pharmacology DRUG RECEPTOR INTERACTIONS.ppt

DRUG RECEPTOR INTERACTIONS

1. 11
DRUG-RECEPTOR DRUG-RECEPTOR
INTERACTIONINTERACTION

2. 22
DDrug - Receptor Bindingrug - Receptor Binding

Covalent bondsCovalent bonds

drug and receptor share a pair of electronsdrug and receptor share a pair of electrons

very strong bondvery strong bond

not very common in pharmacologynot very common in pharmacology

Electrostatic bondsElectrostatic bonds

Attraction due to charge differencesAttraction due to charge differences

Vary in strength Vary in strength

very strong (ionic bonds)very strong (ionic bonds)

very weak (van der Waals forces)very weak (van der Waals forces)

Most commonMost common

3. 33
D + RD + RDR ComplexDR Complex
Affinity – measure of propensity of a drug to Affinity – measure of propensity of a drug to
bind receptor; the attractiveness of drug and bind receptor; the attractiveness of drug and
receptorreceptor

Covalent bonds are stable and essentially Covalent bonds are stable and essentially
irreversibleirreversible

Electrostatic bonds may be strong or Electrostatic bonds may be strong or
weak, but are usually reversibleweak, but are usually reversible
Drug - Receptor BindingDrug - Receptor Binding
Affinity

4. 44
Drug Receptor InteractionDrug Receptor Interaction
Efficacy (or Intrinsic Activity) – ability of a Efficacy (or Intrinsic Activity) – ability of a
bound drug to change the receptor bound drug to change the receptor
in a way that produces an effect; some in a way that produces an effect; some
drugs possess affinity but NOT drugs possess affinity but NOT
efficacyefficacy
DR Complex Effect

5. 55

The first quantitative model of this sort was proposed by The first quantitative model of this sort was proposed by Clark (1920)Clark (1920)

the magnitude of the response is proportional to the formation of DR complexthe magnitude of the response is proportional to the formation of DR complex
ie E ie E  [DR] [DR]

maximal response occurs when all receptors are occupied maximal response occurs when all receptors are occupied ie Eie E
maxmax [R[R
tt]]
Occupation Theory ModelsOccupation Theory Models
(i) a plot of E against [D] will produce a rectangular
hyperbola
(ii) a plot of E against the logarithm of [D] will produce a
sigmoidal curve

6. 66
AssumptionsAssumptions

An all-or-none stimulus is elicited by the combination of An all-or-none stimulus is elicited by the combination of
each receptor site with an agonist molecule.each receptor site with an agonist molecule.

There is summation of these individual stimuli.There is summation of these individual stimuli.

The effect is linearly proportional to the number of The effect is linearly proportional to the number of
stimuli.stimuli.

The maximal stimulus occurs when every receptor site is The maximal stimulus occurs when every receptor site is
occupied by an agonist molecule.occupied by an agonist molecule.

The drug-receptor complex is formed by readily and The drug-receptor complex is formed by readily and
rapidly reversible chemical bonds.rapidly reversible chemical bonds.

The occupation of one receptor does not affect the The occupation of one receptor does not affect the
tendency of other receptors to be occupied.tendency of other receptors to be occupied.

7. 77
Assumptions About Drug Receptor Assumptions About Drug Receptor
InteractionsInteractions

Laws of mass action applyLaws of mass action apply

All receptors are identical and equally All receptors are identical and equally
accessible to drugaccessible to drug

Intensity of response is proportional to Intensity of response is proportional to
the number of receptors occupiedthe number of receptors occupied

The amount of drug which combines The amount of drug which combines
with receptor is negligiblewith receptor is negligible

8. 88
Drug + Free ReceptorDrug-receptor Complex
C (100 - Y)
K
1
K
2
Y
Where:
C = drug concentration
Y= concentration of drug-receptor complex
100 - Y = free receptor concentration

9. 99
Brody (Human Pharmacology)
arithmetic scale logarithmic scale
Based on Clark model (E  [DR]):
EC
50
= K
D

10. 1010
Arithmetic Dose ScaleArithmetic Dose Scale

Rate of change is rapid at first and Rate of change is rapid at first and
becomes progressively smaller as the becomes progressively smaller as the
dose is increaseddose is increased

Eventually, increments in dose produce Eventually, increments in dose produce
no further change in effect i.e., no further change in effect i.e.,
maximal effect for that drug is maximal effect for that drug is
obtainedobtained

Difficult to analyze mathematicallyDifficult to analyze mathematically

11. 1111
Log Dose ScaleLog Dose Scale

transforms hyperbolic curve to a transforms hyperbolic curve to a
sigmoid (almost a straight line)sigmoid (almost a straight line)

compresses dose scalecompresses dose scale

proportionate doses occur at proportionate doses occur at
equal intervalsequal intervals

straightens linestraightens line

easier to analyze mathematicallyeasier to analyze mathematically

12. 1212
DefinitionDefinition
ECEC
5050

The concentration of an agonist The concentration of an agonist
drug producing a response that is drug producing a response that is
50% of maximum50% of maximum

It is a measure of agonist potencyIt is a measure of agonist potency

13. 1313
Why KWhy K
DD  EC EC
5050
Would only be true if all the assumptions of the Clark Would only be true if all the assumptions of the Clark
model were true model were true BUTBUT

effect not always directly proportional to receptor effect not always directly proportional to receptor
occupationoccupation

concentration in the biophase is not known accuratelyconcentration in the biophase is not known accurately

not all receptors may need to be occupied for maximal not all receptors may need to be occupied for maximal
responseresponse
biophase?
What makes conc. in biophase unpredictable?
- immediate vicinity of receptors
Sites of loss

14. 1414
• NMJ  30,000,000 ACh receptors
• activation of only 40,000 required for AP
(twitch of muscle fibre)
• ??
• receptor reserve in tissues
(100-1000x)
E
max  [R

t] ?

15. 1515
Modifications to Clark’s model Modifications to Clark’s model
Clark : E = k’[DR]
k’ is a constant which is a property of the tissue
Ariens (1954) : E =  [DR]
is intrinsic activity, which is a property of the drug
Stephenson (1956): introduced ‘efficacy’
• similar in concept to ‘intrinsic activity’, but
numerically not the same
• a full agonist may produce a maximal response
when occupying fewer than 100% of receptors

16. 1616
Spare receptorsSpare receptors
If a full agonist only requires occupation of 5% of the If a full agonist only requires occupation of 5% of the
available receptors in order to produce a maximal available receptors in order to produce a maximal
response, then 95% of receptors are spare receptors response, then 95% of receptors are spare receptors
for that agonist.for that agonist.
We can also express this by saying there is a receptor We can also express this by saying there is a receptor
reserve of 95% for that agonistreserve of 95% for that agonist..

17. 1717
Agonist DrugsAgonist Drugs

drugs that interact with drugs that interact with andand activate activate
receptors; they possess receptors; they possess both affinity both affinity
and efficacyand efficacy

two typestwo types

Full – an agonist with maximal Full – an agonist with maximal
efficacyefficacy

Partial – an agonist with less then Partial – an agonist with less then
maximal efficacymaximal efficacy

18. 1818
Response
Dose
Full agonist
Partial agonist
Agonist Dose Response Curves

19. 1919
Log concentration-Log concentration-
response curvesresponse curves
Which of these is a partial agonist?
R
e
s
p
o
n
s
e

20. 2020
Antagonist DrugAntagonist Drug

Antagonists interact with the Antagonists interact with the
receptor but do receptor but do NOTNOT change the change the
receptorreceptor

they have affinity but they have affinity but NONO efficacy efficacy

two typestwo types

CompetitiveCompetitive

NoncompetitiveNoncompetitive

21. 2121
Agonists, antagonists and efficacy
drugs acting on receptors can be agonists,
partial agonists or antagonists.
agonists bring about a change in cell function
following combination with a receptor
agonists have both affinity and efficacy at a
receptor site
partial agonists ?
antagonists ?

22. 2222
Differences between full Differences between full
and partial agonistsand partial agonists

Full agonist:Full agonist:

High efficacyHigh efficacy

May only need to May only need to
occupy a fraction of occupy a fraction of
receptors to give a receptors to give a
full maximal full maximal
responseresponse

i.e. may have i.e. may have
receptor reservereceptor reserve

Partial agonistPartial agonist

Lower efficacy than Lower efficacy than
full agonistfull agonist

(by definition) (by definition)
occupies all occupies all
receptors to produce receptors to produce
its maximal its maximal
responseresponse

i.e. has no receptor i.e. has no receptor
reservereserve

Can act as a partial Can act as a partial
antagonistantagonist

23. 2323
Measures of potencyMeasures of potency

Agonist potencyAgonist potency

EC50 EC50

or (-log ) EC50 = pDor (-log ) EC50 = pD
22

Antagonist potencyAntagonist potency

for competitive antagonists, determine for competitive antagonists, determine
the concentration required to produce a the concentration required to produce a
certain degree of rightward shiftcertain degree of rightward shift

i.e. can determine the pAi.e. can determine the pA
22 for a for a
competitive antagonistcompetitive antagonist

24. 2424
Some termsSome terms

desensitisationdesensitisation

tachyphylaxistachyphylaxis

tolerancetolerance

refractorinessrefractoriness

drug resistance drug resistance

down-regulationdown-regulation

25. 2525
Tachyphylaxis
5HT 5HT 5HT 5HT 5HT

26. 2626
DesensitisationDesensitisation may be:may be:

SpecificSpecific

involves effects at the level of the receptorinvolves effects at the level of the receptor

involves only agonists acting at that receptorinvolves only agonists acting at that receptor

Non-specificNon-specific

involves effects distal to the receptor siteinvolves effects distal to the receptor site

involves all agonists whose receptors share a involves all agonists whose receptors share a
common receptor-effector coupling pathwaycommon receptor-effector coupling pathway

27. 2727
DesensitisationDesensitisation can be:can be:

acute:acute:

develops rapidly -usually rapidly reversibledevelops rapidly -usually rapidly reversible

loss of receptor functionloss of receptor function

may involve receptor internalisation without may involve receptor internalisation without
destruction of receptorsdestruction of receptors

chronicchronic

develops slowly - less readily reversibledevelops slowly - less readily reversible

often accompanied by true receptor lossoften accompanied by true receptor loss

may involve internalisation followed by receptor may involve internalisation followed by receptor
destructiondestruction

28. 2828
DownregulationDownregulation

reduction of receptor reduction of receptor number number
(density)(density) * of receptors following * of receptors following
continued exposure to a ligand which continued exposure to a ligand which
has affinity for the binding site has affinity for the binding site
involvedinvolved
* * can involve decreased receptor affinity, but can involve decreased receptor affinity, but
this is less commonthis is less common

29. 2929
Significance of DesensitizationSignificance of Desensitization

protective mechanism/sprotective mechanism/s

internalisation: possible signalling internalisation: possible signalling
functionsfunctions

disease states may be linked to disease states may be linked to
congenital or acquired receptor congenital or acquired receptor
malfunction - e.g. malfunction - e.g. myasthenia gravismyasthenia gravis

receptor desensitisation can be induced receptor desensitisation can be induced
deliberately: e.g. Rdeliberately: e.g. R
xx of prostatic cancer of prostatic cancer

30. 3030
Competitive antagonism
Agonist + increasing concentrations
of antagonist B
log
10
[agonist]
Response
Agonist
alone
D
1 D
2 D
3 D
4
[B] [2B] [3B]

31. 3131
Log conc - response curve
• must study the linear portion
• must examine the maximum
log
10
[agonist]
Response
Agonist
alone
D
1
D
2
[B]

32. 3232
Competitive antagonism
Agonist + increasing concentrations
of antagonist B
log
10
[agonist]
Response
Agonist
alone
D
1 D
2 D
3 D
4
[B] [2B] [3B]

33. 3333
Schild equation
log (dose ratio - 1) = log B - log Kd
B
y = mx - c
log (dose ratio - 1)
log B
log Kd
B
Schild PlotSchild Plot

34. 3434
pApA
22 Definition Definition
pApA
22 = negative logarithm of the = negative logarithm of the
molar concentration of molar concentration of
antagonist which increases the antagonist which increases the
EC50 by 2 foldEC50 by 2 fold
pApA
22 = -log KdB = -log KdB

35. 3535
DR Curve: Whole AnimalDR Curve: Whole Animal

Graded – response measured on a Graded – response measured on a
continuous scalecontinuous scale

Quantal – response is an either/or Quantal – response is an either/or
eventevent

relates dose and frequency of response relates dose and frequency of response
in a population of individualsin a population of individuals

often derived from frequency often derived from frequency
distribution of doses required to distribution of doses required to
produce a specified effectproduce a specified effect

36. 3636
PotencyPotency
Relative position along the dose Relative position along the dose
axis; function of affinity, efficacy axis; function of affinity, efficacy
and proportion of drug that and proportion of drug that
reaches the receptors; only a reaches the receptors; only a
relevant comparison when drugs relevant comparison when drugs
all have the same mechanism of all have the same mechanism of
action and same maximal effect; action and same maximal effect;
has little, if any, clinical has little, if any, clinical
significance.significance.

37. 3737
Analgesia
Dose
hydromorphone
morphine
codeine
aspirin
Relative Potency

38. 3838
Effectiveness, toxicity, lethalityEffectiveness, toxicity, lethality
EDED
5050 - Median Effective Dose 50; the dose - Median Effective Dose 50; the dose
at which 50 percent of the population or at which 50 percent of the population or
sample manifests a given effect; used with sample manifests a given effect; used with
quantal dr curvesquantal dr curves
TDTD
5050 - Median Toxic Dose 50 - dose at - Median Toxic Dose 50 - dose at
which 50 percent of the population which 50 percent of the population
manifests a given toxic effectmanifests a given toxic effect
LDLD
5050 - Median Toxic Dose 50 - dose which - Median Toxic Dose 50 - dose which
kills 50 percent of the subjectskills 50 percent of the subjects

39. 3939
Quantification of drug safetyQuantification of drug safety
Therapeutic Index =
TD
50 or LD
50
ED
50

40. 4040
dose
Drug A
sleep
death
100
50
0
ED
50
LD
50
Percent
Responding

41. 4141
dose
Drug B
sleep
death
100
50
0
ED
50 LD
50
Percent
Responding

42. 4242
Types of AntagonismTypes of Antagonism

Competitive (reversible)Competitive (reversible)

Irreversible (competitive)Irreversible (competitive)

Non competitiveNon competitive

PhysiologicalPhysiological

PharmacokineticPharmacokinetic

ChemicalChemical

43. 4343
Competitive AntagonismCompetitive Antagonism

reversible competitive antagonismreversible competitive antagonism

irreversible (non-equilirium) irreversible (non-equilirium)
competitive antagonismcompetitive antagonism
At the level of the receptor

44. 4444
Reversible Competitive Reversible Competitive
AntagonismAntagonism

Antagonist alone is not able to produce effect,Antagonist alone is not able to produce effect,

·agonist is able in highest concentration ·agonist is able in highest concentration
displaced antagonist from binding sites - in the displaced antagonist from binding sites - in the
presence of antagonist, the agonists log- presence of antagonist, the agonists log-
concentration-effect curve is shifted to the concentration-effect curve is shifted to the
right without change in slope or maximum, right without change in slope or maximum,
the extent of the shift being a measure of the the extent of the shift being a measure of the
agonist dose ratioagonist dose ratio
Is the commonest and most important type of
antagonism, and has two main characteristics

45. 4545
Competitive antagonismCompetitive antagonism

46. 4646
Competitive antagonismCompetitive antagonism

SurmountableSurmountable

Parallel shifts in Parallel shifts in
log CR curveslog CR curves

Reversible on Reversible on
washingwashing

47. 4747
Irreversible Competitive (non-Irreversible Competitive (non-
equilibrium) Antagonismequilibrium) Antagonism

Occurs with drugs that posses reactive Occurs with drugs that posses reactive
groups which form covalent bonds groups which form covalent bonds
with receptor (aspirin, omeprazole, with receptor (aspirin, omeprazole,
MAO inhibitors etc.) -new protein MAO inhibitors etc.) -new protein
should be synthesized to restore should be synthesized to restore
actionaction

48. 4848
Non-competitive Non-competitive
AntagonismAntagonism

Describes the situation where the Describes the situation where the
antagonist blocks at some point the antagonist blocks at some point the
chain of event that leads to the chain of event that leads to the
production of a response (papaverine, production of a response (papaverine,
verapamil …) - the effect will be to verapamil …) - the effect will be to
reduce the slope and maximum of the reduce the slope and maximum of the
agonist log-concentration-effect agonist log-concentration-effect
curve.curve.

49. 4949
Comparison of competitive and non-Comparison of competitive and non-
competitive (irreversible) competitive (irreversible)
antagonistsantagonists

50. 5050
Non-competitive antagonism: Non-competitive antagonism:
(irreversible antagonist)(irreversible antagonist)

Essentially insurmountableEssentially insurmountable

Essentially irreversibleEssentially irreversible

May see initial parallel shift May see initial parallel shift
if spare receptors are if spare receptors are
present in the tissuepresent in the tissue

At high [ ]s of antagonist, At high [ ]s of antagonist,
see depression of maximumsee depression of maximum

Example: haloalkylaminesExample: haloalkylamines

eg phenoxybenzamineeg phenoxybenzamine

51. 5151
Chemical AntagonismChemical Antagonism

Agonist and antagonist form Agonist and antagonist form
inactive complex in solution. inactive complex in solution.

heparin -protamine sulphate, heparin -protamine sulphate,

heavy metals and dimercaprolheavy metals and dimercaprol

52. 5252
Pharmacokinetic Pharmacokinetic
AntagonismAntagonism

Antagonist effectively reduces the Antagonist effectively reduces the
concentration of the active drug concentration of the active drug
at its site of action at its site of action

enzyme induction - warfarin,enzyme induction - warfarin,

decrease of absorption, decrease of absorption,

increase in renal excretion of drugincrease in renal excretion of drug

53. 5353
Physiological AntagonismPhysiological Antagonism

Interaction of two drugs whose Interaction of two drugs whose
opposing action in the body tend opposing action in the body tend
to cancel each other to cancel each other
histamine & histamine & 
2 2- adrenergic agonists - adrenergic agonists
in bronchioles, in bronchioles,

histamine & omeprazole in gastric histamine & omeprazole in gastric
mucosamucosa

54. 5454
Unusual ResponsesUnusual Responses

idiosyncratic response - unusual response idiosyncratic response - unusual response

hyporeactive - less than normal responsehyporeactive - less than normal response

hyperreactive - more than normal responsehyperreactive - more than normal response

hypersensitivity - allergic or other hypersensitivity - allergic or other
immunological reactionimmunological reaction

tolerance - decreased response with tolerance - decreased response with
continued administrationcontinued administration

tachyphylaxis - rapidly developing tolerancetachyphylaxis - rapidly developing tolerance

55. 5555
Drug-drug & drug-food Drug-drug & drug-food
interactionsinteractions

Potentiative response Potentiative response

Therapeutic actionTherapeutic action

Adverse side effectsAdverse side effects

Inhibitory responseInhibitory response

Therapeutic actionTherapeutic action

Adverse side effects Adverse side effects

56. 5656
Mechanisms of drug-drug Mechanisms of drug-drug
interactionsinteractions

Direct chemical or physicalDirect chemical or physical

PharmacokineticPharmacokinetic

PharmacodynamicPharmacodynamic

Combined toxicity Combined toxicity

57. 5757
Drug-Food InteractionsDrug-Food Interactions

Alters rate of absorptionAlters rate of absorption

Inhibition of drug Inhibition of drug
metabolismmetabolism

Grapefruit juice effectGrapefruit juice effect

Increasing drug toxicityIncreasing drug toxicity

MAO inhibitorsMAO inhibitors

58. 5858
Adverse Drug ReactionsAdverse Drug Reactions

identify groups of people with identify groups of people with
increased risk of adverse drug effectsincreased risk of adverse drug effects

define iatrogenic diseasedefine iatrogenic disease

differentiate between idiosyncratic, differentiate between idiosyncratic,
carcinogenic, and teratogenic effectscarcinogenic, and teratogenic effects

determine the basis for intensity of determine the basis for intensity of
allergic reactionsallergic reactions

discuss measures to minimize adverse discuss measures to minimize adverse
drug eventsdrug events

59. 5959
Adverse Drug ReactionsAdverse Drug Reactions

Noxious, unintended and Noxious, unintended and
undesired effects that occur at undesired effects that occur at
normal drug dosesnormal drug doses

Serious ADRs occur in 6.7% of Serious ADRs occur in 6.7% of
hospitalized patientshospitalized patients

60. 6060
Adverse drug reactionsAdverse drug reactions

Side effectSide effect

ToxicityToxicity

Allergic Allergic
reactionreaction

Physical Physical
dependencedependence

Carcinogenic Carcinogenic
effecteffect

61. 6161
Idiosyncratic EffectIdiosyncratic Effect

An uncommon drug An uncommon drug
response from a genetic response from a genetic
predispositionpredisposition

62. 6262
Iatrogenic diseaseIatrogenic disease

disease produced by a disease produced by a
physicianphysician

Derived from Greek words:Derived from Greek words:

“ “Iatros”Iatros”

“ “Genic”Genic”

63. 6363
Teratogenic effectTeratogenic effect

Drug-induced birth defectDrug-induced birth defect

TeratogenTeratogen

Chemical capable of Chemical capable of
causing birth defectcausing birth defect

64. 6464
Individual Variation in Drug Individual Variation in Drug
ResponsesResponses

Factors that influence drug Factors that influence drug
responses:responses:

Body weight, compositionBody weight, composition

AgeAge

GenderGender

PathophysiologyPathophysiology

65. 6565
PlaceboPlacebo

drug devoid of intrinsic drug devoid of intrinsic
pharmacological activitypharmacological activity

66. 6666
Drug toleranceDrug tolerance

Decreased responsiveness to Decreased responsiveness to
a drug due to repeated drug a drug due to repeated drug
administrationadministration

67. 6767
Drug Interactions
The simultaneous usage of several therapeutic agents concurrently is
commonplace, with most patients in general hospitals receiving at least 5
drugs concurrently at some point in their stays.
The median number of drugs administered to patients during
hospitalization is 10-13, with many receiving more than 20 drugs. In
addition, many patients also consume analgesics, cold remedies and
other drugs that are available without a prescription. Furthermore, there
is a universal exposure to other bioactive chemicals found in food
additives, insecticides, cleaning agents and cosmetics.
A major concern is that the administration of one drug will change the
effect of another by enhancing or diminishing its effects at its site of
action.