FACTORS MODIFYING DRUG ACTIONS & EFFECTS

Assoc. Prof. Galya Stavreva, MD, PhD Experimental & Clinical Pharmacology MU − Pleven (2015)

Lecture Outline

Factors Modifying Action of Drugs

• • • • Drugs’ factors Hosts’ factors Physiological Factors Pathological Factors (Diseases) Genetic Factors Environmental Factors Drug interactions A multitude of host, drug & environmental factors influence drug response. Understanding of these factors can guide choice of appropriate drug & dose for individual patient.

• • • • • •

1. Drugs’ factors

Physical properties (physical state, crystal structure, size of particulate solid drugs) determine their absorption and bioavailability, as well - the power of the drug effect.

Physico-chemical properties: lipophilicity, pK-value, the Michaelis affinity constant (Km) - the affinity of an enzyme to its substrate. When the value of Km is the high affinity of the enzyme is low, and vice versa.

Сhemical structure Drug dosage forms Dose: dosis pro dosi; dosis pro die; dosis pro cura (cursu) Repeated and prolonged drug administration: cumulation, tolerance.

2. Physiological Factors

• • • • • • Age Sex Pregnancy Body weight Lactation Food

Drugs and Age of Patients

• • • • • • • Most drugs are developed and tested in young to middle-aged adults Drug consumption is different Dosage regimen cannot be based on body weight or surface area extrapolated from adult dosage Therapeutic disasters:

Gray Baby Syndrom: chloramphenicol Thalidomide: Teratogenic effect Isotretinion (Accutane®): Teratogenic effect

Thalidomide prescribed as a sedative or hypnotic. Afterwards, it was used against nausea and to alleviate morning sickness in pregnant women. Thalidomide became an over the counter drug in Germany on October 1, 1957. Shortly after the drug was sold in Germany, between 5,000 and 7,000 infants were born with phocomelia (malformation of the limbs). Only 40% of these children survived. Throughout the world, about 10,000 cases were reported of infants with phocomelia; only 50% of the 10,000 survived.

AGE PERIODS

• • • • • • • Premature infants:< 36 weeks gestation Full-term infants: 36-40 weeks gestation Neonates: 1st 4 weeks post-natal Infants: 5-32 weeks post-natal Children : 1-12 years Adolescents: 12-16years Geriatrics: > 65 years

Changes in body proportions & composition with growth and aging

70,0% 61,2% 64,6% 60,0% 54,0% water 80,0% protein 13,4% 12,0% 6,0% 2,0% premature (2 kg) 13,4% 3,2% full term (3.5

kg) 12,0% 13,4% 16,5% 18,1% 30,0% 22,4% 13,0% 18,0% 3,0% 4,3% 5,5% 4,0% 1 yr (10 kg) 15 yr (60 kg) adult (70 kg) elder (65 kg) fat minerals From Puig M: Body composition and growth. In Nutrition in Pediatrics, ed. 2, edited by WA Walker and JB Watkins. Hamilton, Ontario, BC Decker, 1996

2.1 Drugs in Neonates

  High body water: >70% of BW gastric acid secretion liver microsomal enzymes; limited metabolic clearance: glucuronidation pathway is not developed the first year plasma protein binding - increase in unbound drug in serum Lower body fat: highly lipid-soluble drugs distribution is diminished (diazepam) GFR & tubular secretion Immaturity of BBB in neonates.

PEDIATRIC PHARMACOLOGY

CHILDREN ARE NOT SMALL ADULTS!

• Compliance problem • Poor communication • Inconvenient dosage forms • Unpalatability • Unreliable measurement • Spillage, etc • Medication dosage: BW versus BSA

There are a few formulae for calculation of dose of the children under 12 years.

• Clark's Rule = •

(Weight of the child in kg /150) X Adult dose

Dilling's Formula= •

(Age/20) X Adult dose

Young's Rule= •

(Age X Adult dose)/Age+12

The dose required for the age between 12 to 16 years will be from ½ to 2/3 of the adult dose.

• • • Dose of sodium bicarbonate for a child of 6 years Adult dose of sodium bicarbonate is 1g (1-4 g).

Young’s Rule the required dose will be = 6 x 1/ (6+12) = 6/20 =0,3g

Body Surface Area for Drug Dosage

• • Calculations based on the child’s weight are inaccurate Physiological differences (body water, fat): larger doses of some drugs on a mg/m2 basis  BSA is calculated from height and weight (nomogram) •  The surface area rule is the most accurate

Approximate child’s dose =

Body surface area X adult dose / 1.7

Approximate child’s dose =

Body surface area of the child X adult dose / 1.7

Calculation of Drug Dosages, 7th Edition Ogden, Sheila J Nomogram image, p. 364, Copyright Elsevier for C4203

PEDIATRIC PHARMACOLOGY

• GIT absorption of ampicillin and amoxicillin is greater in neonates due to decreased gastric acidity.

• Chloramphenicol – Gray-baby syndrome – (inadequate glucouronidation of chloramphenicol with drug accumulation).

• Sulfonamides – Hyperbilirubinemia & Kernicterus • The children can tolerate iron, belladonna preparations relatively better than adult but they can not tolerate opium and morphine preparations except in very small doses.

PEDIATRIC PHARMACOLOGY

• • • • Tetracyclines - permanent teeth staining Corticosteroids - growth & development retardation Antihistaminics - hyperactivity.

Administration of drugs during the first year of life can be a challenge due to rapid changes in body size, body composition, and organ function.

Intramuscular Injections

• • Vastus lateralis is the preferred site for children under the age of 3.

Ventrogluteal site is the preferred site for children over the age of 3.

– The child should be walking.

Remember:

• Children are vulnerable.

• Be kind and patient.

• Enjoy the children; you will receive more than you give.

Anterior view of the location of the vastus lateralis muscle in a young child. 2007 Thomson Delmar Learning, a division of Thomson Learning Inc.

2.2. GERIATRIC PHARMACOLOGY

• • • • • • • Elderly constitute 12% of the population but consume 31% of prescribed drugs in US Elderly more sensitive to drugs and exhibit more variability in response Altered pharmacokinetics Multiple and severe illnesses Multiple drug therapy and usage Poor compliance

“Individualization of treatment is essential: each patient must be monitored for desired responses and adverse responses, and the regime must be adjusted accordingly”

Changes in Geriatric Patients

• • • • body fat (25-30%) - reduces plasma levels of lipid soluble drugs total body water by 25% - increases concentration of water soluble drugs and intensity of response; greater risk for dehydration concentration of serum albumin- malnourishment decreases albumin and results in increased drug levels Metabolism: hepatic functions in elderly and drug levels increase (diazepam, theophylline)

Changes in Geriatric Patients

• Stomach pH ; blood flow ; decrease in gut motility (slow onset) • In the elderly, muscle decreases by 25%. • Excretion: decline (40-50%) of renal function in elderly may lead to higher serum drug levels and longer drug half-life. Reduced renal clearance of active metabolites may enhance therapeutic effect or risk of toxicity (e.g., digoxin, lithium, aminoglycosides, vancomycin)

Pharmacodynamic Changes

• Alterations in receptor levels may change: Beta-blockers less effective in the elderly patients.

• Age-related changes resulting in sensitivity to certain classes of drugs place the elderly at risk for adverse drug reactions • CNS depressants (e.g., benzodiazepines) resulting in delirium, confusion, agitation and sedation • • • Anticoagulants and hemorrhage e.g., in combination with NSAIDs, salicylates.

Alpha-blockers resulting in orthostatic hypotension Anticholinergic medications resulting in dry mouth, constipation, urinary retention, blurred vision, confusion

Effects of Aging on Volume of Distribution (Vd) Aging Effect Vd Effect Examples    body water lean body mass fat stores  plasma protein (albumin)  plasma protein (  1 -acid glycoprotein)  Vd for hydrophilic drugs ethanol, lithium  Vd for for drugs that bind to muscle  Vd for lipophilic drugs digoxin diazepam, trazodone  % of unbound or free drug (active)  % of unbound or free drug (active) diazepam, valproic acid, phenytoin, warfarin quinidine, propranolol, erythromycin, amitriptyline

Polypharmacy Defined

• Treatment with multiple medications (> 5 meds per regimen) for a variety of conditions and symptoms that include excessive or unnecessary medications that place the patient at risk for an adverse drug reaction.

Balance between avoiding excessive or unnecessary use of medications and providing beneficial therapies.

Increased incidence of chronic conditions as the • • • • • • • • Diabetes Hypertension Heart Failure Ischemic Heart Disease Asthma/COPD Arthritis Alzheimer’s Disease Urinary problems

Adverse Drug Reactions in Geriatrics

• Seven times more likely in elderly • 16% of hospital admissions • • • • 50% of all medication-related deaths Drug accumulation secondary to reduced renal function Polypharmacy : dangerous practice (drug-drug interactions) Greater severity of illness Cont.

• • • • Presence of multiple pathologies Increased individual variation Inadequate supervision of long-term therapy Poor patient compliance Reasons for non-compliance include complex drug regimens, intentional non-adherence, and dementia and cognitive impairment.

Start with a low dose and titrate slowly • • • • Simplify regimen (once or twice daily dosing) Consolidate medications Use of blister packs, pill boxes, calendars, watches, other reminders Reduce costs (e.g., generics, pill splitting)

2.3. SEX

• Females body size ; D • Testosterone the rate of biotransformation of drugs • metabolism of some drugs in female (Diazepam) • Females are more susceptible to autonomic drugs (estrogen inhibits choline estrase) • Gynaecomastia is ADR occuring only in men (metoclopramide, chlorpromazine, digitalis) • Antihypertensive drs (clonidine, beta-blockers, diuretics) interfere with sexual function in males.

2.4. Drug Therapy During Pregnancy

Drug treatment in pregnancy is complicated mainly by two aspects: • general concerns do exist regarding potentially harmful effects of drugs on the embryo. The fear of a second disaster as with thalidomide still present; • physiological changes occuring during pregnancy may have an influence on pharmacokinetics and pharmacodynamics and subsequently efficacy of drugs.

1/3 to 1/2 of pregnant women take at least one prescription drug and most take more • Some used to treat pregnancy side effects –Nausea –Pre-eclampsia • –Constipation Some medications used to treat chronic disorders –Hypertension –Diabetes –Epilepsy –Cancer • –Infectious Diseases Drugs of abuse

Pregnancy

• GI transit time is prolonged by about 30-50%. This could alter the rate and amount of absorption and the plasma concentration of drugs, which are either given as slow release forms or those, which are metabolised in the gut wall.

• Vd almost doubles during the later course of pregnancy ; slight increment in renal clearance.

• treatment failures with ampicillin in pregnancy can be due to lower plasma concentrations.

Pregnancy

Plasma concentration/time profile of ampicillin, once after i. v. administration of 500 mg after delivery (= week 0, no pregnancy) and at week 40 of gestation; note, that a dose of 935 mg has been given at week 40 to achieve a comparable Cmax and AUC.

P. Thurmann, Drug treatment in pregnancy. Pharmaca Jugoslavica. 2000;38:59-63.

Pregnancy

• Progesterone influences biotransformation • of drugs, metabolised by CYP3A4 (methyprednisolone).

The microsomal oxidation of carbamazepine • • to it's active metabolite doubles during pregnancy. Cardiac output GFR and renal elimination of drugs.

Lipophilic drugs cross placental barrier & slowly excreted.

The concept of teratology

• One of the most important factors determining the sensitivity of the embryo

is the gestational age:

• During the first 2 weeks applies.

(blastogenesis)

the law of all-or-none • During day 15 to 60 malformations maybe induced, depending on the exact date of exposure

(organo-genesis, embriogenesis).

Birth defects are known to occur in 3-5% of all newborns.

Teratogenesis ( teras, meaning 'monster' or 'marvel‘) • Sensitivity to drugs decreases during the

foetal period

(after 9 week), later exposure to xenobiotics may induce functional defects or growth retardation.

Effects of Teratogens at Specific Stages of Fetal Development

Thalidomide (1957–1961)

USA: 17 babies In 1962 , the United States Congress enacted laws requiring tests for safety during pregnancy before a drug can receive approval for sale in the U.S.

(S)-thalidomide (R)-thalidomide

Thalidomide is racemic: it contains both left- and right-handed isomers. The (

R

) enantiomer is effective against morning sickness .

The (

S

) is teratogenic and causes birth defects .

The enantiomers can interconvert in vivo .

The (

S

) enantiomer intercalates (inserts) into the DNA in G–C (guanine – cytosine) rich regions.

Drugs with documented teratogenic or embryotoxic effect P. Thurmann, Drug treatment in pregnancy. Pharmaca Jugoslavica. 2000;38:59-63.

FDA pregnancy category • A - Controlled studies in women fail to demon-strate a risk to the fetus in the first trimester, and the possibility of fetal harm appears remote (

only 8 drugs: folic acid, vit A, vit C, vit D in physiol. D)

• B - Animal studies do not indicate a risk to the fetus and there are no controlled human studies, or animal studies do show an adverse effect on the fetus but well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus (

250 medicines;

penicillins, erythromycin, metthyldopa, lansoprazole).

Cont.

• C - Studies have shown that the drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.

However, potential benefits may overweight the potential risk (700 drs; atenolol, aminophylline).

• D - Positive evidence of human fetal risk exists, but benefits in certain situations (e.g., life-threatening situations or serious diseases for which safer drugs cannot be used or are ineffective) may make use of the drug acceptable despite its risks

(phenytoine,

metotrexate, doxiciclin, enalapril, cyclophosphamide).

Cont.

• X - Studies in animals or humans have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk clearly outweighs dinoprost).

any possible benefit

(statins,

Whereas categories A to C define the degree of risk, categories D and X offer a risk-benefit evaluation.

Some recommended drugs for selected indications during pregnancy P. Thurmann, Drug treatment in pregnancy. Pharmaca Jugoslavica. 2000;38:59-63.

2.5. Drug Therapy during Breast Feeding Drugs get through breast milk and can effect infant • Little research done on this aspect because of dangers involved in these studies - Adverse effects are described (penicillin, tetracycline) • Concentration of drugs differ in milk. Lipid soluble drugs are in higher concentration; Milk is weakly acidic: weak bases are concentrated.

• Generally most drugs are in too low a concentration to be harmful to infant.

• Some drs can lead to toxicity in the child if enter the milk in pharmacological quantities - laxatives. Cont.

 Some drugs are contraindicated because of known risk: nicotine, amphetamines, lithium, marijuana, anticancer drugs.

 Some drugs to be avoided: amiodarone, TTC, quinolones, aspirin, benzodiazepines.

 The infant should be monitored if betalytics (bradycardia), corticoids (infants´adrenal functions) or lithium (intoxication) are prescribed to mother.

 Others: metronidazole gives milk an unpleasant taste; bromocriptine and diuretics suppress lactation.

Lactation Risk Categories – LRC)

Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)

LACTATION RISK CATEGORIES (LRC) (Hale, 2004; 2008): L1 –

safest:

Paracetamol, Ibuprofen, Epinephrine.

L2 –

safer:

Diclofenac, Fentanyl, Cetirizine, Omeprazole, cephalosporins.

L3 –

moderately safe:

Acarbose, Acetylsalicylic acid, Indometacin, Codeine, Morphine, Midazolam, Triazolam, Acebut о lol, Dimetinden.

L4 –

hazardous:

Ergotamine.

Colchicine, Lithium, Ergobrevine,

L5 –

contraindicated:

ACE inhibitors (enalapril etc.)

PRCs A : controlled studies show no risk B : no evidence of risk in humans C : risk cannot be ruled out D : positive evidence of risk X : contraindicated in pregnancy L1 : safest LRCs L2 : safer L3 : moderately safe L4 : possibly hazardous L5 : contraindicated

2.6. Species and race

• Rabbits are resistant to atr; rats & mice – to digitalis.

• Afro-americans require higher and mongols – lower D of atr & ephedrine to dilate their pupil.

• Beta-blockers and ACE inhibitors are less effective as antihypertensive in afro americans.

• Around 80% of Asian people have a variant of the gene coding for the enzyme alcohol dehydrogenase.

Alcohol flush reaction (also known as Asian flush syndrome, Asian flush) is a condition in which an individual's face or body experiences flushes or blotches as a result of an accumulation of acetaldehyde.

3. Pathological Factors

Diseases cause individual variation in drug response • • •

Renal and liver insufficiency are the main modulators of drug effect.

Renal failure decreases drug elimination.

Liver failure decreases drug metabolism

3.1. Renal Disease

 Renal excretion is reduced in relation to GFR raised plasma levels • tubular function • Plasma albumin • Drugs (and their metabolites) excreted predominantly by the kidney accumulate in renal failure:digoxin-

lithium- gentamycin- penicillin.

• Risk of toxicity after usual doses: aminoglycosides,

digoxin, lithium, enalapril, atenolol, methotrexate

• CLcr – essential in deciding on an appropriate dose regimen

Prescribing for patients with renal disease • • • • Check the renal status • CLCR Consider how the drug is eliminated • if non-renal elimination accounts for less than 50% of total elimination, than dose reduction will probably be necessary monitor therapeutic and unwanted effects • when appropriate also TDM use potentially nephrotoxic drugs - with special care •

aminoglycosides, NSAIDs, ACEI

Nephrotoxicity

• • • Reduction of GF: NSAID – decreased PGI2 – vasoconstriction of afferent arteriole ACEI – decresed AGII – dillatation of efferent arteries renal vasoconstriction – cyclosporin, amphotericin Chronic interstitial nephritis, papillary necrosis (phenacetin, NSAID) Tubular damage (MTX) Praecipitation (sulphonamides)

3.2. Liver disease

There is no reliable biomarker impairment. describing hepatic • • In chronic liver disease :

serum albumin

metabolizing capacity or shows a moderate correlation with drug clearance of drugs. is the most useful index of drug

prothrombin time

also such indices of hepatic function serve mainly to distinguish the severly affected from the milder cases (in contrast to serum cr or Clcr in renal impairment).

Influence of liver disease

• • •

Altered pharmacokinetics

a) increased bioavailability - reduced first-pass metabolism - decreased first-pass activation of pro drugs b) decreased protein binding c) decreased elimination

Altered drug effect Worsening of metabolic state

Liver Disease

• • Prolong duration of action = ↑ (t1/2).

Plasma protein binding for warfarin, • • tolbutamide; adverse effects.

Hepatic blood flow clearance of morphine, propanolol.

Impaired liver microsomal enzymes diazepam- rifampicin- theophylline

Prescribing for patients with liver disease: • if possible, use drugs that are eliminated by routes other than the liver • response and untoward effects should be monitored (and therapy adjusted accordingly) • predictable hepatotoxins (

cytostatic drugs

) should only be used for the strongest of indications • avoid drugs that interfere with hemostasis (

anticoagulants, aspirin

)

Drug-induced hepatotoxicity

Jiwon Kim. An Overview of Drug-Induced Liver Disease US Pharm. 2005;11:HS-10-HS-21.

http://www.uspharmacist.com/index.asp?show=article&page=8_1634.htm

4. Genetic Factors

• • • •

Pharmacogenetics is the study of the relationship b/w genetic factors and drug response.

All key determinants of drug response (transporters, metabolizing enzymes, ion channels, receptors with their couplers and effectors are controlled genetically.

Pharmacogenomics is the use of genetic information to guide the choice of drug & dose on an individual basis.

It intends 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 drug.

Genetic Factors

•

GENETIC POLYMORPHISM The existence in a population of two or more phenotype with respect to the

•

effect of a drug.

Idiosyncrasy abnormal drug reaction due to genetic disorder.

• Acetylation.

• Oxidation.

• Succinylcholine apnea.

• Glucose 6-phosphate dehydrogenase deficiency.

Genetic Factors

•

Polymorphism of N-acetyl transferase 2 gene results in rapid & slow acetilator status

(acetyl transferase - non-microsomal).

• • Isoniazid, sulphonamides, procainamide, etc.

Slow acetylator phenotype - isoniazid peripheral • neuropathy; procainamide-induced lupus.

Rapid acetylator phenotype - hepatitis.

Genetic Factors

•

Pseudocholinesterase deficiency Succinyl choline (Sk. muscle relaxant)

• Succinylcholine apnea due to paralysis of respiratory muscles.

• Malignant hyperthermia By succinyl choline due to inherited inability to chelate calcium by sarcoplasmic reticulum.

abnormal Ca release, muscle spasm, temp.

Genetic Factors

•

Deficiency of Glucose–6 phosphate dehydrogenase (G-6-PD)

G-6-PD deficiency in RBCs is responsible for hemolytic anemia upon exposure to some oxidizing drugs.

•Antimalarial drug: primaquine, quinine.

•Long acting sulphonamides, nalidixic acid.

•Fava beans ( favism).

5. Chronopharmacology

• The study of rhythmic, predictable-in-time differences in the effects and/or pharmacokinetics of drugs. It investigates the effects/side effects of drugs upon temporal changes in biological functions or symptoms of a disease as well as drug effects as a function of biologic timing.

• Circadian Rhythm. A biological rhythm is an adaptive phenomenon to predictable changes in environmental factors linked to the rotation of the earth around its axis in 24 hours as well around the sun in 365 days.

Circadian rhythms are endogenously driven by biological clocks found in single cells, flowers, animals and men and in which "clock genes" are expressed.

Mammalians circadian pacemaker resides in the paired suprachiasmatic nuclei.

Types of rhythm

• • • • • • Ultradian < 20 h Circadian ~ 24 h Infradian > 28 h Circaseptan ~ 7 days Circamensual ~ 30 days Circannual ~ 1 year

CVS

• • • BP rises about 20% immediately after awaking.

2 hrs after arising are the peak hrs for MI, hemorragic stroke, thrombotic events.

Reasons: physical activity catecholamine level platelet aggregation vascular tone intrisic thrombolytic activity

5. Environmental Factors

• • • Microsomal Enzyme Inducers Tobacco Smoke. Smokers metabolize drugs more rapidly than non smoker.

Pollutants are capable of inducing P450 enzymes, such as hydrocarbons present in tobacco smoke, charcoal broiled meat induce CYP 1A.

Industrial workers exposed to some pesticides metabolize certain drugs more rapidly than who are non exposed. Polychlorinated biphenyls used in industry, cruciferous vegetables also induce CYP 1A

Food-Drug Interaction

• Drug-food interactions may decrease absorption:

Calcium containing foods and tetracyclin

•

High fiber foods reduce absorption

Drug-food interactions may increase absorption: •

High calorie food more than doubles the absorption of squinavir

Drug may cause upset stomach if taken without food –Choose alternative drug? –Increase dose if taken with food? –Take shortly before or after meal?

Food-Drug Interaction

• • Grapefruit juice may inhibit metabolism of certain drugs, raise the blood levels (co administration of grapefruit juice produce a 40% increase in blood levels of felodipine drug for hypertension), and lead to toxicity level.

Grapefruit juice may inhibits cytochrome CYP3A isoenzyme and decrease metabolism of certain drugs: One glass (200 ml) is sufficient.

REFERENCE • • • • • • • • • • • • FACTORS MODIFYING DRUG DOSE-RESPONSE RELATIONSHIP M. Imad Damaj, http://www2.courses.vcu.edu/ptxed/m2/powerpoint/download/Damaj%20DR%2 0Modification.PDF

Body composition and growth. In Nutrition in Pediatrics, ed. 2, edited by WA Walker and JB Watkins. Hamilton, Ontario, BC Decker, 1996 Jiwon Kim. An Overview of Drug-Induced Liver Disease US Pharm. 2005;11:HS-10-HS-21.

http://www.uspharmacist.com/index.asp?show=article&page=8_1634.htm

http://www.medpharm-sofia.eu/ P. Thurmann, Drug treatment in pregnancy. Pharmaca Jugoslavica. 2000;38:59-63.

B. G. Katzung, Basic and Clinical Pharmacology, 12th ed., Appleton&Lange, 2012.

H. P. Rang, M. M. Dale, J. M. Ritter, Pharmacology, 7 th ed., Churchill Livingstone, 2012.

Lippincott's Illustrated Reviews Pharmacology, 4th Edition\Chapter 14 Bailey DG. Grapefruit-medication interactions. CMAJ. 2013 Apr 2;185(6):507-8 Journal of Chronotherapy and Drug Delivery (ISSN: 2249-6785)