Pharmcodynamics Flashcards
What is pharmacodynamics?
Drug action on the body: MECHANISM OF ACTION
Biochemical and physiological effects.
Correlation of actions and effects with drug chemical structure, also such effects on the actions of a particular drug or drugs.
Site and mechanism of action.
A certain plasma drug concentration is necessary for the desired level of response. Pharmacokinetic factors determine peak concentrations.
Drugs have desirable (therapeutic) and undesirable (adverse or toxic) effects.
What is Receptor theory
Most drugs act as ligands which bind to receptors which regulate cellular effects (coupling).
Receptors determine the quantitative relationship between drug dose and pharmacological effect.
Receptors are responsible for the selectivity of drug action.
Conformational shape of receptor/molecular targets
3-dimensional proteins, determined by 10, 20, 30 and 40 structure, determined by aa sequence. Hydrophobic portions on inside, hydrophilic portions outside.
Drugs bind to unique 3-D active sites, which determine selectivity.
Note: Rational drug design.
Multiple drug-receptor interactions include covalent bonds, Van der Waals forces, hydrogen bonds, ionic interactions.
Mostly weak reversible interactions.
Conformational shape of receptor/molecular targets
Induced-fit model of drug-receptor interaction.
Drug-receptor interaction induces conformational change in receptor to enhance affinity.
Active site
Complementarity of active site and drug determines affinity. Note: stereo-selectivity
Drugs (inhibitors or blockers) could bind to the active site, or other sites (allosteric) that prevents conformational change.
Chiral molecules
Receptor sites on protein
Receptors exist in multiple states: inactive (closed), active (open) or desensitized (refractory or inactivated).
(a) Molecule fits receptor site, leading to a response
(b) Molecule does not fit receptor site; no response
Drugs may bind to receptor in state-dependent
What is the drug selectivity
The more restricted the cell-type distribution of the receptor targeted by a particular drug, the more selective the drug is likely to be. Eg. Imatinab (tyrosine kinase inhibitor - anticancer drug) targets BCR-ABL tyrosine
kinase protein found only in chronic myeloid leukemia cancer cells.
The more receptor-effector coupling mechanism differ among various cell types that express a particular molecular target for a drug, the more selective the drug is likely to be. Eg. Cat+ channel blockers selectively block pacemakers cells more than ventricular cells.
What are the Receptor Types
Transmembrane ligand-gated & voltage-gated ION CHANNELS
Transmembrane G protein-coupled receptors
Transmembrane enzyme-linked receptors (tyrosine kinases, tyrosine phosphatases, tyrosine-associated, serine/threonine kinases)
Intracellular receptors, including enzymes, transcription regulators, and structural proteins
Extracellular proteins
Cell surface adhesion receptor
Four major receptor types
1) Agonist Na > Activation of condunctance)
2) Agonist G protein> Generation of second message> activation of cell signaling
3) Agonist - Phosphorylation of tyrosines on key signaling molecules- action of cell signaling
4) agonist transport of the nucleus- activation of transcription and translation
Ion channel receptors
Signal molecule binds as a ligand at a specific site on
the receptor Conformational changes open the channel allowing ions to
flow into the cell The change in jon concentration within the cell triggers cellular
responses.
Highly selective for ions they conduct
Functions and mechanisms
Functions:
•Neurotransmission
•Cardiac conduction
•Muscle contraction
•Secretion
Mechanisms:
•Ligand-gated
•Voltage-gated
•controlled by membrane potential
•Second messenger-regulated
The nicotinic receptor at the NMJ
Contains 5 subunit’s surrounding the Na channel. ACh binds to two alpha subunits; binding of ACh results in opening of the Na channel for 1 ms.
What is G protein coupled receptors
Most common- Serpentine
Activation of G proteins causes GDP to be displaced by GTP
Activation of 2nd messager systems
Adenylyl cyclase activation eg beta adrenoceptors
Phospholipase c activation eg alpha adrenoceptors
Major G proteins and actions
•G-stimulatory (Gs): Activates Ca2+ channels, activates adenylyl cyclase
•G-inhibitory (Gi): Activates K+ channels, inhibits adenylyl cyclase
•Gq: Activates phospholipase C
•G12/13: Diverse ion transporter interactions
G protein-coupled receptors
Chemical signal binds as a ligand to a G protein- linked receptor, it then changes its shape and interacts with the G protein
Interaction causes GDP to be displaced and GTP to be bound to the G protein
The active G protein binds to another protein known as an enzyme
The enzyme is activated
G protein hydrolyzes GTP back to GDP
G protein releases from the enzyme and the rxn stops
What is adenylyl cyclase activation
Phospholipase C activation
Signal transduction coupling
