Pharmacokinetics Flashcards
What is Pharmacology
Effect of chemicals on biological entities
Study of drugs: the way drugs react biologically at receptor sites
Study of drug effects: effect the drug has when taken by a person
Considers therapeutic and toxic effects
What are the two main branches of Pharmacology
Pharmacodynamics - The mechanism whereby drugs exert their effect on the body
Pharmacokinetics - The movement of the drug within the body
Mechanism of Action - specific to drug or drug class
Pharmacodynamics
Non specific mechanism - general processes
Pharmacokinetics
What is a Drug
A natural product, chemical substance or pharmaceutical preparation intended for administration to a human or animal to diagnose or treat a disease
What are the benefits of oral administration
Convenient, safe and cost effective
What are the Disadvantages of Oral administration
1st Pass metabolism - Deactivated in the liver
Irritant to the gut
Potential adherence issue
What are the benefits if intravenous administration
Bypasses absorption and as such immediate effect
100% bioavaliability
What are the Disadvantages of IV administration
Increased risk of toxicity
Staffing - patient not able to self administer
If a drug is going ot have an effect on the body its going to need to be
In the right place
At the right concentration
for the right amount of time
What are the 4 main components of Pharmacokinetics
Adsorption
Distribution
Metabolism
Excretion
What effects oral absorption of a drug
Particle size and formulation GIT Enzymes/Acid GIT motility Physicochemical factors Food
What affect will GI Motility have on the absorption of drugs
Rate of gastric emptying determines the rate at which a drug is delivered to the small intestine
Increased motility increases the rate of absorption as the stomach empties more quickly
Decreased motility will decrease the rate of absorption as it takes longer for the drug to reach the small intestine
In hyper motility states absorption may decrease as the drug is not in the small intestine long enough to be absorbed
What form of a drug is needed to be absorbed by the GI tract
Lipophillic and hydrophobic - to pass through the endothelium
What physiochemical factors can effect absoprtion
Physicochemical reactions can occur between food and medicines or medicines and other medicines resulting in reduced absorption
Calcium and Iron can act as chelating agents - inactivating the drug prior to absorption
Example: calcium can form insoluble complexes with some drugs –> affects absorption
Iron salts and many antacids have a similar effect
What affect can food have on the absorption of drugs
May delay gastric emptying
May increase the absoprtion of some drugs
May reduce adverse events eg NSAIDS
What is an acid
A substance with the ability to donate a proton - hydrogen ion and become dissociated
What is a base
A base is a proton acceptor
An alkali is a soluble base
What is Distribution
The process by which the drug is transferred reversibly from the general circulation into the tissues as concentrations in blood increase and from the tissues into blood as blood concentrations decrease
What is Drug protein binding
Some drugs are distrubted around the body bound to plasma proteins
Two main types are Albumin and Glycoproteins
What is the issues with giving two drugs that are highly protein bound
Results in displacement of drug already bound to protein
Produces increased unbound concentration of drug and biological activity
What are some of the Albumin bound drugs
Furosemide Ibuprofen Phenytoin Thiazides Warfarin
What are some of the Glycoprptein bound drugs
Chlorpromazine
Propranolol
TCAs
Lidocaine
What factors can affect drug distribution
- Plasma protein binding
Competition for protein binding sites - Specific drug receptor sites in tissues
e. g. domperidone does not cause extrapyramidal side effects because it doesn’t reach dopamine receptors in the brain - Regional blood flow
Reduced blood flow
Enhanced blood flow - Lipid solubility
Blood/brain barrier - Disease
Liver disease can cause low plasma protein levels
What are the 4 types of ways that drugs can cross the phospholipid bylayer
Passive diffusion
Transporters
Membranous Pores
Vesicle mediated transport - Pinocytosis
Define Simple Diffusion
The movement of a substance from an area of high concentration to an area of low concentration
Ion channels may enable this down a concentration gradient
Define Facilitated Diffusion
Molecules combine with the membrane bound carrier protein - still moving down the concentration gradiaent - Faster process
Define Active transport
Using energy in the form of ATP moves molecules against the concentration gradient
What is Pinocytosis
Molecules engulfed by cell membrane and vesicle formed
Vesicle moved into the cell
Molecule may then be released within the cell
What is the Blood-brain barrier
Functional basis of barrier is reduced capillary permeability owing to:
tight junctions between endothelial cells
decrease in size and number of pores in the endothelial cell membranes
presence of surrounding layer of astrocytes
What are the 4 aspects of drug metabolism
Activation of inactive drug
Production of active drug with increased activity from active drug
Inactivation of active drugs
Change in the nature of the activity
What is First Pass metabolism and when does it occur
Metabolism occurs prior to and during absorption
Intestinal Lumen
Digestive enzyme secreted by the mucosal cells and pancreas
Certain enzymes break down proteins and stop them from being absorbed
Intestinal Wall
Rich in enzymes that further metabolise drugs
Liver
Major site of drug metabolism
Lung
Cells of the lung have high affinity for many drugs and are the site of metabolism for many local hormones
Phases of Metabolism
Phase I Reactions
Oxidation, reduction and hydrolysis
Usually form more reactive products, sometimes toxic
Often involve mixed function oxidase system in which Cytochrome P450 plays a key role
Phase II Reactions
Conjugation
Usually form inactive and readily excretable products
What are the phases of Metabolism in order for a hydrophobic drug to be excreted in the urine
Lipophillic Drug - Phase 1 reaction causes the formation of a more active drug
Phase 2 reaction causes conjugation and it to be transformed into a hydrophillic form - able to be excreted in the urine
What is the significance of the Cytochrome P450 system
Isoenzymes that can inhibit or induce an affect either inhibiting the action or potentiating the affect
What is the affect of an enzyme inducing drug
Enhance the production of liver enzymes which break down drugs
Faster rate of drug breakdown
Larger dose of affected drug needed to get the same clinical effect
What is the affect of an enzyme inhibiting drug
Inhibit the enzymes which break down drugs
Decreased rate of drug breakdown
Smaller dose of affected drug needed to produce the same clinical effect
What can affect drug metabolism
First pass effect
Hepatic blood flow
Liver disease
Genetic factors e.g. acetylation status
Other drugs- hepatic enzyme inducers, hepatic enzyme inhibitors
Age
Impaired hepatic enzyme activity
Elderly
Children < 6 months (especially premature babies)
Define Bioavaliability
Bioavailability is the proportion of a dose which actually gets into the systemic circulation
What can affect bioavaliability
- Pharmaceutical Preparation
Particle size, composition of formulation - Physicochemical Interactions
Other drugs or food may interact with or inactivate the drug - Patient Factors
Malabsorption syndromes, gastrointestinal motility - Pharmacokinetic interactions and first-pass metabolism
What is the definition of Drug Clearance
This is the measure of the removal of drug from the body or the volume of plasma completely emptied of drug per unit time
How can the body excrete or eliminate a drug
1 cFluids:
Urine, bile, sweat, tears, milk
Important for low-molecular weight polar compounds
- Solids:
Hair, faeces
Faecal elimination important for high-molecular weight compounds that are excreted in bile
Distribution of drug along hair shaft can be used to indicate the history of drug intake during the preceding weeks - Gases:
Important only for volatile compounds
What affect can altered renal function have on eliniation
Reduced excretion
Increased renal impairment
active metabolytes may be nephrotoxic
Who is at risk of renal impairment
Elderly - renal blood flow decreases after the age of 30
Neonates
CKD
AKI
How can renal blood flow be estimated
Creatinine Clearance
It is neither passively reabsorbed or actively secreted
Estimation of Creatinine clearance estimates the clearance of drugs filtered at the glomerulus
What is the equation used to calculate the CrCL
Cockcroft-Gault equation
(140-age) x weight x constant
Serum Creatinine
Constant - male 1.23 and female 1.04
True or False
Un-ionised molecules cross phospholipid membranes more readily than their ionised forms
True
True or False
The half-life of a drug is longer in babies than in adults
True
True or False
A decrease in renal function decreases oral bioavailability
False
True or False
The activity of cytochrome enzymes is consistent among individuals
False
True or False
First-pass metabolism may limit the bioavailability of oral drugs
True
