Pharmacogenetics: Gene Response to Medicine

Pharmacogenetics

Pharmacogenetics is the study of how our genes respond to the medications we consume. In other words, it is a study of drug response based on individuals' genetic makeup. Let's study pharmacogenetics using succinylcholine as an example.

Succinylcholine is used during endotracheal intubation to relax the neck muscles so that the ET tube can pass easily. Sometimes, it can relax the diaphragmatic muscles and cause apnea. In certain cases, this can be prolonged, and the patient has to be put on ventilatory support. Succinylcholine is called a Depolarizing skeletal muscle relaxant. It is mainly given for intubation. The drug acts for 5 minutes only. So, the duration of action is for 25-minute, and the drug is metabolized by an enzyme called pseudocholinesterase (Typical pseudocholinesterase). When sucinylcholine is given in a patient with atypical pseudocholinesterase, the duration of action of sucinylcholine is increased, leading to prolonged apnea. The patient is put on ventilatory support, and a FFP or recombinant pseudocholinesterase is given. 

Dibucaine Number

Atypical pseudocholinesterase conditions occur, and then we use testing called Dibucaine number.

If these numbers are detected, there is a high chance of Succinylcholine apnea. So, Succinylcholine can be given according to the Dibucaine number. 

Drug Treatment

If the dibucaine number is 50-60 and 20-30 (Rocuronium is also a skeletal muscle relaxant with a fast onset of action). Rocuronium can be used for intubation. Mivacurium is the Shortest-acting skeletal muscle relaxant. Mivacurium is not used because the enzyme pseudocholinesterase metabolizes it.

Pharmacogenomics

A field of research that studies how a person's genes affect how they respond to medications. It will help to reach the right drug to the right patient. (Based on genetic makeup)

Pharmacogenetic Problem

This can be understood with the help of G6PD.

Drugs Avoid in G6PD Deficient Patients

• Primaquine 
• Tafenoquine
• Chloroquine
• Chloramphenicol
• Sulfonamides
• Methylene blue
• Nitrofurantoin

Metabolism

• The chemical changes that take place in a cell or an organism.
• The enzyme does metabolism in a human. Enzymes are nothing but proteins.
• Certain people don't produce metabolism adequately and are called poor metabolizers. 

1. Cytochrome enzymes (CYP)

2. Acetylation Drugs:

• INH
  • Slow acetylation (prone to peripheral neuropathy)
  • Fast acetylation (prone to Hepatotoxicity)
• Hydralazine (drug-induced Lupus)
• Procainamide (drug-induced Lupus)

3. Glucuronidation

• UDP Glucuronosyltransferase
• E.g., Irinotecan→ treatment of colorectal cancer

  ↓ (UDP GT)

  Metabolized

• The enzyme is not metabolized, causing diarrhea to become severe.

4.  Malignant Hyperthermia

Drugs used in malignant hyperthermia

• Succinylcholine
• Volatile anesthetics (Halothane) → Muscle rigidity, increase in temperature, Rhabdomyolysis (Leads To renal failure).

Pharmacogenetics of Warfarin 

Warfarin is a Vitamin K antagonist. Warfarin Causes the metabolism of 2 7 9 10 and proteins C and S into the active form. To make them active Vitamin K reduce will become vitamin K oxidized and the cycle continues. This is done by an enzyme called vitamin K epoxide. Deficiency of vitamin K epoxide prevents this cycle. Due to that, they are prone to bleeding. If Warfarin is given in this patient it will increase the risk of bleeding.

Frequently Asked Questions:

Q: If the patient has atypical pseudocholinesterase, what will be used for intubation?

Answer: Don't use Mivacurium. Use Rocuronium for intubation.

Q: What is the problem with defective ryanodine receptors?

ANSWER: The sarcoplasmic reticulum releases calcium required for muscle contraction. When succinylcholine/halothane is given, calcium is released more in patients with ryanodine receptors, leading to muscle contraction, increasing temperature, and Rhabdomyolysis. So, the drug of choice for this condition is Dantrolene sodium.

Q: What is the genetic makeup drug response is known as?

Answer: Pharmacogenetics

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