Drug Dealing in Body! PHARMA101 ③

In the last article,➚ we discussed the distribution and toxicity of the drugs. This article will let you know how the body degrades down a drug. So, this is PHARMA101: Metabolism of Drugs. Boost your USMLE preparation by following me on medium and reading PHARMA101.

Our body has an aim when it comes to drug dealing. It is to make it water-soluble. Water-soluble drug form can be excreted by kidneys. This process may be of three methods:-

1. Active Drug Intake→Inactive form{Mostly this occurs}
2. Active Drug Taken by you→Another active Drug {for e.g., Diazepam→Oxazepam(CNS Depressant) }
3. Inactive Drug has taken (Prodrug)→Active Drug in the body

PRODRUGS:-
ALL- ACE Inhibitors except Captopril and Lisinopril
Prefer- Proguanil, Proton Pump Inhibitor, Prednisone
Doing- Dipivefrine
M- Methyl Dopa, Minoxidil, 6-Mercaptopurine
D- L-Dopa
In- Irinotecan
Clinical- Carbimazole, Clopidogrel, Cyclophosphamide
Subjects- Sulfasalazine, Sulindac

How Drug is made Water Soluble?

The drug can be made water-soluble by two methods. Either it is made water-soluble by changing it up to some point or add a bigger water-soluble molecule that will make the complete molecule water-soluble.

1. CAN WE CHANGE THE DRUG? Yes, by any method among oxidation, reduction, hydrolysis, cyclisation or deamination. The final destination is to expose functional groups. The functional group’s exposure makes the drug more water-loving. You may call it Phase-I or Catabolism.
2. CAN WE ADD SOMETHING BIGGER? Yes, we can add glucuronide, glutathione, glycine, acetyl group, a methyl group or sulphate group. This is called Phase-II or Conjugation. The final target is to make the drug water-soluble.

Do Enzymes do anything?

How does all this make sense?

Heparin is taken down by non-microsomal enzymes. You needn’t think much while prescribing this drug!🤩🤩🤩

But, Warfarin is a drug that is taken down by microsomal enzymes. When Warfarin is given with other drugs then there are chances that those drugs can induce or inhibit the microsomal enzymes responsible for the metabolism of Warfarin. An inhibitor will cause toxicity {∴⇩se the dose} and an inducer will eliminate the drug faster {∴⇧se the dose}. I am adding a list of inducers and inhibitors of microsomal enzymes.

INDUCERS:

G- Griseofulvin
P- Phenytoin
R- Rifampicin
S- Smoking
Cell- Carbamazepine(CBZ)
Phone- Phenobarbitone

INHIBITORS:

Vitamin- Valproate
K- Ketoconazole
Can't- Cimetidine
Cause- Ciprofloxacin
Enzyme- Erythromycin
Inhibition- Isonyazine(INH)

Phase I metabolism is carried out by both Microsomal and non-microsomal enzymes. While phase II is carried out by non-microsomal enzymes but glucuronidation is carried out by microsomal enzymes. Phase II reactions are non-cytochrome mediated.

Here the article ends for a general reader but the article starts for future Harvard MD students.

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Dear Doctor,

Now, let me tell you that microsomal enzymes are of two types-

1. Non-cytochrome Enzymes- Phase II reactions are non-cytochrome mediated.
2. Cytochrome Enzymes- Cytochrome P₄₅₀ is the commonest form.

Cytochrome P₄₅₀

Nomenclature:

In CYP3A4.1
CYP→ Cytochrome
3→ Family
A→ Subfamily
4→ Isoform
1→ Gene(Not mentioned always)

Mostly Cytochrome found will be CYP3A4 and the next common will be CYP2D6. They are involved in

• Bile acid formation
• Cholesterol Metabolism

Drugs induced by CYP 3A4

C- Cyclosporin, Ca⁺⁺ Channel Blockers
T- Tacrolimus
S- Statins
C- CAT[Cispride, Astemizole, Terfenadine]__Withdrawn From Market. Task: Find Why?
A- Amiodarone
N- NAVIRs(Drugs ending with NAVIR)

Other Cytochromes:

• CYP2D6:

2→ β Blocker
D→ Depression Drugs{Tricyclic Antidepressants, SSRI, SNRI}
6→ Anti-arrhythmia

• CYP2C9:

C→ Clotting {Warfarin}
9→ Phenytoin

• CYP2C19- Converts Clopidogrel into Active form. Inhibited by Omeprazole.
• CYP1A1- Two Functions:-

1. Converts pro-carcinogens to carcinogens
2. Works on theophylline. The dose of theophylline should be increased in smoking and decreased with ciproflox and erythromycin inhibitors.

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