1.1 Pharmacokinetics Flashcards
Define the following terms:
- Pharmaceutical Process
- Pharmacokinetic Process
- Pharmacodynamic Process
- Therapeutic Process
Pharmaceutical Process: getting the drug into patient
Pharmacokinetic Process: getting drug to the site of action
Pharmacodynamic Process: producing required pharmacological effect
Therapeutic Process: Pharm effect translated to a therapeutic effect
Define the following terms:
- Pharmacokinetics
- Pharmacodynamics
- Pharmacogenetics
Pharmacokinetics: what the body does to the drug
Pharmacodynamics: what the drug does to the body,
Pharmacogenetics: effect of genetic variability on PK and PD
Give 2 importances of Pharmacokinetics
1) essential part of drug regulation: MHRA / FDA
2) elucidates the mechanisms of drug interactions
Give the 5 key factors of Pharmacokinetics (HI DEB)
- Half-life
- Intra-subject variability
- Drug-Drug interactions
- Drug Elimination
- Bioavailability
Give 4 factors affecting drug pharmacokinetics in an individual
- Infection
- Disease
- Stress
- Renal function
- Liver function
Pharmacokinetics is the study of the ________ of drugs and their _____ through the body
movement, metabolites
What 4 general processes determine pharmacokinetics of a drug? (ADME)
Absorption, Distribution, Metabolism, Elimination
How do we calculate Therapeutic index (or ratio)?
Therapeutic index = TD50 / ED50
Define the following:
- TD50
- Therapeutic window
- ED50
TD50: the dose at which toxicity occurs in 50% of cases
Therapeutic window: the range of blood level where the drug is producing the desired effect
ED50: the dose that produces a specific effect in 50% of the population
What is meant by the Therapeutic index and what can be said about a larger TI?
A ratio that compares the blood conc at which a drug becomes toxic and the conc at which the drug is effective
The larger the therapeutic index (TI), the safer the drug is
Define bioavailability?
The fraction of a dose which finds its way into a body compartment, usually the circulation
Compare the bioavailability of an intravenous bolus vs other routes
Intravenous bolus: bioavailability is 100%
Other routes: compare amount reaching the body compartment by that route with intravenous bioavailability
What is meant by AUC and what can be said about IV AUC?
How do we therefore calculate oral bioavailability (F)?
AUC = area under the Curve
IV AUC = Total drug Exposure
oral bioavailability: F = AUC oral / AUC IV
Give 4 factors affecting bioavailability
Absorption:
- drug formulation
- age
- food ie. lipid-soluble > water-soluble
- vomiting / malabsorption
First pass metabolism (extraction ratio)
Compare long (extended release) vs short (immeadiate release) oral drugs in terms of the graph below
Incl which has a higher bioavailability
Extended release: only one dose is required which is delayed being released into the plasma, but results in a sustained ongoing release and therfore a higher conc in plasma (higher bioavailability)
Immediate release: graph shows 4 doses are required in order to maintain drug within theraputic window (lower bioavailability)
Describe the structue of an extended release oral tabel
Extended release drugs have a capsule surrounding them. Within this is the tablet. The capsule consists of a range of beads of different sizes, all containing the SAME conc of drug. The difference in sizes accounts for the sustained plasma conc of the drug due to smaller beads releasing faster than larger ones
What is meant by first pass metabolism?
Metabolism occurring before the drug enters the systemic circulation, the ‘first-pass’ effect
Give 3 locations where first pass metabolism may occur and how
1) Gut Lumen by gastric acid and proteolytic enzymes (+ grapefruit juice)
2) Gut Wall by P-glycoprotein efflux pumps, which pump drugs out of the intestinal enterocytes back into the lumen
3) The Liver
Give 3 examples of drugs in which first pass metabolism occurs in the gut lumen
Benzylpenicillin, insulin, cyclosporin
Give an example of a drug in which first pass metabolism occurs in the gut wall
cyclosporin
Give an example of a drug in which first pass metabolism occurs in the liver
Propranolol (extensively metabolised in the liver)
How do drugs abosrbed in the gut wall enter the liver?
Via the portal vein
What is meant by Drug Distribution?
Its ability to ‘dissolve’ in the body
What 2 key factors influence Drug Distribution?
1) Protein binding
2) Volume of Distribution (Vd) (Theoretical Constant)
In the systemic circulation many drugs are bound to circulating proteins, give 4 examples and which type of drugs bind each
(GALA)
1) Albumin (acidic drugs)
2) Globulins (hormones)
3) Lipoproteins (basic drugs)
4) Acid glycoproteins (basic drugs)
What MUST a drug be in order to have a pharmacological effect and why?
Unbound (free)
Only the fraction of the drug that is not protein-bound can bind to cellular receptors, pass across tissue membranes, gain access to cellular enzymes etc..
What determines a drugs action at a receptor?
Displacement of drugs from binding sites causes what?
Free drug determines its action at receptor
Displacement of drugs from binding sites causes protein binding drug interactions
A drug must be in its free form in order to __1__ or __2__
1) bind to target receptor
2) be eliminated
Changes in protein binding can occur, causing changes in drug distribution
These are only important if 3 criteria are met, list these
1) High protein binding
2) Low Vd
3) Has a narrow therapeutic ratio
Give 4 factors affecting protein binding
- Hypoalbuminaemia
- Pregnancy
- Renal failure
- Displacement by other drug
Drug that is not bound to plasma proteins is available for distribution to ____
Some are distributed only to the body _____, while others are bound extensively in body _____.
tissues, fluids, tissues
How can we measure the distibution of drugs in the tissues?
Volume of distribution (Vd)
What is Vd, how is it calculated and when may it be useful
Volume of Distribution is how widely drug is distributed in body tissues
Vd ~ Dose / [Drug] t0
It is a hypothetical measure, but is useful in understanding dosing regimens
- e.g. 100mg gentamicin dose, peak plasma concentration 5mg/l, then the Vd will be 20 litres.
What is t1/2 and what is it’s relationship to Vd and clearance?
t1/2 ➞ Half life of a drug: the time required for plasma concentration to decrease by half
t1/2 is proportional to Vd BUT inversely proportional to clearance
Describe the 2 phases of drug metabolism in the liver
1) Modification of drug to more reactive or polar metabolite by phase I enzymes via oxidation, reduction, hydrolysis etc.. This exposes the reactive groups
2) Conjugation ➞ phase II enzymes conjugates drug with endogenous molecules ie. glucoronide, sulphate and glutathione. This makes drug water solube
Oxidation and reduction of phase I metabolism are in part dependent on what family of enzymes?
What is their other role?
Cytochrome P450 (CYPs)
Also metabolise toxins such as carcinogens and pesticides
What are the 2 outcomes of a drug following phase II metabolism is the liver?
1) kidney ➞ urine
2) gallbladder ➞ bile
What is the purpose of phase II metabolism in the liver?
The end products of conjugation are water-soluble enabling rapid elimination from the body. They are also usually pharmacologically inactive
What are Pro-drugs and give 2 examples
Pharmacologically inactive compound metabolised to an active one
Eg.
- Inactive enalapril to active enalaprilat
- L-Dopa metabolised to a more active metabolite to improve distribution (crosses blood-brain barrier)
Codine is a prodrug, how does it differ from prevously mentioned prodrugs?
Give one other drug that is also metabolised this way
Codine is a pharmacologically active compound which is metabolised to another active compound morphine
Other drug: Losartan to EXP3174
Give 4 ways in which P450 enzymes can be influenced
1) by enzyme- inducing and enzyme-inhibiting drugs
2) age
3) liver disease
4) hepatic blood flow
5) cigarette and alcohol consumption
What do enzyme- inducing and enzyme-inhibiting drugs do?
Alter the rate of metabolism of other drugs by influencing activity of P450 enzymes
Where are CYP450 located and how do they differ
Give 4 major examples
Present mainly in the liver (some gut and lung). They have genetic differences in metabolism
Major examples: CYP2D6, 2C9, 2C19, 3A4
Give 5 factors that may influence drug metabolism and why
Race: development of pharmacogenetics
Age: metabolism reduced in aged patients and children
Sex: women are slower ethanol metabilisers
Species: drug development
Clinical or physiological condition
What else MUST we consider when prescribing drugs?
Consider OTC and food as drug-drug interactions
Eg. charcoal grill 1A+; grapefruit juice 3A- ????
What is the MAIN route of drug elimination plus 4 other routes?
Main route is the kidney.
Other routes include the lungs, breast milk, sweat, tears, genital secretions, bile, saliva
What 3 processes determine the renal excretion of drugs?
1) Glomerular Filtration
2) Passive tubular reabsorption
3) Active tubular secretion
Explain how drug elimination occur in the nephron?
What is Clearance?
Ability of body to excrete drug (mostly = GFR)
1) If the GFR is reduced then clearance is ______
2) t1/2 is __________ to clearance
3) A reduction in clearance (or GFR) ______ t1/2
reduced, inversely proportional, increases
Drug elimination may either be first order kinetics or zero order kinetics, define each
1st Order kinetics - Linear
Rate of elimination is proportional to drug level. Constant fraction of drug eliminated in unit time. Half life can be defined.
Zero Order kinetics – Non-linear
Rate of elimination is a constant.
What does each of the graphs show?
Both demostrate 1st order kinetics
First graph shows how concentration of the drug decreases by half every 15 mins
Second graph is linear when ln[drug] is plotted against time
(ln[drug] = natural logarithim of plasma conc of drug)
The graph below shows 1st order kinetics, what does the gradient of this line give us and how is it calculated?
k = Elimination Rate Constant = Cl / Vd
(ERC is itself equal to Cl/Vd)
Allows us to calculate the half life of the drug
Zero order kinetics is ______ to predict than linear order kinetics. This means ______ is easier with 1st order kinetics
Harder, dosing
A drug showing first order kinetics is _____ likley to hit the theraputic window. Whereas, ______ levels are more likely to be reached with a drug showing zero order kinetics
More, toxic
What would a graph of Zero order kinetics show and how does this differ from one showing first order kinetics?
Zero: straight line when linear y axis scale plotted against time
First: linear when ln[drug] plotted against time
Zero order shown on image below
Most drugs exhibit _____ order kinetics at high doses. However, drugs within their theraputic window exhibit _____ order kinetics
Explain why
Zero, First
At high doses, the receptors/enzymes become saturated
Give 4 main pharmacokinetic reasons why we would do drug monitoring + 2 others
If the drug has:
- zero order kinetics
- long half-life
- narrow therapeutic window
- at greater risk of drug-drug interactions
Others include:
- know toxic effects (e.g. bone marrow suppression or alteration in U+Es)
- monitoring therapeutic effect (e.g. BP, glucose etc)
Most drugs are given as prescriptions for longer cources of time, what are we trying to achieve?
CpSS ➞ Steady State Concentration in Plasma
During repeated drug administration, a new steady state is achieved in ___ half lives.
Generally this is irrespective of ____ or _____ of administration.
From CpSS, it also takes ___ half live to ______ most of the drug
5, dose, frequency, 5, eliminate
Compare the black vs red line below and state what the red box indicates
Black line: we see the concentration is slowly reaching the theraputic window
Red line: Alternative, where we may administer a loading dose (red box) which is an initial higher dose that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose
