MOST GENERAL TYPES OF TOXICITIES WE ENCOUNTER

MOST GENERAL TYPES OF TOXICITIES WE ENCOUNTER

Mechanism based pharmacology:                                                                                        

ü  A molecule provides desired therapeutic effect by activation of a biological target; however the activation of the same biological target causes unwanted effect also.

ü  Here, there should be a balance between good effects vs. bad effect.  

Formation of reactive metabolites:

ü  We should avoid chemically reactive functional groups in the molecules.  We should also bear in mind the kind of metabolites a drug molecule might end-up with depending on the functional groups on the molecule.  With experience one can make an educational guess of the fate of certain molecules bearing a particular functional group. 

ü  The best way of avoiding reactive metabolites is avoid functional groups which have been shown to cause a problem in the past. This is why you will see very few drugs containing, for example, a nitro group. However, some functional groups are worse than others.

ü  Such reactive metabolites can lead to hepatotoxicity and genotoxicity.

Activation of other receptors, including hERG:

ü  Along with biological target of interest, sometimes the drug molecules can activate other receptors/enzymes – we call this as ‘’off-target toxicity’.

ü  Therefore, before moving onto preclinical studies – these molecules are tested for biological activity against similar biological targets.   For example, our biological target of interest is ‘KINASE A’, then we screen the molecule against several other KINASES which fall under the family of ‘KINASE A’ family.

ü  Potency (and therefore dose) is important as we are looking for a safety margin, i.e. the absolute potency at another receptor is less important than how much less than the potency at the primary receptor it is.

ü  hERG:  The receptor is a potassium ion channel located in cell membranes in the heart, which opens and closes to allow potassium ions to flow out of the cells.  Arrhythmia is a lack of rhythm in the heart beat. A delay of the T wave by 5-10 milliseconds can cause lack of control of the heartbeat, which may lead to a fatal arrhythmia.  This is obviously something to be avoided.

Interactions with other substances:

ü  Many patients take poly-medication.  One substance can affect the metabolism of another.  It’s not just drugs interacting with each other that can cause a problem – they may also interact with foodstuffs, alcohol or herbal medicines.

ü  Drugs are mainly cleared by a group of hepatic enzymes called cytochrome P₄₅₀s or CYPs. CYPs can be further sub-divided into smaller classes of enzymes, all of which have their own structure-activity relationships. The most common CYPs to cause problems are known as 3A4, 2C9, 1A2, 2D6 and 2C19. Compounds with low oral bioavailability and high first pass metabolism are most susceptible to interaction with other medicines which affect CYPs.   The effect of inhibiting these enzymes is that they are then unavailable to metabolize other compound.

Idiosyncratic toxicity:

ü  Idiosyncratic toxicity’ is term to include other toxic effects that we don’t currently understand.

ü  Note that increased potency reduces the possibility of this.

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