pharmacodynamics

Question 1

Can you classify the types of molecular interactions you know

Answer 1

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

Question 2

why are polar molecules more soluble in water?

Answer 2

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

Question 3

how does midazolam exist pre injection and post injection?

Answer 3

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.

Question 4

what is meant by polarity?

Answer 4

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

Question 5

define an isomer..

Answer 5

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

Question 6

classify the different types of isomers you know…

Answer 6

structural
* static = functional, positional, chain
* dynamic = tautomerism

stereoisomers
* geometric
* optical

Question 7

define a structural isomer

Answer 7

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

Question 8

define stereoisomer..

Answer 8

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

Question 9

can you give examples of when isomers have similar vs different properties?

Answer 9

similar - enflurane and isoflurane

different - dihydrocodeine and dobutamine

Question 10

draw enflurane and isoflurane

Answer 10

Question 11

what is meant by tautomerism ?

Answer 11

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.

Question 12

describe the dynamic isomerism of midazolam?

Answer 12

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

Question 13

what is a geometric isomer?

Answer 13

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

Question 14

what is an enatiomer ? give examples in anaesthesia..

Answer 14

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)

Question 15

can you give examples of optical isomers?

Answer 15

bupivacaine = levobupivacaine and dextrobupivacaine. levo is less cardiotoxic

ketamine - S and R - S has less dissociation effects

all inhalation agents except sevoflurane

thalidomide

Question 16

what are diasteriosomers ?

Answer 16

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)

Question 17

what is the clinical significance of isomerism?

Answer 17

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.

Question 18

what is a racemic mixture?

Answer 18

a mixture consisting of both isomers in equal quantities
most forms of ketamine include 50:50 R and S isomers.

Question 19

what is an enantiopure preparation?

Answer 19

one where only one isomer exists
e.g. S-ketamine, levobupivacaine.

Question 20

define an isotope…

Answer 20

atoms of same element with different numbers of neutrons and hence atomic mass. same atomic number/ proton number.
e.g. C12 and C13

Question 21

define genotype and phenotype?

Answer 21

genotype = genes that make up the genome i.e. specific alleles present

phenotype = observable biological trait - depends on both genotype and environment

Question 22

describe structure of a protein

Answer 22

primary - aa chain
secondary - h bond- b pleated/ alpha helices
tertiary = complex bonding, disulphide , H bonds , ionic
quarternary = numerous polypeptide chains

Question 23

define an allele and a gene?

Answer 23

allele = version of a gene
gene = section of DNA coding for a polypeptide chain

Question 24

what are the consequences of mutation?

Answer 24

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

Question 25

describe the structure of the cell membrane..

Answer 25

fluid mosaic model lipid bilayer - hydrophobic tails and hydrophilic phosphate heads. proteins lie within it - carriers, ion channels, receptors, antigens. glycolipids and glycoproteins cholesterol

Question 26

describe the transport across membranes..

Answer 26

simple diffusion fascilated diffusion osmosis active transport - primary and secondary endo/exocytosis

Question 27

what is a receptor?

Answer 27

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.

Question 28

classify the different receptors you know...

Answer 28

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

Question 29

what is meant by constitutive receptor activity ?

Answer 29

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

Question 30

define a ligand...

Answer 30

a chemical messanger capacble of binding and activating/inhibiting receptor activity. can be exogenous or endogenous

Question 31

what is the difference between metabotrophic and ionotrophic receptors?

Answer 31

ionotrophic - ligand gated ion channels - fast response metabotrophic - GPCRs - indirect response via intracellular signalling, slower response

Question 32

describe the structure of a GABA receptor..

Answer 32

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

Question 33

what glutamate receptors do you know?

Answer 33

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

Question 34

what is glycine?

Answer 34

major inhibitory NT in spinal cord binds ionotrophic receptors that increases chloride conductance.

Question 35

what types of intracellular receptors do you know?

Answer 35

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.

Question 36

what is an enzyme?

Answer 36

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.

Question 37

describe how an enzyme works?

Answer 37

lower activation energy and act as a catalyst 2 theories = lock and key, induced fit. highly specific to ligand - complementary shape to active site.

Question 38

what can effect enzyme activity?

Answer 38

pH temperature substrate concentration presence /absence of co-factors

Question 39

describe the michaelis mention model for enzyme kinetics..

Answer 39

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)

Question 40

in enzyme kinetics, what is Km?

Answer 40

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

Question 41

in enzyme kinetics, what is Vmax?

Answer 41

max rate of reaction when all enzymes are saturated.

Question 42

what is a lineweaver burke plot?

Answer 42

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

Question 43

draw a rate of reaction-substrate conc graph for competitive inhibition...

Answer 43

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.

Question 44

draw enzyme kinetic graphs for non-competitive inhibitions..

Answer 44

Km same Vmax reduced effectively like having less enzymes therefore no matter how much substrate conc increased, cant get same Vmax

Question 45

how are enzymes invovled in regulation of cell pathways

Answer 45

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

Question 46

what are allosteric modulators?

Answer 46

these are a form of modulation of enzyme activity they bind a site other than active site and either increase or decrease enzyme activity.

Question 47

what second messangers do you know and what are their functions?

Answer 47

Calcium = exocytosis, contraction, apoptosis cAMP - activates PKA which has a wide range of activities depending on cell.

Question 48

define pharmacodynamics

Answer 48

This describes the effects of a drug on the body. involves drug -receptor interactions, therapeutic reactions, side effects including type A and B

Question 49

how may drugs exert their effect?

Answer 49

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

Question 50

how may drugs affect receptors?

Answer 50

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.

Question 51

how may drugs affect enzyme activity?

Answer 51

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.

Question 52

draw a dose response curve and explain this.

Answer 52

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.

Question 53

define affinity

Answer 53

the tendancy for a drug to bind to its receptor. given by the dissociation constant Kd - the lower this is, the higher the affinity

Question 54

what is Kd?

Answer 54

dissociation constant D + R <--> DR forward reaction = K1 backwards = K2 Kd = K2/K1 = dissociation constant inversely proportional to affintiy. (ka = K1/K2 = affinity constant)

Question 55

define potency

Answer 55

the concentration of drug required to produce specified response. the lower, the more potent

Question 56

define intrinsic activity

Answer 56

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

Question 57

what is the ED50 and EC50

Answer 57

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

Question 58

what is the LD50?

Answer 58

conc required to produce lethal effect in 50% of population

Question 59

how is the therapeutic ratio calculated?

Answer 59

LD50 / ED50

Question 60

draw a dose response curve to show effect of increasing efficacy and potency

Answer 60

Question 61

define a full agonist, partial agonist and inverse agonist

Answer 61

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

Question 62

how can drug antagonists be classified? draw a dose response curve...

Answer 62

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.

Question 63

what is the difference between pharmokinetic, physiological and chemical antagonism?

Answer 63

Physiological antagonism occurs 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 antagonism occurs when a drug reduces the concentration of an agonist by forming a chemical complex such as that seen with chelating agents Pharmacokinetic antagonism occurs when one drug accelerates the metabolism or elimination of another. This is commonly seen with CYP450 enzyme-inducing drugs

Question 64

what is the difference between inverse agonist and antagonist?

Answer 64

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

Question 65

define tolerance

Answer 65

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.

Question 66

what different types of drug tolerance do you know?

Answer 66

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.

Question 67

what is meant by cross tolerance?

Answer 67

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.

Question 68

what is meant by tachyphylaxis?

Answer 68

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.

Question 69

what is the difference between tolerance, desensitisation and tachyphylaxis?

Answer 69

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.

Question 70

what drugs show tolerance commonly?

Answer 70

opioids, benzos, alcohol, nitrates

Question 71

define addiction

Answer 71

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

Question 72

what is drug withdrawal?

Answer 72

physical symptoms that develop in absence of a drug due to the devleopment of tolerance e.g. craving, anxiety, pain , seizures

Question 73

how can drug ADRs be classified?

Answer 73

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.

Question 74

can you tell me about the DoTs classification of ADRs?

Answer 74

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

Question 75

can you give examples of any drugs that cause liver damage..

Answer 75

alcohol halothane hepatitis paracetamol in OD

Question 76

how do drugs interact?

Answer 76

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

Question 77

can you tell me about any herbal/ dietary DDIs?

Answer 77

St johns wart - inducer, reduces warfarins effects. garlic - can potentiate effects of NSAIDs

Question 78

how does buprenorphine work in opioid dependance?

Answer 78

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

Question 79

which receptors produce intracellular messangers?

Answer 79

GPCRs tyrosine kinase

Question 80

which drugs regulate gene transcription?

Answer 80

mineralosteroid - aldosterone corticosteroids = cortisol sex hormones = oestrogen thyroid hormones

Question 81

use ionotrophy as an example of how many drug pathways can merge...

Answer 81

Gs GPCR - adrenaline phosphodiesterase inhibitors - milronone glucagon receptor also increases cAMP levosimendan - increases contractile unit sensitivity to calcium