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MECHANISMS OF DRUG ACTION
Pharmacotherapeutics:
Types of Therapies Acute therapy- urgent use eg atropine for bradycardia
Maintenance therapy designed to help a primary treatment succeed. Eg maintenance chemotherapy to people who have a cancer in remission to prevent a relapse.
Supplemental therapy to supplement lack of certain agents eg iron
Palliative therapy concentrates on reducing the severity of disease symptoms, rather than providing a cure. Eg Phenothiazines to reduce nausea in chemo
Supportive therapy treatment intended to relieve symptoms or help the patient live with them rather than attempt changes in character structure eg education, counsel
Prophylactic therapy prevention eg vaccines
Pharmacodynamics
– The study of molecular interactions between drugs and body constituents
• Formation of a complex between the drug and a cell component – Drug receptor
• The receptor site where the drug acts to initiate a series of biochemical and physiological effects– Site of action
• Molecular events that follow drug-receptor interactions– Mechanisms of action
Pharmacodynamics cont..
– Relate to the biochemical andphysiological actions of drugs
PharmacodynamicsDrug receptors• Cellular macromolecules– Transmembrane ion channels– Transmembrane receptors coupled to intracellular G proteins – Transmembrane receptors with enzymatic cytosolic domains eg
Tyrosine Kinase receptor acts in phosphorylation reaction– Intracellular receptors, including enzymes, DNA andstructural proteins• A single cell may have hundreds of receptor sites– Drugs interact with these receptor sites andproduce a definable pharmacological response
Pharmacodynamics:
Mechanisms of ActionThe ways by which drugs can produce
therapeutic effects: Once the drug is at the site of action, it
can modify the rate (increase or decrease) at which the cells or tissues function.
A drug cannot make a cell or tissue perform a function it was not designed to perform.
Pharmacodynamics:
Mechanisms of Action Receptor interaction eg DNA & chlorambucil
Enzyme interaction eg toposiomerase and DMXAA
Nonspecific interactions (Biophysical e.g alteration of pH in the stomach acid by Antacid Gaviscon)
ReceptorsMost drugs combine (bind) with specific receptorsto produce a particular response. This association or binding takes place by precise physicochemical and steric interactions between specific groups of the drug and the receptor.
1. Proteins a. Carriersb. Receptors
i. G protein-linked ii. Ligand gated channelsiii. Intracellular
c. Enzymes2. DNA
Endogenous compounds act on their Receptors
Neurotransmitter
Neuropeptides
Hormones
Ionshttp://www.morphonix.com/software/education/science/brain/game/specimens/neurotransmitters.gif
–Receptor classification• According to the type of drug that interactswith a specific receptor– Adrenergic» α1, α2, β1, β2, β3– Cholinergic» Muscarinic (M1, M2, M3), nicotinic– Histaminic» H1, H2, H3– Opioid– Serotonergic– Dopaminergic
Receptor
1) PharmacologicalMediator (i.e. Insulin, Norepinephrine, estrogen)
2) BiophysicalSecond messenger system (i,.e. cAMP, PLC, PLA)
3) Molecular or StructuralSubunit composition (i.e. 5HT1A )
4) AnatomicalTissue (i.e muscle vs ganglionic nAChRs)Cellular (i.e. Membrane bound vs Intracellular)
Classification of Receptors
Types of ReceptorsMEMBRANE BOUND RECEPTORS G-Protein-linked receptors
Serotonin, Muscarinic, Dopaminergic, Noradrenergic Enzyme receptors
Tyrosine kinase Ligand-gated ion channel receptors
Nicotinic, GABA, glutamate
INTRACELLULAR AND NUCLEAR RECEPTORS Hormone receptors Autocoid receptors Growth factors receptors Insulin receptors
G Protein–linked Receptors
http://www.sp.uconn.edu/~bi107vc/images/anim/SigtranRA.gif
Enzyme-like Receptors
Ligand-gated Ion-Channel Receptors
Nuclear Receptors
General Principles of Pharmacology
Pharmacodynamics– Drugs-receptorinteractions• Hydrogen andionic binding arethe most common– Require little energy– May be easily broken
Drug-Receptor InteractionsChemical Bonds
Van der Waals Interactions
Hydrophobic Interactions
Drug-Receptor InteractionsDrug-receptor interactions serve as signals to trigger a cascade of events. This cascade or signaling pathway, is a collection of many cellular responses which serve to amplify the signal and produce a final effect.
Effectors are thus the molecules that translate the drug-receptor interaction into changes in cellular activity.
+ EFFECT DRUG DRUG + RECEPTOR DRUG + RECEPTOR EFFECTOR EFFECTOR INTERACTION COMPLEX SYSTEM
STIMULUS BINDING ACTIVATION TRANSDUCTION AMPLIFICATION RESPONSE
SIGNALLING PATHWAY
Receptor Signaling Pathways
Second Messengers:1. Ions (Ca2+, Na+, K+, Cl-)2. cAMP, cGMP, IP3, Diacylglycerol3. DNA binding – Transcriptional regulation.4. Phosphorylated proteins and enzymes via
tyrosine kinase receptors.
Third Messengers:1. Enzymes (PKC, PKA)2. Ions (Ca2+, K+)
Receptor Signaling Pathways
cAMPcGMPDAG and IP3Arachidonic acidNO and CONa+, Ca2+, K+, Cl-
EFFECTORSAdenylate Cyclase (AC)Guadenylyl Cyclase (GC)Phospholipase C (PLC)Phospholipase A (PLA2)Nitric oxide SynthaseIons
SECOND MESSENGER
Receptor Signaling Pathways
R R R R
Receptor Signaling Pathways
Receptor Down-Regulation
Cells can sense the changes in [ligand] Ligand bound to the receptor can cause
desensitization or tolerance of the target cell to the ligand and will then require higher [ligand] to elicit a response
Desensitization is due to changes in properties or location of the receptor known as receptor down-regulation
Desensitization leads to tolerance – loss of effectiveness
3 Methods of Down-Regulation
1) Remove the receptor from the cell surface Receptor-mediated endocytosis Reduced receptor will yield diminished cellular activity
2) Alterations in the receptor that lowers the affinity for the ligand or 3) alterations so cannot initiate changes in cell function Altered by phosphorylation Remain on the surface but cannot respond to ligand
Pharmacodynamics– Drug-receptor affinity• The ability of a drug to interact with areceptor is a function of its chemicalstructure– Expressed by the drug’s dissociation constant (KD)» The concentration of a drug required toachieve 50% occupancy of its receptors– Most drug-receptor interactions are governed bythe law of mass action» To reach equilibrium, drugs move from highconcentration to low concentration
PharmacodynamicsThe response initiated by a drug is a function of its
intrinsic activity• A drug that has a direct stimulatory effect on a receptor is an
agonist– Strong agonist - high intrinsic activity» Produces a significant response when only a smallnumber of receptors are occupied– Weak agonist - intermediate intrinsic activity» Must be bound to many receptors to produce thesame effect as the strong agonist– Partial agonist - low intrinsic activity» Even when all receptors a occupied, it will notproduce the same effect as a strong agonist-- Spare receptor- full response although not all receptors occupied
may be due to involvement of second messengers.
Pharmacodynamics• A drug that inhibits the action of an
agonist is an antagonist– Receptor antagonist - active site binding» Reversible - competitive active site antagonist
– Receptor antagonist - allosteric binding» Irreversible - noncompetitive allosteric antagonist bind
to other than the active site causing distortion in active site
General Principles of Pharmacology– Nonreceptor antagonist» Chemical antagonist - inactivates agonistbefore it has the opportunity to act e.g protamine-heparin» Physiological agonism and antagonism is the mechanism of
substances to induce the same ultimate effects in the body as other substances, as if they were receptor agonists or antagonists, but without binding to the same receptor. Adrenaline induces platelet aggregation and so does hepatocyte growth factor (HGF). Thus, they are physiological agonists to each other.
Pharmacokinetic antagonist- antagonists that limit drug concentration at the active site e.g by decrease absorption or increase metabolism or excretion
Receptor-Mediated EffectsReceptor-Mediated Effects
% % Maximum Maximum
EffectEffect
[Drug][Drug]
Agonist
Antagonist
Partial agonist
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0
1 10010 1000
Dose-Effect ParametersDose-Effect Parameters
PPOTENCY:OTENCY:
EEFFICACY:FFICACY:
The sensitivity of an organ or The sensitivity of an organ or tissue to the drugtissue to the drugthe amount of one drug required to produce a desired effect compared with another agent
The maximum effectThe maximum effectthe drug property that allows the receptor-bound drug to produce its pharmacological effect
PharmacodynamicsEfficacy• The magnitude of response obtained from optimal
receptor site occupancy– Related to intrinsic activity» SAR– “Ceiling dose”
Pharmacodynamics– Potency• Relates two ormore drugs bycomparing thedoses requiredto produce agiven effect– Related toaffinity– Important indeterminingdrug dosage
Comparing Dose-Effect Comparing Dose-Effect CurvesCurves
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% of % of Maximal Maximal
EffectEffect
[Drug][Drug]
Drug ADrug A
Drug CDrug C
Drug BDrug B
Effect =Effect = Maximal effect • [Drug]Maximal effect • [Drug]KKDD + [Drug] + [Drug]
Drug InteractionsDrug Interactions
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% of % of Maximal Maximal
EffectEffect
[Drug][Drug]
AgonistAgonist
Agonist + competitive Agonist + competitive antagonistantagonist
Agonist + non-competitive Agonist + non-competitive antagonistantagonist
Classification of Drug interactions between 2 or more ligands
Describes the response when 2 or more drugs are combined:
Synergism: 1+2+3 > 3 Additive synergism: 1+2+3=6 Potenciation: a from of synergism but larger
response: 1+2+3 > 6
Pharmacodynamics– Toxicity• The undesirable effects associated with the given
therapeutic use of a drug– Exaggerations of direct effects» Example: progression from drowsiness to sedation to
hypnosis to death at increasing dosage levels of a CNS depressant
– Concurrent “side” effects» Example: an antihistamine, which is intended to
antagonize histamine action at H1-receptors may also bind to H3-receptors in the CNS and cause drowsiness
Pharmacodynamics
– Margin of safety• Median effectiveDose – ED50• Median ToxicDose – TD50• TherapeuticIndex TD50/ED50
General Principles of Pharmacology• Pharmacodynamics
– Margin of safety• 99% dose-response curve for theTherapeutic effectvs. Dose-responsecurve for a toxicor the lethal effect
Drug response Variation Idiosyncratic response: rare, due to genetic variation eg
allergic reaction (hypersensitivity), metabolic enzymes Refractory response: decreased sensitivity towards drug
stimulation due to prolonged use or continuous use. Reversible – desensitization , receptor down regulation
Drug resistance: eg antibiotics, antitumor agents Tolerance: Decrease organ response towards agonists
after prolonged exposure at the same dose, occurs within days/ weeks.
Tachyphylaxis is a medical term describing a rapidly decreasing response to a drug following administration of the initial doses.
Causes of response variation Alteration in concentration of drug that reaches the receptor; due
to pharmacokinetic variation ADME Variation in conc. of endogenous receptor ligand eg propranolol
effect on heart rate of athlete due to endogenous catecholamines level.
Alterations in number or function of receptors: due to increase/decrease in number of receptor sites or alteration of efficiency of receptor functioning (coupling). Eg withdrawal symptoms from agonist or tachyphylaxis/ tolerance.
Changes in components of response distal to receptor: eg physiologic adaptation by compensatory measure such as increase in sympathetic nervous tone and fluid retention by the kidney leads to tolerance to antihypertensive vasodilator drugs.
DOSE-EFFECT DOSE-EFFECT RELATIONSHIPRELATIONSHIP
The intensity and duration of a drug’s The intensity and duration of a drug’s effects are a function of the drug dose and effects are a function of the drug dose and
drug concentration at the effect sitedrug concentration at the effect site
Monitoring Dose-EffectMonitoring Dose-Effect LevelLevel
Molecular (e.g, enzyme inhibition)Molecular (e.g, enzyme inhibition) Cellular (Cellular (in vitroin vitro tissue culture, blood cells) tissue culture, blood cells) Tissue or organ (Tissue or organ (in vitroin vitro or or in vivoin vivo)) OrganismOrganism
Endpoint used to measure effect may be Endpoint used to measure effect may be different at each leveldifferent at each level
Overall effect = sum of multiple drug effects Overall effect = sum of multiple drug effects and physiological response to drug effectsand physiological response to drug effects
Endpoints to Monitor Drug EffectEndpoints to Monitor Drug Effect
LLEVELEVEL EENDPOINTNDPOINT
MolecularMolecular Caspase inhibitionCaspase inhibition
CellularCellular Proliferation rate, apoptosisProliferation rate, apoptosis
TumorTumor Response (change in tumor size)Response (change in tumor size)
OrganismOrganism Survival, quality of lifeSurvival, quality of life
Farnesyltransferase Inhibitors for Cancer Farnesyltransferase Inhibitors for Cancer (Ras protein)(Ras protein)
Drug-Receptor InteractionsTheory and assumptions of drug-receptor interactions. Drug Receptor interaction follows simple mass-action
relationships, i.e. only one drug molecule occupies each receptor and binding is reversible (We know now there are some exceptions).
For a given drug the magnitude of the response is proportional to the fraction of total receptor sites occupied by drug molecules.
Combination or binding to receptor causes some event which leads to a response.
Response to a drug is graded or dose-dependent.
Law of Mass ActionWhen a drug (D) combines with a receptor (R), it does so at a rate which is dependent on the concentration of the drug and the concentration of the receptor.
D = drugR = receptorDR = drug-receptor complexk1 = rate for associationk2 = rate for dissociationKD = Dissociation ConstantKA = Affinity Constant
k1
[D] + [R] [DR] k2
k2 = KD = [D][R] k1 [DR]
1 = KA = k1 = [DR] KD k2 [D] [R]
Dose-Effect EndpointsDose-Effect Endpoints
GradedGraded
QuantalQuantal
•• Continuous scale (Continuous scale (dose dose effect)effect)•• Measured in a single biologic unitMeasured in a single biologic unit
•• Relates dose to intensity of effectRelates dose to intensity of effect
•• All-or-none pharmacologic effectAll-or-none pharmacologic effect
•• Population studiesPopulation studies
•• Relates dose to frequency of effectRelates dose to frequency of effect
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Erythropoietin and Erythropoietin and AnemiaAnemia
Erythropoietin Dose [units/kg]Erythropoietin Dose [units/kg]
Peak Peak Hematocrit Hematocrit Increment Increment
[%][%]
Eschbach et al. NEJM 316:73-8, 1987Eschbach et al. NEJM 316:73-8, 1987
Drug-Receptor Drug-Receptor InteractionsInteractions
kk11
kk22
DrugDrug
ReceptorReceptorEffectEffect
Drug-Drug-Receptor Receptor ComplexComplex
Effect =Effect = Maximal effect • [Drug]Maximal effect • [Drug]KKDD + [Drug] + [Drug]
(K(KDD = k = k22/k/k11))
Ligand-binding Ligand-binding domain domain
Effector domain Effector domain
Effect =Effect = [Drug][Drug]KKDD + [Drug] + [Drug]Maximal effectMaximal effect [Drug][Drug]KKDD + [Drug] + [Drug]
Dose-Effect RelationshipDose-Effect Relationship
Effect =Effect = Maximal effect • [Drug]Maximal effect • [Drug]KKDD + [Drug] + [Drug]
Effect =Effect = Maximal effectMaximal effect if [Dose] >> Kif [Dose] >> KDD
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Graded Dose-Effect CurveGraded Dose-Effect Curve
% of % of Maximal Maximal
EffectEffect
[Drug][Drug]ECEC5050
Maximal effectMaximal effect
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Log Dose-Effect CurveLog Dose-Effect Curve
% of % of Maximal Maximal
EffectEffect
[Drug][Drug]
ECEC5050
Application the two curves
Gives critical information in making therapeutic decision
Both curves provides info regarding potency and selectivity of drugs
Graded dose response curve indicates maximal efficacy of drug
Quantal dose-effect curve indicates the potential variablity of responsiveness among individuals
Decisions:* Adapted from Pharmaceutical Executive, January 2000, page 80
PHARMACEUTICAL PRODUCT LIFE CYCLE
Pre-clinical D
evelopment
LeadO
ptimizatio
n
LeadIdentificatio
n
Scale up &
Launch
Post M
arketing
Clinical
Developm
ent
RegulatoryR
eview
PatentExpiration
TRADITIONAL CLINICAL PHASES
• PHASE 1 Healthy Subjects*pharmacology, potency, pharmacokinetic parameters, side-effects
• PHASE 2 Subjects w/ illnessTherapeutic? small group, dose determination for phase 3
• PHASE 3 Pivotal studies in patientsCompare btw test and std drug on larger scale at random
• PHASE 4 Market expansion & surveillanceEfficacy study and side-effects after sales
* Patients used for antineoplastic and anti-HIV drugs.
PHASES OF DRUG DEVELOPMENT