12 - Drug Use in Special Populations 1

How is drug absorption affected in cirrhosis?

Oral drugs are absorbed more slowly but the total remains the same

• The least affected of the ADME

How is drug distribution affected in cirrhosis?

1. Hypoalbuminemia: Less albumin production leads to protein-bound drugs left in free form and causing an effect

2. Ascites: More water for water-soluble drugs to be distributed in, so these drugs need a higher loading dose

When is hypoalbuminemia significant for drug toxicity, and what is an example?

If the drug is highly protein bound AND has a narrow therapeutic index, like phenytoin

How is drug metabolism and elimination affected in cirrhosis?

Hepatic clearance

1. Reduction of liver flow

2. Decreased activity of hepatic drug-metabolizing enzymes

3. Impaired bile secretion

How does liver blood flow relate to drugs, typically?

• The first pass effect occurs to drugs absorbed in the gut, and it’s where the liver metabolizes some off the drug, so a lesser amount makes it to systemic circulation

  • Some drugs are affected more, called high extraction drugs, while low extraction drugs are affected less

What does reduction of liver blood flow mean for drugs, and which type of drug is affected more?

• Reduced blood flow to the liver → blood is sent to the systemic circulation via shunts, and the blood that does go thru the liver passes thru weaker hepatocytes → oral bioavailability rises

• High extraction drugs are affected most → Same pill delivers MORE drug

So how do we adapt to this?

Give less initial and maintenance oral dose for high extraction drugs

How does drug metabolism in the liver work typically?

2 phases

1. Phase 1: CYP450 family makes small changes to molecules

2. Phase 2: Conjugation adds a large water-soluble molecule to the drug

Which phase is more affected by liver damage?

Phase 1, but not every CYP declines as quickly

How does decreased activity of hepatic drug-metabolizing enzymes affect drugs?

Drugs stay in the body longer(Except prodrugs, which get activated less)

How does impaired bile secretion affect drugs?

Some drugs leave the body via bile, so these drugs will accumulate

• This will come with jaundice, itching, etc.

How does cirrhosis/hepatic dysfunction affect renal function?

1. Renal function can be overestimated, because the liver makes less Cr, so it can seem like we’re filtering out creatinine really well, but the liver is just making less

2. Renal function can genuinely decrease too, because cirrhosis causes vasodilation → body thinks arteries are underfilled even though they’re pooled in gut circulation → RAAS, SNS, ADH activates → afferent arteriole vasoconstriction → GFR can collapse

Pharmacodynamics in hepatic disease

Ammonia is often high and causing inhibitory GABA signaling in the brain → Drugs like opioids or other anti-anxiety drugs can add to the depression and cause hepatic encephalopathy

If creatinine clearance is used to measure kidney clearance, what’s the liver equivalent?

There isn’t a perfect test. Albumin/INR/bilirubin can measure function, while ALT/AST can measure hepatocyte injury, but there’s no clear test

Best way to administer drugs in cirrhotic patients, and what’s the exception

“Start low, go slow”, except loading doe of a water-soluble drug

Best painkiller option in cirrhotic patients

Paracetamol, maximum dosage of 2-3 g/d

• But beware liver injury in alcoholic cirrhotic patients

Avoid what painkillers in cirrhosis?

1. NSAIDs: Block COX → reduce prostaglandins → afferent arteriole closes → GFR collapse

2. Morphine: Avoid/use sparingly → can cause hepatic encephalopathy

3. Tramadol: Also an opioid, but milder and can be used occasionally in low doses

Drug Induced Hepatoxicity is also called ___

DILI, drug-induced liver injury

DILI common drug causes

1. Paracetamol

2. Highly active antiretroviral therapy(HAART, used in HIV)

3. Anti-TB

4. Herbal products/dietary supplements

DILI types

1. Intrinsic/predictable: Dose dependent, like paracetamol overdose

2. Idiosyncratic/unpredictable: Small minority of ppl despite normal dosing

DILI symptoms

On a spectrum:

• Asymptomatic liver enzyme elevation

• Acute liver failure

• Malaise/fatigue, anorexia/nausea, RUQ discomfort, fever, jaundice, encephalopathy

DILI diagnosis

Diagnosis of exclusion: Rule out other causes + a new drug with improvement after stopping it

Biggest developmental changes pharmacologically occur in ___

First weeks to first year of life

Link these disaster results to the drug

• Gray baby syndrome

• Kernicterus

• Phocomelia(Severe shortened/absent limbs)

• Gray baby syndrome → Chloramphenicol

• Kernicterus → Sulfonamides

• Phocomelia(Severe shortened/absent limbs) → Thalidomide

How do the kidney and liver change during development early on?

1. Kidney function starts really slow and picks up over months

2. Drug metabolizing enzymes mature at different rates and children use metabolizing pathways that adults don’t really use

How old is a neonate, and how old is an infant, and what are their definitions in Thai?

• Neonate: Up to 28 days old, called ทารกแรกเกิด

• Infant: 1-24 months, called ทารก

What is GA in Thai, and what is the GA of a preterm neonate?

GA = อายุครรภ์

Preterm = < 38 weeks

2 key ideas about drugs via the oral route in pediatrics:

1. Slower gastric emptying and gut motility(Normalizes by 3 months)

2. Higher gastric pH(Normalizes by 6 months)

Slower gastric emptying and gut motility in pediatrics leads to ___

A delayed Tmax with absorption still efficient

Higher gastric pH in pediatrics leads to ___

1. Acid-labile drugs survive more → higher levels in the blood(Eg. penicillin G)

2. Weak acid drugs gets absorbed less because they require an acidic environment → lower levels in blood

Oral bioavailability in infants is ___, so we should use them only in ___ situations

Unreliable, non-life threatening

IM administration in pediatrics

• Age bands

• Best location

• Decreased absorption in neonates due to poor perfusion and small muscle mass/activity

• Increased absorption in infants and children due to high blood flow

• Best location: Anterolateral thigh

Topical administration in pediatrics

• Can cause systemic toxicity due to thinner stratum corneum, more hydrated skin, and high SA/body mass ratio

Do neonates have more or less water than adults, and what drug does this effect?

Neonates have relatively MORE water, and this means that water-soluble drugs/hydrophilic drugs need to be given as a larger dose

Are more or less drugs bound in neonates, and why?

There are MORE free drugs(aka less bound drugs) in neonates, because there’s less albumin, weaker albumin(fetal albumin), less alpha 1 acid glycoprotein(a plasma protein that binds some drugs), more bilirubin competing for binding sites

What is an example of a drug cleared very slowly in the 1st week of life, and why?

Aminoglycosides due to low renal function

Compare metabolic liver enzyme activity in neonates, children, and adults

Neonates: Low → long half-life

Children: High → short half-life

Adult: Medium → medium half-life

Best dosing principle in pediatrics, and most commonly used one

• Best: Body surface area-based, but it changes every day because the BSA keeps increasing 1-2% each day and height is hard to measure, so we only use it for drugs where we really need accuracy

• Most-used: Weight based

How does pregnancy affect drug absorption?

1. Increased nausea and vomiting → Oral drugs are often unreliable/less gets to blood

2. Progesterone → Slows gastric emptying and gut motility → delayed onset type but total absorbed amount isn’t reduced

3. Increased blood flow → Faster IM/SC absorption

4. Increased cardiac output → Faster inhaled drug absorption

How does pregnancy affect drug distribution?

1. Increased body water → Concentration of low V_d/water soluble drugs decrease

2. Increased body fat → Lipid soluble drugs are stored easier and released back into blood over a longer period of time

3. Less serum albumin due to expanded plasma volume dilating it → Protein-bound drugs are found in free form more

How does pregnancy affect drug metabolism?

Some enzymes are increased in activity, some are decreased, some are inconsistent

• Due to estrogen/progesterone changes

How does pregnancy affect drug elimination?

Renal blood flow and GFR increases, so drugs cleared mainly by the kidneys are eliminated faster

Drugs cause around __ of birth defects

4-5%

Teratogen 3 parts

1. It causes a characteristic set of malformations, not random

2. Has a period of exposure, so a drug taken at this time might cause an issue while taken at another time might not

3. Dose-effect relationship: More exposure usually leads to more malformation, and there may be a threshold where nothing happens

This isn’t a diagnostic criteria list, 1 answers if its a teratogen or not, while 2/3 explains the circumstances of when it causes harm

New system of labeling drug safety for pregnancy name

Pregnancy and lactation labeling rule(PLLR)

Risks of drugs in lactation

1. Risk to infant

2. Risk of the process of lactation itself(milk production)

Most drugs in lactation are ___ because

Acceptable, because concentrations in milk are low, and the dose itself is well below a therapeutic dose

Medications that affect lactation

• Dopamine antagonists(Domperidone, metoclopramide, haloperidol) → more milk

• Dopamine agonists(Bromocriptine, cabergoline) → less milk

General rule of breastfeeding in women taking drugs

Most medications are safe for this, generally don’t stop breastfeeding because of maternal drug therapy