3 - Mechanisms of Drug Action Flashcards
What are the 4 overall types of drug antagonism?
Receptor Blockade
Physiological Antagonism
Chemical Antagonism
Pharmacokinetic Antagonism
What is ‘use dependency’?
More a cell/tissue is used that drug is acting on, more rapid/effective drug work because site is in ion channel
Explain the Receptor Blockade form of drug antagonism
- can be competitive or irreversible
COMPETITIVE
- same site as agonist
- shifts Dose-Response curve to the right
- can be overcome by high levels of agonist
- e.g. atropine is a competitive muscarinic co-receptor antagonist
- e.g. propanolol is a Beta 1 and 2 blocker
IRREVERSIBLE
- binds tightly via covalent bonds or to a site different to the active site of the receptor
- no displacement by the agonist
- may bind to the allosteric site
- insurmountable
- e.g. hexamethonium
Explain the Physiological Antagonism form of drug antagonism
different receptors can have opposite effects in the same tissue
co-administration
Vascular tissue: NA acts on adrenoreceptors to cause vasoconstriction.
Histamine acts on H1 receptors to cause dilation.
Explain the Chemical Antagonism form of drug antagonism
- interaction of drugs in solution
- e.g. heavy lead poisoning, demercapol binds with lead, stops effects of lead and makes it more easily excreted
- chelating agent
Explain the Pharmacokinetic Antagonism form of drug antagonism
- decreases concentration of active drug at action site
- can do it in a number of different ways which are reduce absorption, increase metabolism or increase excretion
- e.g. barbiturates, drugs of abuse, used in epilepsy they are enzyme inducers, they can up-regulate liver enzymes that metabolise barbiturates. Therefore, if you then give another drug which is also metabolised by that some group of enzymes, it may be metabolised quicker than expected. Accidental antagonism of the second drug (such as warfarin).
What are the 5 overall ways Drug Intolerance can occur?
- Pharmacokinetic Factors
- Loss of Receptors
- Change in Receptors
- Exhaustion of Mediator Stores
- Physiological Adaptation
How can receptors be up-regulated?
Receptors can be up-regulated if a cell is under-stimulated.
- e.g. denervation supersensitivity in nicotinic skeletal muscle damage where sensory fibres are damaged.
Give an example of a drug type to which tolerance can be built
Benzodiazepines
- with increased use, they decrease in usefulness
- therefore, they are not used to treat epilepsy long-term
How can Pharmacokinetic Factors cause drug tolerance?
- increased use of drug
- causes increased metabolism
- eg. barbiturates
- eg. drink more alcohol, enzymes upregulated, higher tolerance to alcohol, metabolised faster
How can Loss of Receptors cause drug tolerance?
- occurs by membrane endocytosis
- if cell is over-stimulated, the receptors are pinched off in vesicles into the cell
- receptor down- regulation
- Beta-Adrenoreceptors are very susceptible to this
How can Change in Receptors cause drug tolerance?
- receptor desensitisation
- overstimulated so receptors switch off
- conformational change
- e.g. nACHR at NMJ
How can Exhaustion of Mediator Stores cause drug tolerance?
e.g. amphetamine is a stimulant
- passes into the brain rapidly
- acts on NA synapses
- uptake 1 system
- taken up instead of NA
- causes NA leaking out into synaptic cleft in brain
- increases local activity
- response decreases due to repeat use because NA stores get depleted
How can Physiological Adaptation cause drug tolerance?
- related to homeostatic responses e.g. blood pressure
- tolerance to drug side effects whilst keeping the therapeutic effects
What factors are the differences between receptor families based on?
- Molecular structure
- Signal transduction system
What are the 4 overall types of drug receptor?
Type 1 = Ion Channel-Linked (Inotropic)
Type 2= G-Protein-Coupled
Type 3= Kinase-Linked
Type 4= Intracellular Steroid Type
What is the physical structure of Type 1 Receptors?
- number of different subunits (usually 4 or 5)
- extracellular domain of the protein where agonist binds
- transmembrane segments (TMs)
- 4 TM segments in each subunit, so about 16-20 in whole receptor
- individual alpha helices form lining of the ion channel
What is the physical structure of Type 2 Receptors?
- no subunits - 7 TM segments
- the 7 TM segments vary structurally from receptor to receptor
- agonist binding activates G-protein binding loop of receptor
What is the physical structure of Type 3 Receptors?
- only 1 TM receptor
- big extracellular binding domain
- agonist binding activates intracellular domain which is catalytic
- intracellular domain is often tyrosine kinase
- results in phosphorylation of intracellular proteins
What is the physical structure of Type 4 Receptors?
- agonist binds to binding domain
- unravelling of zinc fingers (DNA binding domain)
- zinc finger = amino acid sequence with zinc atom associated
- receptor grips onto DNA
- changes transcription of DNA
