Pharmacodynamics, How drugs work and what does they do? .ppt

Pharmacodynamics, How drugs work and what does they do?

1. Pharmacodynamics
Haftom G. (BPharm., MSc)
Email: [email protected]

2. Pharmacodynamics
Pharmacodynamicsstudiesthephysiologicalandbiochemicaleffectsof
drugsandtheirMOA
Thestudyofwhatdrugsdotothebodyandhowtheydoit.
Drugsinteractwithreceptorstoproducetheircharacteristiceffects.
Doesalldrugs….??

3. Pharmacodynamics
Drugsdoesn’tcreatenewresponses:commonlyaltertherateormagnitudeofan
intrinsiccellularorphysiologicalresponse.
Locationofdrugreceptors
Oftenlocatedonthesurfaceofcellsbutmayalsobelocatedinspecific
intracellularcompartments,suchasthenucleus,orintheextracellular
compartment,asinthecaseofdrugsthattargetcoagulationfactorsand
inflammatorymediators.

4. Pharmacodynamics
Acceptors
Manydrugsalsointeractwithacceptors(e.g.,serumalbumin),which
areentitiesthatdonotdirectlycauseanychangeinbiochemicalor
physiologicalresponsebutcanalterthepharmacokineticsofadrug’s
actions.
???

5. Pharmacodynamics
Biologics:newtypeofdrugsbeingapprovedinrecentyears
Includegeneticallyengineeredenzymesandmonoclonalantibodies.
Geneticallymodifiedvirusesandmicrobes:
E.g.,Oneagentapprovedfortreatingmelanomaisageneticallymodifiedlive
oncolyticherpesvirusthatisinjectedintotumorsthatcannotberemoved
completelybysurgery.

6. Pharmacodynamics
Genetherapy:
Usingvirusesasvectorstoreplacegeneticmutationsthatgiverisetolethaland
debilitatingdiseaseshavealreadybeenapprovedinChinaandEurope(2017).
Thenextgenerationofgenetherapyproductswillbethosecapableoftargeted
genomeeditingusingantisenseoligonucleotidesandRNAiandbydeliveringthe
CRISPR/Cas9genome-editingsystemusingvirusesorgeneticallymodified
microorganisms.

7. Mechanism of drug action (MOA)
1.Physicalaction
oAdsorptiveproperty(activatedcharcoal),Massofthedrug(inbulklaxatives),
oOsmoticactivity(mannitol)
2.Chemicalaction
oAntacids,chelatingagents(Dimercaprol,calciumdisodiumedetate)
3.Throughproteintargets
oIonchannels,carriermolecules,enzymes,receptors

8. Physiological Receptors
•Many drug receptors are proteins that normally serve as receptors for endogenous
regulatory ligands.
•These drug targets are termed physiological receptors.
•Drugs that bind to physiological receptors and mimic the regulatory effects of the
endogenous signaling compounds are termed agonists.

9. Physiological Receptors
•If the drug binds to the same recognition site as the endogenous agonist, the drug is
said to be a primary agonist.
•Allosteric (or allotopic) agonists bind to a different region on the receptor, referred
to as an allosteric or allotopicsite.
•Drugs that block or reduce the action of an agonist are termed antagonists.

10. Protein Targets for drug action
Anycellularmacromoleculetowhichadrugselectivelybindstoelicitits
pharmacologicaleffect
Membranereceptors:E.g.adrenergicreceptorstargetedbyadrenaline
Ionchannels:E.g.voltagegatedNa
+
channelstargetedbylocalanesthetics
Enzymes:E.g.angiotensin-convertingenzymetargetedbycaptopril
Carriermolecules(transporters):E.g.Protonpumptargetedbyomeprazole
10

11. Drug-receptor interaction
•Receptors are any functional macromolecules in a cell to which a drug
binds to produce its effects.
Drug + Receptor Drug-Receptor complex
Response
•Under normal condition, receptor activity is regulated by endogenous compounds
(EDCs)(NTs, Hormones)
•Drugs mimic or block the actions of EDCs.

12. Types of receptors and signal transduction
12

13. Types of receptors
Receptorsareclassifiedinto:
Ligand-gatedionchannelsreceptors
G-protein-coupledreceptors(GPCR)
Kinase-linkedreceptors
Nuclearreceptors
13

14. Fig: Transmembrane signaling mechanisms

15. Figure. Types of receptor-effector linkage 15

16. Fig: Mechanism of activation of the epidermal growth factor (EGF) receptor, a representative receptor
tyrosine kinase.

17. Fig: The nicotinic acetylcholine (ACh) receptor, a ligand-gated ion channel.

18. Fig: Transmembrane topology of a typical “serpentine” GPCR

19. Fig: The cAMPsecond messenger pathway.

20. Types of receptors….
1. CM embedded enzymes
–Span the CM
–LBD is located on cell surface and
enzyme catalytic side is inside
–Fast response (in sec.)
–E.g Insulin receptors
2. Ligand gated ion channel
–Span the CM
–Regulate the flow of iones
–Each is specific for a particular ion
–The channel opens when EL/ agonist/
drug binds
–Response is extremely fast
–E.g nicotinic, GABA receptors

21. Types of receptors …
3.GPCR systems
–3 components: Receptor, G-protein,
and an effector
–Binding activates the receptor, which in
turn activates G-protien, which in turn
activates the effectors
–Response is fast (in sec.)
–Muscarinic ACH, noradrinalin,
serotonin, Histamine receptors
4.Transcriptional factors
–Differ from others in 2 ways
•Found with in the cell
•Delayed Responses
–Activated only by sufficiently lipid
soluble drugs
–Steroid hormone receptors, thyroid
hormone receptors

22. Drugs often work on multiple receptors
•Drugs often work on more than one receptor, and as a result produce more than
one kind of biological response.
•E.g., norepinephrine (NE): sympathetic neurotransmitter
–It relaxesbronchial smooth muscle, butconstrictarterial smooth muscle.
–This results from NE binding to different adrenergic receptor subtypes (α and β).

23. Drugs often work on multiple receptors
•E.g., norepinephrine (NE)….
–Bronchial smooth muscle is rich in β adrenergic receptors, whereas arterial
smooth muscle is rich in α adrenergic receptors.
–When stimulated, the α receptor subtype transduces a different type of
biological signal compared to β adrenergic receptors.
–Each receptor subtype selectively interacts with different G proteins & thus
activate different intracellular messenger pathways, resulting in different
biological responses.

24. Drugs often work on multiple receptors…..
•Fig:A single drug can interact with multiple
receptors. Norepinephrine can deliver two types
of messages by interacting with different
adrenergic receptor subtypes (α and β). These
receptors are coupled to different intracellular
messenger systems, and produce different
responses when stimulated. These receptor
subtypes are not typically expressed in equal
amounts in the same tissue (e.g. vascular
smooth muscle contains more α receptors (α »
β ), whereas bronchial tissue contains more β
receptors (β » α).

25. Drug receptor theories

26. Drug receptor theories
•There are 3 main theories
A.Occupational theory
•Simple occupancy theory
•Modified occupancy theory
B.Rate theory
C.Allosteric theory

27. A. Occupancy theories
I.Simpleoccupancytheory
•Statesthat
–Theintensityofresponseisproportionaltothe#ofreceptoroccupied
–Maximumresponsewilloccurwhenallavailablereceptorshavebeenoccupied.
•Limitations
–Doesnotexplain
•Whyonedrugshouldbemorepotentthananother
•Howonedrugcanhavehighermaximalefficacythananother

28. Occupancy theories….
II.Modified occupancy theory
•Describes two quantities to drugs
1.Affinity-
–refers to the strength of attraction between a drug and its receptor.
–High affinity strongly attracted (potent)
–Low affinity weakly attracted
2.Intrinsic Activity
–Refers to the ability of a drug to activate a receptor
–Reflected in maximal efficacy (intense response)
–Drugs may occupy the same # of receptors but produce different intensity of effects.

29. B. Rate theory
Response the rate at which the drug combines with the R
–Each association of the D with R results in a quantum of excitation.
•Agonist
–Dissociate rapidly from the receptor to enable other successful associations and subsequent
generation of quanta of excitation.
•Antagonist
–Dissociate slowly to prevent the generation of other quanta of excitation.
•Dissociation rate constant is the factor which determines whether a drug is an agonist, antagonist or
partial agonist (according to the rate theory).

30. C. Allosteric theory
•According to this theory, There are two conformations for a
receptor
–Active and Inactive state

31. Types of interaction of drugs with receptors
ReceptorLigandscanbe:
Agonists(fullandpartial):ligandthatcanbindtoaparticularreceptorto
initiateacellularresponse
Antagonist:ligandthatcanbindtoaparticularreceptor,butitcanNOT
initiateacellularresponse
Affinity:abilityofaligandtobindtoareceptors
Intrinsicactivity:itistheabilityofdrugtobringaresponse
31

32. Intrinsic activity (IA):
•Determines the efficacy of a drug
•IA = 1: Full agonist (produce
maximal effects-high efficacy)
•0<IA<1:Partial agonist (produce
only sub-maximal effects
•IA = 0: Antagonist (No efficacy )

33. Agonist vs Antagonist….
•Agonists:
–Drugs that mimic the body’s own regulatory molecules
–Has both affinity and intrinsic activity
•Antagonists:
–Prevent activation by endogenous regulatory molecules or drugs.
–With affinity but with no intrinsic activity

34. Agonists….
•Potency: amount of drug required to produce an effect of given intensity.
–Differences in drug potency are evaluated by comparing EC50 (or ED50) values.
•Efficacy: ability of a drug to produce a maximum response.
–Differences in drug efficacy are evaluated by comparing differences in maximal
response at high drug doses or concentrations.
•Partial agonists: agonists that produce less than a full response when they fully
occupy their receptors. In contrast, full agonists produce a full or maximal response.

35. Potency….
•It is a function of EC
50
•Drug “a” is more potent than drug “b”
•Drugs “b” and “c” are of equal potency (have equal EC
50)
•Configuration of curve with respect to the x-axis gives indication of potency

36. Intrinsic activity (IA)…..
•Related to the attainment of maximum response
•Drugs “a” and “b” have equal IA while “c” has less IA
•Configuration of curve with respect to the Y-axis gives
indication of IA

38. Agonists….
•Fig:Schematic illustration of the
dose-response curves for a series of
agonists (A, B, C and D) that have the
same efficacy, but differ in terms of
theirpotency.The most potent
drug (Drug A) has the lowest EC50
value, and is approximately 20-30
fold more potent than Drug D.

39. Agonists….
•Fig:Dose-response relationships for four
agonists that vary in efficacy. Each drug has
essentially the same EC50 value (equi-potent),
but differ in terms of the maximum response they
can produce at high concentrations that saturate
all available receptor sites.Drug A has a relative
efficacy that is 2 times than Drug C, and ~100
times more than Drug D.

40. Note:
•Drug potency does not necessarily mean therapeutic
superiority.
•Other factors such as adverse drug reactions associated with
the drug need to be considered.

41. Partial agonists
•Has only moderate intrinsic activity
•Maximum response is lower than a full agonist
•They can act as agonist as well as antagonist
–when administered alone to produce moderate receptor activation
–However, blocks the action of a full agonist

42. Receptor antagonism
I.Competitive antagonists
•Compete with agonists in a reversible fission
•When the antagonist is present, the log-dose response curve shifts to the
right.
–Indicates that higher conc. Of an agonist is necessary to achieve the
response as the antagonist is absent
–Results in parallel shift of the dose response curve

43. Receptor antagonism
II.Non-competitive antagonists
•Binds irreversibly to R site no matter how much agonist is given
•The action of the antagonist cannot be overcome
•The shift of the log-response curve is nonparallel

44. Agonist
Agonist
•High affinity
•High intrinsic activity

45. Antagonist
Antagonist
•Have affinity
•No intrinsic activity

46. Reversible Antagonist
Antagonist
•High affinity
•Low intrinsic activity

47. Competitive Antagonist

48. Noncompetitive Antagonist

49. Indirect Agonist
Indirect Agonist

50. Irreversible Antagonist
Irreversible Antagonist
•High affinity
•Low intrinsic activity

51. Competitive and Noncompetitive Antagonists

52. Competitive and Noncompetitive Antagonists….

53. Explanation for the figure in slide No. 51 (previous slide)
•Fig:Examples of Competitive and Noncompetitive Antagonism.
A.Competitive Antagonism, where both the agonist (Isoproterenol) and the antagonist
(Propranolol) bind reversibly to the same receptor subtype (β-adrenoceptor). In the
presence of the competitive antagonist, the dose-response curve is shifted to the right
in a parallel manner.
B.Non-competitive antagonism. Phenoxybenzaminebinds irreversibly (with covalent
bonds) to α-adrenergic receptors. This reduces the fraction of available receptors, and
reduces the maximal effect that can be produced by the agonist.

54. Other Mechanisms of Drug Antagonism
•There are other types of “antagonism” involving drug effects:
•Physiological antagonism: involves drug activation of two different compensatory
biological mechanisms that exist to maintain homeostasis by different mechanisms.
•For example:
•Increased blood pressure by Norepinephrine(via stimulation of α-adrenergic
receptors) can be antagonized by administration ofacetylcholine, which causes
vasodilation bystimulating muscarinic receptors.

55. Other Mechanisms of Drug Antagonism…
•Chemicalantagonism:occurswhenadrugreducestheconcentrationof
anagonistbyformingachemicalcomplex(e.g.chelatingagents).
–Example:protaminesulfateisapositivelychargedsubstancethatwhengiveni.v.
willbindtoheparin,astronglynegativelychargedanticoagulantdrug.
–Asaresult,protaminesulfateadministrationisatypeof“antidote”forheparin
overdose,becauseonceheparinbindstoprotaminesulfate,itcannotexertits
anticoagulanteffects.

56. Other Mechanisms of Drug Antagonism…
•Pharmacokinetic antagonism: occurs when one drug accelerates the
metabolism or elimination of another (e.g. phenobarbital-induced
enzyme induction increases the metabolism of the anticoagulant
coumadin).

57. Dose-Response Relationship

58. Dose-Response Relationship
Therelationshipbetweenintensityofdrugeffectanddruglevel
Hastwocomponents
•Dose-responserelationship
•Plasmaconcentration-responserelationship
Quantificationofdruglevelatthesiteofactionisdifficult
•Henceeitherthedoseadministeredorplasmaconcentrationareconsidered
duringquantification.

59. Dose-response relationship
Response
Dose/ concentration
Response
Log concentration

60. Typical Concentration Vs receptor occupancy curve

62. Plottinglogarithmicscaleofthe
concentrationonthex-axisvs
occupancy(response)resultsina
sigmoidalcurve
Advantagesinclude
Linearityover20-80%oftheoccupancy
(response)
Itcanshowamuchlargerrangeof
concentration

63. Overlappingalogconcentration-occupancycurveonalog
concentration-responsecurverevealsthreescenarios

64. Scenario 1
Identical occupancy and
response curves
K
A= EC
50 meaning half
maximal response at half
maximal occupancy
Maximum response at full
occupancy only

65. Scenario 2
Maximum response attained at
sub-maximal occupancy
K
A> EC
50
This occurs because the
transducer mechanism is very
effective at converting drug-
response interaction in to
response.

66. Scenario 3
Sub-maximalresponseat
fulloccupancy
Drug-receptorinteraction
elicitsweak signal
transducingmechanism
K
A<EC
50

67. Individual variation
Drugresponsecurvesofsameeffect(response)fromdifferentindividuals
ismadeandcomparedforEC
50
SensitiveindividualsdisplaysmallerEC
50valueindicatingthatsmallerdose
ofadrugproduceshigherresponseinthisindividuals.

68. Dose-Response curve
Two types of dose-response curves
•The graded response curve
•Quantal response curve

69. Graded DRCs
Response obtained from the administration of graded dose to a single
animal or patient.
With graded responses, one can obtain a complete dose–response
curve in a single animal or patient.
EC
50is the dose at half maximum response
The curve is continuous

70. Graded DRCs…

71. Quantal DRCs
•Relationshipbetweendoseandsomespecifiedquantumofresponse
amongallindividualstakingthedrug
•Effectiseitherpresentorabsent(allornone)
–E.g.protectionofconvulsionbyanti-epilepticagents.
•Requiresdataobtainedfrommanyindividuals(population).

72. Quantal DRCs
•ED
50:doseatwhich50%ofthosetreatedshowspecific
intensityofeffect
•LD
50:Doseatwhich50%ofthosetreateddie(inanimals)

74. Quantal…
•Fig: Quantal effects. A set of data
obtained after administration of
increasing doses of a drug to a group of
patients, and observation of the
minimum dose at which each patient
responded with the desired outcome.
The results have been plotted as a
histogram, and fit with a gaussiancurve.
μ = mean response; σ = standard
deviation.

75. Therapeutic Index
An estimate of a drugs margin of safety.
Mathematically:
A more realistic estimate of drug safety would include a comparison of the
lowest dose that produces toxicity (LD
1) and the highest dose that
produces maximal therapeutic response (ED
99)

76. Therapeutic Index….
•Fig: The relationship between the
dose-response relationships for
producing therapeutic and toxic
side effects. The Therapeutic
Index (TI) is defined as the ratio
of the TD50/ED50.

77. Fig: Cumulative percentage of patients responding to plasma levels of
warfarin and penicillin.

78. Desensitization and down-regulation of receptors:
•Repeated or continuous administration of an agonist (or an antagonist) may lead to
changes in the responsiveness of the receptor.
•To prevent potential damage to the cell (for example, high concentrations of
calcium, initiating cell death), several mechanisms have evolved to protect a cell
from excessive stimulation.
•When a receptor is exposed to repeated administration of an agonist, the receptor
becomes desensitized resulting in a diminished effect.

79. Desensitization and down-regulation of receptors:
•This phenomenon, called tachyphylaxis, is due to either phosphorylation or a similar
chemical event that renders receptors on the cell surface unresponsive to the ligand.
•In addition, receptors may be down-regulated such that they are internalized and
sequestered within the cell, unavailable for further agonist interaction.
•These receptors may be recycled to the cell surface, restoring sensitivity, or,
alternatively, may be further processed and degraded, decreasing the total number
of receptors available.

80. Desensitization and down-regulation of receptors….
•Some receptors, particularly ion channels, require a finite time following stimulation
before they can be activated again.
•During this recovery phase, unresponsive receptors are said to be “refractory.”
Similarly, repeated exposure of a receptor to an antagonist may result in up-
regulation of receptors, in which receptor reserves are inserted into the membrane,
increasing the total number of receptors available.
•Up-regulation of receptors can make the cells more sensitive to agonists and/or
more resistant to the effect of the antagonist

81. Fig: Desensitization of
receptors

82. Factors that modify drug effect
and drug dosage

83. Factors…
Body weight?
Age
Infants
•Small volume of body fluid compartment
•Incomplete development of the BBB
•Undeveloped renal system
•Undeveloped enzyme system
Old people: deteriorated body functions

84. Factors…
Sex
Body size, body composition
Route of administration
Time of administration
Physiological variables: fluid and electrolyte balance, acid-base status, blood flow
and body temperature
Tolerance to drugs

85. Factors…
Pathological factors
Alter pharmacokinetics and pharmacodynamicparameters.
Special attention is given to renal and hepatic problems
Genetic factors
Emotional factors….placebo

86. Factors…
Nutritional state
Starvation causes decreased protein synthesis (drug metabolizing enzymes),
hence enhanced drug effect.
Environmental
More of a hypnotic drug is required to induce hypnosis during day time than
during night
More dose of antihypertensive drug is required to lower blood pressure in cold
weather than in hot one.

87. Drug interaction
Iftwoormoredrugsaregiventogethertheymightinteract
Interactionoccursattwostages
Atpharmacokineticlevel
At the level of absorption, distribution, biotransformation or excretion
Atpharmacodynamiclevel
Atthelevelofreceptorsandbeyond

88. Types of drug interaction
Synergism: action of a drug increased by another
Additive (1+1>1)
Effect of (A+B) = Effect of A + Effect of B
Side effects are better tolerated as the same synergy might not work for the adverse effects
of the drugs.
Potentiation (Supra-additive) (1+0>1)
Effect of (A+B) > Effect of A + Effect of B
Especially if one is inactive as such

89. Types of drug interaction
Antagonism:actionofonedruginhibitstheactionofanother
Physical:E.g.,charcoalandalkaloids
Chemical:E.g.,Nitratesandcyanideradicals
Physiological/functional:E.g.,…
Pharmacologicalantagonism:E.g.,…

90. Types of drug action
Systemic action Vs local action
Direct action Vs Indirect action
Primary action Vs Secondary action
Selective Vs non-selective action

91. Drug adverse effects and drug toxicities
Theseareeffectsnotfavorabletothepatient
Expectedadverseeffects
Sideeffects:effectsobservedattherapeuticdose
Toxiceffects:effectsobservedatlargerconcentrations
Acutetoxicity:acuteadministrationoflargerdoses.
Chronictoxicity:usuallywithprolongedandrepeateduseofadrug.

92. Drug adverse effects and drug toxicities
Unexpectedadverseeffects
Hypersensitivity reactions:abnormal response due to antigenic nature of some
drugs
Allergy
Anaphylaxis:extremesensitivitytoantigenicsubstanceandsubsequentcirculatorycollapse
Idiosyncratic reactions: genetically determined abnormal reactivity to a drug.

93. Drug adverse effects and drug toxicities
Carcinogenic?
Teratogenic?

94. The FDA pregnancy risk categories?????
Category Definition Management Strategy
A Adequate and well-controlled studies in pregnant
womenhave failed to demonstrate a risk to the fetus
in the firsttrimester of pregnancy
Because studies are not able to rule
out the possibility of
harm, (name of drug) should be
used during pregnancy only
if clearly indicated
B Animal reproduction studies have failed to
demonstrate arisk to the fetus, but there are no
adequate and well controlled studies of pregnant
women. Or animal studiesdemonstrate a risk, and
adequate and well-controlledstudies in pregnant
women have not been done during thefirst
trimester
Because the studies of humans
cannot rule out the
possibility of harm, (name of drug)
should be used during
pregnancy only if clearly needed

95. The FDA pregnancy risk categories
Category Definition Management Strategy
C Animal reproduction studies have
shown an adverse effect on the fetus,
but there are no adequate and well-
controlled studies of humans. The
benefits from the use of the drug in
pregnant women might be acceptable
despite its potential risks. Or animal
studies have not been conducted and
there are no adequate and well-
controlled studies of humans.
(Name of drug) should be
given to pregnant women
only if clearly needed.

96. The FDA pregnancy risk categories
Category Definition Management Strategy
D There is positive evidence of human
fetal risk based on adverse reaction
data from investigational or marketing
experience or studies of humans, but
the potential benefits from the use of
the drug in pregnant women might be
acceptable despite its potential risks.
If this drug is used during
pregnancy, or if the
patient becomes pregnant
while taking this drug, the
patient should be apprised
of the potential hazard to
the fetus.

97. The FDA pregnancy risk categories
CategoryDefinition Management Strategy
X Studies in animals or humans have
demonstrated fetal abnormalities or
there is positive evidence of fetal risk
based on adverse reaction reports from
investigational or marketing experience,
or both. The risk involved in the use of
the drug in pregnant women clearly
outweighs any possible benefits.
(Name of drug) is
contraindicated in women
who are or might become
pregnant. If this drug is used
during pregnancy, or if the
patient becomes pregnant
while taking this drug, the
patient should be apprised of
the potential hazard to the
fetus.

99. Thank you!