Pharnacokinetics Flashcards
What is pharmacokinetics?
What the drug does in the body
What are the four main pharmacokinetic processes?
Absorption
Distribution
Metabolism (largely by liver)
Elimination (largely by kidney)
What are two main types of drug administration?
Enteral - delivery into internal environment of body (GI tract)
Parenteral - delivery via other routes (not GI)
Give three examples of enteral drug administration
Oral
Sublingual
Rectal
Give three examples of parenteral drug administration
Intravenous
Subcutaneous
Intramuscular
Where do drugs administrated orally get absorbed?
In the small intestine - constant GI movement- presenting drug molecules to GI epithelia.
What is the typical transit time for Drug Absorption in the Small Intestine?
3-5 hours
How are drugs absorbed at the molecular level? (4)
Passive Diffusion
Facilitated Diffusion
Primary / Secondary Active Transport
Pinocytosis
What molecules/drugs can be absorbed by passive diffusion?
Lipophillic drugs/steroids diffuse free,h across PM down concentration gradient
Weak acids/bases (protonated/deprotonated species) can diffuse across PM
What is absorbed by facilitated diffusion by solute carrier transport?
Molecules/solutes with net ionic charge (within GI pH range) cross the GI plasma membrane through a channel. Passive process based on electrochemical gradient
What are the two main types of solute carriers (SLC)?
OATs - organic anion transporters (For weak acids)
OCTs - organic cation transporters (for weak bases)
What two absorption processes can solute carriers be used in?
Facilitated diffusion
Secondary active transport
What is secondary active transport?
Transport driven by pre-existing electrochemical gradient (cotransport), does not utilise ATP directly
What factors effect drug absorption?
Physicochemical Factors
• GI length /SA
• Drug lipophilicity / pKa
• Density of SLC expression in GI
GI Physiology
• Blood Flow: e.g. Increase post meal
• GI Motility: e.g. Slow post meal
• Food /pH: Food can reduce/increase uptake
What is “first pass” metabolism?
The drastic reduction in concentration of drug reaching systemic circulation (affects therapeutic potential)
Give examples of where first pass metabolism occurs
Gut lumen - gut/bacterial enzymes
Gut wall/liver - metabolism by cytochrome p450s (phase 1 enzymes) and conjugating enzymes (phase 2 enzymes)
What does bioavailability mean?
Fraction of a defined dose which reaches its way into a specific body compartment (Circulation is the most common reference compartment, therefore when a medication is administered intravenously, its bioavailability is 100%.)
What is the most common bioavailability comparison?
Oral vs IV
What is drug distribution?
How drugs journey through the body to reach/interact sigh therapeutic and non-therapeutic targets and their interaction with other molecules
What are the stages of drug distribution?
Bulk food - large distance from arteries to capillaries
Diffusion - capillaries to interstitial fluid to cell membranes
Barriers to diffusion- interactions/permeability/non target binding
Capillary permeability differs depending on location in the body. What are the 3 main types of capillary permeability?
- Continuous - little transfer e.g.BBB
- Fenestrated - small fenestrations in the endothelium e.g. Small intestine and kidneys
- Sinusoid - incomplete basement membrane and intercellular gaps in endothelium e.g. Liver
What two major factors affect distribution of drugs?
Drug molecule lipophilicity/hydrophillicity - effects entry to cells
Degree of drug binding to plasma/tissue proteins e.g. Plasma proteins such as albumin and globulins. Binding to these proteins decreases free drugs available for binding
What are the three (simplified) main body fluid compartments?
Plasma Water - 3 Litres
Extracellular Water (Plasma Water + Interstitial) - 14 Litres
Total Body Water - Plasma Water + Interstitial Water + Intracellular Water - 42 Litres
Increasing penetration by drug into Interstitial and Intracellular Fluid compartments leads to what?
Decreasing Plasma Drug Concentration Increasing Vd (volume of distribution)
Why is volume of distribution (Vd) apparent?
Models group the main fluid compartments as if it is “all one compartment”
What does a smaller Vd value signify?
less penetration of Interstitial/Intracellular Fluid Compartment
What does a larger Vd value signify?
Greater penetration of Interstitial/Intracellular Fluid Compartment
What units are Vd given in?
Litres (assume ‘standard’ 70 kg body weight)
Litres/kg (more referenced to individual patient body weight)
List 6 things that can effect Vd?
Changes in regional blood flow Marked +/- changes in body weight Renal Failure Pregnancy Paediatrics/Neonates/Pre-term Geriatrics Cancer patients Anaesthetics
What is drug elimination?
Covers metabolic and excretory processes (closely integrated). Removes both exogenous and endogenous molecular species
What enzymes carry out phase 1 metabolism?
Cytochrome P450 Enzymes - haem containing isoenzymes located on external face of the ER
What do Cytochrome P450 Enzymes do?
Catalyse redox, dealkylation, hydroxylation reactions. Metabolises a wide range of molecules, increases there ionic charge
What happens to metabolised drugs after phase 1 metabolism?
May be eliminated directly
Or go onto phase 2 metabolism
Phase 1 metabolism can activate some pro-drugs, give an example.
Codeine to morphine, which has much higher affinity for µ opioid receptor.
What is phase 2 metabolism?
Carried mainly by hepatic enzymes - mainly cytosolic enzymes
More rapid kinetics than phase 1
Enhance hydrophobicity further by increasing ionic charge, enhances renal elimination
What do the cytosolic hepatic enzymes of phase 2 drug metabolism catalyse?
Sulphation, glucathione conjugation, methylation, N-acetylation
What happens to the products of phase 1 and phase 2 metabolism?
Molecular weight less than 300 - to the kidney for excretion in urine
Molecular weight more that 300 - to gallbladder for excretion into bile
6 main cytochrome P450 isoenzymes metabolism _______ of prescription drugs.
90%
What factors effect drug metabolism? (5)
Age (elderly, paediatrics)
Sex e.g. Alcohol metabolism slower in women
General health, dietary, disease
Other drugs - may induce if inhibit cytochrome P450
Genetic variability/polymorphism etc
How may concurrent drug administration induce cytochrome P450s?
Increased transcription, increased translation and slower degradation of CYP450.
If other drug in the body is metabolised by induced CYP450 then its rate of elimination is increased (plasma levels of drug falls)
What is Carbamezepine (CBZ) ?
An examokd of a CYP450 inducer.
CBZ is an anti-epileptic metabolised by CYP3A4 (CBZ induces CYP3A4 - lowering its own levels)
How may concurrent drug administration inhibit cytochrome P450s?
May be by competitive or non-competitive inhibition.
If another drug is metabolised by inhibited CYP450 isozyme then its
rate of elimination will be slowed down (plasma levels increase)
How is grapefruit juice an example of a CYP450 inhibitor?
Grapefruit juice inhibits CYP3A4, which metabolises Verapimil (used to treat high blood pressure), consequence may be reduced BP and fainting
Giver an example of genetic variation in cytochrome p450s
CYP2C19 - not expressed in 5% caucasians and 30% Asians. Functions in metabolism of Valium, omeprazole
Give an example of genetic polymorphism in cytochrome P450 metabolism?
CYP2D6 used to convert codeine to morphine. CYP2D6 categorised into poor/normal/ultra rapid metabolisers.
Poor codeine to morphine - may not experience pain relief
Ultra rapid codeine to morphine - lead to morphine intoxication/ADR
What genetic variation does CYP2D6 (converts codeine to morphine) show?
CYP2D6 not expressed in 7% Caucasians and hyperactive in 30% East Africans
What are the routes of drug elimination?
Kidney (main) Bile Lung Breast milk Sweat Tears
What are the three processes of renal excretion?
- Glomerular Filtration
- Active tubular secretion
- Passive tubular reabsorption
What happens in glomerular filtration of renal excretion?
Free drugs enters glomerular filtrate via bowmans capsule
What happens in active tubular secretion of renal excretion?
Proximal tubule – high expression of OATs and OCTs, carry ionised molecules into filtrate. Followed in by water
What happens in distal tubular reabsorption of renal excretion?
Passive reabsorption of lipid-soluble unionised drug which has been concentrated (so tubule concentration > perivascular concentration)
What is clearance?
Defined as the rate of elimination of a drug from the body
“The volume of plasma that is completely cleared of drug per unit time”
What is total body clearance the sum of (for most drugs)
Hepatic clearance and renal clearance
What is clearance measured in?
ml/min
Clearance I’d referenced to Vd (apparent volume of distribution), therefore can be thought of as _____________________
Apparent rate of elimination
Along with Vd, clearance can be used to predict what?
How long the drug will stay in the body
Give an estimate of drug half life
Using clearance (and Vd) to estimate his long a drug will stay in the body is clinically important for?
Designing dose schedule
Therapeutic regime levels
Minimising ADRs
Define drug half life
amount of time it takes for the concentration a drug in plasma to decrease to half of the concentration it had when it was first measured
What shape in the Log plasma [drug] vs time
Linear
Why is the Log plasma [drug] vs time linear?
Because the The rate of Metabolism or Excretion is proportional to Concentration of Drug
What happens to the kinetics when elimination processes become saturated?
Becomes rate limited - they cannot go any faster, saturated or zero order kinetics
(Occurs at higher drug doses)
What does a zero order drug elimination curve look like?
Y axis - relative rate of elimination
X axis [drug]
Initial curve increases exponentially, linear. (First order)
The as [drug] increases, rate of elimination levels off - reaches limit of capacity (zero order)
What is the clinical importance of zero order kinetics?
Drugs at/near therapeutic dose with saturation kinetics more likely to show ADRs or toxicity.
Give examples of patient groups that might need monitoring of therapeutic drug dose (due to zero order kinetics)
Elderly/infants Ruth decreased or immature capacity
Polypharmacy - competing at same processes
Serious ill patients - e.g, cancer, liver disease, alcoholic
Reduced hepatic or renal capacity - easier to saturate
