Pharmacodynamics:
Pharmacodynamics refers that what the drug does to the body. In other words, drug binds to receptors and show their action by producing similar physiological signal molecules.
Principle of drug action:
- Stimulation
- Depression
- Irritation
- Replacement
- Cytotoxic action
Mechanism of drug action:
- Enzymes:
Enzymes are very important target for drug action. Drug can either increase or decrease the enzymatic response or enzymatically mediated reaction. Some of the enzymes are activated by receptors and primary or secondary messengers.
Example:
Adrenaline (Neurotransmitter) bind on the adrenergic receptor that present on heart muscle. After then in response, G-protein (Gs) stimulates the cell membrane bound enzymes adenylyl cyclase converting ATP into cAMP which action to cause contraction of heart muscle.
Ion-channel:
Ion-channel are proteins that helps in allows to move ions in or out of the cell. Ion-channels have specificity for the specific ions to move in or out of the cell.
Example:
Sodium ion-channel allows to move sodium ions from outside to inside of the cell, results in depolarization of the neuron cells.
Transporters:
Transporters are the proteins that act as a carrier proteins. By transporters mechanism, drugs are translocated across the cell membrane by binding with it.
Example:
Receptor:
It is defined as a macromolecules or binding site located on the surface of cell that recognize the signal molecule/ drug that bound with it and initiates response. All receptor have specificity for specific ligand/ molecule/ drug.
Example:
Acetylcholine only binds on Cholinergic receptor.
Epinephrine or Norepinephrine only binds on Adrenergic receptor.
Theories of Receptors:
Hypothesis of Clark:
Effectiveness of Drug effect is depends on the maximum receptors occupied by drugs.
Based on 'Law of mass action'.
Hypothesis of Ariens and Stephenson:
Effectiveness of drug effect depends as long as receptor occupied by the drugs means drug which has high affinity to specific receptor have longer effect or drug which has low affinity to specific receptor have lower effect.
Based on 'Occupational theory'.
Hypothesis of Paton:
Drug effect is doesn't depends on the receptors occupation, its depends on the proper stimulus given by the drug.
Based on 'Rate theory'.
Hypothesis of Emil Fischer:
It is Lock and key hypothesis theory, drug fitted into a domain of receptor just like key fitted into a lock.
Based on 'Intrinsic activity'.
Transducer mechanism:
It is a complex multistep processes that provide for the amplification of the signal, integrating signal received from extracellular to intracellular at each steps.
By which a cell is able to produce a response.
Divided into four categories:
1. G-protein coupled receptor (GPCR)
2. Ion-channel receptor
3. Transmembrane enzyme-linked receptor
4. Transmembrane JAK-STAT binding receptor
G-protein coupled receptor:
It is a 7 alpha-helical transmembrane spanning hydrophobic amino acid segment that present on a cell membrane which has three extracellular loops and three intracellular loops.
Binding site for ligand/drug somewhere on helical and intracellular recognition site bound to coupling G-protein which has alpha and beta-gamma subunits where alpha subunit bound to GDP in an inactivate state.
Mechanism when ligand/drug binds to GPCR:
Step1- When ligand/drug binds to receptor then it cause alpha subunit of G-protein which bound to GDP that converted into GTP.
Step2- Alpha subunit of G-protein activated after bounds to GTP and start detachment from beta-gamma subunit and and interact with a target site to show their effect.
Step3- After effect GTP bound alpha subunit G-protein hydrolysis to form GDP bound G-protein by the action of GTPase enzyme.
Step4- Formation of GDP bound alpha subunit start reunites with beta-gamma subunit.
Numbers of alpha subunit of G-protein distinguishes:
Gs - Adenylyl cyclase activation - cAMP pathway - Ca2+
Gi - Adenylyl cyclase inhibition
Gq - Phospholipase C - IP3-DAG pathway
Major pathway through GPCR:
Adenylyl cyclase - cAMP pathway:
When ligand/drug binds to receptor then it cause alpha subunit of G-protein which bound to GDP that converted into GTP. Alpha subunit of G-protein activated after bounds to GTP and start detachment from beta-gamma subunit and and interact with a target site adenylyl cyclase (primary messenger), Adenylyl cyclase activates cAMP form ATP. cAMP activates protein kinase A which activates troponin, phospholamban, activates endoplasmic recticulum that cause moblization of calcum ions and activates calcium ion channels which allow calcium ions inside the cell where troponin binds with calcium ion cause contraction of muscle. After contraction muscle wants to relax then phosphlamban cause to sequestering of calcium ions in sarcoplasmic recticulum.
Phospholipase C - IP3-DAG pathway:
When ligand/drug binds to receptor then it cause alpha subunit of G-protein which bound to GDP that converted into GTP. Alpha subunit of G-protein activated after bounds to GTP and start detachment from beta-gamma subunit and and interact with a target site phospholipase C (primary messenger).
Phospholipase C converts PIP2 into DAG and IP3.
DAG activates protein kinase C which further function and IP3 cause moblization of Calcium ions from endoplasmic or sarcoplasmic recticulum. Calcium ion interact with calmodullil (CAM) and activates MLCK to cause contraction.
CHANNEL REGULATION :
Channel regulation generally work through beta-gamma dimer of G-protein which dissociates the functioning of other G-proteins (like Gs, Gi, Go) to maintain the physiological functioning of cells.
ION CHANNEL RECEPTORS :
Receptors are present on cell surface act as ion channels. These receptors are called ligand gated ion channels. When ligand binds to receptors which opens the channel of specific ions such as sodium ions, potassium ions, Calcium ions or chloride ions.
Examples:
GABA-A receptors -> GABA - Chloride ion channel complex
TRANSMEMBRANE JAK-STAT BINDING RECEPTORS:
These type of receptors have no intracellular catalytic domain. Extracellular ligand cause dimerization and activates the intracellular domain for binding to free moving JAK (Janus kinase) molecule. Then activated JAK phosphorylates the tyrosine residue on the intracellular site and allow to bind with another protein STAT (signal transducer and activator of transcription) and phosphorylates it also. Phosphorylated STAT dissociates from intracellular site and move to the nucleus to regulates transcription, results in biological response.
EXAMPLES:
Cytokines, hormones, prolactin act through this type of receptors.
TRANSMEMBRANE ENZYME LINKED RECEPTORS:
Receptors made up of large extracellular ligand binding domain connected through a single transmembrane helical peptide chain to intracellular site which have enzymatic action. The enzyme present is protein kinase which Phosphorylates tyrosine residue and allow to binds with substrate protein which have SH2 domain protein and Phosphorylated. Then release from intracellular site and produces response.
EXAMPLES:
Insulin, epidermal growth factor, nerve growth factor, etc.
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