation; slower degradation
  2. increased, fall
  3. 1-2 weeks
32
Q

Phase I Metabolism: CYP450 Induction

Give an example of CYP450 Induction:

A

Carbamezepine (CBZ)

  • CBZ is an anti-epileptic metabolised by CYP3A4
  • CBZ induces CYP3A4 – lowering its own levels affecting control of epilepsy
  • CBZ needs careful monitoring in first few month post prescription
33
Q

Phase I Metabolism: CYP450 Inhibition

CYP450 Inhibition

  1. Concurrent administration of certain drugs (including just the one drug) can inhibit specific CYP450 isozymes. Inhibition mechanism via: ?
  2. If another drug in body metabolised by inhibited CYP450 isozyme then its rate of elimination will be ? Plasma levels of drug will then ?
  3. For patient can have serious side effects consequences if levels rise significantly. Inhibition process occurs within?
A
  1. competitive/non-competitive inhibition
  2. slowed down, increase
  3. 1 to a few days
34
Q

Phase I Metabolism: CYP450 Inhibition

Examples of CYP450 Inhibition: ?

A
  • Grapefruit Juice inhibits CYP3A4
  • CYP3A4 metabolises Verapimil used to treat high blood pressure (BP)
  • Consequence can be much reduced BP and fainting
35
Q

Phase I Metabolism: Genetic Factors

Genetic Variation

  1. CYP2C9: Not expressed in:
  2. CYP2C19: Not expressed in: ?

Prescriptive Practice Review

• Need to consider safety/efficacy if not metabolised /rapidly metabolised

A
  1. 1% Caucasians; 1% Africans

• Metabolises NSAIDs, Tolbutamide, Phenytoin

  1. 5% Caucasians; 30% Asians

• Metabolises Omeprazole, Valium, Phenytoin

36
Q

Drug Metabolism: Genetic Polymorphism

  • Genetic Polymorphism: Codeine and CYP2D6

‘Pro-drugs’ activated by Phase I metabolism to active species

Earlier example: Codeine to Morphine

  • CYP2D6 gene highly polymorphic
  • CYP2D6 variants categorized into: poor; normal/high; ultrarapid metabolisers

Poor - codeine to morphine - may not experience pain relief

Ultrarapid - codeine to morphine - lead to morphine intoxication/ADRs

Genetic Variation/Polymorphism

    • CYP2D6: Not expressed in: ?
      - Example of Polymorphism
      - Metabolises ?
A
  1. 7% Caucasians; Hyperactive 30% East Africans

Codeine, TCAs

37
Q

Drug Elimination

  1. Routes of Drug elimination ?
A
  • Main route of drug elimination is kidney
  • Other routes: bile; lung; breast milk (deliver to baby); sweat, tears; genital secretions; saliva
38
Q
  1. Renal Excretion. Three Processes:
A
    • Glomerular Filtration
      - Active tubular secretion
      - Passive tubular reabsorption
39
Q
  1. Glomerular Filtration
    - Glomerulus = ?% renal blood flow
    - ? drug enter via Bowman’s capsule
  2. Proximal Tubular Secretion
    - Remaining ?% blood via peritubular capillaries
    - High Expression of ? Function?
    - Raison d’etre of Phase I and II metabolism
    - Facilitated Diffusion/Secondary Active Transport
    - Along tubule length water resorbed
    - In tubule [Solutes] inc
    - Therefore lipophilics pass back into blood
    - Henderson-Hasselbach

+ If tubular pH and molecule species pKa favourable

+ Get neutral AH or B species - reabsorbed by blood

  1. Distal Tubular Reabsorption

Examples:

  • OATs: ?
  • OCTs: ?
  • Transport subject to competition between drugs can effect pharmacokinetics/ therapeutics
A
    • 20
      - Unbound
    • 80
      - OATs and OCTs & Carry ionised molecules
    • Urate (Gout); Penicillins; NSAIDs; Antivirals
      - Morphine; Histamine; Chlorpromazine
40
Q

Recognise equations used for Clearance and drug Half Life LO

  1. What is Clearance?
  2. Total Drug Clearance consists of that from all routes. For most drugs -
    Total Body Clearance = ?
A
  1. The rate of Elimination of a drug from the body OR

The Volume of Plasma that is completely cleared of the drug per unit time

  1. Total Body Clearance = Hepatic Clearance + Renal Clearance
41
Q

Clearance is formally defined as: The Volume of Plasma that is completely cleared of the drug per unit time

  1. CL measured in ?
  2. But this ‘Volume’ is really referenced to ?
  3. Real Plasma Volume is = ?

Real Volume of Plasma cannot be ‘completely’ cleared of drug via glomerular filtration/ tubular secretion. In model, CL better thought of as ‘Apparent Rate of Elimination’.

A
  1. ml/min or ml.min-1
  2. Vd: the apparent volume of distrubution
  3. 3 Litres
42
Q

CL and Vd

  1. • Along with the concept of Vd clearance predicts how long drug will stay in body

• Clinically Essential for informing:

  1. In short answers ‘How long is drug in body and doing any therapeutic good? Together CL & Vd provide estimate of ?
A
    • Designing dosing schedule
      - Therapeutic regimes levels
      - Minimising ADRs
  2. ‘Drug Half-Life’ or t1/2
43
Q

Drug Half Life

  1. Defined as?
  2. • T 1/2 is dependent on Vd & CL
    • If CL stays same and Vd increases then t 1/12 also ?
    • If CL increases & Vd stays the same then t1/2 ?
  3. How do you work out T1/2
A
  1. The amount of time over which the concentration a drug in plasma decreases to one half of that concentration value it had when it was first measured
  2. increases

decreases

  1. (Image)
46
Q

Linear Elimination Kinetics:

Why are they Linear ?

A
  • The rate of Metabolism or Excretion is proportional to Concentration of Drug
  • That is if there are

Plenty of Phase I/II enzyme sites

Plenty of OAT/OCT Transporters

• Then the rate of metabolism /transport will be proportional to the number of molecules occupying a catalytic/ carrier site per unit time

47
Q

Why are they Linear ?

Hypothetical Examples

• Hepatic Phase I CYP450 Metabolism for Pretend Drug o If there are no molecules then the rate is none there is nothing to catalyse/transport

o If the plasma concentration is 50 uM then lets say rate is 10 million molecules/second

o If the plasma concentration is 100 uM then the rate is ?

o If the plasma concentration is 200 uM then the rate is ?

o Equally as molecules removed over time the plasma concentration decreases

o Catalytic rate then also decreases in this exponential fashion (Linear Kinetics)

A

20 million molecules/second

40 million molecules/second

48
Q

Linear Elimination Kinetics:

What happens when Elimination Processes become Saturated?

A
  • When processes are saturated they become rate limited
  • They cannot go any faster said to be saturated
  • Parallels with

o Computer processing speed

o Car engine

o Eating pies, doughnuts or chewing a toffee

• When this happens the Elimination kinetics are referred to as Saturated or Zero Order

49
Q

What is this graph showing?

A

Drug Elimination: Saturation or Zero Order Kinetics

50
Q

What is this graph showing?

A

Saturated Zero Order Drug Elimination

Most drugs exhibit zero order kinetics at higher doses

  • NOTE : Y axis is Rate of Elimination
  • As [drug] increases Rate of elimination Levels off
  • Reaches limit of capacity –cannot chew toffees any faster !
  • This has important clinical implications !
51
Q

Clinical Importance: Zero Order Kinetics

  • Drugs at or near therapeutic dose with saturation kinetics
  • More likely to result in ADRs/Toxicity
  • Fixed rate of elimination per unit time
  • Relatively small dose changes can
  • Produce large increments in plasma [drug]
  • Lead to serious toxicity
  • Half life is not calculable cannot easily predict dosage regimes
  • ‘Narrowing ‘ therapeutic window
  • Greater risk of drug-drug interactions due to taking up sites
52
Q

Clinical Importance: Zero Order Kinetics
Drug Monitoring Patient Groups

  • Relatively few drugs in adults with Zero Order Kinetics at therapeutic dose
  • Problem in elderly /infants with decreased/immature capacity
  • Polypharmacy - competing at same processes
  • Similarly problem in seriously ill – cancer liver disease alcoholic
  • Reduced hepatic renal capacity easier to saturate
  • Example drugs: Phenytoin; Prozac; Alcohol; MDMA
  • Paracetamol at high dose (>20 tablets) saturate Phase I & II – can be fatal
53
Q

Clinical Importance: Zero Order Kinetics

Drug Monitoring Patient Groups

  • Relatively few drugs in adults with Zero Order Kinetics at therapeutic dose
  • Problem in elderly /infants with decreased/immature capacity
  • Polypharmacy - competing at same processes
  • Similarly problem in seriously ill – cancer liver disease alcoholic
  • Reduced hepatic renal capacity easier to saturate
  • Example drugs: Phenytoin; Prozac; Alcohol; MDMA
  • Paracetamol at high dose

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