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
what glutamate receptors do you know?
glutamate major excitatory NT
ionotrophic
- AMPA - 4 subunits - cation channel
- NMDA - 4 subunits - cation channel - requires glutamate and removal of Mg plug (reliant on depolarisation) - hence slower response, responsible for neuromodulation.
- kainate
metabotrophic - GluR
what is glycine?
major inhibitory NT in spinal cord
binds ionotrophic receptors that increases chloride conductance.
what types of intracellular receptors do you know?
type 1 = cytoplasmic - oestrogen
type 2 = nuclear - thyroxine
these often have intrinsic transcriptional activity and hence act via chnages to gene expression therefore slower onset but longer lasting.
what is an enzyme?
enzyme is a protein molecule that acts as a biological catalyst. it lowers the activation energy of a reaction such that it occurs quicker.
enzymes support anabolism, catabolism and regulate many cellular pathways.
they are highly specific to one substrate/ligand.
describe how an enzyme works?
lower activation energy and act as a catalyst
2 theories = lock and key, induced fit.
highly specific to ligand - complementary shape to active site.
what can effect enzyme activity?
pH
temperature
substrate concentration
presence /absence of co-factors
describe the michaelis mention model for enzyme kinetics..
Michaelis-Menten kinetics is a mathematical model used to describe the rate of enzymatic reactions.
states that the reaction is an equilbrium between Enzyme and substrate and ES complex
E + S <=> ES –> E + P
the first reaction equilbrium has K1 as forward rate and K-1 as backwards. second reaction is K2.
We can see as [S] increases, pushes reaction towards right and rate of reaction will increase (1st order kinetics). however max capacity reached when enzymes are saturated = Vmax (0 order kinetics i.e. constant rate of reaction)
the michaelis menton equation states that at Vo i.e. initial rate the following is true (see image)
in enzyme kinetics, what is Km?
michaelis constant = substrate conc at which the velocity is half its max. specific for each substrate/enzyme reaction.
the lower the Km , the higher the affinity for the enzyme
km = (K-1 + K2) / K1
in enzyme kinetics, what is Vmax?
max rate of reaction when all enzymes are saturated.
what is a lineweaver burke plot?
using michaelis equation
we can take the reciprical
which then can be plotted on a straight line
hence can be used to determine Vmax and Km
draw a rate of reaction-substrate conc graph for competitive inhibition…
Vmax will be the same
Km will be lower
the effects of competitive inhibition can be overcome by increasing substrate conc. therefore can eventually reach same Vmax just at a higher conc of substrate.
draw enzyme kinetic graphs for non-competitive inhibitions..
Km same
Vmax reduced
effectively like having less enzymes
therefore no matter how much substrate conc increased, cant get same Vmax
how are enzymes invovled in regulation of cell pathways
phosphorylation / dephosphorylation can activate other enzymes / cellular machinery.
hence kinases and phosphorylases are often involved in regulating cellular pathways.
e.g. a protein kinase will simultaneously phosphorylase glycogen synthase to activate it whilst phosphorylating glycogen phosphorylase to deactivate it. this will promote glycogen synthesis by 2 mechanisms.
another example is proteolytic enzymes e.g. coagulation cascade - a chain of proteolysis results in activation and amplification
what are allosteric modulators?
these are a form of modulation of enzyme activity
they bind a site other than active site and either increase or decrease enzyme activity.
what second messangers do you know and what are their functions?
Calcium = exocytosis, contraction, apoptosis
cAMP - activates PKA which has a wide range of activities depending on cell.
define pharmacodynamics
This describes the effects of a drug on the body. involves drug -receptor interactions, therapeutic reactions, side effects including type A and B
how may drugs exert their effect?
physicochemical interactions = neutralisation (antacids - sodium citrate) , chelation (suggamadex) , osmotic effects (mannitol), adsorption (charcoal)
Receptors - e.g. b blockers (GPCR), benzos (Ionotrophic) , insulin (tyrsoine kinase), intracellular (steroids)
enzymes e.g. acetylcholinesterase inhibitors , ACE inhibitors
ion channels e.g. local anaesthetics
how may drugs affect receptors?
direct ligands - orthosteric site - same site as endogenous ligand e.g. B blockers
Allosteric modulators e.g. benzodiazepines
may be agonists or antagonists. e.g. opioids vs b blockers
may interact via variety of bonds e.g h bonds (short term), phosphorylation / acetylation etc may last longer or be irreversible.
how may drugs affect enzyme activity?
may act as competitive antagonists or non-competitive which could be reversible or irreversible.
competitive = bind active site, prevent substrate binding, increasing substrate conc can overcome this. e.g. neostigmine, NSAIDs, ACEi
non competitive = bind at site away from active site, causes conformational change in enzyme and no longer able to bind substrate. effectively less enzyme e.g. digoxin
irreversible = acts like non-competitive but effects last longer. can bind active site or alternative e.g. aspirin
some drugs have enzyme like activity e.g. amylase , streptokinase, alteplase.
draw a dose response curve and explain this.
dose on x axis
response on y
initially many free sites on receptors so as drug conc increases, rapid rise in response
as drug conc increases further , a greater number of receptors become occupied and less available therefore rate starts to level off until a maximum
the max response is when all receptors are occupied or the cells max intrinsic activity has been reached e.g. intracellular pathways maximised.
can also be plotted as a semi log scale for easier interpretation = sigmoid.
define affinity
the tendancy for a drug to bind to its receptor. given by the dissociation constant Kd - the lower this is, the higher the affinity
what is Kd?
dissociation constant
D + R <–> DR
forward reaction = K1
backwards = K2
Kd = K2/K1 = dissociation constant
inversely proportional to affintiy.
(ka = K1/K2 = affinity constant)
define potency
the concentration of drug required to produce specified response. the lower, the more potent
define intrinsic activity
the extent to which a drug activates or stimulates the receptor once bound.
i.e. ability for drug to produce a max response once its bound to receptor.
can range from 0 to 1, 1 being max response, 0 being no effect.
also known as efficacy
what is the ED50 and EC50
EC50 = conc of drug in serum that produces half the max response - refers to the potentcy
ED50 = dose of drug that produces half max response
what is the LD50?
conc required to produce lethal effect in 50% of population
how is the therapeutic ratio calculated?
LD50 / ED50
draw a dose response curve to show effect of increasing efficacy and potency
define a full agonist, partial agonist and inverse agonist
agonist = a drug that binds to a receptor and produces maximal responses i.e. has an efficacy of 1
partial agonist = drug that binds to a receptor but doesnt produce max response efficacy less than 1 e.g. bupronorphine
inverse agonist = drug that binds receptor and reduces frequency of receptor activation. efficacy less than 0. e.g. atropine works in this way
how can drug antagonists be classified? draw a dose response curve…
competitive - competes for same site as agonist. hence effects overcome by increasing agonist dose. partial agonist can also act in this way in presence of full agonist
noncompetitive - binds site away from active site. effectively reduces no. of targets available. hence reduces the ability to produce max response.
what is the difference between pharmokinetic, physiological and chemical antagonism?
Physiological antagonismoccurs when two different receptor mechanisms oppose each other e.g. NA acts via a1 to cause vasoconstriction, Adrenaline acts via beta to cause vasodilation.
Chemical antagonismoccurs when a drug reduces the concentration of an agonist by forming a chemical complex such as that seen with chelating agents
Pharmacokinetic antagonismoccurs when one drug accelerates the metabolism or elimination of another. This is commonly seen with CYP450 enzyme-inducing drugs
what is the difference between inverse agonist and antagonist?
antagonist blocks receptor - has efficacy of 0 . returns response to baseline, blocks both agonist and inverse agonist effects.
inverse agonist - promotes the inactivated state of receptor and thus can reduce the constitional activity and has efficacy of less than 1
define tolerance
tolerance is the development of resistance to a drug. a larger dose is needed than previously to produce the same response
e.g. cocaine users become tolerant and need more to feel euphoric.
this may be due to a variety of mechanisms e.g. increased metabolism, down regulation of receptors, uncoupling of signalling pathways
the lethal dose/ side effects of the drug is not neccessarily reduced - therefore becomes dangerous.
what different types of drug tolerance do you know?
innate
* genetic makeup can make an individual more or less tolerant of a drug
* e.g. alleles of CYP2D6 can result in poor metabolism of codeine to morphine.
acquired
- pharmacokinetic - induction of liver enzymes with repeated exposure
- pharmacodynamic - after repeated exposure responses are less e.g. down reg of receptors or uncoupling signalling pathways, weaker cell response
- behavioural tolerance - able to physically cope despite the effects of drug e.g. alcoholics.
what is meant by cross tolerance?
tolerance to a new drug due to similarities in metabolism/ action
e.g. tolerance to all opioids if tolerant to one
e.g. tolerance to inhaled anaesthetic agents after chronic alcoholism.
what is meant by tachyphylaxis?
rapidly diminishing response to repeat drug administration
usually wihtin mins-hour
e.g. ephedrine - releases NA stores.
eventually exhausted so no further response
hydralazine also shows this.
what is the difference between tolerance, desensitisation and tachyphylaxis?
Tolerance = A need for a larger dose to achieve the same clinical effect,
Tachyphylaxis = a rapid decrease in response to a drug, when repeated doses are given over a relatively short period of time.
Desensitisation = slower decrease in response over a longer period of time, and may be due to several factors. E.g. on a cellular level – reduction of receptor no/ function. Can lead to tolerance.
what drugs show tolerance commonly?
opioids, benzos, alcohol, nitrates
define addiction
the behavioural response that results in constantly seeking/ consuming a drug despite its harmful effects in those who have become dependant on a drug.
closely linked to tolerance
what is drug withdrawal?
physical symptoms that develop in absence of a drug due to the devleopment of tolerance e.g. craving, anxiety, pain , seizures
how can drug ADRs be classified?
type A = augmented and related to pharmodynamics of the drug. e.g. bradycardia with B blocker use.
type B = bizzare - not dose related and not predictable e.g. sux apnoea or MH, anaphylaxis
type C = chronic - these are time and dose related e.g. cirrhosis in alcoholics
type D = delayed - time related
type E = end of use - e.g. rebound HTN with stopping clonidine
type F = failure - e.g. pregnancy when using COCP.
can you tell me about the DoTs classification of ADRs?
split into Dose related, time related and susceptibility
dose - may be excess amount, collateral effects e.g. hyperkalaemia in ACEi , or low dose but in susceptible person.
time -
- may be due to being given too rapidly
- early , intermediate and late reactions
susceptibility due to age, genetics, ethnicity
can you give examples of any drugs that cause liver damage..
alcohol
halothane hepatitis
paracetamol in OD
how do drugs interact?
drug interactions occur when the action of one drug influences the effect of another.
it can be divided into physiochemical, pharmacokinetic and pharmacodynamic
physiochemical:
* incompatibility - some drugs are incompatible and will precipitate before given e.g. thio and sux.
* neutralisation - heparin and protamine
* chelation - sugamadex
pharmacokinetic
* adsorption - activated charcoal, prokinetics (metaclopramide, erythromycin) , second gas effect
* distribution - any drug altering CO, protein binding displacement e.g NSAIDs, phenytoin and warfarin
* metabolism - CYP450 inducers and inhibitors e.g. ethanol induces CYP 2E1 - volatiles
* elimination - anything affecting CO, probenecid and penicillin (inhibits secretion, prolongs action), alkalinisation of urine helps eliminate aspirin
pharmacodynamics
* summation - similar additive actions e.g. benzos and propofol or different anaesthetic agents MAC
* potentiation - one drug prolongs effects of another but has no effect alone - magnesium
* synergism = their combined effect is more than just added. e.g. propofol and remifentanil
* antagonism = 2 drugs with opposite effects e.g. opioids and naloxone.
these interactions may be direct at same receptor or indirect via different pathways/ receptors e.g. adrenaline and milrinone
can you tell me about any herbal/ dietary DDIs?
St johns wart - inducer, reduces warfarins effects.
garlic - can potentiate effects of NSAIDs
how does buprenorphine work in opioid dependance?
partial agonist at u receptor
in presence of morphine acts as an antagonist
but in its absence gives some analgesic/opioid effects so reduces withdrawal but prevents full effect of morphine
which receptors produce intracellular messangers?
GPCRs
tyrosine kinase
which drugs regulate gene transcription?
mineralosteroid - aldosterone
corticosteroids = cortisol
sex hormones = oestrogen
thyroid hormones
use ionotrophy as an example of how many drug pathways can merge…
Gs GPCR - adrenaline
phosphodiesterase inhibitors - milronone
glucagon receptor also increases cAMP
levosimendan - increases contractile unit sensitivity to calcium
