How do drugs work? Flashcards
what are the 4 ways how drugs are distributed through the body?
- Absorption - dependent on a variety of factors eg.solubility
- Distribution - may bind to plasma proteins so there is a ratio of bound/free drug. Only free drug can bind to receptor to exert effect
- Metabolism - needed for inactivation and excretion
- Excretion - most commonly via urine
What is it called when receptors number are increased or decreased?
Increase = up-regulation
Decrease = down-regulation
( may occur to chronically low (up-regulation) or high concentration( down-regulation)of agonist to optimise sensitivity
what are the 2 properties of agonists?
- Affinity - strength of binding to receptor
- efficacy - intrinsic activity
indices a conformational change in the receptor and activation of a response
what is an antagonist?
ligand which blocks the receptor, has affinity but not efficacy so does not activate a response
eg. antihistamines, beta-blockers
What happens to the intracellular signal chemical in the cell
The first messenger ligand does not enter the cell, binding of the signal chemical to its receptor initiates a series of chemical changes which activates intracellular second messengers in the cell
what are the stages of signal transduction?
- Direct opening of ion channels
- direct activation of enzymes
- Indirect activation/inactivation of enzymes
indirect opening/closing of ion channel
involves a G-protein (molecular switch) - intracellular second messengers involved include eg. cyclic nucleotides (cAMP), IP3, DAG and Ca2+ ions
Give an example of an enzyme linked receptor and what it does
Tyrosine kinase receptors
- Activation of the receptor by its agonist causes the transfer of a phosphate group onto specific amino acids in the receptor itself. This results in the recruitment of proteins from the cytosol, which become scaffolded to the receptor. This scaffold transmits the signalling information to the cell
what are the 3 protein components of G-protein coupled receptors?
- Seven transmembrane receptor where the ligand binds
- G-protein (switch coupling receptor to effector enzyme)
3.Effector enzyme
What does GTP bound and GDP bound mean for GPCRs
GTP bound= G protein is active/ON
GDP bound = G protein is inactive/OFF
The G protein itself is an enzyme which converts GTP to GDP and thereby switches itself and the system off
How does GPCR signalling work during activation ?
Activation: Agonist activation of receptors induces its 3D shape or conformational change thereby enabling it to interact with a G protein. The G protein loses GDP and gains GTP (Switched on). The activated G protein interacts with specific second messengers which alter biochemical machinery inside the cell by interacting with specific target molecules. These either phosphorylate other specific proteins or release intracellular store of Ca2+
How does GPCR signalling work during de-activation?
-agonist dissociates from receptor
- G proteins own GTPase activity converts the bound GTP to GDP (switched off)
- G protein interaction with the effector enzyme ceases and the effector enzyme activity returns to normal
- the second messenger molecules are broken down and their target proteins are no longer activated
What is Ca2+ and where is it found?
- important for regulation of smooth muscle
It is a second messenger but it neither produced or destroyed - moves between compartments (mostly in the ER or SR) and the effects are concentration dependant
What are the actions of Ca2+
Activation of specific protein kinases, ion channels
Regulation of activity of many enzymes
how can calcium get into cells?
Calcium channels (PMCA) voltage gated channels (VOC) and ligand gated channels
What are two target receptors for drugs in the GI tract?
- Histamine receptors
Target: parietal cells - decreased gastric acid secretion
-Opioid receptors
eg. loperamide
Target: myenteric plexus/opioid receptors - decreased peristalsis, increased tone of anal sphincter
