Drug Therapy Across The Lifespan

Year1,Semester 2

At the end of the lecture, the student should be able to:

1. List ways in which drug absorption, distribution, metabolism and excretion are altered by age and the consequent effects of drug action.

2. Describe pediatric dosage considerations3. Describe the pharmacological properties

that influence drug transfer both across the placenta and into the breast milk

4. Describe factors that determine the teratogenic potential of drugs once they enter the embryonic/foetal circulation.

Learning outcomesDescribe altered physiology and

polypharmacy in the elderly.Identify common herbal and traditional

medicines.List potential interactions between herbal

and conventional medicene.

Key termsPolypharmacy, Pediatric dosage,Carrier mediated transport, teratogens,Mutagens,`carcinogens,Transdermal drug administration,Non compliance, `passive diffusion,Herbal medicines, conventional medicines.

Absorption and Drug ActionThe function of the gastrointestinal tract is

different in very young and the elderly.Infants and the very elderly tend to be the

most sensitive to the effects of the drugs.Common problem is the slowed peristalsis

and the gastric emptying time.Activity and concentrations of digestive

secretions are lower in newborns .Infants and elderly require special

considerations for medication administration.

Absorption and drug actionAn example can be: absorption of medicines given

intramuscularly may be affected by the differences in muscle mass, blood flow to the muscles, and muscle inactivity of patients who are bedridden.

Topical administration of drugs in infants is effective though the outer layer of the skin (stratum corneum) is not fully developed. The reason being that the skin at this stage would be fully hydrated and thus the water soluble drugs are absorbed more easily.

Infants wearing plastic coated diapers are also more susceptible to skin absorption because plastic acts as an occlusive dressing that increases hydration of the skin.

Inflammation also increases the drug absorption (e.g. nappy rash)

Absorption and Drug Action Transdermal administration in elderly is

always unpredictable. Dermal thickness usually decreases with

aging which may enhance absorption but there can be some factors which diminish absorption. Example, drying of skin,wrinkles,and a decrease in hair follicles.

With aging there will be decreased cardiac output and diminished tissue perfusion. This may affect transdermal drug absorption.

Absorption and Drug ActionDrug administration through oral route may be

difficult for the infants and elderly to swallow. The medication needs to be crushed and mixed with water.

Taste becomes a factor when administering liquid medications because liquid medications comes in contact with the taste buds.

However, time release tablets, enteric coated tablets and sublingual tablets should not be crushed because of the effect of the absorption rate and potential for the toxicity.

Absorption and Drug ActionInfants and elderly often have less teeth to

chew the medications.Elderly patients usually have reduced

salivary flow and this makes chewing and swallowing more difficult.

Gastrointestinal absorption of medicines is often influenced by a variety of factors. E.g.-gastric pH,gastric emptying time, motility of GI tract, enzymatic activity, blood flow of the mucous lining of the stomach and intestines, permeability and maturation of the mucosal membrane and the concurrent disease processes.(discuss in pairs)

Distribution and drug actionDistribution refers to the ways in which

drugs are transported by the circulating fluids to the site of action (receptors)

Medicines are transported either dissolved in the circulating water (in blood) of the body or bound to the plasma proteins within the blood. Body water composition changes with age. The total body water content for a preterm is 83% and for an adult is 60%.Infants have larger Volume of Distribution for water soluble drugs and may require higher doses in milligram per kilogram than the elderly.

Distribution and Drug ActionBody weight of a preterm consists of very little fat, a full term newborn also have little fat whereas an adult has a lot of fat compared to the infants and children so the drugs which are fat soluble should be given in smaller amounts to infants since there is less fat to bind to the drugs. The highly fat soluble drugs require longer onset of action, may accumulate in fat tissues, prolonging their action and increasing potential for toxicity.

Distribution and drug action Drugs that are insoluble are transported in

the circulation by being bound to plasma proteins (albumin and globulin)

Protein binding is reduced in preterm infants because of:

1. Decreased plasma protein concentration2. Lower binding capacity of protein3. Decreased affinity of proteins for drug

binding

Drugs which have lower protein binding in neonate than in adults are phenobarbitol,phenytoin,theophilline,propanalol, lignocaine,penicillin and chloramphenicol

Distribution and drug actionDrugs used in treating neonates may compete

for binding sites.Some drugs can displace bilirubin from the

protein binding sites and allow the bilirubin to pass into the brain causing Kernicterus( is the degeneration of brain nerve cells caused by binding of bilirubin to the cells).

Metabolism in drug actionMetabolism is the process by which body

inactivates medicines.It is controlled by factors such as

genes,diet,age,and maturity of enzyme systems in liver. All enzyme systems are present at birth but they mature at different rates.

The weight of the liver, the number of functioning hepatic cells, and hepatic blood flow decrease with age. This results in slow metabolism of drugs in elderly.

Metabolism and drug actionThis can also be caused by presence of liver

disease or renal failureDrugs that are extensively metabolized by the

liver (e.g. morphine, lignocaine, propanalol) can have prolong duration of action if the hepatic blood flow is reduced.

Dosages and timing of these medications must be adjusted to prevent drug accumulation and toxicity.

Drug metabolism can be affected at all ages by genetics,smoking,diet,gender,and other medicines.

(Discuss in pairs)

Excretion and drug actionIs the process by which metabolites of the drugs

and the active drug itself are excreted from the body.

(Fill in the Blanks)The primary routes are through________ and

___________. The other routes are_________,___________,_________ and ________.

Renal function reaches to an adult level at 1 year of age

As body matures, important physiologic changes take place in the kidneys, including decreased renal blood flow caused by arthrosclerosis and reduced cardiac output, a loss of glomeruli,and decreased tubular function.

Usually elderly show a deterioration in the renal clearance of drugs. The action of the drugs may be prolonged in this case and may accumulate to toxic levels if no adjustment of dosages is considered

Pediatric Dosage ConsiderationIn children, organ systems are not matured

yet.e.g. kidneys, liver, and the circulatory system.

Muscle mass in children is lower but the body water percentage is higher.

These factors affect absorption, distribution, metabolism and excretion of drugs. The physiological differences between adults and children suggest that pharmacokinetic behavior of some drugs vary according to the age.

A dose administered to an adult is never equivalent to the pediatrics.

Pediatric Dosage ConsiderationsAge and body weight is very important in

calculating the pediatric dosage.

Pediatric Dosage ConsiderationsDosage adjustments are very important to

consider in pediatrics to prevent toxicities.Therfore,it is equally important to obtain

accurate height and weight measurements on a regular basis.

It is also important to accurately measure and administer medications to pediatric patients. Oral and parenteral medications available in powder form should be diluted properly according to the manufacturers directions to allow accurate measurements of solution being administered

PregnancyDuring pregnancy any chemical or drug

substances consumed and absorbed may reach the fetus by way of the maternal circulation and cross the placenta or be transferred to the baby and newborn via breast milk.

Drugs cross the placenta and induce adverse fetal effects. This depends on the pharmacological properties of the drugs e.g. the type of drug, the drug concentration and fetal age.

Transfer of drugs across the placenta depends on the physicochemical properties of the drug, protein binding and lipid solubility.

PregnancyTransfer of drugs primarily involves simple

diffusion.In pregnancy, low molecular weight drugs

which are lipophilic,ionized and non-protein bounded are able to cross the placenta, while drugs of high molecular weight cross very poorly.

All forms of drugs in maternal circulation can be easily transferred to the colostrums and breast milk.

Drugs are handled by different pathways in the infant and the fetus, so the impact of maternal medications on the infant is probably less as the drug is diluted in the maternal circulation and the amount of milk taken by the infant is often small.

If neonates hepatic and renal systems are immatured then metabolism and excretion of drugs taken would be affected.

Drug concentrations in the maternal circulation depends on the relationship of several factors:

- dosing and route of administration - drugs distribution - its protein binding - maternal metabolism and excretion

Drug factors that enhance drug excretion into the milk are higher degree of ionization, low molecular weight of the drugs, greater fat solubility and higher concentration of drugs.

Transfer of drugs into milk occurs by both passive diffusion and carrier mediated transport.

Teratogenic Potential of Drugs1st trimester, when the embryo is developing is

most vulnerable to the teratogenic effects of various drugs and chemicals.

Drugs can exert a beneficial effect in the fetus, cause adverse effects or act as teratogens,mutagens or carcinogens.

3-12 weeks of pregnancy is when the extremities(arms,legs, and toes), central nervous system (CNS) ,muscle and organs are developing most rapidly-teratogens can cause birth defects characterized by the absence or malformation of arms and legs.

Use of cocaine–has resulted in spontaneous abortion, fetal hypoxia, premature delivery, and congenital abnormalities ( skull defect, cardiac abnormality), cerebral infarction or stroke.

Altered physiology and polypharmacy in elderly Polypharmacy- refers to use of multiple

medications by a patient.

The elderly use more drugs because illness is more common in older persons.e.g. Cardiovascular Diseases,Arthritis,Gastrointestinal Disorders, and Bladder Dysfunction.

Altered drug effects are common in elderly patients but can often be avoided. We should be aware of age related changes in drug absorption,distribution,metabolismand elimination. Doctors may need to adjust drug dose, frequency, or the choice of drug altogether as they consider the physiologic changes of aging.

Group Activity1. Identify common herbal and traditional

medicine (brain storm)Debate:

2. We believe that herbal medicine is better than conventional medicine /disagree (1 from each group)

Common herbal medicinesAloe Vera-member of the lily family. Juice of

the leaves used for skin applications, burns, used in many shampoos and conditioners.

Garlic-member of the onion family. Consuming large amounts of garlic prevent heart disease.

Ginger-used as an antiemetic in nausea associated with travel or pregnancy.

ReferencesPorth, C.M. (2004). Essentials of Path

physiology: Concepts of Altered States. Philadelphia; Lippincott Williams & Wilkins.