Pharmacokinetics Flashcards
What is pharmacokinetics?
What the body does to the drug, depends on hepatic/kidney function, genetics, age, sex, body composition, weight, drug’s water/lipid solubility, molecular weight, protein binding ability
What is pharmacodynamics?
What the drug does to the body once it gets to the site of action
What are the four main steps of pharmacokinetics?
Absorption
Distribution
Metabolism
Excretion
Why is pharmacokinetics important?
- Prescribing safely
- Critical to new medicines research and development
- Ability to enhance efficacy and reduce toxicity of drugs
- Understanding what can go wrong with drug dosing and drug-interactions
Why is it beneficial to understand pharmacokinetics?
- Choose appropriate drug/dose for patient with renal or hepatic impairment
- Predict some drug-drug interactions and avoid giving certain combinations of drugs - potential for reduced efficacy or side effects
- Explain why people react differently to some drugs
- Understand the potential risks in dosing some drugs and monitor drug levels to ensure safety and efficacy - narrow therapeutic index drugs
- Choose appropriate route of administration for a drug e.g. IV or oral
What is absorption?
How the drug enters the systemic circulation following administration
How do the majority of molecules move around the body?
Bulk flow (blood, lymph, CSF) Diffusion (molecule by molecule, short distances only)
What are the four main ways in which drugs are absorbed?
Passive diffusion through lipid
Facilitated passive diffusion
Active transport
Pinocytosis
With which molecules will passive diffusion work best to absorb a drug?
Small and limi-soluble molecules
What is the process of facilitated passive diffusion?
Polar molecules, drug substrate attaches to carrier and moves through cell membrane
What is pinocytosis?
Particle engulfed by cell, membrane encloses fluid and forms a vesicle which detaches and moves into cell - depends on energy, applicable to protein-based drugs
When will diffusion through a lipid occur most readily?
- High concentration gradient
- Low molecular weight
- High lipid solubility
- Low degree of ionization
- Large surface area
What are the major routes of administration?
- Oral
- Sublingual (under tongue)
- rectal
- Topical
- Transdermal
- Inhalation
- Injection (subcutaneous, intramuscular, intravenous, intrathecal - spinal column, intravitreal - eye)
Where does absorption of drugs mainly occur?
Small intestine
Factors affecting how much of a drug is absorbed from the GI tract
- Particle site and formulation
- Physiochemical factors
- Gut content (fasted vs fed)
- GI motility - gastric emptying determines how quickly drug delivered to small intestine
- Splanchnic blood flow - blood flow to GI tract
Why is IV administration of a drug beneficial?
- Direct administration into plasma
- Rapid onset and full absorption of drug
- When rapid effect needed or if oral absorption likely to be poor
- When drug is rapidly metabolized/eliminated, a loading dose (bolus) may need to be given which is then followed with infusion to maintain blood concentrations
What is bioavailability?
The fraction of the administered dose that reaches the circulation as the parent drug
Why is the bioavailability of IV drugs 1?
100% of it reaches blood stream
Why might there incomplete bioavailability for oral administration of a drug?
- Incomplete absorption and loss in feces - molecule is too polar to be absorbed or tablet did not release all contents
- First pass metabolism (fraction of drug lost during absorption) in gut lumen, during passage across gut wall or by liver before drug reaches systemic circulation
- Bioavailability has important therapeutic implications because it is the major factor determining the drug dosage fo different routes of administration
- If drug bioavailability = 0.1, oral dose will need to be 10x higher than IV dose
What is the distribution of a drug?
How it is transferred between plasma and tissue
Mostly passive diffusion
What is the distribution of a drug dependent on?
Blood flow speed and lipid solubility
Which organs are normally well perfused?
Brain, liver, kidneys, GI tract
Which organs are normally poorly perfused?
Skin, skeletal muscle, bone, fat
How does a drug distribute when taken orally?
Even filling across all compartments
How does a drug distribute when injected?
Fills brain, heart etc initially, then redistributes
What is protein binding?
Many drugs bind to plasma to intracellular proteins
Usually reversible
Lowers free concentration of drug available (causes pharmacological effect)
What is the volume of distribution?
Theoretical volume to contain total amount of administered drug equal to the concentration in the blood plasma
Characteristics of low Vd drugs?
Large, water soluble, stay within plasma and well perfused organs
Characteristics of high Vd drugs
Small, lipid soluble, distribute across all compartments
What is elimination?
Metabolism + excretion
How are larger molecules normally excreted?
Bile
How are smaller molecules normally excreted?
Really
What are the 3 phase 1 reactions?
oxidation, reduction, hydrolysis
What are the 2 phase 2 reactions?
Sulphate, glucuronide
Where is main site of drug metabolism?
Liver
Aims to make drug more soluble for kidneys
Lipid soluble molecule changes to water soluble
What is phase 1 of elimination?
Non-synthetic reactions, aims to produce molecules suitable for phase 2
What is phase 2 of elimination?
Addition of endogenous substances to increase water solubility - increases polarity and is more easily excreted
Problems with first pass metabolism
- Requiring significantly higher doses orally than IV due to reduced bioavailability
- Marked individual variations occur in the extent of first-pass metabolism, both in the activities of drug-metabolizing enzymes and also as a result of variation in hepatic blood flow
- Examples of drugs: lidocaine, salbutamol etc
What is a pro-drug?
Metabolised for administration to a pharmacologically active metabolite, may be inactive until metabolised
What is a first order reaction?
Elimination is proportional to drug concentration, loses constant fraction per time unit
What is a zero order reaction?
Elimination of constant quantity per time unit
What is half life?
Time taken for the plasma concentration fo a drug to decrease by 50%
What is the elimination constant K?
Rate of drug removal from body
What is the shape of the graph of ln against time for a first order reaction?
Straight line
Characteristics of K for first order reaction?
Constant, independent of drug concentration
What is clearance?
Volume of plasma in vascular compartment cleared of drug per unit time by metabolism and excretion
How to calculate clearance
rate of elimination from body / drug concentration in plasma
How to calculate clearance using K
Cl = K x Vd
What is repeated administration?
Fixed dose at regular time interval
What is a loafing dose?
Single dose needed to produce desired steady state concentration
How to calculate loading dose
Css x Vd
How would you change dosage if the patient had low cardiac output?
Reduce dose, give more slowly
How would you change dosage if the patient had hepatic/renal impairment?
Increase dosage intervals, reduce dose
Effects of drug interactions
Increase/decrease in drug effect or synergistic effects (combined effect is greater than sum of combined separate effects)
How to calculate therapeutic index
(dose resulting in toxicity) / (dose giving therapeutic response)
What is the therapeutic index?
Safety margin
What does a high therapeutic index indicate?
Low risk of toxicity
What does a low therapeutic index indicate?
High risk of toxicity
Pharmacokinetic drug interactions in absorption
Physio-chemical reactions in GI tract
Pharmacokinetic drug interactions in distribution
Protein binding displacement - increased free drug
Pharmacokinetic drug interactions in elimination
Enzyme inhibition (enhanced activity) and enzyme induction (decreased activity)
Examples of enzyme inhibitors
Grapefruit juice, excess alcohol, sodium valproate, erythromycin, cimetidine
Examples of enzyme inducers
Alcohol consumption, cigarettes, sprouts, anticonvulsants, spironolactone
