Childhood age classes, Tissue Volumes and Other Helpful Facts and Numbers

Neonate

0-28 days

fe of renally cleared drugs

>30%

Amino acids that can be phosphorylated

Serine, threonine and tyrosine (just three!)

Chronic Kidney Disease

GFR <60mL/min/1.73 sqm OR evidence of injury (haematuria or proteinuria)

Surface area of the Small Intestine

Size of a tennis court (250 sqm); 7 metres long

Small Intestine pH

6-7.5 from duodenum to ileum

Plasma Volume

3 L

Blood Volume

7 L

Extracellular water volume

15 L

Intracellular water volume

27 L

Total body water volume

42 L

Infant

>28 days - 12 months

Tissue sequestration volume of distribution

>70 L

Toddler

12-23 months

Preschool Child

2-5 years

School age child

6-11 years

Adolescent

12-17 years

Nephron proximal tubule absorption

100% of filtered glucose and amino acids/proteins, 70% of filtered water and ions (Cl, Na, K, HCO3)

Nephron descending Loop of Henle reabsorption

Water only

(*no solutes reabsorbed*)

Nephron ascending Loop of Henle reabsorption

Solutes (Na, K, Cl, Ca, Mg) only (*no water reabsorbed!*)

Nephron distal tubule and collecting duct reabsorption

Solutes (ions) and water reabsorption

Water reabsorption is regulated by ADH (vasopressin) and aldosterone

Glomerular Filtration Rate in a healthy young adult

120 mL/min

Average GFR of a healthy elderly person 60+ years

75-85 mL/min

CrCl in moderate kidney impairment

< 50-60 mL/min

CrCl in severe kidney impairment

< 30 mL/min

Urine pH range

pH 5-8

Ideal Body Weight

Adjusted Ideal Body Weight

Serum Creatinine Reference Levels (Male and Female)

Male: 60-120 micromol/L

Female: 50-110 micromol/L

Ideal Body Weight Formula (Male and Female)

Male: 50 + 0.9*(height - 152cm)

Female: 45.5 + 0.9*(height - 152cm)

When to adjust dose for renal impairment? And how?

When GFR <60 mL/min

By increasing dose interval or reducing dose

At what age is GI absorption comparable to adults?

By 3 months of age

At what age is enzyme metabolism activity greater than in adults?

At the ages 2-3 years old (toddlerhood)

Which enzymes exhibit increasing activity during pregnancy?

CYP3A4, CYP2C9, CYP2D6, UGT

Which enzymes exhibit decreasing activity during pregnancy?

CYP1A2, CYP2C19, NAT2

The AEIOU of when to initiate dialysis

A: Acidosis

E: Electrolyte disturbance (particularly hyperkalaemia)

I: Intoxication

O: Overload (of volume/fluids)

U: Uremia

The two driving forces of dialysis

Convection and diffusion

Dialysis should be started for patients with what GFR?

GFR <30 mL/min; CKD stages G4 and G5

Drugs banned in sport

Anabolic agents, diuretics, hormones, stimulants

Glucocorticosteroids (oral, injectable, rectal banned, EXCEPT inhaled and intranasal - no exemption required)

Beta-2-antagonists (EXCEPT salbutamol (Ventolin) when inhaled max 6 puffs in 8 hours, max 16 puffs in 24 hours for asthma/allergies; salmeterol (Seretide) max 8 puffs in 24 hours - no exemption required)

Beta-blockers for precision sports

A therapeutic use exemption (TUE) can be applied for at ASDMAC (Australian Sports Drug Medical Advisory Committee)

Best Sports Drug Resources

GlobalDro, Sports Integrity Australia, World Anti-doping Agency

Type A ADR treatment

Withhold and/or reduce dose

Type B ADR

Withhold drug and do not rechallenge (drug is now contraindicated) - use an alternative agent

Type I Hypersensitivity

Ig-E mediated; the foreign substance interacts with the Ig-E of mast-cells and basophils, causing the cells to degranulate and release factors

Anaphylaxis, urticaria (hives/rash), asthma, food allergies, hay fever, dermatitis

Type II Hypersensitivity

Ig-G and Ig-M (antibody) mediated; the foreign substance has interacted with surface receptors of cells, making them appear foreign to the immune system, such that the immune system launches an attack at the cells and causes cell death (they get phagocytosed by macrophages or lysed by cytotoxic cells and the complement system).

Onset of TENS/SJS vs Onset of DRESS

TENS/SJS: 4-28 days of first exposure (within days; within the month!)

DRESS: 2-6 weeks of first exposure

Rule of 3’s for epidemiology of events

If event occurs in 1 in x number of people, then you will have a 95% chance of seeing it occur at least once in 3x number of people.

When to TDM - “ACT”

Age - the very young and very old

Complex/Critical (ICU)/Comorbidities/Concomitant meds

Tricky drug (drug ADME)

What is a biosensor?

A device that measures levels of a substance in situ and produces a signal proportional with the concentration of substance present.

E.g. glucose sensors, INR units, urate sensors, aptamer-based biosensors

Random Testing vs Blanket Testing vs Targeted Testing vs Voluntary Testing

Random Testing: unannounced testing of persons

Blanket Testing: everyone tested at once

Targeted Testing: testing of suspicious persons

Voluntary Testing: people can choose to take the initiative to get tested if they want to

Hospital ICU levels requiring a pharmacist

Levels 4, 5 and 6.

Which drugs bind to which plasma proteins?

Acidic drugs bind to albumin (which has many basic sites)

Basic drugs bind to alpha-1-acid glycoprotein (which is acidic)

Neutral drugs bind to lipoproteins

Average difference of Cmax and AUC between bioequivalent brands

Less than 5%

Bioequivalence means that the…

90% confidence interval of the ratio of Cmax and AUC between brands conform within 0.80 to 1.25

Which drugs are most vulnerable to drug-drug interactions affecting renal clearance?

High fe (renally cleared), net secretion drugs

Where does tubular secretion and tubular reabsorption occur in the nephron?

Secretion into the proximal tubule

Reabsorption from the distal tubule

Which factors affect tubular reabsorption?

Urinary pH (pKa in the middle of 5-8) and urinary excretion rate.

Which drugs should we use with caution in renal impairment?

Drugs with high fe, narrow safety margin, long half-life and active metabolites.

Creatinine Clearance vs GFR?

CrCl makes GFR look better than it is by about 15%.

(CrCl overestimates GFR by about 15%)

Which hepatic zone does drug biotransformation take place?

Zone 3 (centrilobular): surrounding the central vein. This is the most anaerobic zone.

What biotransformed/metabolic by-products are excreted into bile?

Molecules that are polar and over 500 g/mol (the larger the molecule, the more biliary excretion it experiences). E.g. conjugates.

Does reduced CLint affect the bioavailability and AUC of high EH drugs?

Yes!

It does not affect hepatic CL (because it is not a determining factor) but it massively affects bioavailability because high EH drugs experience extensive first pass metabolism usually - so reduced CLint affects the amount of first pass metabolism!

Antidrug antibodies…

Increase clearance of therapeutic proteins; may or may not affect efficacy

FcRn…

prolongs the half-life of monoclonal antibodies. Will not affect peptide drugs, only monoclonal antibody drugs which have the Fc region!

Characteristics of metabolites

More polar, more acidic, more albumin (plasma protein) bound, smaller volume of distribution

Type of Phase I and Phase II metabolism of codeine

From codeine to morphine via O-demethylation by CYP2D6, then from morphine to morphine-6-glucuronide via glucuronidation by UGT2B7

Metabolism of Irinotecan (topoisomerase inhibitor prodrug)

From irinotecan to SN38 active but toxic metabolite via carbamate (ester) hydrolysis by CES1 or CES2, then elimination of the active yet toxic metabolite via glucuronidation by UGT1A1.

So, UGT1A1 poor metabolisers will suffer toxicity - neutropenia and diarrhoea - when treated by this drug.

How does Phase I and Phase II metabolism change in the elderly?

Phase I decreases because of reduced oxygen from reduced blood flow/perfusion (BUT the same number of enzymes are present!)

Phase II is unaffected by ageing.

MATE transporters

Renal secretion of cations via H+ or Na coupled antiport mechanisms

Bumetanide, frusemide

Loop diuretics

• Distal tubule acting

• Sodium-potassium-chloride co-transporter inhibition

• Loss of water and sodium: Blocks reabsorption of sodium

• Loss of potassium: hypokalaemia inducing

• Diuresis: increases urine flow rate

Frusemide relies on active transport by OAT1 to enter tubule and reach site of action to exert its diuretic effect.