AIMS AND OBJECTIVESPharmacodynamics can be defined as thestudy of the pharmacological effects of drugsand their mechanism of action.The objectives of the analysis of drug actionare to understand the interactions betweendrug and target cells, and to characterize thefull sequence and scope of action of eachdrug.
Such a complete analysis provides thebasis for both the rational therapeuticuse of a drug, and the development ofnew and better therapeutic agents.
RECEPTORSSpecialized target macromoleculespresent on the CELL SURFACE orINTRACELLULARLY.
They are the specific molecules in abiological system with which drugsinteract to produce changes in thefunction of the system.RECEPTORS
Among the most important drugreceptors are the cellular proteinswhose normal function is to act asreceptors for endogenous regulatoryligands i.e. Hormones,Neurotransmitters.RECEPTORS
Two functional domains with in the receptors:1. Ligand binding domain2. Effector domainDrug + Receptor Drug ReceptorComplex↓Biological EffectRECEPTORS
1. LIGAND GATED IONCHANNELSThe ligand gated trans membrane ionchannels that are responsible for theregulation of flow of ions across cellmembrane.Changes in membrane potential or ionconcentration with-in cell → Effects
2. G-PROTEIN COUPLEDRECEPTORSBinding of the ligand to extra cellularsurface of the trans membrane receptoractivates Gs protein.The α sub unit of Gs protein dissociatesand activates ADENYLYL CYCLASE.
This results in the production ofcAMP, the second messenger, thatregulates protein phosphorylationand produces biological activity.2. G-PROTEIN COUPLEDRECEPTORS
3. ENZYME LINKEDRECEPTORS The receptor has two hetrodimers eachcontaining an α subunit and a ßsubunit. α subunit is extra cellular andconstitutes the recognition site. ß subunit spans the membrane andcontains a Tysosine kinase.
When insulin binds to the α subunit,Tyrosine Kinase activity in the ß subunitis stimulated. This causes phosphorylation (activation)of IRS. This phosphorylation triggers differentactions of insulin.IRS: Insulin receptor substrate (1-6)3. ENZYME LINKEDRECEPTORS
Though α ß dimeric form is capable ofbinding insulin, it has lower affinity thanα α ß ß tetrameric form.3. ENZYME LINKEDRECEPTORS
4. INTRA CELLULARRECEPTORThe receptor is entirely intra cellular.The ligand (lipid soluble) crosses thecell membrane and combines with thereceptor.
The activated receptor then enters thenucleus where it binds to specific DNAsequences → Effects.The response is obtained after about 30minutes and the duration of the response(hours to days) is much greater than thatof other receptor families.4. INTRA CELLULARRECEPTOR
DRUGS WHICH ACTINDEPENDETLY OFRECEPTORS• ANTACIDS• CHELATING AGENTS• OSMOTICALLY ACTIVE DRUGSDiuretics (Mannitol)Cathartics (Methyl Cellulose)• VOLATILE GENERAL ANAESTHETICS
OTHER CLASSES OFPROTEINS THAT HAVE BEENCLEARLY IDENTIFIED ASRECEPTORS1. ENZYMESDrugs inhibit the enzymes andproduce effects.Dihydrofolate reductase is thereceptor for METHOTREXATE
2. TRANSPORT PROTEINSNa+/ K+ATPaseThe membrane receptor forcardioactive Digitalis Glycosides.OTHER CLASSES OFPROTEINS THAT HAVE BEENCLEARLY IDENTIFIED ASRECEPTORS
3. STRUCTURAL PROTEINSTubulin: The receptor forCholchicine, a drug used in thetreatment of GOUT.OTHER CLASSES OFPROTEINS THAT HAVE BEENCLEARLY IDENTIFIED ASRECEPTORS
AGONISTDRUGS RECEPTORSPhenylephrineHistamineAcetylcholineMorphineα1H1, H2M, NOpioidA drug which activates the receptors andelicits maximum response
ANTAGONISTA drug which occupies the receptors, butinstead of activation the receptors areblockedDRUGS RECEPTORSAtropinePrazosinDimetaneRanitidineNaloxoneMα1H1H2OPIOIDAgonists as drugs; Antagonists as drugs
PARTIAL AGONISTA partial agonist has EFFICACY greater thanzero, but less than the full agonist.Partial agonist: Elicits sub maximal responseFull agonist: Elicits maximal response
The tendency of a drug to bind to thereceptors is governed by its AFFINITY, butthe tendency for it to activate the receptors,after binding with the receptors, is denotedby its EFFICACY.PARTIAL AGONIST
A partial agonist will produce sub maximalresponse even if 100% of the receptors areoccupied. A partial agonist may act as an antagonistof the full agonist.PARTIAL AGONIST
Example:The beta blockers: Pindolol, Acebutololß1 andß2 receptors are partially activated, butare unable to respond to the agonistEpinephrine.PARTIAL AGONIST