Drug Interactions - Pharmacodynamic Interactions

Pharmacodynamic Interactions

The change in an organism's response on administration of a drug is an important factor in pharmacodynamic interactions. These changes are extraordinarily difficult to classify given the wide variety of modes of action that exist and the fact that many drugs can cause their effect through a number of different mechanisms. This wide diversity also means that, in all but the most obvious cases, it is important to investigate and understand these mechanisms. The well-founded suspicion exists that there are more unknown interactions that known ones.

Pharmacodynamic interactions can occur on:

1. Pharmacological receptors: Receptor interactions are the most easily defined, but they are also the most common. From a pharmacodynamic perspective, two drugs can be considered to be:
   1. Homodynamic, if they act on the same receptor. They, in turn can be:
      1. Pure agonists, if they bind to the main locus of the receptor, causing a similar effect to that of the main drug.
      2. Partial agonists if, on binding to one of the receptor’s secondary loci, they have the same effect as the main drug, but with a lower intensity.
      3. Antagonists, if they bind directly to the receptor’s main locus but their effect is opposite to that of the main drug. Which, in turn can be:
         1. Competitive antagonists, if they compete with the main drug to bind with the receptor. The amount of antagonist or main drug that binds with the receptor will depend on the concentrations of each one in the plasma.
         2. Uncompetitive antagonists, when the antagonist binds to the receptor irreversibly and is not released until the receptor is saturated. In principle the quantity of antagonist and agonist that binds to the receptor will depend on their concentrations. However, the presence of the antagonist will cause the main drug to be released from the receptor regardless of the main drug’s concentration, therefore all the receptors will eventually become occupied by the antagonist.
   2. Heterodynamic competitors, if they act on distinct receptors.
2. Signal transduction mechanisms: these are molecular processes that commence after the interaction of the drug with the receptor. For example, it is known that hypoglycaemia (low blood glucose) in an organism produces a release of catecholamines, which trigger compensation mechanisms thereby increasing blood glucose levels. The release of catecholamines also triggers a series of symptoms, which allows the organism to recognise what is happening and which act as a stimulant for preventative action (eating sugars). Should a patient be taking a drug such as insulin, which reduces glycaemia, and also be taking another drug such as certain beta-blockers for heart disease, then the beta-blockers will act to block the adrenaline receptors. This will block the reaction triggered by the catecholamines should a hypoglycaemic episode occur. Therefore, the body will not adopt corrective mechanisms and there will be an increased risk of a serious reaction resulting from the ingestion of both drugs at the same time.
3. Antagonic physiological systems: Imagine a drug A that acts on a certain organ. This effect will increase with increasing concentrations of physiological substance S in the organism. Now imagine a drug B that acts on another organ, which increases the amount of substance S. If both drugs are taken simultaneously it is possible that drug A could cause an adverse reaction in the organism as its effect will be indirectly increased by the action of drug B. An actual example of this interaction is found in the concomitant use of digoxin and furosemide. The former acts on cardiac fibres and its effect is increased if there are low levels of potassium (K) in blood plasma. Furosemide is a diuretic that lowers arterial tension but which favours the loss of K+. This could lead to hypopotassaemia (low levels of potassium in the blood), which could increase the toxicity of digoxin.