 Pharmacogenetics is the study of how genetic variations affect

both the pharmacokinetics of drugs and the pharmacodynamic

responses.

 Pharmacogenomics is the use of genetic information to guide the

choice of drug and dose on an individual basis.

 A relationship is drawn between how a patient responds to a drug

with his genetic makeup.

 The purpose is to identify individuals who are either more likely

or less likely to respond to a drug, as well as those who require
altered dose of certain drugs.
 Maximize drug efficacy

 Minimize drug toxicity

 Predict patients who will respond to intervention

 Aid in new drug development

 Some specific genetic defects which lead to
discontinuous variation in drug responses –

 Case scenarios:
 Case 1: A healthy 25-year-old man is undergoing a brief surgical
procedure requiring general anesthesia. He underwent an
unremarkable intubation and induction of anesthesia using IV
succinylcholine and inhaled halothane. During the surgery the
patient develops muscle rigidity and tachycardia, and his
temperature rapidly rises.

A. Explain the reaction that is occurring in the patient?

B. Explain the genetic basis for the same

 Malignant hyperthermia after halothane –

 Genetically determined reaction occurs in subjects having abnormal

RyR1 (Ryanodine receptor) calcium channel at the sarcoplasmic
reticulum of skeletal muscles.

 This channel is triggered by halothane to release massive amounts of

Ca2+ intracellularly causing persistent muscle contraction and
increased heat production.

 Treatment –
 Rapid external cooling,
 Bicarbonate infusion,
 100% O2 inhalation and
 I.V. Dantrolene
Case 2: 15 year old girl, diagnosed with chronic tonsillitis is
posted for tonsillectomy. It was decided to take her up for surgery
under general anesthesia. To ease the intubation Inj.
Succinylcholine was administered but, even after 10 minutes No
neuromuscular recovery was noted.
Succinylcholine apnoea was suspected and Fresh Frozen plasma
was administered. After 30 minutes patient was found to have
spontaneous respiratory attempts.

A. Explain the reason for failure of neuromuscular recovery from

Succinylcholine.

--Explain the genetic basis for the same

How did fresh frozen plasma help in recovery?
 Atypical pseudocholinesterase and prolonged succinylcholine
apnoea.

 Succinylcholine
rapidly hydrolysed by
plasma pseudocholinesterase

Succinylmonocholine

Succinic acid + choline (action lasts 5–8 min).

 Some patients have genetically determined abnormality of this
enzyme –

▪ Enzyme not functioning well (atypical)

▪ Low affinity for SCh

▪ Deficiency of pseudocholinesterase.
 Subjects homozygous for the abnormal enzyme (1 in > 3000
population), SCh causes prolonged phase II blockade resulting
in muscle paralysis and apnoea lasting 4–6 hours, because
SCh is a poor substrate for the more specific AChE found at
the motor end plate.

 However, duration of paralysis is increased only by 2–3 times

in subjects who are heterozygous for the abnormal enzyme (1
in ~ 50), or have only relative deficiency.
Case 3:

A 21 years old male present to the hospital with fever on and off.
He was diagnosed as Malaria fever and treated with primaquine
drug. After 1 day he become pale, yellowing of the skin and whites
of the eyes (jaundice), dark urine, fatigue, shortness of breath, and
a rapid heart rate.

A. What is the probable diagnosis?

B. How to explain for this genetic basis?

 G-6PD (Glucose-6-phosphate Dehydrogenase) -

 Oxidant drugs (eg-primaquine etc) may produce hemolysis in

patients with deficiency of this enzyme.

 This X-linked monogenic trait is more common in the

Mediterranean, African and Southeast Asian races.

 Haemolysis is largely dose related.

 Several variants of the G-6PD gene occur in the population

resulting in differing severity of haemolysis triggered by different
oxidizing drugs.
Case 4:

A 32 years old male present to the hospital with fever on and off
and cough with blood stained sputum.
He was diagnosed as Pulmonary TB and treated with primary
drugs: Isoniazid , Rifampin, Pyrazinamide and streptomycin.
After 3months, he complaints as numbness over lower limbs and
tingling sensation over all the limbs.

A. What is the probable diagnosis?

B. How to explain for this genetic basis?

--Isoniazid drug induced peripheral neuropathy.

-- For that avoidance need to add Tab.Pyridoxine 10mg for daily

once
 Acetylator polymorphism:
 Some individuals are slow acetylators and some are fast acetylators.

 Drugs metabolized by this route may be ineffective in fast acetylators

and may show toxicity in slow acetylators.

 Important drugs metabolized by acetylation include (remembered as

SHIP )

Note:
 All SHIP drugs can also cause lupus erythematosis.
 Isoniazid is majorly metabolized by N-acetylation by NAT2 gene.

 Polymorphism of N-acetyl transferase 2 (NAT2) gene results in

rapid and slow acetylator status.

 Rate of INH acetylation shows genetic variation. There are either:

 Slow acetylators (60–70% of Indians) t½ of INH is 3 hr.

 Fast acetylators (30–40% of Indians) t½ of INH is 1 hr.

 Isoniazid neuropathy, occurs in Slow acetylators while

hepatotoxicity is seen in fast acetylators
Other drugs show pharmacogenomic
effects:
 Thiopurine methyl transferase (TPMT) deficiency - increases
risk of severe bone marrow toxicity by 6-mercaptopurine and
azathioprine

 Irinotecan induced neutropenia and diarrhoea is more in patients

with UGT1A1 *28 allele of glucuronyl transferase.

 Over expression of P-gp results in tumour resistance to many

cancer chemotherapeutic drugs, because it pumps out the drug
from the tumour cells

 Severe 5-fluorouracil toxicity occurs in patients with

dihydropyrimidine dehydrogenase (DPD) deficiency.
 Inability to hydroxylate phenytoin results in toxicity at usual
doses.

 Resistance to coumarin anticoagulants is due to an abnormal

enzyme vitamin K epoxide reductase (VKOR) that regenerates
the reduced form of vit. K.
 This form has low affinity for the coumarins
 Many genes are involved in drug action, making the drug
target very difficult.

 Insufficient validation of study results.

 Identification of smaller inter-individual variation in

everyone’s genes is difficult.

 Expensive

 Ethical issues
 It required a shift in clinician attitude and beliefs “not one
dose fits all”

 Paucity of studies demonstrating improved clinical benefit

from use of pharmacogenomic data
◦ Still much to be learned

 Genome wide interrogation will likely be important to get the

entire picture
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