pharmacodynamics Flashcards
Can you classify the types of molecular interactions you know
intramolecular
* covalent - shared pair of electrons, usually simple gases.
* ionic - electrostatic attraction between positive and negative ions due to transfer of electrons, soluble in water
intermolecular
* van der waals - at any one time random organisation of electron can get electron clouds of negative charge which repel others/ attract positive.
* H bonds - permanent dipoles exist when one atom is strongly electronegative e.g. O2
* hydrophobic/hydrophilic interactions
why are polar molecules more soluble in water?
H20 has permanent dipoles
forms H bonds easily
polar molecules can easily interact and form H bonds within H20 molecules to disolve.
e.g. NaCl
how does midazolam exist pre injection and post injection?
midazolam is a weak base with pKa of 6.1. in aqueous solution it is held at pH of 3.5. at this pH it is below its pH and hence ionised and water soluble.
when injected and pH now 7.4, its above its pKa so becomes unionised, lipid soluble and can cross BBB
this conversion from ionised to non-ionised is also an example of tautomorism as it closes its loop structure in blood.
what is meant by polarity?
a molecule is said to be polar when it exhibits areas of slight negative/ positive charge
usually due to differences in electronegativity of atoms
e.g. water
define an isomer..
molecules of same formula but different arrangments of atoms in space. they may be structural or stereoisomers of which there are further classifications.
isomers often result in different pharmacodynamics and kinetics of a drug. sometimes with one being very useful and the other being harmful e.g. thalidomide
classify the different types of isomers you know…
structural
* static = functional, positional, chain
* dynamic = tautomerism
stereoisomers
* geometric
* optical
define a structural isomer
same chemical formula
different chemical structure i.e. different bonding between atoms
may be due to different functional group, different position of functional group or different chain arrangments.
enflurane and isoflurane
define stereoisomer..
same molecular formula and chemical structure but different 3D spatial arrangement
can be due to rigid C=C (geometric isomerism) or optical isomerism around chiral carbon
can you give examples of when isomers have similar vs different properties?
similar - enflurane and isoflurane
different - dihydrocodeine and dobutamine
draw enflurane and isoflurane
what is meant by tautomerism ?
the existance of 2 isomers within the same molecule i.e. in different conditions (pH) a molecule can change its structure.
e.g. thiopentone , weak acid
pKa 7.6
held in solution 10.5 whereby ionised so exists in enol form which is water soluble.
once injected and pH 7.4 changes to ketone form which is lipid soluble.
describe the dynamic isomerism of midazolam?
midazolam pKa of 6.1
weak base
in solution ph of 3.4 promotes open ring structure - no benzene ring
in body at ph 7.4 - closed ring structure - lipid soluble
what is a geometric isomer?
form of steroisomerism whereby there are different groups attached to a rigid C=C and thus different organisation in space
may be Cis where both groups are on the same side
or trans where they are on opposite sides
e.g. cisatracium and mivacurium both have these isomers
what is an enatiomer ? give examples in anaesthesia..
an entantiomer is a form of isomerism which results from chiral centre resulting in optical isomers.
a chiral carbon is a carbon bonded to 4 different groups and thus due to organisation / arrangment these can exist as 2 states / mirror images of one another.
they are non-superimposable
previously named based on the direction they polarise light = L and D
now named based on if there is a clockwise or anticlockwise direction from group with highest molecular weight to lowest = R and S (R is clockwise)
can you give examples of optical isomers?
bupivacaine = levobupivacaine and dextrobupivacaine. levo is less cardiotoxic
ketamine - S and R - S has less dissociation effects
all inhalation agents except sevoflurane
thalidomide
what are diasteriosomers ?
form of sterioisomerism where there is more than 1 chiral centre hence multiple versions/ combinations exist (calculated by x^2 , where x is number of chiral centres)
atracurium has 4 chiral centres and 10 isomers. (should be 16 but some internal symmetry means only 10)
what is the clinical significance of isomerism?
isomerism is clinically significant when developing drugs.
Development of drugs can result in racemix of isomers whereby one drug is more efficious than the other.
it might be that one has no effect, is less potent/ effective, or is actually toxic (thalidomide for nausea in pregnancy)
e.g.
S ketamine - greater potency so less needed, better recovery, less psychoactive effects/ emergence phenomena
e.g. cisatracurium is more potent so less needed. less laudanosine and histamine.
e.g. levobupivacaine less cardiotoxic.
what is a racemic mixture?
a mixture consisting of both isomers in equal quantities
most forms of ketamine include 50:50 R and S isomers.
what is an enantiopure preparation?
one where only one isomer exists
e.g. S-ketamine, levobupivacaine.
define an isotope…
atoms of same element with different numbers of neutrons and hence atomic mass. same atomic number/ proton number.
e.g. C12 and C13
define genotype and phenotype?
genotype = genes that make up the genome i.e. specific alleles present
phenotype = observable biological trait - depends on both genotype and environment
describe structure of a protein
primary - aa chain
secondary - h bond- b pleated/ alpha helices
tertiary = complex bonding, disulphide , H bonds , ionic
quarternary = numerous polypeptide chains
define an allele and a gene?
allele = version of a gene
gene = section of DNA coding for a polypeptide chain
what are the consequences of mutation?
single mutation
- point mutation - no change in aa due to overlap in genetic code , change in single aa, stop codon
insertion / deletion - of 3 - remove one aa, of 1 or 2 - frame shift mutation
describe the structure of the cell membrane..
fluid mosaic model
lipid bilayer - hydrophobic tails and hydrophilic phosphate heads.
proteins lie within it - carriers, ion channels, receptors, antigens.
glycolipids and glycoproteins
cholesterol
describe the transport across membranes..
simple diffusion
fascilated diffusion
osmosis
active transport - primary and secondary
endo/exocytosis
what is a receptor?
molecularly this is a molecule (usually a protein) that can bind a specific ligand due to complementary shapes and initate a cellular response
physiologically - a type of tissue responsible for detecting a stimulus e.g. retina has photoreceptors - rods and cons.
classify the different receptors you know…
GPCR
* 7 transmembrane domain associated with intracellular G protein consisting of a,b,g
* e.g. mAChR, adrenoceptors
* activation of receptor causes GDP to swap for GTP and then Ga and Gbg to dissociation. Ga can activate/inhibit adenylate cyclase or PLC. Gbg has other effects.
* single amplification
* eventually GTP is hydrolysed back to GDP and subunits reassociate and deactivates
tyrosine kinase
* plasma membrane receptor containing single transmembrane domain. when bound to ligand, dimerises with another and intracellular portion has intrinsic enzyme activity = tyrosine kinase
* e.g. insulin, EPO
ionotrophic
* ligand gated ion channels
* nAChR , NMDA, AMPA
intracellular
* thyroid and oestropgen
* slower actions
* rely on transcription factor activation and gene expression
what is meant by constitutive receptor activity ?
now accepted that receptors exist in active/non active form as an equilbrium
they can signal without ligands but activity is low
ligands promotes active form
define a ligand…
a chemical messanger capacble of binding and activating/inhibiting receptor activity.
can be exogenous or endogenous
what is the difference between metabotrophic and ionotrophic receptors?
ionotrophic - ligand gated ion channels - fast response
metabotrophic - GPCRs - indirect response via intracellular signalling, slower response
describe the structure of a GABA receptor..
GABA receptors come in 2 forms GABAa and GABA b
GABAa receptor is a pentameric ligand gated ion channel.
consists of 1a, 2 b and g
endogenous ligand = GABA
also has many exogenous ligands e.g. benzo, propofol, volatiles.
when activated, ion channel opens, allowing chloride conductance and hyperpolarisation of the cell. reduces firing of AP.
ligand = GABA = binds between a and b subunits
drugs often act as allosteric modulators and increase frequency or length of opening.
GABAb = GPCR