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Pharmacokinetics Flashcards

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1
Q

Define pharmacokinetics

A

the branch of pharmacology concerned with the movement of drugs within the body

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2
Q

What are the 4 main processes in drug therapy

A

Absorption
Distribution
Metabolism
Elimination

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3
Q

What are the 2 ways of drug administration?

A 
Enteral
• Delivery into internal environment of body  - GI Tract
- Oral
- Sublingual
- Rectal

Parenteral
• Delivery via all other routes that are not the GI  - includes
- Intravenous
- Subcutaneous
- Intramuscular
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4
Q

Briefly describe drug absorption

A
  • 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
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5
Q

What is the typical transit time through the small intestine?

A

3-5 hours

Varying motility 1-10 hours

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6
Q

What is the pH of the small intestine?

A

Weakly acidic

6-7

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7
Q

What are 4 ways of drug absorption at a molecular level

A

 Passive Diffusion
 Facilitated Diffusion
 Primary / Secondary Active Transport
 Pinocytosis

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8
Q

What is passive diffusion?

A

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

  • 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 - so is Lipophilic
  • Lipophilic species crosses GI epithelia
  • Over transit time 4-5 hrs and very large GI Surface Area valproate diffuses into GI capillary bed
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9
Q

What is SLC transport?

A

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) molecules

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10
Q

What are OATs and OCTs?

A

Organic Anion/Cation transporters

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

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11
Q

Aside from facilitated diffusion, how else can SLCs enables transport?
Give examples

A

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
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12
Q

Name 3 physicochemical factors which affect drug absorption

A

Physicochemical Factors
• GI length /SA
• Drug lipophilicity / pKa
• Density of SLC expression in GI

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13
Q

Describe GI blood flor, motility and pH

A
  • 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
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14
Q

Describe first pass metabolism

A

First Pass Metabolism of drugs by GI and Liver
• Gut Lumen: Gut/Bacterial Enzymes - can denature some drugs
• Gut Wall/Liver: Some drugs metabolised by two major enzyme groups
- Cytochrome P450s - Phase I Enzymes
- Conjugating - Phase II Enzymes
• Much larger expression of Phase I &II Enzymes in Liver
• ‘First Pass’ metabolism: Reduces availability of drug reaching systemic circulation - therefore affects therapeutic potential

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15
Q

What is bioavailability?

A

Bioavailability Definition
• Fraction of a defined dose which reaches its way into a specific body compartment
• CVS (Circulation) is most common reference compartment
• For CVS/Circulatory Compartment Bioavailability Reference - 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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16
Q

How is oral bioavailability (F) measured?

A

On a graph of plasma conc against time post dose (h)

Measure:
• Total Area Under Curve for IV route
• Total Area Under Curve for Oral route

• F = Amount reaching Systemic Circulation / Total drug Given IV

F(oral) = AUC (oral) / AUC (IV)

  • F between 0 and 1
  • Informs choice of administration route
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17
Q

What is drug distribution?

A

How drug journeys through body
• To reach and interact with therapeutic and non-therapeutic target
• Interacts with other molecules and how affects the above

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18
Q

What happens in the first stage of drug distribution?

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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19
Q

Describe capillary permeability

A
  • Differing levels of capillary permeability
  • Enables variation in entry by charged drugs into tissue interstitial fluid
  • From there on to Target site (s)
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20
Q

Name 2 major actors which affect drug distribution

A

Drug molecule lipophilicity/hydrophilicity

Degree of drug binding to plasma and/or tissue proteins

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21
Q

What is the effect of drug molecule lipophilicty/hydrophilicity on drug distribution?

Study These Flashcards
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

22
Q

What is the effect of the degree of drug binding to plasma and/or tissue proteins on drug distribution?

Study These Flashcards
A

Degree of drug binding to plasma and/or tissue proteins
• In circulation many drugs bind to proteins e.g.
- Albumin Globulins
- Lipoproteins Acid glycoproteins
• 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% )

23
Q

Describe a simple model to represent body fluid compartments

Study These Flashcards
A

Plasma water - contains plasma water - 3L

Extracellular water - contains plasma water and interstitial water - 14L (protein binding)

Total body water - contains plasma water, interstitial water and intracellular water - 42L (protein binding and lipid partitioning)

24
Q

What does increasing drug penetration into interstitial and intracellular compartments lead to?

Study These Flashcards
A

Increasing Penetration by Drug into Interstitial and Intracellular Fluid Compartments Leads to
 Decreasing Plasma Drug Concentration
 Increasing Vd

25
What is Vd?
‘Apparent’ Volume of Distribution • Smaller Vd values - less penetration of Interstitial/Intracellular Fluid Compartment values • Larger Vd values - greater penetration of Interstitial/Intracellular Fluid Compartment Volume of Distribution (Vd) = Drug Dose / [Plasma Drug]t=0 • More ‘pretending’ pretend drug fully distributes throughout the body at time zero • Vd units: Litres (assume ‘standard’ 70 kg body wt. ) Litres/kg (more referenced to individual patient body wt. )
26
What is the purpose of Vd
Apparent’ Volume of Distribution (Vd) • Models grouping of main fluid compartments as though ‘All One Compartment’ • Hence ‘Apparent’ it’s a very useful ‘Pretend’ • Provides summary measure of drug molecule behaviour in distribution • Referenced to Plasma concentration – easiest to measure • Summarises movement out of Plasma -> Interstitial -> Intracellular Compartment • Vd value dependent on push factors described
27
What is 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
28
Where does drug metabolism largely take place?
• Drug Metabolism largely takes place in Liver via Phase 1 and II enzymes • Enzymes expressed throughout body tissues • Very large hepatic reserve – also ‘first port of call’ after GI absorption - Increasing amount of ionic charge -more charges - easier to remove from he body
29
What is the role of phase I and II enzymes?
* Metabolise drugs - increase ionic charge enhance renal elimination * Lipophilic drugs diffuse out renal tubules back into plasma * Once metabolised - drugs usually inactivated - not always
30
Give an overview of drug metabolism phase I
Phase 1 Metabolism is carried out by Cytochrome P450 Enzymes • Phase 1 enzymes collectively refer to as CYP450s • Large group of > 50 isozymes located on external face of ER • Catalyse: redox; dealkylation; hydroxylation reactions • CYP450s are versatile generalists – metabolise very wide range of molecules • Metabolised drugs have increased ionic charge • Metabolised drug eliminated directly or go onto Phase II • * Some ‘pro-drugs’ activated by Phase I metabolism to active species
31
What can phase 1 metabolism activate?
Phase 1 Metabolism can activate prodrugs Some ‘pro-drugs’ activated by Phase I metabolism to active species • Example: 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
32
Give n overview of drug metabolism phase II
Phase 1I Metabolism is carried out by Hepatic Enzymes • Phase I1 enzymes - mainly cytosolic enzymes • Phase II still generalists but exhibit more rapid kinetics than CYP450s • Enhance hydrophilicity by further  ionic charge - add to Phase I • Catalyse: Sulphation, Glucorinadation, Glutathione conjugation, Methylation, N-acetylation • Phase II metabolised drugs further increased ionic charge • Phase II metabolism enhances renal elimination
33
What are cytochrome P450 enzymes?
Cytochrome P450 enzymes include three superfamilies • Three superfamilies CYP 1 2 and 3 • Isozyme members in each family coded by suffix: e.g. CYP3A4 • Six isozymes metabolise  90% prescription drugs • Other isozymes exhibit very variable hepatic expression • Each isozyme optimally metabolise specific drugs but do show overlap
34
What factors affect drug metabolism?
Many Factors of Direct Clinical Relevance • 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 CYP450s: Induction and Inhibition and Genetic Factors • Other drugs (Rx/OTC) can induce or inhibit CYP450s • Genetic variability/polymorphism/ non expression affects CYP450s
35
What is CYP450 induction?
CYP450 Induction • Concurrent administration of certain drugs (including just the one drug) can induce specific CYP450 isozymes • Induction mechanism via: increased transcription, increased translation, slower degradation • If another drug in body metabolised by induced CYP450 isozyme then its rate of elimination will be increased • Plasma levels of drug will then fall • For patient can have serious therapeutic consequences if levels drop significantly • Induction process typically occurs over 1-2 weeks
36
Give an example of CYP450 induction
Examples of CYP450 Induction: 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
37
What is CYP450 inhibition?
CYP450 Inhibition • Concurrent administration of certain drugs (including just the one drug) can inhibit specific CYP450 isozymes • Inhibition mechanism via: competitive/non-competitive inhibition • If another drug in body metabolised by inhibited CYP450 isozyme then its rate of elimination will be slowed down • Plasma levels of drug will then increase • For patient can have serious side effects consequences if levels rise significantly • Inhibition process occurs within one to a few days
38
Give an example of CYP450 inhibition
Examples of CYP450 Inhibition: Grapefruit Juice • Grapefruit Juice inhibits CYP3A4 • CYP3A4 metabolises Verapimil used to treat high blood pressure (BP) • Consequence can be much reduced BP and fainting
39
What genetic factors can affect phase I metabolism?
Genetic variation, polymorphism
40
How can genetic variation affect phase I metabolism?
Genetic Variation • CYP2C9: Not expressed in: 1% Caucasians; 1% Africans • Metabolises NSAIDs, Tolbutamide, Phenytoin • CYP2C19: Not expressed in: 5% Caucasians; 30% Asians • Metabolises Omeprazole, Valium, Phenytoin Prescriptive Practice Review • Need to consider safety/efficacy if not metabolised /rapidly metabolised
41
How can polymorphism affect phase I metabolism?
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 * CYP2D6: Not expressed in: 7%; Hyperactive (Polymorphism) 30% East Africans * Metabolises Codeine, TCAs
42
What are the main routes of drug elimination?
Routes of Drug Elimination • Main route of drug elimination is kidney. • Other routes: bile; lung; breast milk (deliver to baby); sweat, tears; genital secretions; saliva
43
Name the 3 processes in renal excretion
Glomerular filtration Active tubular secretion Passive tubular reabsorption
44
What happens to the drug in glomerular filtration
Glomerulus approx = 205 renal blood flow | Unbound drug enter via bowman capsule
45
What happens to the drug in proximal tubular secretion?
* Remaining 80% blood via peritubular capillaries * High Expression of OATs and OCTs * Carry ionised molecules * Raison d’etre of Phase I and II metabolism * Facilitated Diffusion/Secondary Active Transport * Along tubule length water resorbed * In tubule [Solutes] increase * 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
46
What happens in distal tubular reabsorption?
Examples • OATs: Urate (Gout); Penicillins; NSAIDs; Antivirals • OCTs: Morphine; Histamine; Chlorpromazine • Transport subject to competition between drugs can affect pharmacokinetics/therapeutics
47
What is clearance?
* Clearance is defined as the rate of Elimination of a drug from the body * Total Drug Clearance consists of that from all routes – for most drugs Total Body Clearance = Hepatic Clearance + Renal Clearance
48
What is Clearance formally defined as and what are the units?
Clearance or CL • Clearance is formally defined as: ‘…The Volume of Plasma that is completely cleared of the drug per unit time…’ • CL measured in ml/min or ml.min-1 • But this is really referenced to Vd, the Apparent Volume of Distribution • Real Plasma Volume is approx = 3Litres • Given 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’
49
What is the clinical relevance of CL and Vd?
CL and Vd • Along with the concept of Vd, clearance predicts how long drug will stay in body • Clinically Essential for informing - Designing dosing schedule - Therapeutic regimes levels - Minimising ADRs * In short answers ‘How long is drug in body and doing any therapeutic good ? * Together CL and Vd provide estimate of ‘Drug Half-Life’ or t1/2
50
What is half life?
Drug Half Life • Defined as ‘… 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…’.
51
Give an equation for t1/2? How is t1/2 affected by CL and Vd?
T1/2 = (0.693 * Vd) / CL | Round to 0.7 in exam
52
How is 1/2 life determined graphically?
Drug conc against time Draw line at where conc is halved Linear if log drug conc

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