Pharmacology - An Illustrated Review

3. Pharmacogenetics and Other Special Considerations

The pharmacokinetics and pharmacodynamics of a drug may be altered by genetic conditions, age-related conditions, and pregnancy, altering the drug effects and influencing drug choice and dosing regimens.

3.1 Pharmacogenetics

Pharmacogenetics is concerned with hereditary differences that contribute to variations in responses to drugs. Although pharmacogenetic disorders are inherited, they may not be recognized until the individual is challenged with the drug and exhibits an abnormal response (Fig. 3.1). Some common examples of pharmacogenetic disorders are listed in Table 3.1.

Glucose-6-phosphate dehydrogenase

Glucose-6-phosphate dehydrogenase catalyzes the conversion of glucose to ribose 5-phosphate in the pentose phosphate pathway. Nicotinamide adenine dinucleotide phosphate (NADPH) and H+ are also produced. Ribose 5-phosphate is a precursor of nucleotide biosynthesis, and NADPH is involved in the biosynthesis of fatty acids and in protecting cells from oxidative damage.

 

Porphyria

Porphyrias are a rare group of diseases in which there are errors in the pathway of heme biosynthesis. This causes the precursors of heme, porphyrins, to build up in the body. Porphyrias primarily affect the nervous system (acute porphyria) and skin (cutaneous porphyria). Symptoms of acute porphyria include colicky abdominal pain with vomiting or constipation, peripheral neuritis (especially motor), seizures, and mental disturbances, such as psychosis, depression, and anxiety. Skin manifestations include itching, blistering, erythema (redness of the skin), and skin edema. Treatment for both types of porphyria involves avoiding/treating precipitating factors. Acute porphyria may also require the administration of pain medication, IV fluids to correct electrolyte imbalances and treat dehydration, and the IV injection of hemin or hematin (heme arginate) which are forms of heme. Cutaneous porphyria may require repeated blood draws to reduce the iron content of the body which reduces porphyrins, activated charcoal to absorb excess porphyrins and facilitate faster excretion, and beta carotene (a vitamin A precursor) to promote healthy skin.

 

  Table 3.1 image Pharmacogenetic Disorders

Disorder

Cause

Abnormally Low Amounts of Enzymes or Defective Proteins

Succinylcholine apnea

Caused by an atypical plasma cholinesterase, resulting in prolonged muscle relaxation and apnea after administration of succinylcholine

Acetylation polymorphism

Rapid and slow acetylators differ by a single autosomal gene. Slow acetylation is a recessive trait. The phenotype determines the rate of N-acetylation of drugs such as isoniazid and sulfonamides.

Drug-induced lupus erythematous is more common in slow acetylators following exposure to hydralazine and procainamide due to their slow metabolism.

Hemolytic anemia

Glucose-6-phosphate dehydrogenase deficiency, an X-linked defect, may result in hemolytic anemia after exposure to primaquine and certain other oxidizing drugs.

Abnormalities in cytochrome P-450

Debrisoquine-4-hydroxylase deficiency was one of the first adverse effects attributed to low levels of a form of cytochrome P-450 (CYP 2D6), which metabolizes many drugs.

Increased Resistance to Drugs

Heritable insensitivity to warfarin anticoagulants

This condition is probably related to abnormal proteins which synthesize vitamin K-dependent clotting factors. Affinity is decreased for warfarin, but not for vitamin K.

Responses Indirectly Related to Drug Metabolism

Induction of drug-metabolizing enzymes

This increases heme biosynthesis through increased activity of aminolevulinic acid synthetase. This may result in various types of porphyria in people who are slow to metabolize heme precursors.

Drug-induced lupus erythematous

Drug-induced lupus erythematous (DIL) is an autoimmune disease caused by the chronic use of certain drugs, most commonly hydralazine (an antihypertensive drug), procainamide (an anticonvulsant drug), and isoniazid (an antibiotic). DIL is thought to be caused by slow acetylation of the drug by a portion of the population. Symptoms are similar to those caused by systemic lupus erythematous (SLE), the more common and more serious form of lupus. These include joint pain (arthalgia), swelling, and stiffness; muscle pain (mylagia), fatigue, pericarditis (inflammation of the pericaridium surrounding the heart), and pleuritis (inflammation of the pleura surrounding the lungs). Treatment involves discontinuing the causal drug, NSAIDs (nonsteroidal antiinflammatory drugs) to treat pain and inflammation, and corticosteroids to treat inflammation.

 

3.2 The Pediatric Patient

Children are not just small adults. To appropriately treat the pediatric patient, the clinician must appreciate that children differ physiologically and psychologically from adults.

When prescribing drugs for children,

– A “child” usually refers to someone 12 years of age or under.

– Dosages of drugs for children are usually expressed per kilogram of body weight to account for age and weight differences.

– If possible, avoid painful intramuscular injections.

Fig. 3.1 image Genetic variants in pharmacokinetics.

Azathiopurine and mercaptopurine (immunosuppressant drugs) are metabolized more slowly in people with a genetic disorder affecting the enzyme thiopurine methyltransferase (TPMT). This causes toxic plasma drug levels to accumulate, resulting in damage to bone marrow.

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3.3 The Elderly Patient

In addition to the physiological changes that occur as a person ages, chronic diseases are more common. The use of multiple drugs, or polypharmacy, is also more common in this population. Polypharmacy can increase the chance of adverse reactions and drug interactions, leading to morbidity and mortality. It has also been shown to decrease compliance.

When prescribing drugs for the elderly,

1. Minimize polypharmacy.

– Avoid excessive or inappropriate consumption of drugs, but do prescribe adequately when necessary.

– Review and simplify drug regimens periodically.

2. Consider the form of the drug.

– Some elderly patients may have difficulty swallowing tablets, so prescribe liquid preparations when possible.

3. Consider sensitivity.

– As we age, our target organs, especially the central nervous system, are more susceptible to drugs, so all drugs should be used with caution.

4. Reduce the dose.

– It is prudent to assume at least mild renal impairment when prescribing for any elderly patient. Generally, the doses given should be lower than for healthy adults.

– Dose reduction should be proportional to creatinine clearance in more severe cases.

– Drugs with long half-lifes should be avoided.

Acute illness may lead to a rapid decline in renal function, especially if coupled with dehydration. This is particularly relevant when prescribing drugs with a narrow therapeutic index (e.g., digoxin, a cardiac glycoside used to treat heart failure).

3.4 The Pregnant Patient

During pregnancy, any drug given to the mother that crosses the blood–brain barrier will also cross the placenta and exert an effect on the unborn child. Some of these effects can be predicted from our understanding of the pharmacokinetics of the drug given, but others cannot. The clinician should assess the risks to the unborn child of a drug for use during pregnancy.

When prescribing a drug for a pregnant patient, consider

1. Stage of development of the unborn child

– A severe consequence of a drug given in the first trimester would be mal formation of the unborn child, as this is when organ development is occurring (Fig. 3.2). After the first trimester, drugs may cause functional disturbances, as the child has formed but is growing and maturing. Drugs given at term or during labor may affect the neonate.

2. Ability of the drug to pass through the placenta

– The placental syncytiotrophoblast forms a diffusion barrier between the maternal circulation and the capillaries of the fetal umbilical cord (Fig. 3.2). However, it is permeable to most drugs (especially low-molecular-weight, non-ionized, non-protein-bound drugs), so any systemically-acting drug given to the mother during pregnancy can reach the fetus.

Fig. 3.2 image Pregnancy: fetal damage due to drugs.

The sequelae of a drug taken during pregnancy depends on the stage of fetal development and the ability of the drug to cross the placenta.

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3. Teratogenicity of the drug

– Drugs that are known teratogenic agents are listed in any pharmacopeia and the clinician should become familiar with these. This will allow for an educated analysis of the risk of teratogenesis to be made. Unfortunately, the teratogenic potential of new drugs often cannot be established.

4. The effect on the fetus of discontinuing the drug

– The clinician must also consider the effect on the unborn child of discontinuing a drug (this may happen if the mother continues receiving the drug, but the child is born, thus severing its supply). The child may suffer from withdrawal effects and should be treated accordingly.

Physiological changes in pregnancy

Maternal physiology changes during pregnancy. In the cardiovascular system, blood volume increases (> 50% of pre-pregnancy levels), heart rate increases (10–15%), stroke volume increases (30%), cardiac output increases (up to 60%), and blood pressure (especially diastolic) drops in the first and second trimesters but rises to nonpregnant levels at term. In the respiratory system, ventilation increases (40%), and oxygen consumption increases (20%). In the kidneys, glomerular filtration increases (60%), renal plasma flow increases (50–70%), and there is glycosuria (as glucose reabsorption mechanisms become saturated). In the GI tract, there is decreased esophageal tone, decreased gastric acid production, increased mucus production, and decreased gut motility. These physiological parameters return to normal after parturition.

 

3.5 The Breastfed Child

The physiology of a neonate (child younger than 30 days old) is markedly different from older children and adults. Low-molecular-weight, non-ionized, non-protein-bound drugs passively diffuse into breast cells and may be ingested by the neonate via breast milk (Fig. 3.3). A drug that is considered relatively safe during pregnancy due to its relative inability to cross the placenta may be more readily secreted into breast milk and is therefore not safe for the breastfed infant (e.g., chloramphenicol can accumulate to toxic levels in breastfed infants causing bone marrow suppression).

Physiology of Neonates

The physiology of neonates differs from that of older children and adults. Notably, neonates have immature active transport systems for organic anions and cations, an immature liver microsomal system for drug metabolism, a lower glomerular filtration rate; a reduced ability to glucuronidate phase 1 metabolism products causing delayed elimination of drugs, and a differing target organ sensitivity to drugs.

 

Fig. 3.3 image Lactation: maternal intake of drugs.

Drugs taken by a nursing mother can be secreted in breast milk and ingested by the baby. The effect that this has on the baby will depend on the extent of drug transfer into the milk (which determines the dose to the baby) and how the baby metabolizes and eliminates the drug.

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