Lecture 2; Mechanisms of action Flashcards
Whats the difference between drug and medicine?
Drug: chemical/substance that USUALLY used to treat a disease/condition
Medicine: is USED to treat a disease/condition
Describe the dose to effect and the main parameters involved:
Dose -> Concentration:
- Determined by pharmacokinetics
- CL (Clearance), Vd (Volume of distribution)
Concentration -> Effect
- Determined by Pharmacodynamics
- Emax, EC50
How are concentrations of medicines measured in a patient?
Plasma concentrations are measured
It would be more ideal to measure concentration at site of action as this would be a more realistic measure
What are the four primary targets of medicines?
- Ion channels
- Enzymes
- Carrier molecules
- Receptors
(Most medicines produce effect by binding to proteins and causing a conformational change)
What are the exceptions to the four primary targets of medicines?
- Cytokines and DNA
What are receptors?
Proteins which specifically recognise a particular neurotransmitter/hormone and upon binding undergo a conformation change leading to activation/inhibition of cell signalling
What are the four main families of receptor?
- Ligand gated ion channels
- G-protein coupled receptors
- tyrosine kinase/cytokine receptors
- Nuclear/steroid hormone receptors
(Increasing time to effect as you move down the list)
Define: Affinity, Efficacy, Agonist, Antagonist
Affinity: Attraction of a ligand (drug) for a receptor
Efficacy: (Intrinsic activity)
Agonists: Have affinity and efficacy (mimics endogenous compounds)
Antagonists: Have affinity but NO efficacy (prevents)
Describe 3 important properties of ligand gated ion channels, its timecourse and tertiary structure
- Fast signal transmission (ms)
- All multi-subunit complexes
3 imp properties:
- Activated in response to specific ligands
- Conduct ions through otherwise impermeable cell membranes
- Select among different ions
Describe the function structure of the nicotinic ACh ion channel:
- Five TM2 helices are sharply kinked inwards halfway through the membrane forming a constriction
- TM2 helices are believed to snap to attention when ACh binds, opneing the channel
Give some medicine examples of GABA(a) ion channels as targets:
Benzodiazapines i.e valium (agonist) and barbituates i.e flumazenil (antagonist)
GABA (a) binds to the ion channel, confirmation change and Cl flows in and hyperpolarises the neuron
How do g protein coupled receptors work?
Ligand binds g-Protein, activating it and causing it to rise intracellular messangers i.e cAMP, IP3 etc and these impact the nucelus
How do g-protein couples receptors work? what are some drugs that target these?
inc. cAMP and PKA etc etc
B-adrenoreceptors i.e propranolol
Adenosine receptors i.e caffeine, theophylline
How do tyrosine kinase receptors work?
Receptor functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins
Mediates the actions of growth factors, cytokines and certain hormones i.e insulin
Whats an example of a tyrosine kinase receptor?
VEGFR2
- Ligand stimulated receptor dimerisation and autophosphorylation, triggers pathway
- Activaiton serves to promote endothelial health
What are some protein kinase inhibitors and what do they do? (tyrosine kinase receptors)
- Trastuzumab is used in those with HER-2 genes (Which upregulate EGF), to prevent enhanced VEGFR activation
More specific than traditional cancer drugs
Where are nuclear/steroid hormone receptors?
Receptor in cytoplasm of cell, thus ligand must be able to cross membrane i.e lipid soluble
How do drugs bind to receptors? and whats the implications of binding strength?
- Van der waals forces (Weak forces)
- H bonding (stronger)
- Ionic interactions (stronger than H bonds)
- Covalent (essentially irreversible)
(These stronger binding means the receptors are generally recycled every 7 days, may or may not be recycled)
How does affinity and drug concentration relate?
The higher the affinity of the drug for the receptor, the lower the concentration at which it procuces a given effect.
What is Emax and EC50?
Emax = Concentration to produce maximum effect
EC50 = Concentration to produce 50% effect
What is dose vs concentration?
Dose is the actual amount of medicine administered
Concentration is what that dose produces in the body
What is potency?
How left shifted the EC50 is, i.e how little concentration to produce the 50% effect. (more potent = lower EC50)
EC50 is used to measure the potency of an agonist.
What demonstrates potency, EC50 and EMax?
Dose response curves
Are concentration response curves good for describing affinity?
No, receptor response and response is not strictly proportional
- Considerable amplification could occur i.e low recept. occupancy for max response
- Many factors downstream might interact to produce maximal response
What is efficacy?
The ability of a drug to bind to a receptor and cause a change in the receptors action is termed efficacy and measured by Emax.
- drug with positive efficacy = will activate a receptor to promote a cellular response = Agonist
- drug with negative efficacy = will bind a receptor to decrease basal receptor activity = Inverse agonist
- A drug with no efficacy will bind to the receptors but have no effect on activity = Antagonist
Describe agonism:
Drugs that ellicit max tissue response are full agonists, drugs that produce less are partial agonists
- Full agonists can produce a graded response then!
NB: partial agonists cannot produce maximal response even at 100% receptor occupancy and therefore are less likely to trigger receptor plasticity.
What are the types of agonisms?
Full agonist
Partial agonist
Antagonist
NB: Inverse agonist (Bidirectional response)
What are antagonists?
- Compound that does not activate or inactivate the receptor
- Antagonists have affinity but NO efficacy
- Defined by how they bind to the receptor i.e reversible and irreversible competitive antagonism
What is a a reversible competitive antagonism? List 3 examples
- Bind in a reversible manner to the receptor to compete directly with the agonist binding
I.e Metoprolol, Naloxone, Losartan
What is irreversible competitive antagonism? List an example:
Drug covalently binds to the receptor. Not reversible. Reduces the number of receptors available to the agonist.
I.e Clopidogrel. (antiplatelet)
With an example, describe receptor terminology:
Adrenergic receptors (Family) Alpha or beta (Sub-family) A1 A2 B1 B2 (Subtype)
Why is selectivity for sub types important? give an example
- Preferential binding to a certain subtype leads to a greater effect at that subtype than others
i. e salbutamol at b2 (lungs) rather than b1 (heart)
Lack of selectivity can lead to unwanted drug effects i.e fenoterol
What are typical vs atypical anti-psychotics?
Typical: Dopamine antagonists i.e haloperidol (like zombies)
Atypical: Dopamine and 5HT antagonists i.e quetiapine (non-selective)
Discuss receptor plasticity:
- Receptor states and populations do not remain constant over time
- This plasticity is largely responsible for the changes that occur in effectiveness of chronic drug (or endogenous compound) over time
i. e tolerance, insulin resistance
I.e population dependent on drug exposure
Describe the regulation of receptors:
- Changes in receptor states i.e Desensitisation / exhaustion of mediators
- Change in receptor populations i.e Up or down regulation
Describe how desensitisation and internalisation of receptors occurs?
In some instances receptors are sensitised and then internalised / broken down and not replaced.
Depends on the external environment
What can happen with chronic salbumatol use?
Chronic agonist administration can lead to down regulation i.e
- Chronic salbutamol can cause internalisation of receptors -> less receptors available for stimulation -> Decreased broncodilation
Thus recommended daily limit b/c toxicity and receptor plasticity
What can chronic antagonist use lead to?
Chronic antagonist administration can lead to up regulation
- I.e chronic propranalol can increase synthesis of B1 receptors in the heart -> less antagonism -> Decreased drug effect (therapeutic failure) increasing HR and BP
Describe the time course rapid desensitisation:
Receptors that rapidly desensitise can rapidly resensitise
But this cant be distinguished from the response because it is too rapid
What are 3 clinically significant concerns of receptor desensitisation and examples:
Tolerence i.e morphine, salbutamol
Adverse effects i.e antipsychotics (D2 antagonists)
Therapeutics effects i.e tricyclic antidepressants
What are some non-protein receptor targets?
Non-protein receptor targets
- Enzymes (COX inhibitors)
- Carrier proteins (TCAs and SSRIs)
- Ion Channels (local anaesthetic)
Non-protein targets
- Soluble ligands i.e inflam mediators
- DNA
What are some examples of enzymes that are targeted by drugs and how?
- Cyclooxygenase and NSAIDS - used to treat pain and inflammation
- HMG CoA reductase and statins, used for lowering cholesterol
- Cholinesterase inhibitors i.e donepezil use for dementia b/c loss of ACh activity
Describe how NSAIDS work
NSAIDS inhibit cyclo-oxygenase that converts arachidonate to cylic endoperoxides this would eventuall lead to prostaglandin production that generates pain etc
What are the effects of cyclooxygenase inhibition?
NSADI inhibition of COX1 and COX2
- > Dec inflam
- > Dec pain
- > Dec fever
BUT ALSO
- Reduction of homeostatic pathways involved in:
- Kidney function (possible AKI) and maintenance of gastric mucosa (ulcers)
Whats the solution to avoiding the potential adverse effects of cyclooxygenase inhibitors?
COX2 selective inhibitors (Coxibs)
- Greater safety against GI side effects
- Increased risk of CV event though = strict regulation
Whats an example of a drug thats the enzyme HMG-CoA?
Statins i.e simvastatin
Decreases synthesis of cholesterol
Describe some drugs that interact with carrier proteins:
Drugs that interact wtih monoamine neurotransmitter uptake proteins:
- Fluoxtine (SSRI) (takes weeks, not conclusive as to why)
- SNRI i.e venlaflaxine
What are some drugs that act on ion channels?
Voltage gated ion channels
- Lignocaine (local anaesthetic)
- Ca channel blockers i.e verpamil and nifedipine
What are biopharmaceuticals?
Medicines of biological origin
What are some examples of biopharmaceuticals?
Peptides
Gene therapy
Cell therapy
Monoclonal ABs (bind targets and signal to immune system for destruction)
What are some examples of monocloncal antibodies:
Infliximab
Trastuzumab
Why are biologics used in asthma?
5% dont respond to traditional therapies
Target specific chemokines using AB based therapy
Can reduce need for corticosteroids
