Drug receptor interactions

Question	Answer
Explain the concept of drug distribution within the body	not all of drug ends up in target tissue perhaps just 2% rest of drug in other compartments act as a reserve volume so drug can have a longer lasting effect
Where else in the body may the drug end up apart from target tissue?	other tissue (50%) fat (25%) plasma protein (13%) - bound drug plasma (10%) - unbound drug
What is meant by the phrase 'bound drug'?	drug attached to proteins in blood plasma the less attached a drug is the more efficiently it can transverse cell membranes or diffuse
What is the formula to calculate volume of distribution?	amount of drug in the body divided by plasma concentration
What does volume of distribution tell you?	how extensively the drug is distributed to the rest of the body compared to the plasma
Why can the volume of distribution be so high in comparison to the volume in specific compartments?	VOD is not an actual compartment so volume can be higher than any actual compartment drug may be concentrated and bound in peripheral tissues rather than circulating in plasma
What is drug distribution?	process by which drug reversibly leaves the blood stream and enters extra-cellular fluid and/or cells
What are the major compartments in the body that drugs may be distributed to?	water (TBW = 0.6 x body weight) -total body fluid (0.6 L/Kg) -extracellular fluid (0.2 L/Kg) -blood (0.08 L/Kg) -plasma (0.04 L/Kg) fat -brain, adipose tissue, cell membranes solid -bone, muscle
What are most drugs able to do?	bind to plasma proteins (main one being albumin)
Explain the process of protein binding	free drug molecules are carried around the body as a drug-protein complex till they get to their peripheral tissues protein bound drugs can't activate receptors till they're free
What does the efficacy of a drug depend upon?	the free drug concentration around target tissue (so basically how much of the drug is in its unbound form which makes it easier to transverse cell membranes and diffuse)
When are drugs active?	when they are free when bound they are inert - pharmacologically inactive
What is usually established between the bound and free forms of a drug?	equilibrium this may be upset by the loss or gain of plasma proteins
What three things are true for the bound drug as a result of it being retained in the circulatory system?	the bound drug is... non-diffusible not metabolized not excreted
Why may there be competition between drugs for protein binding?	a lot of drugs bind to the same plasma proteins and as people get older they may take more than one drug
What is the difference between Warfarin and phenytoin?	phenytoin - anti-epileptic warfarin - blood thinner - prevents blood from coagulating and forming clots in blood vessels - given to patients with cardiac arrhythmia
Stopping or starting a drug that binds to a protein changes the level of other drugs that bind to that same protein. Explain how using Warfarin and phenytoin as an example	usually both drugs bind to active site of albumin when patient goes for surgery W is stopped more binding sites available for P to bind to less P exists in free, active form sub-therapeutic levels of free P dosage of P may need to be increased
Even when there is the free drug it's ability to have an effect on their target is dependent on...	capillary structure e.g. fenestrated capillaries are more open chemical nature of drug e.g. uncharged protonated drug is lipophilic so can pass through lipid layer more easily blood flow through tissue e.g. blood not equally distributed, blood flow through target tissue may not be very high presence of non-active binding sites e.g. protein in tissue may bind to drug rendering it in inactive form
What are the four different types of receptor?	ligand gated ion channels G-protein coupled receptors receptor tyrosine kinases (enzyme linked) nuclear receptors
Describe the structure of G-protein coupled receptors	most abundant class of receptors 7 transmembrane spanning domain structures first identified in the rhodopsin receptor in the retina (but are found all over the body)
How can these 7 spanning domains be refined even further?	can be divided into multiple classes based on structure and function >1000 GPCRs for smell alone
Explain how G-protein coupled receptors (GPCR) work	agonist binds to receptor triggers a confrontational change in receptor receptor activated G-protein made up of A+BG subunits initially bound together to intracellular side of GPCR subunit separation; A in 1D, BG in other direction both activate different intracellular second messenger systems second messenger activates cell signalling
Explain how GPRCs work in terms of GDP (Guanine diphosphate) and GTP (Guanine triphosphate)	conformational change allows GPRC to act as a guanine nucleotide exchange factor bound GDP exchanged for GTP dissociation of Ga-GTP and Gby subunits both 'sides' can act as effectors by interacting with different second messenger systems agonist dissociates from transmembrane receptor GTP hydrolysed alpha subunit regenerated and re-associated with Gby dimer to form 'resting' G-protein so process can start again
What are RGSs used for?	these are also known an GTP-ase activating proteins turns G-protein's activity off thus terminating signalling
Explain how ligand gated ion channels work	ligand binds to ion channel which is normally closed to keep ions in ECF causes conformational change in receptor so receptor opens allowing flow of ions across cell membrane changes potential across cell membrane
When ligand gated ion channels are activated the membrane potential is affected. What are the two possible results of this?	1. neuronal excitation Na+ influx - nicotinic Ca+ influx - glutamate 2. neuronal inhibition Cl- influx -GABA (gamma aminobutyric acid)
Explain how receptor tyrosine kinases work	two identical receptors sat in plasma membrane as monomers two ligands bind to monomers monomers come together forming a dimer now potentially active ATP->ADP + Pi phosphate attaches to tyrosine kinase sections intracellularly creates active form (phosphorylated dimer) which can activate intracellular proteins to illicit a cellular response
When are nuclear receptors used?	when you have lipid soluble hormones as these are intracellular receptors that sit in cytoplasm in inactive form not embedded within plasma membrane
How are nuclear receptors made even more inactive?	usually have inhibitory proteins stuck on which means binding site is covered up
Explain how nuclear receptors work	lipid soluble hormones cross plasma membrane and bind to receptors receptor moves into nucleus activates DNA by binding to regulatory regions that respond to receptor-hormone complex leads to transcription, RNA production
Give two examples of lipid soluble hormones	oestrogen testosterone
How long do the different receptors take in comparison to each other?	milliseconds - LGIC seconds - GPCR minutes-hours - RTK hours - NR
Comment on the difference and similarity between tachyphylaxis and tolerance	both are linked to reduced drug effect but with the former this happens almost immediately (shorter time scale)
Explain five different mechanisms for tachyphylaxis/tolerance	receptor desensitized or loss of receptors -uncoupling of signalling cascade receptor internalisation or up-regulation -taken back into endosomes and internalized, less spare receptors physiological adaptation -need more receptors to be active exhaustion of mediators -what if all ATP used up or GPCR? increased metabolic degradation -drug taken away from body quicker
Give one example of tachyphylaxis	salbutamol (B2 adrenergic agonist) polymorphism of B2A receptor either Arg or Gly at position 16 asthmatics with Arg-16 suffer significant decline in effectiveness of salbutamol with repeated doses

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	Created by Ifeoma Ezepue about 9 years ago