Pharmacology - kinetics/dynamics and interactions Flashcards
Pharmacodynamics
DRUG’s effect on body
Drug’s effect on cellular receptors via signal transduction
Pharmacokinetics
BODY’s effect on the drugs
What does 1 + 1 = 2 mean in pharmacodynamics terms?
Summation
What is summation? [pharmacodynamics]
If give two drugs with the same effects, at the same time, there is an additive effect
What does 1 + 1 = >2 mean in pharmacodynamics terms?
Synergism
What is synergism ? [pharmacodynamics]
If give two drugs with the same effect, the effect seen is greater than expected
What does 1 + 1 = 0 mean in pharmacodynamics terms?
Antagonism
What is antagonism? [pharmacodynamics]
The effects of the two drugs is cancelling the other out/ blocking the action of the other (sometimes done on purpose e.g. correcting an overdose)
What does 1 + 1 = 1 + 1.5 mean in pharmacodynamics terms?
Potentiation
What is potentiation? [pharmacodynamics]
If give 2 drugs that are excreted at the same time and place in the body, one will be excreted but the other will be forced to stay in the body longer and therefore have more of an effect than if it were given alone/excreted normally
Debatable as to whether this is pharmacokinetics or pharmacodynamics - as involves excretion too
What is the acronym for pharmacokinetics?
ADME Absorption Distribution Metabolism Excretion
Physiochemical
Drugs reacting with other drugs
Includes: aDsorption, precipitation, chelation, neutralisation
Mechanisms of absorption
Passive or facilitated diffusion
Active transport
Endocytosis
Variables of absorption
- pH - unionised molecules are able to pass through phospholipid layer but not ionised portions of drugs)
Vascularity - Surface area
- Contact time (e.g. taken with food/trauma = slower gastric emptying so longer before it reaches intestines)
- Motility (of GI tract)
- Solubility (fat etc may take up the drug before it gets to the correct place)
- Complex formation (if complexes, of drug molecules that have combined, form, they wont be small enough to be absorbed)
- Coatings or formulations - enteric coating (resistant to acidic stomach) or modified release (dissolve slower) mean the tablets can have an effect in desired part of body instead
- First pass metabolism - drug may get absorbed into the blood but is drained into liver and destroyed/altered
- Enzymes - needs to resist intestinal enzymes and colonic bacterial enzymes
Bioavailability
The rate and extent to which an administered drug reaches the systemic circulation. A comparison of how much of the oral drug does this vs the IV drug
(IV drugs = 100%)
How is bioavailability calculated on a graph?
Oral area under the curve / IV area under the curve x100
= %
What is ‘Area under the curve’?
measure of actual body exposure to the drug after administration
= mg/L x h
Factors affecting bioavailability
1st pass metabolism Solubility Chemical instability (e.g. GI enzyme destruction of insulin) motility acidity
What do Cmax and Tmax mean on bioavailability curves? (blood conc vs time curves)
Cmax = peak plasma conc after drug administration Tmax = time to reach Cmax
Volume of distribution (Vd)
Extent to which a drug goes to the effect/target site as opposed to other tissues, bloodstream, binds to proteins
total amount of drug in body (dose) / conc of drug in plasma (measured)
Small/low volume of distribution
Drugs tend to stay in blood and to go target area e.g. muscle relaxants
High volume of distribution
Drugs tend to go all over the body to other tissues - diffuse into peripheral tissue compartment and distributed in total body water
Factors affecting distribution
Blood flow (Brain's > muscles) Capillary permeability Plasma protein binding! Tissue protein binding Lipophilicity (ability to cross membranes)
What is the function of metabolism (relating to drugs)?
Convert lipid soluble drugs into water soluble drugs that can be excreted by the kidneys
Usually INactivates drugs but can also convert prodrugs into active drugs
Give the 2 outcomes for what happens if the enzyme required for a drug’s metabolism is inhibited by another drug
- The drug will not be converted to it’s metabolites to will be in the body longer so = more of an effect
- The drug may need converting to a more active or potent form to work = less of an effect on the body
Give the outcome for what happens if the enzyme required for a drug’s metabolism is induced by another drug
Drug A will induce the enzyme and therefore increase the metabolism of Drug B -> decreased therapeutic effects of drug B (opposite for pro-drugs)
Describe a 1st order reaction (rates)
Rate is directly proportional to the drug conc
It is catalysed by enzymes that aren’t saturated.
When considering elimination = a constant fraction of the drug is eliminated per unit time
Describe a 0 order reaction (rates)
Rate is constant
Enzymes are saturated by high drug doses.
Unaffected by increase in conc
Describe a Phase 1 metabolism reaction
ADD a FUNCTIONAL group hence permitting conjugation.
Polarise lipophilic drugs via reduction, oxidation, hydrolysis etc.
Catalysed by CYP450 system (commonly but not always)
Products can be active/inactive, smaller, polar/not.
Reaction is mainly microsomal
Describe a Phase 2 metabolism reaction
Adds endogenous compound to increase polarity and therefore water solubility. CONJUGATION reaction.
e.g. adding glucuronic acid or acetyl etc to polarise the drugs to be eliminated by renal or biliary systems.
Synthetic reaction.
Products are inactive, larger, polar and water soluble.
Reaction is microsomal, mitochondrial and cytoplasmic
Routes of excretion
Renally (most) Intestines - faecal Bile Lungs Breast milk
What is renal excretion dependent on?
pH - weak bases are cleared faster in acidic urine (and visa versa)
Solubility - drug/metabolite must be sufficiently polar (role of phase II metabolism) as if it is lipophilic it will be reabsorbed in the tubules
What can renal dysfunction lead to?
Drug or its metabolites accumulation
Example of weakly acidic drugs
Aspirin
Ibuprofen
Paracetamol
Warfarin
Example of weakly basic drugs
Salbutamol
Propranolol
Amphetamine
Risk factors of drug interactions - issues with the patient
Polypharmacy - Prescribed, over the counter, herbal Old age (links to the above and below) Hepatic or renal disease Genetic - slow/fast metabolism
Risk factors of drug interactions - issues with the drugs
Narrow therapeutic index
Steep dose/response curve
Saturable metabolism
Definition of drug
A compound that is administered and has a physiological or therapeutic effect
Weakly basic drugs are excreted best/quickly in ____ urine
acidic (low pH)
Weakly acidic drugs are excreted best/quickly in ____ urine
basic (high pH)
Weakly basic drugs are absorbed/reabsorbed best in ___ solutions?
Basic (high pH) - as more of the drug is unionised (so can cross lipid membranes)
Weakly acidic drugs are absorbed/reabsorbed best in ___ solutions?
Acidic (low pH) - as more of the drug is unionised (so can cross lipid membranes)
Clearance definition
The volume of plasma that can be completely cleared of drug per unit time (mls/min)
ALSO
rate of appearance in urine / plasma conc
ALSO
Clearance = dose / area under curve for IV drug
Clearance = dose x bioavailability / area under curve for oral drug with bioavailability <1
Steady state
Infusion dosage = rate of elimination
i.e. intake is in equilibrium with elimination
How is the rate of elimination related to the volume of distribution if the drug has a high Vd?
inversely proportional
Because if it has a high Vd, it will have a low plasma conc so elimination will take longer
Loading dose equation
Css x Vd
steady state conc x volume of distribution
Loading dose =
A high initial dose given to load the system so the time taken to achieve a steady state is reduced (useful in drugs with long half lives as these take ages to reach a steady state but we may want the therapeutic effect before this time)
Maintenance dose equation (NOTE = same equation for working out the steady state conc with orally administered drugs where we can change this conc by altering dose or interval)
Css = D x F / t x Cl
steady state = dose x bioavailability / time interval between doses x clearance
Druggability (aka ligandability)
the ability of a protein target to bind small molecules with high affinity
(allows the molecule to alter the function of the protein(
Drug targets
Receptors
Enzymes
Transporters
Ion channels
Emax =
max response achievable from a certain dose (= efficacy)
Intrinsic acitivity =
The ability of a drug-receptor complex to produce a max functional response.
Emax of partial agonist / Emax of full agonist
EC50 = potency. What would a low EC50 mean?
More potent
Adding an antagonist to an agonist would shift the response-logarithmic conc graph to the ___?
right
- more agonist require to illicit same response
It would be shifted right and down if it was a Non-competitive antagnoist
Receptor reserve
Where the agonist only needs to activate a small number of the existing receptors to produce the max response
i.e. there are spare receptors present - this is good in cases where an irreversible antagonist is added as the agonist is still able to produce max response even if some receptors are bound/out of use.
This is also good as, without this, if receptor number were to reduce, more drug would be needed for the same effect and potency would be reduced
