Pharmokinetics Flashcards
What is pharmacology?
Branch of medicine and biolgy concerned with the study of drug action.Interactions that occur between a living organisms that affect normal/abnormal biochemical function
What is a drug?
Any man-made, natural or endogenous molecule that exerts a biochemical/ physiological effect on a cell/tissue/organ/organism
What does endogenous mean?
(Made) within the body
What do drugs usually act on?
Target proteins
What is a receptor?
Protein molecules whose function is to recognise and respond to endogenous chemical signals
What is the difference between a receptor and a drug target
Receptor - recognise and respond to chemical signals
Drug target -other macromolecules that drugs interact with to produce their effects
What is the importance of pinpointing the receptor locations?
Allows drugs to target specific tissues
Allows predictions of side effects (if the receptors are found in other parts of the body too)
How much does the chemical nature of the drug have to match that of the target molecule?
Almost perfectly
Drug-receptor interactions are dynamic. What does this mean?
Drugs bond to the receptor molecules (non-covalently) to form the active form of the complex. After this itcan dissociate for the cycle to repeat itself.
What is the definition of specificity?
How many receptors can the drug bind to and how many drugs can the receptor molecules bind? The greater the number, the lower the specificity.
What is the definition of affinity?
How strong is the (non-covalent) bonding between the drug and the receptor molecule?
Measured by the dissociation constant of the DR complex.
What is the definition of the dissociation constant?
The concentration at which half the drug is bound to the receptor at equilibrium.
Like rate constant/ half-life
what is the name of the law thatstates that the rate of a chemical reaction is proportional to the product of themassesof the reactants?
Law of mass action
If all the receptors for the drug are bound, will increasng dosage increate the rate of binding?
No - No additional positive effects
If the drug is able to bind to other receptor molecules, what effect would this have on the free solution?
Concentration of drug in free solution decreases
What is an agonist?
Drug that produces a positive effect when bound to a receptor
What is an antagonist?
Drug that reduces the effect of an agonist at a given receptor
What is an inverse agonist?
A drug that produces a negative effect when bound to a receptor.
What is efficacy (Emax)?
The maximum response achievable from a drug
What is potency?
The dose of a drug required to produce a specific effect of given intensity
What 2 things does the potency of a drug depend on?
Efficacy and affinity
True or false? The rate that a drug binds to receptor molecules can be linked to the activity that we can see (response)
True - Response/ Effect equation
How can the concentration of the agonist bound to the receptor be displaced?
An artificially introduced antagonistCompetitive antagonism
What is non-competitive antagonism?
Where an antagonist may not bind to the same part of the target siteAnon-competitive antagonistbinds to an allosteric (non-agonist) site on the receptor -prevents activation of the receptor.
What is inverse agonism?
An agent (inverse agonist)binds to the same receptor as anagonistbut induces anoppositeresponseto that of the agonist.
What is the difference between an antagonist and an agonist?
Antagonist usually blocks the receptor thus reducing the effect of the agonistInverse agonists do result in an effect but it’sthe opposite to the agonist
True or false? You can antagonise inverse agonism just as much as normal agonism?
True
What type of receptor is responsible for the largest number of prescriptions given out in the UK?
Nuclear receptors
What is the most important thing to remember when thinking about drug targets?
The type of receptor and effector system
What is the structure of nuclear receptors?
Monomeric; separate receptor and DNA-binding domains
What is the effector and coupling for nuclear receptors?
Gene transcriptionCoupling via DNA
Give a positive and negative or inverse agonists
+ They have less of an effect in comparision to normal agonists- The receptor is actually doing something as a result of their binding (negative effect)
What is pharmokinetics?
Factors that determine the active concentration of the drug at the active site
What is absorbtion?
The mechanism of accumulation of the drug in a body compartment following administration
What is distribution?
The way in which a drug reaches each organ of the bodyDrugs get ‘all over the place’ in varying degrees
What is metabolism?
The chemical alteration of a drug into (ultimately) its inactive formsThe body will get rid of the foreign stuff
What is excretion?
Removal of the drug and/or its metabolites from the body
What is the importance of plasma in pharmacology?
A key measurement of how much drug is active in the patient’s systemThe least invasive way to get a good measurement
Where is the main site of metabolism?
The liver
What is the difference between ionised and unionised drugs in terms of absorption?
Ionised - Will not pass through membrane unless there’s a specific transport molecule
Unionised - Will pass through lipid membrane (speed/ ease dependent on lipophilicity)
What is the relationship between pH and pKa for drug ionisation?
Drugs will be ionised when pH isopposite to pKa
What proteins do drugs bind to?
Plasma/ tissue proteins
What is ‘volume of distribution’?
Theoretical volume that the total amount of administrated drug would have to occupy (if it were uniformly distributed), to provide the same concentration as is in blood plasma.
What does liver metabolism usually do to drugs?
Inactivates drugs
Metabolites may remain active
Even before the substance accumulates, the liver is trying to get rid of it
What is a prodrug?
An inactive/ weakly active substance that has an active metabolite
How can the liver metabolise drugs?
Oxidation Reduction Hydrolysis Hydration Conjugation CondensationIsomerization
What are the 3 main mechanistic processes that allow the kidneys to regulate the chemical constituents in the blood?
Glomerular filtration
Tubular Secretion
Tubular Resorption
What is Cp?
Drug concentration in plasma; assumed to relate to extracellular fluid surrounding cells
What is Cmax?
Maximum plasma concentration following a given dose
What is Tmax?
The time between drug dose and achieving Cmax
What is used to adjust dosing regimen, based on experimental estimates and patient data.
Parameters
What is Kabs?
A rate constant which governs the transfer of the drug to its central compartment
Kabs is assumed to be directly proportional to what?
The amount of drug that is still unabsorbed
What happens as a result of slow absorption?
Cmax is reduced
Duration of action is increased
What happens to Cp once absorption is complete?
It declines with the same t1/2
This happens irrespective of the rate of absorption
What is important to note about the description of Vd?
It is an apparent volume rather than a specific anatomical compartment
What is C0?
Initial concentration
What is the term used to describe the time taken for Cp to fall by 50%?
Elimination half-life
What is a ‘loading dose’?
Adoseofmedication,oftenlargerthansubsequentdoses,administeredforthepurposeofestablishingatherapeuticlevel ofthemedication.
What are the limitations of the single compartment model?
- Over simplification
- Assumes rate of absorption, metabolism and excretion are directly proportional to drug concentration in the compartment.
- Different tissue compartments may affect time courses of drug distribution
What is the difference between the single-compartment model and the two-compartment model?
Two-compartment model has a peripheral compartment represented by tissues
Drugs enter second compartment via central (plasma) compartment
An extra exponential component is added to the Cp time course
Double exponential kinetics features two phases. What are they?
Fast phase (alpha) Slow phase (ß)
What is the fast phase of the Cp time course?
Represents transfer between central and peripheral compartments (plasma-> tissues)
What is the main limitation of double exponential kinetics?
Some drugs are not equally soluble across all tissues
What is saturation kinetics?
Alternative explanation for elimination from plasma - disappearance is linear, irrespective of dose or Cp
What are the implications of saturation kinetics?
Duration of action is more depedent on dose - the first probably saturated the enzymes involved
Relationship between dose and steady state Cp is steep and unpredictable - more likely to experience side effects because it is easy to pass the therapeutic window
Drugs with these kinetics are difficult to administer effectively so may be rejected in development
What arethe cytochrome P450 enzymes?
Haem proteins, 3 of which are involved in drug metabolism
Differ from one another and in the specificity of the reactions they catalyze
Induced/ inhibited by many substances resulting in drug interactions- one drug enhances the toxicity or reduces the therapeutic effect of another drug.
What is irreversible binding?
An antagonist binding covalently to the receptor and cannot be displaced by competing ligands or washing.
