Inactivating drugs phases: metabolism and drug's half-life

Inactivating drugs phases: metabolism and drug's half-life

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  Drugs used as a treatment without causing poisoning to patients because of the mechanism happening in the human body, which works on inactivating these drugs, then eliminate them. This is one main reason why we do not experience poisoning. It is called metabolism so this works as a defensive mechanism, making drugs less toxic and less effective; however it is not a rule because very few drugs can be more effective when they are metabolized. Also, metabolism leads to production of products with increased polarity, which allows the drug to be eliminated.  

Metabolism of the drugs:

It usually occurs in the liver, sometime in the lungs or the gut. Phase one of drug metabolism starts in the live, since the drug is taken orally before reaching the systematic circulation. Cytochrome P450, or CYPs, are a family of enzymes, located abundantly in the liver cells but also located through the body cells. This huge family of enzymes contain different enzymes, which each can metabolize different drug. For example, CYP2C9 metabolizes Ibuprofen, Warfarin, and others, whereas CYP1A2 metabolizes Theophyllin, Caffeine, Paracytamol, Naproxen, and others. The processes involve in  metabolizing a drug are: 

*oxidation

*hydrolysis

*hydroxylation

Drugs are usually lipophilic. Lipophilic molecules are reabsorbed in the distal convoluted tubules. On the other hand, hydrophilic drugs are readily excreted. 

Kinetics of metabolism:

First-order kinetics 

Zero-order kinetics 

In first-order kinetics, the drug concentration is directly proportional to the metabolic rate i.e. ( a constant fraction of drug is metabolized per unit of time, with each half-life the concentration decreases by 50%. ) Half-life of elimination is the period of time required for the concentration or amount of drug in the body to be reduced by one-half. However, in zero-order kinetics, the drug concentration is not proportional to the metabolic rate i.e. ( a constant amount of drug is metabolized per unit of time; it happens when the doses are very large, for example, aspirin and ethanol are given in a large dose. )

Reactions of drug metabolism involve phase one and phase two, as mentioned above. The kidney can not excrete the lipophilic drugs that across the cellular membranes easily, which reabsorbed then in the distal convoluted tubules. As a result, the lipophilic molecules are metabolized first in the liver, to more polar and water solubility through these phases of reactions. 

In phase one lipophilic molecules are converted to more polar molecules by adding polar functional group ( OH, NH₂, COOH ) The reactions involved in this phase are: reduction, oxidation, and hydrolysis. The reactions in phase one, usually decrease pharmacologic activity but sometimes increase or have no effect on it. Phase Ι has two forms; phase Ι reactions utilizing the P450 system, and phase Ι reactions not involving the P450 system. In phase Ι reactions utilizing the CYP450 system, or microsomal mixed-function oxidases, which are important for the metabolism of many endogenous compounds and exogenous substances. CYPs are superfamily of heme containing isozymes. There are six isozymes are responsible for the vast majority of CYP450 catalyzed reactions, involving: CYP-3A4, CYP-2E1, CYP-2C19, CYP-1A2, CYP-2D6, CYP-2C9/10. NOTE: CYP450 enzymes exhibit considerable genetic variability among individuals and racial groups. On the other hand, phase Ι reactions not involving the CYP450 system are alcohol dehydrogenation, hydrolysis, and oxidation. 

In phase two conjugation reactions with polar groups occur. If the metabolite from phase Ι metabolism is sufficiently polar; it can be excreted by the kidneys. However, many phase Ι metabolites are still too lipophilic to be excreted. The conjugation reaction of drugs occurs in glucuronate (the basic bond), sulfate, glycine, glutathione, acetate, and methyl. Phase ΙΙ products are more hydrophilic, making it easy to eliminate through the urine and the bile, and therapeutically inactive in usual. In this phase, the final product is less effective than the original compound or has no effect; however, in rare cases the final products of phase ΙΙ can have a powerful effect than the original compound, for example, morphine-6-glucuronide is more potent that morphine! 

Drugs interactions are enzymatic inhibition and enzymatic induction. Enzymatic inhibition is the inhibition of the enzymes responsible for drug (A) metabolism, by drug (B) resulting an increase of the drug (A) concentration in the plasma and its activity. Whereas, enzymatic induction is the induction of the enzymes responsible for drug (A) metabolism, by drug (B) resulting a decrease of the drug (A) concentration in the plasma and its activity.