Mechanisms of drug action Flashcards
List the 4 types of drug antagonism
1) Receptor blockade
2) Physiological antagonism
3) Chemical antagonism
4) Pharmacokinetic antagonism
Why do we need to be careful when co-administering drugs
Co-administering drugs can diminish the response of another drug- so we may need to change doses or look for different classes- to select ones that don’t interact.
Summarise receptor blockade
§ Two forms of this (explained above) – competitive and irreversible.
§ Receptor blockade can also display “Use-dependency” of ion channel blockers, i.e. Local anaesthetic.
i. Use-Dependency = The more the cell is active/used, the faster the block is absorbed and blocks the ion channels.
Explain how receptor blockade works
Non-competitive antagonism describes the situation where the antagonist blocks at some point downstream from the agonist binding site on the receptor, and interrupts the chain of events that leads to the production of a response by the agonist.
Describe the effects of receptor blockade
The effect will be to reduce the slope and maximum of the agonist log concentration-response curve, although it is quite possible for some degree of rightward shift to occur too.
Give some examples of drugs that use the receptor blockade
Ketamine enters the ion channel pore of the NMDA receptor blocking it, thus preventing ion flux through the channels.
Drugs such as verapamil and nifedipine prevent the influx of Ca2+ through the cell membrane and thus non-selectively block the contraction of smooth muscle produced drugs acting at any receptor that couples to these calcium channels.
Explain use dependency
If the tissue is more active, a certain drug ( such as an ion channel blocker) will act more completely and faster because if the tissue is more active- more of the ion channels will be open- allowing the drug to get into the ion channel and block it.
Relate use dependency to local anaesthetics
The alpha, delta and C nociceptive neurones are firing rapidly (lots of action potentials generated when soft tissue is damaged to relay pain). Therefore local anaesthetics act preferentially on these neurones compared to other types of neurones (showing selectivity to the pain neurones).
Summarise physiological antagonism
§ Drugs that counters the effect of another substance by acting on different receptors.
i. I.E. If the body has too much NA and thus too much vasoconstriction, histamine can be delivered to counter the vasoconstriction (by acting on H1 receptors instead of adrenergic receptors)
Different receptors opposite effects in same tissue
e.g. NA + histamine on B.P
NA acts on alpha reeptors to constrict blood vessels and raise BP
Histamine acts on H1 receptor to cause vasodilation and decrease BP
Explain physiological antagonism- giving examples
Physiological antagonism is a term used loosely to describe the interaction of two drugs where opposing actions in the body tend to cancel each other. For example, histamine acts on receptors of the parietal cells of the gastric mucosa to stimulate acid secretion.
While omeprazole blocks this effect by inhibiting the proton pump; the two drugs can be said to act as physiological antagonists.
Summarise chemical antagonism
§ Drugs that interacts in solution to antagonise a reaction (as opposed to binding to specific receptors).
i. I.E. If people have heavy metal poisoning, you give dimercaprol (chelating agent) to bind the heavy metal and form non-toxic clumps which can be excreted (before they get absorbed).
Explain chemical antagonism
It refers to the uncommon situation where the two substances combine in solution; as a result the effect of the active drug is lost.
Examples include the use of chelating agents (dimercaprol) that bind to heavy metals (Pb2+) and reduce their toxicity, and the use of the neutralising antibody infliximab, which has an anti-inflammatory action due to its ability to sequester the inflammatory cytokine TNF.
Summarise pharmacokinetic antagonism
§ Drugs (agonists) that are administered, are antagonised by the body itself that reduces the concentration of the active drug at the site of action.
i. I.E. reduced absorption, blocked distribution, increased metabolism, increased excretion.
Explain pharmacokinetic antagonism
Pharmacokinetic antagonism describes the situation in which the ‘antagonist’ effectively reduces the concentration of the active drug at its site of action. This can happen in various ways:
The rate of metabolic degradation of the active drug may be increased (e.g the reduction of the anticoagulant effect of warfarin when an agent that accelerates its hepatic metabolism, such as phenytoin is given)
Alternatively, the rate of absorption from the G.I tract ma be reduced, or the rate of renal excretion may be increased.
Describe the use of barbiturates
Use to treat epilepsy, and are used in surgery and in general anaesthesia
Explain the clinical importance of barbiturates
When used over a long period of time, they are enzyme inducers. This means that they increase the expression of enzymes that metabolise barbiturates in the liver. Warfarin (and also TCAs) are metabolised by the same system of enzymes. This results in warfarin being metabolised more quickly and thus a higher dose is needed to produce the intended effect ( blood clotting time can be measures by analysing a drop of blood from the thumb- this is called the prothrombin time test
What is meant by drug tolerance
This is the gradual decrease in responsiveness to a drug with repeated administration (occurs over days or weeks)
Describe the issue of tolerance with benzodiazepines
Anti-convulsant and anti-anxiolytic drugs- but lose their effectiveness over time
List the 4 methods of drug tolerance
Pharmacokinetic factors Loss of receptors Change in receptors Exhaustion of mediator stores Physiological adaptation
How do pharmacokinetic factors lead to tolerance
§ Due to an increased rate of metabolism.
i. E.G. Barbiturates, alcohol.
Explain how pharmacokinetic factors lead to tolerance
Tolerance to some drugs, for example barbiturates and ethanol, occurs partly because repeated administration of the same dose produces a progressively lower plasma concentration, as a result of increased plasma concentration (increased expression of the enzymes that metabolise them i.e the cytochrome P450 enzymes for barbiturates)
The degree of tolerance that results is generally modest, and in both of these examples other mechanisms contribute to the substantial tolerance that occurs.
However, the pronounced tolerance to nitrovasodilators results mainly from decreased metabolism, which reduces the release of the active mediator, nitric oxide.
Summarise loss of receptors as a cause of tolerance
- Loss of receptors; (N.B. There can also be receptor “up-regulation” – Denervation supersensitivity)
§ Due to membrane endocytosis of receptors (through receptor “down-regulation”).
i. E.G. beta-adrenoceptors.
Explain why we see a loss of receptors
Prolonged exposure to agonists often results in a gradual decrease in the number of receptors expressed on the cell surface, as a result of internalisation of receptors. This is seen for beta adrenorecdeptors and is slower than the uncoupling process seen in the change of receptors. Similar changes have been described for other types of receptor, including those for various peptides. The internalised receptors are taken into the cell by endocytosis of patches of the membrane, a process that normally depends on receptor phosphorylation and the subsequent binding or arrestin proteins to the phosphorylated receptor.
This type of adaptation is common for hormone receptors and has obvious relevance to the effects produced when drugs are used for extended periods. It is generally an unwanted complication when agonist drugs are used clinically.
Describe receptor upregulation in denervation super sensitivity
Soft tissue damage can damage the afferent alpha motor neurones to the skeletal muscle- resulting in a loss of input. The skeletal muscle responds to this by increasing the expression of receptors on the pain fibres to amplify the incoming signal to maintain its normal output- receptor expression is fluid.
