Lecture 5 Flashcards
What is an important pre-requiste for proper drug action?
An important prerequisite for proper drug action is the non-uniform distribution of drugs within the body
Name and explain the 4 different levels which drugs act on
- Molecular - biomolecules as immediate targets of drugs
- Cellular - biochemical constituents in the process of transduction
- Tissue - alteration of organ function
- System - alteration of system function
What are most drug-receptor interactions mediated by?
- Most drug-receptor interactions are mediated by NON-COVALENT bonds, which are reversible
- In contrast to covalent bonds, there is no formation of a shared electron pair, but drugs attach to their site of action by multiple non-covalent contacts!
Drug-receptor interactions
- Highly stable ion-ion electrostatic attraction
- Partial charge dipole-ion electrostatic attraction
- Partial charge dipole-dipole electrostatic attraction
- Low strength van de Waals’ electrostatic attraction between apolar groups
- Hydrophobic interactions of apolar molecules in an aqueous environment
How do most drug molecules produce their effects?
Most drug molecules produce their effects by binding to protein domains.
Name the four major groups of regulatory proteins involved as primary drug targets
- Receptors
- Ion channels
- Enzymes
- Carrier
look at slide 12
What does it mean when the specificity of drug action is reciprocal?
- Individual classes of drugs bind only to certain molecular and cellular targets.
- Individual molecular and cellular targets recognize only certain classes of drugs.
What does it mean when the specificity of drug action is dose-dependent?
- specificity of drug action is usually strictly dose-dependent
Increasing the dose of drug (above its therapeutic range) will often affect molecular targets other than the principal pharmacological one, thus causing toxic side-effects.
Name examples of receptors (target) and its agonist (effector)
Nicotinic acetylcholine receptor - Nicotine
Beta-adrenoreceptor - Isoprenaline
Name examples of ion channels (target) and its modulator (effector)
- Voltage-dep. Na+-channel - Lidocaine
- Voltage-dep. Ca2+-channel - Nifedipine
Examples of Enzymes (receptor) and its inhibitor (effector)
- Acetylcholinesterase - Neostigmine
- Cyclooxygenase - Aspirin
Examples of carriers (target) and inhibitor (effectors)
- Choline carrier - Hemicholinium
- Na+/K+ pump - Ouabain
Agonist
Drug - that binds and activates its respective receptor
Drug D1 (agonist) D1 + R -> D1-R -> D1-R * -> Response
Affinity
Tendency of a drug to bind to a receptor.
Receptor occupation by drug is governed by affinity.
Efficacy
Tendency of a drug, once bound, to activate the receptor. Receptor activation by bound drug is governed by efficacy.
Antagonist
Drug that binds to receptor without triggering activation, thus preventing binding of agonist/physiological ligand.
Drug D2 (antagonist) D2 + R -> D2-R -> No Response
Maximal pharmacological response
The maximal response on a particular receptor differs between chemically related agonists
Maximal pharmacological Response
The maximal response on a particular receptor differs between chemically related agonists
Maximal response
- The largest response that a tissue is capable of giving, if triggered by a specific substance at high concentration.
- Due to toxic side effects, the therapeutic dose might be considerably lower than the maximal response dose.
Full agonist
A drug that can produce a maximal response
Partial agonist
A drug that can only trigger a sub-maximal response
When might a partial agonist act as a full agonist?
- if a tissue contains a so-called ‘receptor reserve’ (due to poor intrinsic efficacy), then an otherwise partial agonist may act as a full agonist.
- poor efficacy may be offset by activating a larger number of receptors, as would be required by a proper full agonist.
intrinsic efficacy = refers to the ability of a drug to produce a maximal biological response at a given receptor or target site
Competitive Antagonist
- Substance that has no intrinsic efficacy and binds reversibly with receptor.
- Pharmacologically it dilutes the receptor concentration, causing a parallel shift of the dose-response curve.
- Importantly, an increase of agonist dose can return tissue response to normal.
Irreversible antagonist
- Substance that triggers a blocking effect that cannot be reversed by increasing the agonist concentratoin
Nicotinic acetylcholine receptor
- Prototype of a ligand-gated ion channel of pharmacological importance
- Part of a superfamily of neutrotransmitter-gated ion channels
- 16 different cDNAs have been cloned from different species
Competitive antagonst of nicotinic acetylcholine receptor
Tubocurarine
-Drug competes with native ligand, the neurotransmitter acetylcholine, for the receptor
-But drug does not initiate a biological response (nAChR ion channel opening)
What are the 16 different types of cDNA that have been cloned from different species?
- α-subunits 1 to 9
- β-subunits 1 to 4
- δ-subunits
- γ-subunits
- ε-subunits
What are the three main branches of nAChr gene family?
- Muscle nAChRs (NMJ)
- Heteromeric neuronal nAChRs
- Homomeric neuronal nAChRs
Agonist of Nicotinic acetylcholine receptor
Suxamethonium
-Agonistic drug depolarizes the neuromuscular junction
-But does not dissociate rapidly from the nAChR complex causing a neuromuscular block
Molecular approaches used in the structural analysis of pharmacologically important protein receptors
- Protein purification and characterization
- Affinity purification and characterization
- Protein/peptide N-terminal sequence analysis
- Mass spectrometric analysis of protein subunits
- Cloning and sequencing of cDNA
- High-resolution x-ray crystallography
- High-resolution cryo-electron microscopy
- Differential co-immuno precipitation methodology
- Chemical cross-linking analysis
- Native two-dimensional gel electrophoresis
- Gel filtration analysis
