CHRONOTHERAPEUTICS

Question 1

DRUG EFFECTS AND CIRCADIAN RYTHM?

Answer 1

• DRUG EFFECTIVENESS DIFFERS BY THE TIME OF THE DAY (IMPORTANT WHEN YOU ADMINISTER SOME DRUGS, EFFECTIVENESS WON’T BE THE SAME E.G. IN THE MORNING AND IN THE EVENING)
• BECAUSE E.G. ABUNDANCE OF SOME RECEPTORS VARIES ACCORDING TO CIRCADIAN RYTHMS, SO IF A DRUG TARGETS THEM THE TIME OF ADMINISTRATION IS IMPORTANT)
• NOT ALWAYS FOLLOWED BY HOSPITALS, NEGLECTING THE EVIDENCE FOR WHEN IT IS BEST TO USE A CERTAIN DRUG

Question 2

BIOEQUIVALENCE?

Answer 2

Bioequivalence is a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two proprietary preparations of a drug. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same (COMPARISON OF BIOAVAILABILITY OF 2 OR MORE DRUGS CONTAINING THE SAME ACTIVE INGREDIENT)

Question 3

DETERMINANTS OF PHARMACOKINETICS?

Answer 3

ADME

ABSORPTION (THE MOVEMENT OF DRUG FROM THE SITE OF ADMINISTRATION TO THE BLOOD CIRCULATION)

DISTRIBUTION (TRANSPORT OF DRUG FROM INTRAVASCULAR TO EXTRAVASCULAR SPACE)

METABOLISM (CHEMICAL TRANSFORMATION OF DRUGS)

EXCRETION (REMOVAL OF DRUG, UNCHANGED OR METABOLISED)

+ SOMETIMES T ADDED (FOR TOXICITY, ADMET)

ALL 5 UNDER THE INFLUENCE OF CIRCADIAN CLOCK/RYTHM!!!!!!!!!!!!!!

Question 4

WHICH PROCESSES ORAL DRUGS ARE SUSCEPTIBLE TO HAVE STRONG CIRCADIAN RYTHMS, THUS INFLUENCING DRUG PHARMACOKINETICS?

Answer 4

• GASTRIC pH
• GASTRIC EMPTYING
• GASTRIC BLOOD FLOW
• GUT MOTILITY
• BILE SYNTHESIS AND EXCRETION
• LIVER DRUG METABOLISM
• RENAL BLOOD FLOW
• GLOMERULAR FILTRATION RATE
• DRUG TRANSPORT
• URINE Ph

Question 5

EXAMPLE OF DRUG MOLECULES THAT HAVE BEEN SHOWN TO BE UNDER CIRCADIAN CONTROL IN SOME ASPECT - THEOPHYLLINE?

Answer 5

THEOPHYLLINE:

• PDE INHIBITOR
• ADENOSINE A2BETA INHIBITOR
• USED AGAINST ASTHMA
• Theophylline is a type of medicine called a bronchodilator
• AIRWAY CALIBER IS UNDER CIRCADIAN CONTROL, REACHING MAXIMUM CONTRICTION AT AROUND 4AM; THIS CONSTRICTION IS MUCH STRONGER IN ASTHMA PATIENTS THAN HEALTHY INDIVIDUALS, LEADING TO COUGHING
• THEOPHYLLINE IS THEREFORE MORE EFFECTIVE IF TAKEN IN THE EVENING (IF SAME DOSE TAKEN IN THE MORNING, EFFECTS WON’T BE THE SAME)

Question 6

EXAMPLE OF DRUG MOLECULES THAT HAVE BEEN SHOWN TO BE UNDER CIRCADIAN CONTROL IN SOME ASPECT - APAP AKA ACETAMINOPHEN AKA PARACETAMOL AKA TYLANOL (BRAND NAME)?

Answer 6

• MOST COMMON ANALGESIC
• RESPONSIBLE FOR HALF OF ALL ACUTE LIVER FAILURES IN THE US

APAP MECHANISM OF HEPATOTOXICITY:

• SOME APAP GETS ELIMINATED, BUT MAJORITY GOES TO LIVER (1ST PHASE METABOLISM)
• IN THE LIVER, IT’S IN THE NAPQI FORM, HIGHLY REACTIVE
• SOME NAPQI CONVERTED TO GST AND ELIMINATED
• SOME NAPQI LEADS TO TOXICITY (LEADING TO CELLULAR NECROSIS)
• THE EXTENT OF TOXICITY ASSOCIATED WITH THE CLOCK (WHEN THE CLOCK GENE IS DEACTIVATED, THERE IS NO TOXICITY, PROVING ASSOCIATION)
• HUMANS WOULD LIKELY BE MOST SUSCEPTIBLE TO APAP TOXICITY IN THE MORNING/BEFORE NOON/AROUND NOON

Question 7

HALF LIFE OF MOST DRUGS THAT TARGET CIRCADIAN GENES?

Answer 7

< 6 HRS

Question 8

A1/A2a AGONISTS?

Answer 8

Alpha-adrenergic agonists are a class of sympathomimetic agents that selectively stimulates alpha adrenergic receptors. The alpha-adrenergic receptor has two subclasses α1 and α2. Alpha 2 receptors are associated with sympatholytic properties. Alpha-adrenergic agonists have the opposite function of alpha blockers. Alpha adrenoreceptor ligands mimic the action of epinephrine and norepinephrine signaling in the heart, smooth muscle and central nervous system, with norepinephrine being the highest affinity.

Question 9

CHRONODRUGS/CHRONOMEDICINE?

Answer 9

Chronomedicine is best defined as the application of chronobiology in order to understand the pattern of disease, which can be related to disturbances of circadian rhythm. The field of chronomedicine explores the interaction between biological rhythms, medicine and drugs.

Most knowledge of medications has been derived from single-and multiple-dose investigations in which pharmacokinetic and pharmacodynamic phenomena have been evaluated following one, usually, daytime drug administration. Chronopharmacologic studies involving the evaluation of such phenomena after each of several different clock-hour treatments during the day-and night time.