IC11 PK of drugs for thyroid disorders

Question 1

carbimazole indication

Answer 1

hyperthyroidism

Question 2

carbimazole MOA

Answer 2

Inhibit thyroid peroxidase
Reduces thyroid hormone synthesis (T3 & T4 output)

Question 3

carbimazole PK
absorption

Answer 3

Oral; OD dosing
Converted to active methimazole in serum after absorption

Question 4

carbimazole PK
distribution

t1/2, protein binding, clinical effects & time for clinical outcomes

Answer 4

• t1/2 = 4-6 hours
  Clinical effects lasts 1 day due to concentration in thyroid (acting on peroxidases)
• No binding to plasma protein
• Produces >90% inhibition of thyroid organification of iodine within 12 hours
• Clinical response may take 3-6 weeks after initiation of treatment
  T4 = long t1/2; thyroid stores of hormones need to be depleted for effects to be seen ⇒ counsel patient to continue drug therapy even if no improvements

Question 5

carbimazole PK
metabolism

Answer 5

CYP450 in liver & FMO enzymes

Question 6

carbimazole PK
excretion

Answer 6

• > 90% PO carbimazole excreted in urine as methimazole or its metabolites; rest in faeces (enterohepatic circulation, secreted back into guts)
• ~7% methimazole excreted unchanged in urine

Question 7

carbimazole AE

R, JP, N, J, H

Answer 7

Rashes
Joint pains
Nausea
Jaundice
Agranulocytosis (rare)
Hypothyroidism (due to over treatment)
* monitor thyroid size and serum TSH level
* Once reduced thyroid size & achieved normal TSH level → dose should be titrated (reduced) to avoid hypothyroidism

Question 8

levothyroxine indication

Answer 8

hypothyroidism

Question 9

levothyroxine MOA

Answer 9

1. is a synthetic T4; will get deionised to T3
2. binds to thyroid hormone receptor
3. dimerisation of TR & RXR
4. Interaction with DNA
5. Synthesis of proteins required for cell viability

Question 10

levothyroxine PK
absorption

F, ideal condition, onset, location

Answer 10

Oral; F= 70-80%

To taken on empty stomach with water; 30 mins before meal
* Dietary fibre can cause erratic absorption
* Fasting increases absorption

Onset: 3-5 days (IV: 6-8 hours)

Mainly absorbed in duodenum & jejunum
* Affected by gastric pH (do not take with antacids & PPIs)

Question 11

levothyroxine PK
distribution

protein binding, t1/2

Answer 11

Highly plasma protein bound (>99%)
t1/2 = 7 days → OD dosing

Question 12

levothyroxine PK
metabolism

Answer 12

Major site for degradation of T3 & T4 = Liver
* Metabolised by glucuronidation & sulphation

Deionisation of T4 to T3 in kidney

Question 13

levothyroxine PK
excretion

Answer 13

Kidneys primarily excrete T3 & T4
Metabolites in urine & faeces

Question 14

levothyroxine AE

A, A, D, I, HL (severe: H, S)

Answer 14

Reduced appetite, Anxiety, Diarrhoea, Difficulty sleeping, Hair loss

Severe: Heart issues (ie: arrhythmias, high BP, pain, HF) & seizures

Question 15

levothyroxine
case: Myoxedema coma

Answer 15

Reduced blood flow to GI → affects gut absorption of oral levothyroxine
* Important for distribution of drug

Requires IV Liothyronine (synthetic T3) or IV levothyroxine

Question 16

Monitoring thyroid function (after levothyroxine therapy)

Answer 16

• Serum TSH: to monitor for adequate replacement
• TSH should be measured 6-8 weeks after initiation of, or a change in levothyroxine dose
  Need to re-establish baseline if dose is adjusted
• Persistently elevated TSH levels may happen due to inadequate dosing, poor compliance, malabsorption, drug or food interaction