S2) Pharmacokinetics Flashcards
What is pharmacokinetics?
Pharmacokinetics is the study of the movement of a drug into and out of the body
“What the body does to the drug”
What is pharmacodynamics?
Pharmacodynamics is the study of drug effect and mechanisms of action
“What the drug does to the body”
What is pharmacogenetics?
Pharmacogenetics is the effect of genetic variability on the pharmaco- kinetics/dynamics of a drug on an individual
What are the two forms of drug administration?
- Enteral – delivery into internal environment of body (GI tract)
- Paraenteral – delivery via all other routes that are not the GI
What are the 9 different types of drug administration into the body?
- Oral
- Intravenous
- Intramuscular
- Transdermal
- Inhalation
- Subcutaneous
- Sublingual
- Intrathecal
- Rectal
Briefly, identify and describe the four main processes involved in drug therapy?
- Pharmaceutical process – “Is the drug getting into the patient?”
- Pharmacokinetic process – “Is the drug getting to its site of action?”
- Pharamcodynamic process – “Is the drug producing its required pharmacological effect?”
- Therapeutic process – “Is the pharmacological effect being translated into a therapeutic effect?”
What are the four processes involved in pharmacokinetics?
- Drug in:
I. Absorption
II. Distribution
- Drug out:
I. Metabolism
II. Excretion
What is bioavailability?
Bioavailability is the fraction of a dose which finds its way into a body compartment (absorption) (usually the circulation)
drug entered via iV bolus will have 100% bioavailability
it’s the amount of free drug ready to use
How does one calculate oral bioavailability?
Oral Bioavailability (F) = AUCoral / AUCIV
What are the factors which affect bioavailability?
- Absorption – drug formulation, age, food, vomiting / malabsorption
- First pass metabolism
What is first pass metabolism?
First pass metabolism is any metabolism occurring before the drug enters the systemic circulation
Identify three common locations where first pass metabolism occurs
- The Gut Lumen
- The Gut Wall
- The Liver
What is drug distribution?
The distribution of a drug refers to its ability to ‘dissolve’ in the body and getting drug to the right place
What are the two factors affecting drug distribution?
- blood flow, structure of capillary
- is tissue well vascularised
- lipophilicity and hydrophilicity
- Protein binding (albumin and glycoproteins)
- Volume of Distribution (Vd)
In three steps, explain how protein binding determines drug distribution
⇒ In systemic circulation, many drugs are bound to circulating proteins
⇒ Most drugs must be unbound to have a pharmacological effect
⇒ The free fraction of the drug can bind to cellular receptors, then gain access to cellular enzymes
Once in the systemic circulation, many drugs are bound to circulating proteins.
Provide four examples of this
- Albumin (acidic drugs)
- Globulins (hormones)
- Lipoproteins (basic drugs)
- Acid glycoproteins (basic drugs)
What happens when a drug is displaced from its binding site?
Displacement of drugs from binding sites causes protein binding drug interactions
the drug is now considered a free drug
Changes in protein binding can occur, causing changes in drug distribution. However, these are only important if 3 criteria are met.
What are these criteria?
- High protein binding
- Low Vd
- Has a narrow therapeutic ratio
Identify four factors which affect protein binding
- Hypoalbuminaemia
- Pregnancy
- Renal failure
- Displacement by other drugs
If a drug is not bound to plasma proteins, it is available for distribution to the tissues of the body.
How can one measure the tissue distribution of a drug?
Volume of distribution
What is volume of distribution?
Volume of distribution is a measure of how widely a drug is distributed in body tissues
link between the dose and the amount we can measure in the plasma of the patient
How can one calculate volume of distribution?
Volume of distribution (Vd) = Dose / [Drug]plasma
Identify six factors which might affect the tissue distribution of a drug
- Specific receptor sites in tissues
- Regional blood flow
- Lipid solubility
- Active transport
- Disease states
- Drug interactions
What are the end products of drug metabolism (usually)?
- After conjugation, water-soluble metabolites are formed
- Usually, they are pharmacologically inactive
Describe two circumstances where drug metabolism produces active metabolites
- Pharmacologically inactive compound → pharmacologically active compound e.g. pro-drugs
- Pharmacologically active compound → other active compounds eg. codeine to morphine
Phase I metabolism involves oxidation and reduction reactions.
Which group of enzymes control these reactions?
Cytochrome p450 family of enzymes
Explain how drugs can control the activity of Cytochrome P450 enzymes
Enzyme-inducing and enzyme-inhibiting drugs that alter the rate of metabolism of other drugs
Identify five other factors, apart from drugs, which influences the activity of cytochrome p450 enzymes
- Age
- Liver disease
- Hepatic blood flow
- Cigarette use
- Alcohol consumption
What are Cytochrome P450 isoenzymes and what do they do?
- CYP450s are a super family of isoforms responsible for approximately 90% human drug metabolism through oxidative reactions
- They metabolise toxins such as carcinogens and pesticides
Where are Cytochrome P450 isoenzymes found?
CYP450s are present mainly in the liver (some gut and lung)
Identify 5 factors which might affect drug metabolism
- Race (development of pharmacogenetics)
- Age (reduced in aged patients & children)
- Sex
- Species
- Clinical / physiological condition
What is the main route of drug elimination?
The main route of drug elimination is the kidney
Identify 5 other routes of drug elimination
- Lungs
- Breast milk
- Sweat
- Tears
- Genital secretions
Three processes determine the renal excretion of drugs.
Identify these
- Glomerular Filtration
- Passive tubular reabsorption
- Active tubular secretion
What is clearance?
Clearance is the ability of body to excrete drug (mostly = GFR) per unit Time mL/min
Describe the relationship of clearance with GFR and t1/2
- GFR is directly proportional to clearance
- t<strong>1/2</strong> is inversely proportional to clearance
i.e. a reduction in clearance (/ GFR) increases t1/2
Describe the features of 1st Order kinetics – linear
- Rate of elimination is proportional to drug level
- Constant fraction of drug eliminated in unit time
- t1/2 can be defined
Describe the features of Zero Order kinetics – non-linear
Rate of elimination is constant
dose change can produce unpredictable change In plasma and so half life will not be predictable
How does one calculate the elimination rate constant (k)?
k = Cl / Vd
How does one calculate half life (t1/2)?
t<strong>1/2</strong> = ln2 / k
Most drugs exhibit zero order kinetics at high doses.
Why is this?
Because the receptors / enzymes become saturated
Zero order drugs are more likely to result in toxicity, hence, drug monitoring essential.
Why does this occur?
- Fixed rate of elimination per unit time
- “Small” dose changes may produce large increments in [plasma] which may lead to toxicity
Provide 5 reasons for drug monitoring
- Zero order kinetics
- Long half-life
- Narrow therapeutic window
- Greater risk of drug-drug interactions
- Known toxic effects e.g. bone marrow suppression
What is the steady state (CpSS) of the drug?
- Steady state (CpSS) refers to the situation where the overall intake of a drug is in dynamic equilibrium with its elimination
- Usually, 4-5 half lives are required to reach steady state
Loading doses are employed to reach CpSS more rapidly.
What are loading doses?
- A loading dose is an initial higher dose of a drug that is given at the start of a drug course before dropping down to a lower maintenance dose
- Useful for drugs that have a long systemic half-life (eliminated slowly)
- when you give a drug it will be eliminated but by new frequent doses you up the dose to reach the original conc
How does one calculate loading doses?
Loading Dose = Vd x [Drug]target
or CSSxVd
modified release preparation
- if elimination is rapid there will be a large fluctuation seen in the plasma
- modified release will help make plasma conc more dependent on rate if absorption vs elimination
- help with adherence
modified release preparation
- if elimination is rapid there will be a large fluctuation seen in the plasma
- modified release will help make plasma conc more dependent on rate if absorption vs elimination
- it means there is an extended release of the medication
- help with adherence
examples of some CYP isoenzymes and their action
what are some things that influence pharmacokinetics
- bioavailability
- half life
- drug elimination
- drug-drug interactions
what is the unit for concentration
amount per volume
mg/L
phase 1 and phase 2 enzymes involved in metabolism
what is the pathway for the liver excreting drugs
- high molecular weight metabolites conjugated with glucuronic acid
- bile conjugates
- enterohepatic circulation → environment for recycling drugs
- endogenous: bilirubin and steroid hormones
why is volume of distribution known as apparent?
the hypothetical amount of plasma needed to maintain the entire drug concentration but this could mean 200L of plasma needed to contain the whole drug dose but realistically you don’t have 200L of plasma
what is enterohepatic circulation?
allows for recycling of metabolised and non-metabolised compounds
is responsible for reabsorbing bile
what is sequestration into fats?
- involved in volume of distribution
- sometimes drug is transported to fats and proteins → areas of the body where the drug is stored but does not act (waste of drug)
clearance formula
rate of elimination from the body/drug conc in plasma (mL/min)
what happens to the elimination rate when the conc of the drug is high
- there is more drug per volume
- more drug in the same volume is cleared
- there will be a higher elimination rate (mg/min)
what causes a high half life?
- low clearance
- high volume of distribution
signs that you have prescribed successfully
- feeling → MSK, mood and energy
- appearance - rash, infection
- reduced frequency of seizures and migraines
- primary and secondary prevention
what does selectivity mean?
- ratio of drug that achieves a level of response at one receptor subtype vs conc of drug needed at another receptor subtype
what is efficacy?
- ability to produce max response of a particular system (vasodialation)
factors that effect the steady state
- drug clearance
- dosing interval
- dose
