Pharmacodynamics

Question 1

What mechanisms of action can a drug have?

NEEDS REVIEW - specifically last section

Answer 1

Physicochemical
Antacids
Neutralise stomach acid
Chelating agents
Sugammadex (Rocuronium)
Dicobalt edetate (Cyanide ions)
Osmotic diuretics
Mannitol

Ion channels
Inhibitors
Local anaesthetics
Anti-epileptics
Anti-arrhythmics
Allosteric modulators
GABA - Benzos/barbiturates

Receptors
Membrane receptors
G-protein couples
Tyrosine Kinase
Guanilyl cyclase
Intracellular receptors
Cytoplasmic (Steroid receptors)
Nuclear (Steroid receptors)

Enzyme interaction
Stimulants
Inhibitors
Reversible competitive (Naloxone for opioid)
Reversible non-competitive (Ketamine at NMDA)
Irreversible (Clopidogrel for platelets)

Question 2

Explain theories as to how inhaled general anaesthetic agents work.

Answer 2

Inhaled agents induce a loss of consciousness and response to painful stimuli in a reversible manner, with the site of action believed to be in the brain & spinal cord.

Meyer-Overton hypothesis describes relationship between lipid solubility & potency - the greater the solubility, the lower dose to induce deep anaesthesia, suggesting that any lipid soluble drug could induce anaesthesia as a result.

However this doesn’t explain how the S & R enantimers of etomidate are equally lipid soluble, but only R-etomidate induces anaesthesia.

A subsequent theory involved the highly lipid-soluble drugs infiltrating the phospholipid bilayer & increasing its thickness, disrupting signal transmission. However, thickness also increases with temperature, without the same effect - conversely, increasing temperature increases anaesthetic agent requirement.

Nowadays, it is accepted that there are specific protein targets, with lipophilic binding sites, explaining the correlation with potency.

Question 3

What is the definition of an agonist?

Answer 3

A substrate for a receptor that elicits a response - classified as:

Full agonist
Significant affinity and full IA (IA is 1)
Produces maximal response at the necessary dose - Eg morphine at opioid receptors

Partial agonist
High affinity, but only partial IA (IA is 0-1)
Cannot produce maximal response, regardless of dose (such as buprenorphine at the μ opioid receptor).
Given on its own, or with a small dose of full agonist, it acts as a partial agonist.
Alongside a large dose of full agonist, it acts as a competitive antagonist by occupying receptors

Inverse agonist
Significant affinity and any degree of IA, but with an opposite effect to the endogenous agonist - such as atropine & acetylcholine at the muscarinic receptor.

IA = Intrinsic Activity

Question 4

What is the definition of an antagonist?

Answer 4

A ligand or substrate with affinity but no intrinsic activity - it will bind to a receptor or enzyme, but produce no response - classified as:

Irreversible
No amount of increasing concentration of agonist will overcome the blockade. The antagonist may bind at the active site, or at a different allosteric site.
Aspirin & clopidogrel irreversibly inhibit platelets.

Reversible
Competitive at the same receptor (the effect of the antagonist may be overcome by increasing agonist concentration)
NMBDs, Naloxone at opioid receptor.

Non-competitive (Prevent receptor activation through allosteric conformational changes, and increasing the dose of agonist will not overcome blockade)
Ketamine at the NMDA receptor

In contrast with an inverse agonist (which has its own physiological effect in competition with the agonist), a competitive antagonist will have zero effect

Question 5

Discuss the dose-response & log dose-response curves

IMAGES

Answer 5

Dose-response is a graph of substrate concentration (X axis), against response (Y axis), with a hyperbolic curve.

As concentration of substrate increases from zero, there is a rapid increase due to increasing receptor occupancy.
As the proportion of available receptors decreases, the curve flattens off to an asymptote at 100% response. Ka is the concentration when 50% of receptors are occupied.

The log dose-response curve is semilogarithmic, with the log substrate concentration on the X axis, against response on the Y axis.
This compresses the curve to a sigmoid curve, facilitating comparison of different curves, and making Ka easier to identify.

Question 6

What factors change the shape of the log dose-response curve?

IMAGE

Answer 6

Potency
A more potent drug shifts the curve leftward (less drug will elicit the smallest response)
The height of the graph remains the same, as the maximum achievable response is unchanged

Presence of antagonist
Graph shifts rightward for a competitive agonist, with the same height. The Dose ratio describes the extent of right shift (how much the agonist dose needs to increase to elicit the same dose)

For a non-competitive agonist, the curve is right-shifted, and the maximal height is reduced, as the maximal response is also reduced.

Presence of partial agonist
A partial agonist will not shift the curve left or right, but limit the maximal height, as the agonist cannot achieve maximal response.

Question 7

Discuss how drugs bind to receptors

Answer 7

Drug + Receptor <-> Drug-receptor complex

Reversible process, driven by the concentration of each component.

The velocity of the forward reaction is given by
~~~

V = K1 x [Drug] x [Receptor]

The reverse reaction is given by 

V = K2 x [Drug-receptor complex]
~~~

At equilibrium, these occur at the same rate. The equilibrium dissociation constant is Kd, and defined as K2/K1
The reciprocal is Ka - the equilibrium association constant, used as a measure of the strength of drug-receptor binding.

Receptors exist in an equilibrium between active/inactive states
Active is favoured by presence of an agonist
Inactive is favoures in the absence of an agonist - antagonists do not alter the equilibrium

Question 8

Explain affinity and intrinsic activity

Answer 8

Affinity
The strength of the attraction and bond between a ligand and a binding site on a receptor. Avidity is the cumulative affinity in context of multivalent receptors and ligands.
This is determined by Ka or Kd - the lower the Kd, the higher the potency

Intrinsic activity (IA)
The magnitude of the effect produced as a result of the substrate binding to the receptor
IA = 1 reflects full efficacy - a full agonist
IA = 0 reflects no efficacy - an antagonist
IA of 0 to 1 suggests some positive efficacy, as seen with a partial agonist
IA of -1 to 0 is seen for negative agonists

Ka and Kd are reciprocal (the affinity constant vs dissociation constant)

Question 9

How does potency relate the speed of onset?

Answer 9

Potency is the dose of drug required to elicit a given clinical response

Drugs with a lower potency require a larger dose for a clinical response, meaning a larger concentration gradient is established

In many cases, lower potency drugs have faster onset
(Alfentanil vs fentanyl, and rocuronium vs vecuronium)

This is known as Bowman’s principle

Question 10

What is meant by the term spare receptors?

Answer 10

Only a small proportion of the available receptors need to be occupied by an agonist to achieve maximal response - as seen with the nicotinic ACh receptors at the NMJ

This provides a safety net in case some receptors become inactivated, such as by an exogenous toxin

Hence, rocuronium must occupy over 75% of receptors before clinical response is seen.

Question 11

Compare & contrast tolerance, desensitisation, and tachyphylaxis

Answer 11

Tolerance
The need for a larger dose to achieve the same clinical effect, for a variety of reasons:
Faster metabolism due to hepatic enzyme induction (chronic EtOH)
Homeostatic response & adaptation (Reduced seizure threshold in chronic EtOH)
Receptor upregulation (Rebound HTN after prolonged use of clonidine)
Faster removal of drug from the body

Tachyphylaxis
Rapid decrease in response to a drug whenr epeated doses are given over a short period of time
Usually as a result of depleting endogenous stores of a neurotransmitter more rapidly than they can be restored - for instance release of noradrenaline using ephedrie.

Desensitisation
A slower decrease in response over a longer period of time, may be due to:
Change in receptor shape/structure
Reduction in receptor number due to downregulation in expression - for instance cardiac β receptors after continued exposure to dobutamine

Question 12

What are withdrawal and addiction?

Answer 12

Withdrawal describes a clinical response after cessation of a drug
This may be due to up- or down-regulation of receptors, and changing of the body’s set-point to acclimatise to the continued presence of the drug - for instance alcohol and opioids

Addiction describes the behaviour seen as a result of dependence, such as compulsive usage, obsessive thoughts, and drug seeking behaviour.