Drug receptor interactions Flashcards
what happens if the drug is pronated
it is stored in the fat stores
what happens if the drug is unpronated
- It can go in to the fluid compartment of the body and can be distributed around the body
what is volume distribution
Amount of drug in the body/ plasma concentration
work out the volume distribution of a 50mg dose of drug A results in plasma concentration of 0.1mg per litre
Vd = 50 mg/0.1mg/L
Volume of distribution = 500 litres
Drug A is extensively distributed to other parts of the body and is not in the plasma
what does the volume distribution tell us
- Tells us how extensively the drug is distributed to the rest of the body compared to the plasma
- not an actual compartment
- So volume can be higher than any actual compartment
- Can be used to work out the half life
what is drug distribution
- This is a process by which the drug reversibly leaves the blood stream and enters extra cellular fluid and or cells
what happens to the volume distribution of drugs that are bound in the peripheral tissues
Durgs that are bound in peripheral tissues the drugs concentration in the plasma may drop to very low levels, even though the total amount in the body is large, as a result the Vd may exceed the total volume of the body
e.g. quinacrine (anti-protozoal) may have a Vd of around 50,000 L in persons with average body volume of 70L.
Or
A drug that is completely retained in the plasma compartment will have a Vd equal to the plasma volume (about 4% of body weight).
what happens once the drug is absorbed into the plasma
Once absorbed in to the plasma the drug can be distributed to one of three fluid compartments these are the intracellular fluid, water, or extracellular fluid
what do protein binding drugs bind to
- Drugs bind to blood plasma protein such as albumin
- Plasma proteins carry the drug around the body
- Drugs that are bound are not able to activate receptors until they are free
what is efficacy determined by
- Efficacy is determined by free drug concentration around the target tissue (how effective a drug is is determined by how free the drug concentration is around the target tissue)
- Dependent on how many drugs your taking because they are all competitivity for the drug protein complex
what happens to the drug when it gets to the target tissue
- Even when it is free drug its ability to have an affect on the target is dependent on
- Capillary structure
- Chemical nature of the drug
- Blood flow through the tissue
- Presence of non-active binding sites
describe the free versus the protein bound drug
- Only active when free
- Inactive when bound
- Equilibrium between bound and free forms
- Bound drug is non diffusible, not metabolised, not excreted
- Competition between drugs for protein binding
- Not bound – large effect on cells, short amount of time in the body
- Bound tightly – smaller effect on cells, last longer in the body so wont need to dose as often as not bound drugs
what is an example of competition as a protein binding drug
- Sotpign or starting a drug that binds to protein chances the level of other protein bound drugs
- For example, warfarin and phenytoin
- Normally both warfarin and phenytoin bind to albumin
- Patient goes for surgery
- Warfarin stopped
- More sites for phenytoin to bind to albumin
- Sub-therapeutic levels (not active) of free phenytoin
what can very large drugs not do
cannot cross the capillary and stay in the plasma
what is it rare to get
an even drug distribution
describe G protein coupled receptors
- Most abundant class of receptors
- 7 transmembrane (folded in and out of the membrane 7 times_ domain structure identified from the rhodopsin receptor
- Can be divided into multiple classes based on structure and function
- Agonist binding triggers a conformational change
- Triggers activation of associated G protein which in turns initiates a down stream signalling cascade
describe ligand gated channel receptors
- Ligand binds of receptor outside and this opens the channel allowing ions to flow in and out
- Changes the electrical propertiesof the cell
- Used in the nervous system
describe examples of ligand gated ion channels
Na+ - nicotinic (neuronal excitation) causes depolarisation
Ca+ - glutamate (NMDA) (neuronal excitation) causes depolarisation
Cl- - GABA (neuronal inhibition) action potentials need to be a lot stronger in order to overcome the GABA
describe receptor tyrosine kinase
- Usually two of them – make a dimer
- When the ligand binds to the receptors and causes the receptors to come together
- The tyrosine’s are then phosphorylated by ATP and this activates the receptor causing a cellular response
describe nuclear receptors
- Slowest receptor
- Lipid soluble substance gets across plasma membrane
- Binds to receptor inside the cell in the cytoplasm
- Receptor binds the hormone and carries it to the nuclear envelope into the nucleus where the nuclear receptor can bind to the DNA and cause the activation or repression of DNA transcription and translation mechanism
Describe examples of nuclear receptors
Endocrine receptors = androgen, oestrogen, glucocorticoid, mineralcorticoid, progesterone, throid hormone receptors
Vitamins = vitamin A, vitamin D
describe how long it takes receptors to become dynamic
- Ligand gated ion channel – milli seconds
- GPCR – seconds
- Receptor tyrosine kinase – minutes to hours
- Nuclear receptor – hours
what is tachphylaxis
actue tolerance rapid and repeated administration of drug in shorter intervals
what is tolerance
chronic longer term administration can reduce drug effect
what is the mechanism for tachyphylaxis
- Receptor desenstitzed – many receptor effector systems incorporate desensitisation mechanisms for preventing excessive activation when agonist continues to be present
- Receptor internalisation – internalisation of the B-adrenocepetors which means they are not available on the plasma membrane antagonism – decreased drug effect, not made visible to the drug
- Physiological adaptation (receptor increase or response to drug changes) – chronic propranolol which is a beta block can cause increased synthesis of beta 1 recepotrs in the heart = less antagonism = decreased drug effect, side effects to drugs such as nausea and sleepiness decline with continued administration of the drug
- Exhaustion of mediators – depeletion of signalling molecules or essential intermediate required for response, G protein coupled receptors can lead to depletion of the 2nd messengers
- Increased metabolic degradation – increased rate of metabolism and or elimination – ethanol induces the expression of metabolic enzymes that degrade the drug = low plasma drug concentration
what are the examples of tachphylaxis
- Many drugs acting on the autonomic nervous system
- Salbutamol (beta2 adrenergic agonist)
- Polymorphism of beta 2 adrenergic receptor – Arg-16 or Gly-16
- Arg016 indiiduals suffer significant decline in effectiveness of salbutamol with repeated doses
- Intranasal decongestants (oxymetazoline) for less than 3 days this leads to tachyphylaxis of response and rebound congestion
- Cause – alpha adrenoreceptor mediated down regulation and desensitization of response
