FACTORS MODIFY PHARMACOLOGY ACTIONS

DR DATTEN BANGUN, MSc,Sp.FKDept.Farmakologi & Therapeutik

Fak.Kedokteran BiomedisUSU,MEDAN

Purpose of Drug Therapy

• “… to prevent, control or cure various disease states.”

• To achieve this, the right drug dose must be delivered to the tissues

• Every doctor must know…– speed of onset of drug action– intensity of drug effect– duration of drug action

Key Points

• The most important properties of an ideal drug are: effectiveness, safety, and selectivity.

• If the drug is not effective, it should not be used.• There is no such drug as safe drug: all drugs can cause

harm.• There is no such thing as selective drug: all drugs can

cause side effects.• The objective of drug therapy is to provide maximum

benefit within minimum harm.• Because all patients are unique, drug therapy must be

tailored to each individual.

General ConceptsDrug Dose

Administration

Drug Effect or Response

Pharmaceutical

Pharmacokinetics

Pharmacodynamics

Pharmacotherapeutics

Disintegrationof Drug

Absorption/distributionmetabolism/excretion

Drug/ReceptorInteraction

Therapeutic Objective

To provide maximum benefit with minimum harm

Factors that determine Intensity of Response

* Administration- dosage size and route* Pharmacokinetic processes* Pharmacodynamics* Individual Variations

Factors that determine the intensity of drug response

FACTORS MODIFYING DRUG ACTION

I. Physiological Factors. II. Pathological Factors (Diseases). III. Genetic Factors. IV. Environmental Factors. V. Interaction with other drugs.

FACTORS MODIFYING DRUG ACTIONS

Individuals vary in drug effect from time to time & from other individuals

Nature of systemic effects of drugs depends on following factors:Physiological factors (age, sex, pregnancy, lactation, body wt., food)Pathological state (kidney or liver disease)Environmental factors

cont.

Psychological /emotional state

Interaction with other drugs (drug-drug interactions)

I. Physiological factors

i) Age Extreme of age show extreme drug

sensitivity Newborn babies & elderly= greater & more

prolonged effect of drugs b/c of less efficient drug metabolism & renal functions

InfantsPremature infants= poor renal & hepatic functions more

sensitive to various drugs

E.g., Chloramphenicol = Gray baby syndrome

(inadequate metabolism) Ampicillin & morphine = GIT absorption

(less acidity) Tetrycycline = staining of teeth Corticosteroids = retardation of growth in

children

Elderly

• Renal & hepatic function decline slowly after middle age

• Activity of hepatic microsomal enzymes decline with age

• Vd of lipid soluble drugs increases• Elderly require less due to degenerative

changes in kidney, liver, brain, heartCont.,

E.g., Diazepam & benzodiazepines = t1/2 Digoxin = Vd

Benzodiazepines= more confusion & less sedation in elderly

Hypotensive dugs= postural hypotension in elderly

ii) Sex/Gender

• Response & dose= different in men & women• Metabolism of some drugs= less in women

(more adipose tissues)E.g., alcohol, diazepam • Women require lesser dose than male

Pregnancy• Causes several physiological changes that influence drug

disposition.

• Volume of drug distribution is increased(total body water may increase by up to 8 liters) providing large space for water soluble drugs.

Maternal plasma albumin concentration is reduced,more free drugs will be available

• Metabolic rate is increased, so the free drugs will be available for elimination.

• Cardiac out put is increased, leading to increased renal

blood flow and glomerular filtration and increased renal elimination of drugs.

• Lipophilic molecules readily traverse placental barrier. Drugs that are transferred to fetus are slowly eliminated.

iii) Pregnancy• Avoid drugs during pregnancy due to teratogenic

effectsReasons• Lipophilic drugs cross placental barrier • CO • GFR & renal elimination • Vd• Metabolism of some drugs

E.g., pregnant uterus becomes more sensitive to oxytocin

Pregnancy Safety Index (US FDA)Category A: - controlled studies in women (+) - fail to demonstrate a risk to the fetus in 1st semester and

laterCategory B: - animal- reproduction studies : * no foetal risk, but no controlled studies in

pregnant women * shown an adverse effect, but not confirmed

in controlled studies in women in 1st semester or laterCategory C:

- studies in animal revealed adverse effect (teratogenic or embryogenic or other)

- no controlled studies in women Drugs should be given only if the potential

benefit justifies the potential risk to the fetus

Pregnancy Safety Index (US FDA)

Category D: - there is positive evidence of human foetal risk, but the benefits

for the pregnant women may be acceptable (if the drug is needed in a life –threatening situation)

Category X: - studies in animal and human being foetal

abnormalities - evidence of foetal risk based on human experience - the risk of the use of the drugs in pregnant women

outweights any possible benefit The drug is contraindicated in women who are or

may become pregnant

iv) Lactation

Avoid drugs during lactation due to harm to baby

Drugs easily appear in milk but < therapeutic dose

E.g., tetracycline, sedatives, hypnotics, opoids

V) Body wt./surface area & size

• Conc. Of drug at site of action=ratio b/w body wt. & amount of drug

• D/f quantity of drug for light & heavier persons

• D/f quantity of drug for smaller & larger persons

• Low amount of drug for smaller perosns

vi) food

• Some drugs have interaction with food and they alter the response of drug

• E.g., toxic symptoms appear after eating of cheese, red wine & chicken liver if patient is taking MAOI (more release of NA=fatal cerebral hemorrhage)

Food Presence of fatty food in stomach delays gastric

emptying,the plasma concentration of rifampicin and ampicillin may be much reduced if taken on full stomach

Calcium in milk interferes with absorption of tetracyclines and iron.

Substituting protein for fats and carbohydrates in diet ,increases drug oxidation rates.

Charcoal grilled beef, cabbage, alcohol increases metabolism

Protein malnutrition affects pharmacokinetics of several drugs.

Citrus flavinoids in grape fruit (but not in orange juice) significantly increases absorption of cyclosporin calcium antagonists and probably other drugs

Metabolism – Interaction with food

• Cytochrome P-450 in GI, liver Grapefruit juice made from frozen concentrate will alter this enzyme

• Many drugs for AIDS, HTN

• Effects occur 24 hours after ingestion

Grapefruit Inhibits Metabolism of Many Drugs

• Inactivates metabolizing intestinal enzyme resulting in enhanced activity and possible toxicity

• Effect persists for 72 hours so it is not helpful to separate the drug and the grapefruit

• Many hospitals and health care centers have taken grapefruit products off the menu entirely

• Pathological condition modify drug action

E.g., impaired renal function = drug excretion = drug accumulation

Liver disease= metabolism of drug=accumulation

Cont.

II. Pathological state

PATHOLOGICAL FACTORS

• DISEASES can cause individual variations in drug response.

• Pharmacokinetic variations; Absorption: • Gastric and intestinal stasis during an attack of

Migraine interferes absorption of drugs

• Resection of gut may lead to malabsorption of iron,folic acid and fat soluble vitamins and of vit B12 after ileal resection

• Diarrhea increases the motility of the gut and decreases absorption.

• Hypoalbuminaemia from any cause such as nephrotic syndrome, burn,malnutrition,sepsis allows higher proportion of albumin free drug in plasma which is readily available for metabolism and elimination but there can be risk with initial dose for drugs which are to be highly protein bound

•

• Disease can cause pharmacokinetic or pharmacodynamic variation

a) PK variation Variation in absorption

Gastric statis –in migraineMalbsorption ---ileal or pancreatic disease

Cont.

Variation in distribution

• Altered PPB of phenytoin in chronic renal failure (binding of phenytoin to PPB

Variation in metabolismHepatic cirrhosis & portal HTN

Variation in excretionAcute and /or chronic renal failure

Pharmacodynamic alterations

Variation in receptors• In mysthania gravis, nephrogenic diabetes inspidus,

familial hypercholesterolemia

III. Genetic factors

• It affects drug action due to genetic differences among the races & certain persons in same population

• Genetic variation is an important source of PK variability

Examples:a) Genetic polymorphism= fast/slow acetylators

(hydralazine, procainamide, isoniazid)Cont.

• Plasma choline estrase variant (suxamethonium)

• Hydrooxylase polymorphism (extensive or poor metabolism of debrisoquine)

Ethnic differences in drug metabolism = propranolol, hemolytic anemia due to some oxidizing agents (primaquine, sulphonamides)

• Plasma choline estrase variant (suxamethonium)

• Hydrooxylase polymorphism (extensive or poor metabolism of debrisoquine)

Ethnic differences in drug metabolism = propranolol, hemolytic anemia due to some oxidizing agents (primaquine, sulphonamides)

G6PD (glucose-6-phosphate dehydrogenase) enzyme deficiency

• X-chromosome-linked • Can lead to neonatal jaundice, hemolytic anemia or

acute hemolysis• Most common in African, Middle Eastern, and

Southeast Asians• Also called favism• Fava beans or pollen, Vitamin K or Vitamin C can

cause hemolysis

IV. Environmental factors

Microsomal enzyme inducers

e.g., Hydrocarbons in tobacco smoke, charcoal broiled meat induce CYP1A

Smokers metabolize drugs more rapidly than non smokers

Temperature• Addition of mild to moderate hypothermia

decreases the systemic clearance of CY450 metabolizes drugs between 7-22% per degree Celsius below 37c during cooling. The addition of hypothermia decreases the potency and efficacy of certain drugs .

• The therapeutic index of certain drugs is narrowed during hypothermia.

• Therapeutic hypothermia has shown decrease in neurologic damage in patients experiencing cardiac arrest.

Timings

• It has been observed that endogenous body clock (circadian cycle) may affect the response of the drug.e.g. In CHD(coronary heart diseases) short acting calcium channel blockers seem to be less effective than beta blockers in reducing ischemic events during the night and early morning

Psychological Factors

• Psychological factors can influence individual responses to drugs.

• When placebo drugs are given patients receiving them can report therapeutic and adverse effects.

• Another factor can be patient’s willingness to follow prescribed dosage regimens.

Psychological state

• General anesthetics required in dose for nervous & anxious patients

• Higher doses of chlorpromazine needed in schizophrenics

• Placebos (inert dosage form) produce therapeutic benefits in psychomotor angina pectoris & bronchitis in asthma

Interaction with other drugs

• Administration of one drug (A) can alter action of another drug (B) by PK or PD mechanisms

• This is c/d drug-drug interaction• May be desired or beneficial like multidrug

treatment of tuberculosis• Or undesirable or harmful

Gender• Evidences show that men and women may

respond differently to same drugs

• This may be due to body size, and amount of body fats.

• But there are also some less easily explained differences in gender –specific drug response

• Aspirin shows greater benefit in men than women in cardiovascular diseases

• There appears to be difference in the activity of liver enzymes b/w men and women

• Since the activity of enzymes vary that can result in major difference in drug response

• This difference in liver activity may explain why women routinely wakes up from general anesthesia several minutes before a man given an equal dose.

It has been observed that women with red hair and fair skin are particularly responsive to effects of the analgesic Pentazosine than man of same character.

Interaction out side the body

• Drugs are added to reservoir or syringes to make drugs soluble they are prepared in salt forms, mixing these drugs may lead to precipitation (incompatibility)

• Dilution in reservoir may also lead to loss of stability.

• Protamine in zinc may bind with soluble insulin and delay its effects.

PHARMACOKINETIC Factors• Drug act remotely from target site to alter plasma

concentratione.g. enzyme induction /inhibition

interaction may be synergistic or antagonistic.

Drug interaction can occur at

1. out side the body2. At site of absorption3. During drug distribution4. During drug metabolism5. During drug excretion.6. On receptor or body system.

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PHARMACODYNAMIC INTERACTIONS• Both drugs act at same target site exerting synergism

or antagonism

• Drugs may act at same or different receptors or process.

• eg alcohal + benzpdiazepines (sedation)

• Morphine + Naloxone ( to reverse opoid overdose)

• Rifampicin + INH ( effective anti TB combination.)

Thank you for your attention