FACTORS MODIFYING DRUG FACTORS MODIFYING DRUG ACTIONS & EFFECTSACTIONS & EFFECTS

Assoc. Prof. Galya Stavreva, MD, PhDExperimental & Clinical Pharmacology

MU − Pleven (2015)

Lecture Outline Factors Modifying Action of Drugs

• Drugs’ factors• Hosts’ factorsPhysiological FactorsPathological 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.

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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

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

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.

2.1 Drugs in Neonates

PEDIATRIC PHARMACOLOGY

CHILDREN ARECHILDREN ARENOTNOTSMALL ADULTS!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

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

Approximate child’s dose =Body surface area of the child X adult dose / 1.7

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.

2007 Thomson Delmar Learning, a division of Thomson Learning Inc.

Anterior view of the location of the vastus lateralis muscle in a young

child.

Remember:Remember:•Children are vulnerable.Children are vulnerable.•Be kind and patient.Be kind and patient.•Enjoy the children; Enjoy the children; you will receive more you will receive more than you give.than you give.

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 higherserum 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 waterbody water Vd for Vd for

hydrophilic drugshydrophilic drugsethanol, lithium

lean body masslean body mass Vd for for drugs Vd for for drugs that bind to that bind to musclemuscle

digoxin

fat storesfat stores Vd for lipophilic Vd for lipophilic drugsdrugs

diazepam, trazodone

plasma protein plasma protein (albumin)(albumin)

% of unbound % of unbound or free drug or free drug (active)(active)

diazepam, valproic acid, phenytoin, warfarin

plasma protein plasma protein

((11-acid -acid glycoprotein)glycoprotein)

% of unbound % of unbound or free drug or free drug (active)(active)

quinidine, propranolol, erythromycin, amitriptyline

Polypharmacy Defined

• Treatment with multiple medications (> 5meds 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 orunnecessary use of medications andproviding 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 complianceReasons 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 biotransformationof drugs, metabolised by CYP3A4 (methyprednisolone).• The microsomal oxidation of carbamazepineto 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 (blastogenesis) the law of all-or-none applies. •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 FetalDevelopment

Thalidomide (1957–1961)

In 1962, the United States Congressenacted laws requiring tests for safety during pregnancybefore a drug can receive approval for sale in the U.S.

USA: 17babies

Thalidomide is racemic: it contains both left- and right-handedisomers. The (R) enantiomer is effective against morning sickness.The (S) is teratogenic and causes birth defects. The enantiomerscan interconvert in vivo. The (S) enantiomer intercalates (inserts)into the DNA in G–C (guanine – cytosine) rich regions.

(S)-thalidomide (R)-thalidomide

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 any possible benefit (statins, dinoprost).

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 FeedingDrugs 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)Lactation Risk Categories – LRC)

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

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

L1 – safest: Paracetamol, Ibuprofen, Epinephrine.

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

L2 – safer: Diclofenac, Fentanyl, Cetirizine, Omeprazole, cephalosporins.

L3 – moderately safe: Acarbose, Acetylsalicylic acid, Indometacin, Codeine, Morphine, Midazolam, Triazolam, Acebutоlol, Dimetinden. L4 – hazardous: Colchicine, Lithium, Ergobrevine, Ergotamine.

L5 – contraindicated: ACE inhibitors (enalapril etc.)

PRCsPRCs LRCsLRCs

AA:: controlled studies controlled studies show no riskshow no risk BB:: no evidence of risk in no evidence of risk in humanshumans CC:: risk cannot be ruled risk cannot be ruled outout DD:: positive evidence of positive evidence of riskrisk XX:: contraindicated in contraindicated in pregnancypregnancy

L1L1:: safest safest

L2L2:: safer safer

L3L3:: moderately safe moderately safe

L4L4:: possibly hazardous possibly hazardous

L5L5:: contraindicated 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 FactorsDiseases 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 DiseaseRenal 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

NephrotoxicityReduction 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)

There is no reliable biomarker describing hepatic impairment.

In chronic liver disease :• serum albumin is the most useful index of drug

metabolizing capacity or prothrombin time also shows a moderate correlation with drug clearance of drugs.

• 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).

3.2. Liver disease

Influence of liver disease• Altered pharmacokinetics

a) increased bioavailability- reduced first-pass metabolism- decreased first-pass activation of pro-

drugsb) decreased protein bindingc) 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 diseasePrescribing 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 POLYMORPHISMThe existence in a population of two ormore phenotype with respect to theeffect 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

peripheralneuropathy; procainamide-induced lupus.• Rapid acetylator phenotype - hepatitis.

•Pseudocholinesterase deficiency Succinyl choline (Sk. muscle relaxant)•Succinylcholine apnea due to paralysis of respiratory muscles.•Malignant hyperthermiaBy succinyl choline due to inherited inability to chelate calcium by sarcoplasmic reticulum.abnormal Ca release, muscle spasm, temp.

Genetic Factors

Genetic Factors

•Deficiency of Glucose–6 phosphatedehydrogenase (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 tetracyclinHigh 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%20Modification.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, 7th 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)