Pharmacokinetics Flashcards
Define pharmacokinetics
the branch of pharmacology concerned with the movement of drugs within the body
What are the 4 main processes in drug therapy
Absorption
Distribution
Metabolism
Elimination
What are the 2 ways of drug administration?
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
Briefly describe 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
What is the typical transit time through the small intestine?
3-5 hours
Varying motility 1-10 hours
What is the pH of the small intestine?
Weakly acidic
6-7
What are 4 ways of drug absorption at a molecular level
Passive Diffusion
Facilitated Diffusion
Primary / Secondary Active Transport
Pinocytosis
What is passive diffusion?
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
What is SLC transport?
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
What are OATs and OCTs?
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
Aside from facilitated diffusion, how else can SLCs enables transport?
Give examples
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
Name 3 physicochemical factors which affect drug absorption
Physicochemical Factors
• GI length /SA
• Drug lipophilicity / pKa
• Density of SLC expression in GI
Describe GI blood flor, motility and pH
- 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
Describe first pass metabolism
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
What is bioavailability?
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)
How is oral bioavailability (F) measured?
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
What is drug distribution?
How drug journeys through body
• To reach and interact with therapeutic and non-therapeutic target
• Interacts with other molecules and how affects the above
What happens in the first stage of drug distribution?
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
Describe capillary permeability
- Differing levels of capillary permeability
- Enables variation in entry by charged drugs into tissue interstitial fluid
- From there on to Target site (s)
Name 2 major actors which affect drug distribution
Drug molecule lipophilicity/hydrophilicity
Degree of drug binding to plasma and/or tissue proteins