Anda di halaman 1dari 18

1

THERAPEUTIC DRUG MONITORING

ANTIEPILEPTIC DRUGS

1. Carbamazepine
Pharmacocinétinetics
 Elimination: active anticonvulsant metabolite, 10,11-epoxide.
 Therapeutic window (Cp): 4 – 12 μg/ml ,(F)=0.8, ( S)=1, (Vd)=1.4 L/kg
(Cl)=0.064 L/h/kg, (T1/2) =15 h en steady state , (T1/2)=30-35 h en dose
unique., (𝛼) =0.2 – 0.3, Peak absorption =6h
Problem

1) Calculate the daily dose for Mss XUE 36 years old and 60 kg weight, at
the beginning of treatment and at the second week to achieve Cp of
6mcg/ml.
2) Under this regimen, after two months of treatment, crises seem not
stabilized and on lab check the Cp measured is 4 μg/ml. Explain the raison
for the low Cp and calculate the new dose to adjust the concentration
to 6 μg/ml.

𝑨𝑵𝑺𝑾𝑬𝑹 𝟏

At the beggining of the treatment , patient will need loading dose

 𝐴𝑡 𝑏𝑒𝑔𝑔𝑖𝑛𝑖𝑛𝑔 𝑜𝑓 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 , 𝐷𝐴𝐼𝐿𝑌 𝐷𝑂𝑆𝐸 = 𝐷𝑎(𝐿𝑜𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒)


𝑉𝑑∗𝑐𝑝
 𝐷𝑎 =
𝑆∗𝐹
 𝑡ℎ𝑒 𝑑𝑜𝑠𝑒 𝑤𝑎𝑠 𝑔𝑖𝑣𝑒𝑛 𝑑𝑎𝑖𝑙𝑦 𝑖𝑚𝑝𝑙𝑦 𝑡ℎ𝑎𝑡 𝑡ℎ𝑒 𝑑𝑜𝑠𝑖𝑛𝑔 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙 Ʈ = 24ℎ
1.4𝑙
 𝑇ℎ𝑢𝑠 , 𝑣𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝑑𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑖𝑜𝑛𝑠 (𝑉𝑑) = 60𝑘𝑔 ∗ = 84𝑙
𝑘𝑔
 A) 84𝑙 ∗ 6𝑚𝑔/𝑙
𝑇ℎ𝑒 𝑙𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 𝐷𝑎 = = 630𝑚𝑔 𝑐𝑎𝑟𝑏𝑎𝑚𝑎𝑧𝑒𝑝𝑖𝑛𝑒
1 ∗ 0.8

At the second week , patient will need the maintainence dose

 𝐶𝑙 = 0.064𝑙/ℎ/𝑘𝑔 ∗ 60𝑘𝑔 = 3.84𝑙/ℎ


0.693 0.693
 𝐾𝑒 = = = 0.0462/ℎ
𝑡½ 15ℎ
 𝑑𝑟𝑢𝑔 𝑤𝑎𝑠 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑 𝑑𝑎𝑖𝑙𝑦 , 𝑖𝑚𝑝𝑙𝑦 𝑡ℎ𝑎𝑡 Ʈ = 24ℎ
2

𝑀𝑎𝑖𝑛𝑡𝑎𝑖𝑛𝑒𝑛𝑐𝑒 𝑑𝑜𝑠𝑒
𝑄𝑜
𝐶𝐸 =
𝑘𝑒𝑉𝑑Ʈ
3.84𝑙 6𝑚𝑔
 𝐷𝑚 = 𝑄𝑜 = 𝐶𝑙 ∗ Ʈ ∗ 𝐶𝐸 = ∗ 24ℎ ∗ =
ℎ 𝑙
552.96𝑚 𝑜𝑓 𝑐𝑎𝑟𝑏𝑎𝑚𝑎𝑧𝑒𝑝𝑖𝑛𝑒

𝐶𝑙∗Ʈ∗𝐶𝐸 552.96𝑀𝐺
 𝑄𝑜 ⇎ 𝐷𝑚 𝑤ℎ𝑒𝑟𝑒 𝐹 = 0.8 , 𝐷𝑚 = = = 692.2𝑚𝑔
𝑆∗𝐹 1∗0.8

𝑨𝑵𝑺𝑾𝑬𝑹 𝟐
𝑑𝑜𝑠𝑒 552.96𝑚𝑔
 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑖𝑛𝑑𝑖𝑣𝑖𝑑𝑢𝑎𝑙 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝑟𝑎𝑡𝑒 = = =
𝐶𝐸∗Ʈ 4∗24
5.76𝑙
𝑖𝑠 𝑣𝑒𝑟𝑦 𝑓𝑎𝑠𝑡𝑒𝑟 , 𝑡ℎ𝑒 𝑟𝑒𝑎𝑠𝑜𝑛 𝑤ℎ𝑦 𝑡ℎ𝑒 𝑑𝑜𝑠𝑒 𝑖𝑠 𝑟𝑒𝑚𝑎𝑖𝑛 𝑏𝑒𝑙𝑜𝑤


 𝑨𝒕 𝑡ℎ𝑒 𝑠𝑒𝑐𝑜𝑛𝑑 𝑤𝑒𝑒𝑘 𝑡𝑜 𝑎𝑐ℎ𝑖𝑣𝑒 𝑡ℎ𝑒 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 6𝑚𝑐𝑔/𝑚𝑙
6𝑚𝑔
𝑒𝑞𝑢𝑎𝑙 𝑡𝑜 𝑡𝑜 𝑚𝑎𝑖𝑛𝑡𝑎𝑖𝑛 𝑡ℎ𝑖𝑠 𝑝𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 @𝑆𝑡𝑒𝑎𝑑𝑦 𝑠𝑎𝑡𝑒
𝑚𝑙
6𝑚𝑔
 𝑙𝑒𝑡 𝑎𝑠𝑠𝑢𝑚𝑒 𝑡ℎ𝑎𝑡 𝑡ℎ𝑒 𝑖𝑠 𝑡ℎ𝑒 𝑚𝑒𝑑𝑖𝑎𝑛 𝑝𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐 𝑜𝑓 𝑐𝑎𝑟𝑏𝑎𝑚𝑎𝑧𝑒𝑝𝑖𝑛𝑒
𝑚𝑙
4𝑚𝑐𝑔 12𝑚𝑐𝑔
 𝑡ℎ𝑒𝑟𝑎𝑝𝑒𝑢𝑝𝑖𝑐 𝑤𝑖𝑛𝑑𝑜𝑤 𝑢𝑝 𝑡𝑜
𝑚𝑙 𝑚𝑙
𝑄𝑜 𝑄𝑜 𝑄𝑜
 𝑎𝑝𝑝𝑙𝑦 𝑡ℎ𝑒 𝑓𝑜𝑟𝑚𝑢𝑙𝑎 = 𝐶𝐸 = = 𝑡ℎ𝑢𝑠 𝐶𝑙 =
𝑉𝑑∗𝐾𝑒∗Ʈ 𝐶𝑙∗Ʈ 𝐶𝐸∗Ʈ

𝟒𝐦𝐜𝐠 𝟒𝒎𝒈
𝐀𝐭 𝐜𝐨𝐧𝐜𝐞𝐧𝐭𝐫𝐚𝐭𝐢𝐨𝐧 𝐜𝐩 = 𝒐𝒓 𝒕𝒉𝒆 𝒅𝒓𝒖𝒈 𝒄𝒍𝒆𝒂𝒓𝒂𝒏𝒄𝒆 𝒊𝒔
𝐦𝐥 𝒍

552.96𝑚𝑔
 𝐶𝑙 = 4𝑚𝑔 = 5.76𝑙/ℎ
𝑙
∗24ℎ

𝟔𝐦𝐜𝐠 𝟔𝒎𝒈
𝐀𝐭 𝐜𝐨𝐧𝐜𝐞𝐧𝐭𝐫𝐚𝐭𝐢𝐨𝐧 𝐨𝐟 𝒐𝒓 𝒕𝒉𝒆 𝒅𝒐𝒔𝒆 𝑸𝒐 𝒘𝒊𝒍𝒍 𝒃𝒆
𝐦𝐥 𝒎𝒍

 Administration rate = CE ∗ CL = 6mg/l ∗ 5.76l/h = 34.56mg/h


3
6𝑚𝑔 5.76𝑙
 𝑄𝑜 = 𝐶𝐸 ∗ 𝐶𝑙 ∗ Ʈ = ∗ ∗ 24ℎ = 829.44𝑚𝑔 𝑜𝑓 𝑡𝑒𝑔𝑟𝑒𝑡𝑜𝑙
𝑙 ℎ
𝑄𝑜 829.44𝑚𝑔
 𝐹 = 0.8 𝑎𝑛𝑑 𝑆 = 1 , 𝐷𝑚(𝐴𝑑𝑗𝑢𝑠𝑡) = = = 1036.8𝑚𝑔
𝑆𝐹 1∗0.8

2. Ethosuximide

Pharmacotherapeutics
- Anticonvulsivant recommanded in petit mal;
- Forms (capsules 250 mg ; solution per os 250 mg/5 ml) ;
- Posology usual : adults 15 à 30 mg/kg/day 2x ; child 3 -6 years 250 mg/day
1x

Pharmacokinetics
- Elimination as metabolites 80% and unchanged in urine 20%.
- (Cp): 40 – 100 μg/ml , (F)=1, (S)=1, (Vd)=0.7 L/kg
- Cleance (Cl) adult = 0.23 L/day/kg , Clairance (Cl) enfant=0.39 L/day/kg
- (T1/2) adult = 50 h , (T1/2) infant = 30 h

Problem

3) A young boy 8 years and 25 kg presents at the hospital with absence


syndrome for which he has been on Ethosuximide 250mg two time a day.
What is the expected minimum Cp at the steady state?
4) If at this regimen the Cp is 35 mg/L and the clinic outcome is not achieved
properly, what interpretation you give to this and show how to adjust
the dosing.

𝐀𝐍𝐒𝐖𝐄𝐑 𝟑

𝑇ℎ𝑒 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑤𝑖𝑡ℎ (𝑔𝑖𝑣𝑒𝑛)

 𝑦𝑒𝑎𝑟𝑠 = 8𝑦𝑒𝑎𝑟𝑠 , 𝑤𝑒𝑖𝑔ℎ𝑡 = 25𝑘𝑔 , Ʈ = 12ℎ, 𝐷𝑜𝑠𝑒 =


250𝑚𝑔 , 𝑖𝑑𝑒𝑎𝑙 𝑉𝑑 = ? , 𝑟𝑒𝑎𝑙 𝑉𝑑 =? ? , 𝑖𝑑𝑒𝑎𝑙 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝑖𝑛𝑓𝑎𝑛𝑡 =
0.39𝑙 /𝑑𝑎𝑦 / 𝑘𝑔
4

 𝑟𝑒𝑎𝑙 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝑜𝑓 𝑖𝑛𝑓𝑎𝑛𝑡 (𝐶𝑙) = 25𝑘𝑔 ∗ 0.39𝑙 /𝑑𝑎𝑦 / 𝑘𝑔 =


9.75𝑙 /𝑑𝑎𝑦 = 0.40625𝑙 /ℎ
𝑄𝑜 1
 𝐶𝑝𝑚𝑖𝑛 (𝑠𝑠) = ( )𝑒 −𝑘𝑒Ʈ ↔ 𝑉𝑑 =? ? ,, 𝑘𝑒 =? ? ?
𝑉𝑑 1−𝑒 −𝑘𝑒Ʈ

 𝑇ℎ𝑢𝑠 𝑡ℎ𝑒 𝑝𝑒𝑟𝑠𝑜𝑛 𝑤𝑖𝑡ℎ 8𝑦𝑒𝑎𝑟𝑠 𝑜𝑙𝑑 𝑎𝑛𝑑 25𝑘𝑔 , 𝑖𝑠 𝑛𝑜𝑡 𝑦𝑒𝑡 𝑎𝑛 𝑎𝑑𝑢𝑙𝑡 𝑡ℎ𝑢𝑠
 𝑡ℎ𝑒 ℎ𝑎𝑙𝑓 𝑙𝑖𝑓𝑒 & 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝑖𝑛𝑓𝑎𝑛𝑡 𝑖𝑠 𝑝𝑢𝑡 𝑢𝑛𝑑𝑒𝑟 𝑐𝑜𝑛𝑠𝑖𝑑𝑒𝑟𝑎𝑡𝑖𝑜𝑛
0.7𝑙 0.693𝑉𝑑
 𝑉𝑑 = ∗ 25𝑘𝑔 = 17.5𝑙 𝐶𝑙 = 𝑘𝑒 ∗ 𝑉𝑑 𝑜𝑟 𝑎𝑛𝑑
𝑘𝑔 𝑡½
𝐶𝑙 0.40625𝑙/ℎ
 𝐾𝑒 = = = 0.0232/ℎ
𝑉𝑑 17.5𝑙
250𝑚𝑔 1 250𝑚𝑔 𝑒 −0.2784
 𝐶𝑝𝑚𝑖𝑛 (𝑠𝑠) = ( −0.0232∗12
)𝑒 −0.0232∗12 = ( )
17.5𝑙 1−𝑒 17.5𝑙 1−𝑒 −0.2784

250𝑚𝑔 0.75699
 𝐶𝑝𝑚𝑖𝑛 (𝑠𝑠) = ( ) = 44.5𝑚𝑔/𝑙
17.5𝑙 0.24301

44.5𝑚𝑔
𝑇ℎ𝑒 𝐶𝑝 𝑚𝑖𝑛𝑖𝑚𝑢𝑚 𝑎𝑡 𝑠𝑡𝑒𝑎𝑑𝑦 𝑠𝑡𝑎𝑡𝑒 𝑖𝑠 𝑜𝑓 𝑒𝑡ℎ𝑜𝑠𝑢𝑥𝑢𝑚𝑖𝑑𝑒 𝑓𝑜𝑟 𝑜𝑢𝑟 𝑝𝑎𝑡𝑖𝑒𝑛 𝑖𝑠
𝑙
𝐀𝐍𝐒𝐖𝐄𝐑 𝟒

𝟏𝒎𝒄𝒈/𝒎𝒍 = 𝟏𝒎𝒈/𝒍

 𝐸𝑡ℎ𝑜𝑠𝑢𝑥𝑖𝑚𝑖𝑑𝑒 𝑇ℎ𝑒𝑟𝑎𝑝𝑒𝑢𝑡𝑖𝑐 𝑤𝑖𝑛𝑑𝑜𝑤 = 40𝑚𝑐𝑔/𝑚𝑙 − 100𝑚𝑐𝑔/𝑚𝑙


 𝑇ℎ𝑒 𝑝𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑖𝑠 𝑓𝑜𝑢𝑛𝑑 𝑡𝑜 𝑏𝑒 35𝑚𝑐𝑔/𝑚𝑙, 𝑤ℎ𝑦

 The reason of faster decrease in the plasma below therapeutic window


is due to the rapid clearance.
𝑄𝑜 𝑄𝑜 𝑄𝑜
 𝑇ℎ𝑢𝑠 𝐶𝐸 = = ↔ 𝐶𝑙 =
𝑉𝑑∗𝑘𝑒∗Ʈ 𝐶𝑙∗Ʈ 𝐶𝐸∗Ʈ
250𝑚𝑔
 𝐴𝑡 𝑐𝑝 = 35𝑚𝑔/𝑙 , 𝐶𝑙 = = 0.595𝑙/ℎ
35𝑚𝑔/𝑙∗12ℎ
 𝑡ℎ𝑢𝑠 𝑡ℎ𝑒 𝑑𝑜𝑠𝑒 𝑤𝑖𝑙𝑙 𝑏𝑒 𝑎𝑑𝑗𝑢𝑠𝑡𝑒𝑑 𝑎𝑐𝑐𝑜𝑟𝑑𝑖𝑛𝑔 𝑡ℎ𝑖𝑠 𝑐𝑙𝑒𝑎𝑟𝑛𝑐𝑒 𝑤ℎ𝑒𝑟𝑒 𝑡ℎ𝑒

 𝑄𝑜 = 𝐶𝐸 ∗ 𝐶𝑙 ∗ Ʈ
44.5𝑚𝑔 0.595𝑙
⇒ ∗ ∗ 12ℎ = 𝟑𝟏𝟕. 𝟕𝟓𝐦𝐠 𝐨𝐟 𝐞𝐭𝐡𝐨𝐬𝐮𝐱𝐢𝐦𝐢𝐝𝐞
𝑙 𝑙

3. Phenobarbital

Pharmacotherapeutics
- Barbiturate long acting used in convulsive crises and insomnia ;
5

- Forms (tablets 100 mg ; 50 mg ; injection) ;


- Dosing (2 mg/kg/day per os or IM).

Pharmacokinetics
- Inducer of metabolism ;
- (Cp):10 – 30 mg/L , (F)=1, ( S)=0.9 (sodium salt), (Vd)=0.6 à 0.7 L/kg
- (Cl) adult=4 ml/h/kg, (Cl) child >1 year =2 times adult dose
- (T1/2) adult= 5 days, (𝛼)=0.5, Cl (hemodialysis)=3 L/h

Problems

5) Mr X aged 39 with 70 kg developed convulsive seizures after a car


accident that triggered cranial trauma. He has been prescribed
Phenobarbital to control seizures. Calculate the loading dose needed to
achieve directly the therapeutic concentration.
6) Calculate the maintenance dose needed to keep Cp into the therapeutic
window after the initial loading dose
7) Calculate the time required to attain the steady state concentration of
20 mg/l if the loading dose is not administered.
8) Another patient aged 25 years and weighing 70 kg presenting chronic renal
failure is taking 60 mg phenobarbital 2 times a day to achieve 20 mg/L at
steady state. Three months late, the renal failure state worsens and he is
prescribed dialysis sessions every 6 hours to be repeated 3 times a week.
Discuss whether the replacement dose is necessary or not and how to
calculate it if necessary.

𝑨𝑵𝑺𝑾𝑬𝑹 𝟓

 𝑇ℎ𝑒 𝑙𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 𝑓𝑜𝑟 𝑀𝑟 𝑋 𝑎𝑔𝑒𝑑 39 𝑤𝑖𝑡ℎ 70𝑘𝑔


𝑉𝑑∗𝐶𝑝
 𝐿𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 𝐷𝑎 = ↔ 𝑉𝑑 =? ? 𝐶𝑝 =? ? , 𝑆 = 0.9 𝑎𝑛𝑑 𝐹 = 1
𝑆∗𝐹
7𝑙
o 𝐼𝑑𝑒𝑎𝑙 𝑉𝑑 𝑖𝑠 𝑣𝑎𝑟𝑖𝑒𝑠 𝑓𝑟𝑜𝑚 0.6 𝑡𝑜 𝑜. 𝑡ℎ𝑢𝑠 𝑙𝑒𝑡 𝑚𝑖𝑛𝑖𝑚𝑢𝑚 𝑉𝑑
𝑘𝑔
0.6𝑙
o 𝑇ℎ𝑒 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑟𝑒𝑎𝑙 𝑉𝑑 = ∗ 70𝑘𝑔 = 42𝑙
𝑘𝑔
30𝑚𝑔 10𝑚𝑔
o 𝑇ℎ𝑒 𝐶𝑝 = − = 20𝑚𝑔/𝑙
𝑙 𝑙
20𝑚𝑔
42𝑙 ∗
𝐿𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 𝐷𝑎 𝑎𝑡 min 𝐶𝑙𝑒𝑎𝑟𝑛𝑐𝑒 = 𝑙 = 933.3𝑚𝑔
0.9 ∗ 1
6

49𝑙∗20𝑚𝑔/𝑙
 𝑙𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 𝑎𝑡 𝑡ℎ𝑒 max 𝑐𝑙𝑒𝑎𝑟 = = 1088.88𝑚𝑔
0.9∗1

𝐀𝐍𝐒𝐖𝐄𝐑 𝟔

o 𝑴𝒂𝒊𝒏𝒕𝒂𝒊𝒏𝒆𝒏𝒄𝒆 𝒅𝒐𝒔𝒆 𝑫𝒎 = 𝑫𝒂(𝟏 − 𝒆−𝒌𝒆Ʈ ) ↔ 𝑫𝒂 =


𝟗𝟑𝟑. 𝟑𝒎𝒈 𝒂𝒏𝒅 𝒌𝒆 =? , Ʈ =?

𝒍𝒏 𝑪𝒎𝒂𝒙−𝒍𝒏 𝑪𝒎𝒊𝒏 𝟎.𝟔𝟗𝟑


o Ʈ𝒎𝒂𝒙 = Ʈ = ↔ 𝒌𝒆 = ⇒ Ʈ=
𝑲𝒆 𝒕½
(𝒍𝒏𝑪𝒎𝒂𝒙−𝒍𝒏𝑪𝒎𝒊𝒏)∗𝒕½
𝟎.𝟔𝟗𝟑
(𝒍𝒏𝟑𝟎−𝒍𝒏𝟏𝟎)∗(𝟓∗𝟐𝟒)
o Ʈ= = 𝟏𝟗𝟎𝒉 ↔ 𝟕. 𝟗𝟐𝒅𝒂𝒚
𝟎.𝟔𝟗𝟑
𝟎.𝟔𝟗𝟑 𝟎.𝟔𝟗𝟑
o 𝒌𝒆 (𝒇𝒐𝒓 𝒂𝒅𝒖𝒍𝒕) = 𝒕½
= (𝟓∗𝟐𝟒) = 𝟎. 𝟎𝟎𝟓𝟕𝟕𝟓/𝒉
 𝐼𝑓 𝐿𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 𝑖𝑠 933.3𝑚𝑔 𝑎𝑡 𝑉𝑑 𝑜𝑓 42𝑙
 Maintainence dose Dm will be = Da(1 − e−keƮ )
 ⇒ 𝑫𝒎 = 𝟗𝟑𝟑. 𝟑𝒎𝒈(𝟏 − 𝒆−𝟎.𝟎𝟎𝟓𝟕𝟕𝟓∗𝟏𝟗𝟎 ) = 𝟗𝟑𝟑. 𝟑𝒎𝒈(𝟏 − 𝟎. 𝟑𝟑𝟑𝟕𝟖)

 ⇒ 𝑫𝒎 = 𝟔𝟐𝟏. 𝟕𝟖𝒎𝒈 𝒐𝒇 𝑷𝒉𝒆𝒏𝒐𝒃𝒂𝒓𝒃𝒊𝒕𝒂𝒍/ 𝟕. 𝟗𝟐𝒅𝒂𝒚


𝟔𝟐𝟏.𝟕𝟖𝒎𝒈
 ⇒ 𝒅𝒂𝒊𝒍𝒚 𝑫𝒎 = = 𝟕𝟖. 𝟓𝒎𝒈/𝒅𝒂𝒚
𝟕.𝟗𝟐𝒅𝒂𝒚

𝑺𝒖𝒎𝒎𝒂𝒓𝒚 𝒐𝒇 𝑸𝒖𝒆𝒔𝒕𝒊𝒐𝒏 𝟓, 𝟔 𝑴𝒂𝒙 𝒓𝒆𝒔𝒖𝒍𝒕 𝒂𝒓𝒆 𝒐𝒏 𝒅𝒓𝒂𝒇𝒕


𝒓𝒂𝒏𝒈𝒆 𝒊𝒅𝒆𝒂𝒍 𝑽𝒅 𝒑𝒂𝒕𝒊𝒆𝒏𝒕 𝑽𝒅 𝑫𝒂 𝑫𝒎 𝐷𝑚
𝑷𝒂𝒓𝒂𝒎𝒆𝒕𝒆𝒓 𝑑𝑎𝑦
𝟕. 𝟗𝟐𝒅𝒂𝒚 𝟕. 𝟗𝟐𝒅𝒂𝒚

𝒎𝒊𝒏𝒊𝒎𝒖𝒎 𝟎. 𝟔𝒍/𝒌𝒈 𝟒𝟐𝒍 𝟗𝟑𝟑. 𝟑𝒎𝒈 𝟔𝟐𝟏. 𝟕𝟖𝒎𝒈 78.50𝑚𝑔

𝒎𝒆𝒂𝒏 𝟎. 𝟔𝟓𝒍/𝒌𝒈 𝟒𝟓. 𝟓𝒍 𝟏𝟎𝟏𝟏𝒎𝒈 𝟔𝟕𝟑. 𝟔𝟎𝒎𝒈 85.05𝑚𝑔

𝒎𝒂𝒙𝒊𝒎𝒖𝒎 𝟎. 𝟕𝒍/𝒌𝒈 𝟒𝟗𝒍 𝟏𝟎𝟖𝟖. 𝟖𝟖𝒎𝒈 𝟕𝟐𝟓. 𝟒𝟑𝒎𝒈 91.59𝑚𝑔

𝐀𝐍𝐒𝐖𝐄𝐑 𝟕

𝑻𝒉𝒆 𝒕𝒊𝒎𝒆 𝒓𝒆𝒒𝒖𝒊𝒓𝒆 𝒕𝒐 𝒂𝒄𝒉𝒊𝒆𝒗𝒆 𝒕𝒉𝒆 𝒔𝒕𝒆𝒂𝒅𝒚 𝒔𝒕𝒂𝒕𝒆 𝒐𝒇 𝟐𝟎𝒎𝒈/𝒍


𝒊𝒇 𝒕𝒉𝒆 𝒍𝒐𝒂𝒅𝒊𝒏𝒈 𝒅𝒐𝒔𝒆 𝒊𝒔 𝒏𝒐𝒕 𝒂𝒅𝒎𝒊𝒏𝒊𝒔𝒕𝒆𝒓𝒆𝒅
𝒅𝒐𝒔𝒆 𝟏
 𝑪𝒑 = ( −𝒌𝒆Ʈ ) 𝒆𝒌𝒆𝒕
𝑽𝒅 𝟏−𝒆
𝟔𝟐𝟏.𝟕𝟖 𝒆−𝟎.𝟎𝟎𝟓𝟕𝟕𝟓𝒕 𝒆−𝟎.𝟎𝟎𝟓𝟕𝟕𝟓𝒕
 𝟐𝟎 = ( −𝟎.𝟎𝟎𝟓𝟕𝟕𝟓∗𝟏𝟗𝟎
) ⇒ 𝟐𝟎 = 𝟏𝟒. 𝟕𝟖𝟓 ( )
𝟒𝟐 𝟏−𝒆 𝟎.𝟔𝟔𝟔𝟐
7

𝟐𝟎
 ⇒ 𝒆−𝟎.𝟎𝟎𝟓𝟕𝟕𝟓𝒕 = ( ) ∗ 𝟎. 𝟔𝟔𝟔𝟐 ⇒ 𝒆−𝟎.𝟎𝟎𝟓𝟕𝟕𝟓𝒕 = 𝟎. 𝟗𝟎𝟏𝟏𝟖
𝟏𝟒.𝟕𝟖𝟓
 −𝟎. 𝟎𝟎𝟓𝟕𝟕𝟓𝒕 = 𝒍𝒏𝟎. 𝟗𝟎𝟏𝟏𝟖
𝒍𝒏𝟎.𝟗𝟎𝟏𝟏𝟖
 𝒕=−
𝟎.𝟎𝟎𝟓𝟕𝟕𝟓
 ⇒ 𝒕 = 𝟏𝟖𝒉 , 𝒏𝒆𝒆𝒅 𝒕𝒐 𝒓𝒆𝒂𝒄𝒉 𝒔𝒕𝒆𝒂𝒅𝒚 𝒊𝒔 𝑫𝒂 𝒊𝒔 𝒂𝒃𝒔𝒆𝒏𝒕

𝐀𝐍𝐒𝐖𝐄𝐑 𝟖

o 𝑇ℎ𝑒 𝑔𝑖𝑣𝑒𝑛 , 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑎𝑔𝑒𝑑 25𝑦𝑒𝑎𝑟𝑠 𝑎𝑛𝑑 𝑤𝑒𝑖𝑔ℎ 70𝑘𝑔


o 𝑡𝑎𝑘𝑖𝑛𝑔 𝐷𝑜𝑠𝑒 = 60𝑚𝑔 𝑝ℎ𝑒𝑛𝑜𝑏𝑎𝑟𝑏𝑖𝑡𝑎𝑙 , 𝑡𝑤𝑖𝑐𝑒 𝑑𝑎𝑦 ↔ Ʈ = 12ℎ
o 𝐶𝑝 = 20𝑚𝑔/𝑙 𝑎𝑡 𝑠𝑡𝑒𝑎𝑑𝑦 𝑠𝑡𝑎𝑡𝑒

𝟑𝒎𝒐𝒏𝒕𝒉 𝒍𝒂𝒕𝒆

 𝐓𝐡𝐞 𝐩𝐚𝐭𝐢𝐞𝐧𝐭 𝐢𝐬 𝐩𝐮𝐭 𝐮𝐧𝐝𝐞𝐫 𝐇𝐞𝐦𝐨𝐝𝐢𝐚𝐥𝐲𝐬𝐢𝐬 𝐞𝐯𝐞𝐫𝐲 𝟔𝐡, 𝟑𝐱 𝐰𝐞𝐞𝐤

𝑨𝒏𝒔𝒘𝒆𝒓 𝟖𝒂, 𝒅𝒐𝒆𝒔 𝑫 𝒓𝒆𝒑𝒍𝒂𝒄𝒆𝒎𝒆𝒏𝒕 𝒏𝒆𝒄𝒆𝒔𝒔𝒂𝒓𝒚? ?

 1. 𝑡ℎ𝑒 𝑑𝑟𝑢𝑔 ℎ𝑎𝑙𝑓 𝑙𝑖𝑓𝑒 𝑖𝑠 5𝑑𝑎𝑦 ↔ 120ℎ ≥ 2ℎ, 𝑐𝑜𝑛𝑑𝑖𝑜𝑛 𝑓𝑢𝑙𝑙𝑓𝑖𝑙𝑙𝑒𝑑


 𝑑𝑟𝑢𝑔 𝑐𝑙𝑒𝑎𝑟𝑛𝑐𝑒 = 4𝑚𝑙/ℎ/𝑘𝑔 ∗ 70𝑘𝑔 = 280𝑚𝑙/ℎ = 4.666𝑚𝑙/𝑚𝑖𝑛
3𝑙 3000𝑚𝑙
+𝑑𝑖𝑎𝑙𝑦𝑧𝑎𝑏𝑙𝑒 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 = = = 50𝑚𝑙/𝑚𝑖𝑛
ℎ 60𝑚𝑖𝑛
 2. 𝑡ℎ𝑒 𝑡𝑜𝑡𝑎𝑙 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝐶𝑙 = 50𝑚𝑙/𝑚𝑖𝑛 + 4.666𝑚𝑙/𝑚𝑖𝑛 = 54.666𝑚𝑙/𝑚𝑖𝑛 ≤
500𝑚𝑙/𝑚𝑖𝑛 𝑖. 𝑒 𝑐𝑜𝑛𝑑𝑖𝑡𝑖𝑜𝑛 𝑜𝑓 𝐷 𝑟𝑒𝑝𝑙𝑎𝑐𝑒𝑚𝑒𝑛𝑡 𝑖𝑠 𝑎𝑙𝑠𝑜 𝑓𝑢𝑙𝑙𝑓𝑖𝑙𝑙𝑒𝑑
𝑉𝑑 42𝑙
 𝑇ℎ𝑒 𝑑𝑖𝑎𝑙𝑖𝑠𝑎𝑏𝑙𝑒 𝑣𝑜𝑙𝑢𝑚𝑒 (𝑉𝑑 ′ ) = = = 84𝑙
𝛼 0.5
 3. 𝑉𝑑 ′ ≤ 250𝑙 𝑡ℎ𝑢𝑠 3𝑟𝑑 𝑐𝑜𝑛𝑑𝑖𝑡𝑖𝑜𝑛 𝑖𝑠 𝑓𝑢𝑙𝑙𝑓𝑖𝑙𝑙𝑒𝑑
 𝑐𝑜𝑛𝑐𝑙𝑢𝑠𝑖𝑜𝑛 𝑖𝑠 𝑡ℎ𝑎𝑡 𝑡ℎ𝑒 𝑟𝑒𝑝𝑙𝑎𝑐𝑒𝑚𝑒𝑛𝑡 𝑑𝑜𝑠𝑒 𝑛𝑒𝑒𝑑𝑒𝑑(𝑟𝑒𝑞𝑢𝑖𝑟𝑒𝑑)𝑓𝑜𝑟 𝑡ℎ𝑒 𝑝𝑎𝑡𝑖𝑒𝑛𝑡

−𝑪𝒍 𝒕𝒐𝒕𝒂𝒍∗𝑻𝒅
 𝑨𝒏𝒔𝒘𝒆𝒓 𝟖𝒃, 𝑫 𝒓𝒆𝒑𝒍𝒂𝒄𝒆𝒎𝒆𝒏𝒕 = 𝑽𝒅 ∗ 𝑪𝒑 ( 𝟏 − 𝒆 ) 𝑽𝒅

 𝑻𝒐𝒕𝒂𝒍 𝒄𝒍𝒆𝒂𝒓𝒂𝒏𝒄𝒆 = 𝑪𝒍 𝒑𝒂𝒕𝒊𝒆𝒏𝒕 + 𝑪𝒍 𝒉𝒆𝒎𝒐𝒅𝒊𝒂𝒍𝒚𝒔𝒊𝒔 = 𝟐𝟖𝟎𝒎𝒍/𝒉 +


𝟑𝒍/𝒉 = 𝟑. 𝟐𝟖𝒍/𝒉
 𝑻𝒅: 𝒕𝒊𝒎𝒆 𝒐𝒇 𝒅𝒊𝒂𝒍𝒚𝒔𝒊 𝒊𝒏𝒕𝒆𝒓𝒗𝒂𝒍 = 𝟔𝒉
𝟑.𝟐𝟖𝒍
𝑪𝒍𝒆𝒂𝒓𝒏𝒄𝒆 𝒕𝒐𝒕𝒂𝒍∗𝑻𝒅 𝒉
∗𝟔𝒉
 𝑻𝒉𝒖𝒔 = = 𝟎. 𝟒𝟔𝟖𝟓𝟕
𝑽𝒅 𝟒𝟐𝒍

𝟐𝟎𝒎𝒈
 𝑫 𝒓𝒆𝒑𝒍𝒂𝒄𝒆𝒎𝒆𝒏𝒕 = 𝟒𝟐𝒍 ∗ (𝟏 − 𝒆−𝟎.𝟒𝟔𝟖𝟓𝟕 ) ⇒ 𝑫𝒓𝒆𝒑 =
𝒍
𝟖𝟒𝟎𝒎𝒈(𝟏 − 𝟎. 𝟔𝟐𝟓𝟖𝟗) ⇒ 𝑫 𝒓𝒆𝒑𝒍𝒂𝒄𝒆𝒎𝒆𝒏𝒕 = 𝟑𝟏𝟒. 𝟐𝟒𝒎𝒈
8

𝟐𝟎𝒎𝒈
 𝑫𝒓𝒆𝒑𝒍 = 𝟒𝟗𝒍 ∗ (𝟏 − 𝒆−𝟎.𝟒𝟎𝟏𝟔𝟑 ) = 𝟑𝟐𝟓. 𝟏𝟓𝒎𝒈
𝒍
𝟑𝟏𝟒.𝟐𝟒+𝟑𝟐𝟓.𝟏𝟓𝒎𝒈
 𝑴𝒆𝒂𝒏 𝒓𝒆𝒑𝒍𝒂𝒄𝒆𝒎𝒆𝒏𝒕 𝒅𝒐𝒔𝒆 = 𝟑𝟏𝟗. 𝟔𝟗𝒎𝒈
𝟐

𝑰𝒏 𝒔𝒖𝒎𝒎𝒂𝒓𝒚,
𝒓𝒂𝒏𝒈𝒆 𝒊𝒅𝒆𝒂𝒍 𝑽𝒅 𝒑𝒂𝒕𝒊𝒆𝒏𝒕 𝑽𝒅 𝒗𝒅 𝑫𝒓 𝑫𝒓𝒆𝒑𝒍
𝑷𝒂𝒓𝒂𝒎𝒆𝒕𝒆𝒓 𝑽𝒅′ =
𝜶 𝟕. 𝟗𝟐𝒅𝒂𝒚 𝒅𝒂𝒚

𝒎𝒊𝒏𝒊𝒎𝒖𝒎 𝟎. 𝟔𝒍/𝒌𝒈 𝟒𝟐𝒍 𝟖𝟒𝒍 𝟑𝟏𝟒. 𝟐𝟒𝒎𝒈 𝟑𝟗. 𝟔𝟕𝒎𝒈

𝒎𝒆𝒂𝒏 𝟎. 𝟔𝟓𝒍/𝒌𝒈 𝟒𝟓. 𝟓𝒍 𝟗𝟏𝒍 𝟑𝟏𝟗. 𝟔𝟗𝒎𝒈 𝟒𝟎. 𝟑𝟔𝒎𝒈

𝒎𝒂𝒙𝒊𝒎𝒖𝒎 𝟎. 𝟕𝒍/𝒌𝒈 𝟒𝟗𝒍 𝟗𝟖𝒍 𝟑𝟐𝟓. 𝟏𝟓𝒎𝒈 𝟒𝟏. 𝟎𝟓𝒎𝒈

 𝑻𝒉𝒖𝒔 , 𝒕𝒐 𝒇𝒊𝒏𝒅 𝒕𝒉𝒆 𝒑𝒂𝒕𝒊𝒆𝒏𝒕 𝒅𝒐𝒔𝒆 = 𝒅𝒐𝒔𝒆 + 𝑫𝒓𝒆𝒑𝒍𝒂𝒄𝒆𝒎𝒆𝒏𝒕


 𝒑𝒂𝒕𝒊𝒆𝒏𝒕 𝒏𝒆𝒘 𝒅𝒐𝒔𝒆 = 𝟔𝟎𝒎𝒈 + 𝑫 𝒓𝒆𝒑𝒍𝒂𝒄𝒆𝒎𝒆𝒏𝒕

ANTIARRYTHMIC DRUGS

4. Lidocaine

Pharmacotherapeutics :
- Antiarrythmic indicated in severe ventricular arrhythmias.
- Local Anesthetic.

Pharmacokinetics
- Important first pass effect.
- The myocardium is located in the central compartment (two compartment model)
- (CE)=1 –5 mg/L , (F)=0.3 , S)=1
- patient condition Normal CHF Cirrhosis
V1 0.5 L/kg 0.3 L/kg 0.6 L/kg
Vd 1.3 L/kg 0.88L/kg 2.3 L/kg
- Clearance (Cl) 10ml/min/kg 6ml/min/kg 6ml/min/kg
- (T1/2) 𝛼 8 min 8 min 8 min
- (T1/2) β 100 min 100 min 300 min
Problems
9

9) Mr TOM 55 years old with 70 kg is admitted in emergency room for heart failure
probably due to myocardium infarction. He presents with premature ventricular
contractions against which lidocaine is prescribed. Calculate the loading dose needed
to readily achieve the therapeutic effect and illustrate how to take this dose.
10) For the same patient find the maintenance dose to achieve 2mg/L at steady state.

𝐀𝐍𝐒𝐖𝐄𝐑 𝟗𝐀

𝑇ℎ𝑒 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑔𝑖𝑣𝑒𝑛 , 𝑀𝑟 𝑇𝑜𝑚 55𝑦𝑒𝑎𝑟𝑠 𝑎𝑛𝑑 𝑊𝑒𝑖𝑔ℎ 70𝑘𝑔 ℎ𝑎𝑣𝑒 ℎ𝑒𝑎𝑟𝑡 𝑓𝑎𝑖𝑙𝑢𝑟𝑒
𝐼𝑛𝑖𝑡𝑖𝑎𝑙𝑙𝑦 𝑙𝑖𝑐𝑜𝑐𝑎𝑖𝑛𝑒 𝑑𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑒 𝑖𝑛𝑡𝑜 𝑐𝑒𝑛𝑡𝑟𝑎𝑙 𝑐𝑜𝑚𝑝𝑎𝑟𝑡𝑚𝑒𝑛𝑡
𝐻𝑒𝑎𝑟𝑡, 𝑙𝑢𝑛𝑔 , 𝑙𝑖𝑣𝑒𝑟, 𝑘𝑖𝑑𝑛𝑒𝑦 𝑎𝑛𝑑 𝑏𝑟𝑎𝑖𝑛 𝑤ℎ𝑒𝑛 𝑔𝑖𝑣𝑒𝑛 𝐼𝑉
𝑇ℎ𝑢𝑠 𝐿𝑖𝑑𝑜𝑐𝑎𝑖𝑛𝑒 𝑤ℎ𝑒𝑛 𝑔𝑖𝑣𝑒𝑛 𝐼𝑉, 𝑡ℎ𝑒 𝐼𝑛𝑖𝑡𝑖𝑎𝑙 𝑉𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝑑𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑖𝑜𝑛 𝑖𝑠
𝑝𝑟𝑒𝑓𝑓𝑒𝑟𝑒𝑑 𝑓𝑖𝑟𝑠𝑡 𝑡𝑜 𝑑𝑒𝑡𝑒𝑟𝑚𝑖𝑛𝑒 𝑙𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒

𝒘𝒉𝒆𝒏 𝑳𝒊𝒅𝒐𝒄𝒂𝒊𝒏𝒆 𝒊𝒔 𝒈𝒊𝒗𝒆𝒏 𝑰𝑽


0.3𝑙
 𝑉1 (𝐶𝐻𝐹) = ∗ 70𝑘𝑔 = 21𝑙 , 𝑠 = 1 𝑎𝑛𝑑 𝑓𝑜𝑟 𝐼𝑣 ⇒ 𝐹 = 1
𝑘𝑔
3𝑚𝑔
 𝐷𝑎 = 𝐶𝐸 (𝑚𝑒𝑎𝑛) ∗ 𝑉1 = ∗ 21𝑙 = 63𝑚𝑔 𝑙𝑜𝑎𝑑𝑖𝑛𝑔 𝑙𝑖𝑑𝑜𝑐𝑎𝑖𝑛𝑒 𝐼𝑉
𝑙

𝑾𝒉𝒆𝒏 𝑳𝒊𝒄𝒂𝒊𝒏𝒆 𝒊𝒔 𝑮𝒊𝒗𝒆𝒏 𝒃𝒚 𝒐𝒕𝒉𝒆𝒓 𝒓𝒐𝒖𝒕𝒆


0.3𝑙 0.88𝑙 1.18𝑙
 𝑉𝑑 𝑡𝑜𝑡𝑎𝑙 = + =
𝑘𝑔 𝑘𝑔 𝑘𝑔
1.18𝑙
 𝑃𝑎𝑡𝑖𝑒𝑛𝑡 𝑉𝑑 = 70𝑘𝑔 ∗ = 82𝑙
𝑘𝑔
3𝑚𝑔
𝐶𝐸∗𝑉𝑑 ∗82𝑙
 𝐿𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 𝑛𝑜𝑛 𝐼𝑉 (𝐷𝑎) = = 𝑙
= 820𝑚𝑔 𝑙𝑜𝑎𝑑𝑖𝑛𝑔 𝑜𝑟𝑎𝑙
𝑆∗𝐹 1∗0.3
3𝑚𝑔
 𝐷𝑎 = 𝐶𝐸 (𝑚𝑒𝑎𝑛) ∗ 𝑉1 = ∗ 21𝑙 = 63𝑚𝑔 𝑙𝑜𝑎𝑑𝑖𝑛𝑔 𝑙𝑖𝑑𝑜𝑐𝑎𝑖𝑛𝑒 𝐼𝑉
𝑙
3𝑚𝑔
𝐶𝐸∗𝑉𝑑 ∗82𝑙
 𝐿𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 𝑛𝑜𝑛 𝐼𝑉 (𝐷𝑎) = = 𝑙
= 820𝑚𝑔 𝑙𝑜𝑎𝑑𝑖𝑛𝑔 𝑜𝑟𝑎𝑙
𝑆∗𝐹 1∗0.3

𝐀𝐍𝐒𝐖𝐄𝐑 𝟗𝐁
𝐻𝑜𝑤 𝑡ℎ𝑒 𝑑𝑜𝑠𝑒 𝑤𝑖𝑙𝑙 𝑏𝑒 𝑡𝑎𝑘𝑒𝑛
𝐶𝑚𝑎𝑥
𝐷𝑚 𝐷𝑚 𝑚𝑎𝑥 ln 𝐶𝑚𝑖𝑛
 𝑊ℎ𝑖𝑙𝑒 = ⇒ 𝐷𝑜𝑠𝑖𝑛𝑔 𝑖𝑛𝑡𝑒𝑟𝑣𝑎𝑙 = Ʈ = Ʈ𝑚𝑎𝑥 =
Ʈ Ʈ𝑚𝑎𝑥 𝐾𝑒
0.693 0.693
 𝐾𝑒 = = = 0.086625/𝑚𝑖𝑛
𝑡½ 8𝑚𝑖𝑛
 𝒍𝒏𝟏
𝟓
𝒍𝒏𝟓
 Ʈ= = = 𝟏𝟖. 𝟓𝟖𝒎𝒊𝒏 (𝒅𝒐𝒔𝒊𝒏𝒈 𝒊𝒏𝒕𝒆𝒓𝒗𝒂𝒍,
𝟎.𝟎𝟖𝟔𝟔𝟐𝟓 𝟎.𝟎𝟖𝟔𝟔𝟐𝟓
 𝒕𝒉𝒆 𝒅𝒐𝒔𝒆 𝒘𝒊𝒍𝒍 𝒃𝒆 𝒕𝒂𝒌𝒆𝒏 𝒆𝒗𝒆𝒓𝒚 𝟏𝟖𝒎𝒊𝒏)
10

𝐀𝐍𝐒𝐖𝐄𝐑 𝟏𝟎
𝑄𝑜
 𝐶𝐸 = 𝑜𝑟 𝑄𝑜 = 𝐶𝐸 ∗ 𝑘𝑒 ∗ 𝑉𝑑 ∗ Ʈ ⇒ 𝑄𝑜 = 𝐶𝐸 ∗ 𝐶𝑙 ∗ Ʈ 𝑎𝑛𝑑
𝐾𝑒∗𝑉𝑑∗Ʈ
𝐶𝐸∗𝐶𝑙∗Ʈ
 𝑖𝑓 𝑄𝑜 = 𝑆𝐹𝐷𝑚, 𝐷𝑚 = 𝑊ℎ𝑒𝑛 𝑆 = 𝐹 = 1 ⇒
𝑆∗𝐹
𝐹𝑜𝑟 𝑡ℎ𝑖𝑠 𝑐𝑎𝑠𝑒 𝑄𝑜 = 𝐷𝑚
 𝑃𝑎𝑡𝑖𝑒𝑛𝑡 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 (𝐶𝑙) = 6𝑚𝑙/𝑚𝑖𝑛/𝑘𝑔 ∗ 70𝑘𝑔 = 420𝑚𝑙/𝑚𝑖𝑛
2𝑚𝑔 0.420𝑙
 𝑄𝑜 = ∗ ∗ 18.58𝑚𝑖𝑛 = 15.6072𝑚𝑔 𝑜𝑓 𝑚𝑖𝑛𝑡𝑒𝑛𝑒𝑛𝑐𝑒 𝐼𝑛𝑗𝑒𝑐𝑡𝑖𝑜𝑛
𝑙 𝑚𝑖𝑛

𝑸𝒐 𝟏𝟓. 𝟔𝟎𝟕𝟐𝒎𝒈
𝑰𝒇 𝑸𝒐 ⇎ 𝑫𝒎 ↔ 𝑫𝒎 = = = 𝟓𝟐. 𝟎𝟐𝟒𝒎𝒈 𝒐𝒇 𝑳𝒊𝒅𝒐𝒄𝒂𝒊𝒏𝒆
𝑺𝑭 𝟏 ∗ 𝟎. 𝟑

5. Procainamide

Pharmacotherapeutics :
- Antiarrythmic drug for ventricular tachycardia ;
- Usual doses (250 mg -500 mg every 3 to 4 hours in IV, IM or peroral.
- Standard loading dose is 15 mg/kg.

Pharmacokinetics
- Elimination via kidney and liver ;
- The metabolite N-acetylprocainamide is active.
- (CE)=4 –8 mg/L , (F)=0.85 , ( S)=0.87 (HCl) , (Vd)=2 L/kg
- Renal Clearance (Cl) =3x Clcreatinine, Clearance (Cl) acetylation =0.13 L/h/kg
- Clearance (Cl) other =0.1 L/h/kg , (T1/2) 𝛼 = 5 min, (T1/2) β = 3 hrs
Problems

11) A male patient aged 62 years old and 70 kg weight presents premature
ventricular contractions not responding to lidocaine treatment. He has been
found having myocardium infarction and renal failure with SCrss of 1.3 mg/dL
and CLcr as 50 ml/min. Calculate the IV loading dose to achieve the Cp of 8
mg/L.
12) For the same patient find the maintenance dose to achieve 6 mg/L Cpss.

𝐀𝐍𝐒𝐖𝐄𝐑 𝟏𝟏.

 𝐴 𝑚𝑎𝑙𝑒 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑎𝑔𝑒 62𝑦𝑒𝑎𝑟𝑠, 𝑤𝑒𝑖𝑔ℎ𝑡 =


70𝑘𝑔 𝑑𝑜𝑒𝑠 𝑛𝑜𝑡 𝑟𝑒𝑠𝑝𝑜𝑛𝑑 𝑡𝑜 𝑖𝑑𝑜𝑐𝑎𝑖𝑛𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡
11

 𝐻𝑎𝑠 𝑚𝑦𝑜𝑐𝑎𝑟𝑑𝑖𝑢𝑚 𝑖𝑛𝑓𝑎𝑟𝑐𝑡𝑖𝑜𝑛 𝑎𝑛𝑑 𝑟𝑒𝑛𝑎𝑙 𝑓𝑎𝑖𝑙𝑢𝑟𝑒 𝑤𝑖𝑡ℎ 𝑆𝐶𝑟𝑠𝑠 =


1.3𝑚𝑔/𝑑𝑙 𝑎𝑛𝑑 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝐶𝑙𝐶𝑟 = 50𝑚𝑙/𝑚𝑖𝑚
 𝐼𝑉 𝐿𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 𝑡𝑜 𝑎𝑐ℎ𝑖𝑒𝑣𝑒 𝐶𝑝 𝑜𝑓 8𝑚𝑔/𝑙 =? ? ?

 𝐹𝑜𝑟 𝑖𝑛𝑗𝑒𝑐𝑡𝑖𝑜𝑛(𝐼𝑉) , 𝐼𝑛𝑠𝑡𝑒𝑎𝑑 𝑜𝑓 𝐹 = 0.85 , 𝑡ℎ𝑢𝑠 𝐹 𝑤𝑖𝑙𝑙 𝑏𝑒 =


1 𝑎𝑛𝑑 𝑡ℎ𝑒 𝑠𝑎𝑙𝑡 𝑓𝑎𝑐𝑡𝑜𝑟 𝑤𝑖𝑙𝑙 𝑟𝑒𝑚𝑎𝑖𝑛 𝑎𝑠 𝑢𝑠𝑢𝑎𝑙 𝑆 = 0.87 , 𝑐𝑝 =
8𝑚𝑔 2𝑙
𝑎𝑛𝑑 𝑡ℎ𝑒 𝑉𝑑 = ∗ 70𝑘𝑔 = 140𝑙
𝑙 𝑘𝑔

8𝑚𝑔
𝑉𝑑∗𝐶𝑝 140𝑙∗
 𝐷𝑎 (𝐿𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 𝐼𝑉 ) = = 𝑙
= 1287.3𝑚𝑔 ↔ IV(F=1)
𝑆∗𝐹 0.87∗1
140𝑙∗8𝑚𝑔/𝑙
 𝑃𝑟𝑜𝑐𝑎𝑖𝑛𝑎𝑚𝑖𝑑𝑒 𝑜𝑟𝑎𝑙 (𝐷𝑎) = = 1514.5𝑚𝑔
0.87∗0.85

𝐀𝐍𝐒𝐖𝐄𝐑 𝟏𝟐
𝑄𝑜
 𝐶𝐸 = ⇒ 𝑄𝑜 = 𝐶𝐸 ∗ 𝐾𝑒 ∗ 𝑉𝑑 ∗ Ʈ = 𝐶𝐸 ∗ 𝐶𝑙(𝑡𝑜𝑡𝑎𝑙 ) ∗ Ʈ
𝑉𝑑∗𝐾𝑒∗Ʈ
 𝐹𝑜𝑟 𝐼𝑉, 𝐹 = 1 𝑎𝑛𝑑 𝑃𝑟𝑜𝑐𝑎𝑖𝑛𝑎𝑚𝑖𝑑𝑒 𝐻𝐶𝑙 𝑤𝑖𝑡ℎ 𝑆 = 0.87 , 𝑄𝑜 = 𝑆𝐹𝐷𝑚
𝐶𝐸∗𝐶𝑙 𝑇𝑜𝑡𝑎𝑙∗Ʈ
 𝐷𝑚 = 𝐶𝑙 𝑡𝑜𝑡𝑎𝑙 =? ? 𝑎𝑛𝑑 Ʈ = 3ℎ 𝑜𝑟 4ℎ
𝑆∗𝐹
 𝐶𝑙 𝑡𝑜𝑡𝑎𝑙 = 𝑅𝑒𝑛𝑎𝑙 𝐶𝑙 + 𝐿𝑖𝑣𝑒𝑟 𝐶𝑙 + 𝑂𝑡ℎ𝑒𝑟 𝐶𝑙
 𝑅𝑒𝑛𝑎𝑙 𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 = 3 ∗ 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝑜𝑟
𝑤𝑒𝑖𝑔ℎ𝑡 (140−𝑎𝑔𝑒) 70(140−62)
 𝐶𝑙𝐶𝑟𝑠𝑠 = = = 58.33𝑚𝑙/
72∗𝑆𝑟𝐶𝑟𝑠𝑠 72∗1.3
min 𝑓𝑟𝑜𝑚 𝑡ℎ𝑒 𝑞𝑢𝑒𝑠𝑡𝑜𝑛 𝑤𝑒 ℎ𝑎𝑣𝑒 𝐶𝑙𝐶𝑟𝑠𝑠 = 50𝑚𝑙/
min 𝑙𝑒𝑡 𝑡𝑎𝑘𝑒 𝑖𝑡 𝑖𝑛 𝑢𝑠𝑒.
 𝑃𝑎𝑡𝑖𝑒𝑛𝑡 𝑟𝑒𝑛𝑎𝑙 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 = 3 ∗ 50𝑚𝑙/𝑚𝑖𝑛 = 150𝑚𝑙/𝑚𝑖𝑛 = 9𝑙/ℎ
 𝐻𝑒𝑝𝑎𝑡𝑖𝑐 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 (𝑎𝑐𝑒𝑡𝑦𝑙𝑎𝑡𝑖𝑜𝑛) = 0.13𝑙/ℎ /𝑘𝑔 ∗ 70𝑘𝑔 = 9.1𝑙/ℎ
 𝑂𝑡ℎ𝑒𝑟 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 = 0.1𝑙/ℎ/𝑘𝑔 ∗ 70𝑘𝑔 = 7𝑙/ℎ
 𝑪𝒍 𝒕𝒐𝒕𝒂𝒍 = 𝟗𝒍/𝒉 + 𝟗. 𝟏𝒍/𝒉 + 𝟕𝒍/𝒉 = 𝟐𝟓𝒍/𝒉

6𝑚𝑔 25𝑙
𝐶𝐸 ∗ 𝐶𝑙 𝑇𝑜𝑡𝑎𝑙 ∗ Ʈ ∗ ∗ 3ℎ
𝐷𝑚 (𝐼𝑉 𝑎𝑛𝑑 Ʈ = 3) = = 𝑙 ℎ = 517.24𝑚𝑔
𝑆∗𝐹 0.87 ∗ 1
6𝑚𝑔 25𝑙
𝐶𝐸 ∗ 𝐶𝑙 𝑇𝑜𝑡𝑎𝑙 ∗ Ʈ ∗ ∗ 3ℎ
𝐷𝑚 (𝑜𝑟𝑎𝑙 𝑎𝑛𝑑 Ʈ = 3) = = 𝑙 ℎ = 608.52𝑚𝑔
𝑆∗𝐹 0.87 ∗ 0.85
12

6𝑚𝑔 25𝑙
𝐶𝐸 ∗ 𝐶𝑙 𝑇𝑜𝑡𝑎𝑙 ∗ Ʈ ∗ ∗ 4ℎ
𝐷𝑚 (𝐼𝑉 𝑎𝑛𝑑 Ʈ = 4) = = 𝑙 ℎ = 689.65𝑚𝑔
𝑆∗𝐹 0.87 ∗ 1
6𝑚𝑔 25𝑙
𝐶𝐸 ∗ 𝐶𝑙 𝑇𝑜𝑡𝑎𝑙 ∗ Ʈ ∗ ∗ 4ℎ
𝐷𝑚 (𝑜𝑟𝑎𝑙 𝑎𝑛𝑑 Ʈ = 4) = = 𝑙 ℎ = 811.34𝑚𝑔
𝑆∗𝐹 0.87 ∗ 0.87

𝑃𝑅𝑂𝐶𝐴𝐼𝑁𝐴𝑀𝐼𝐷𝐸 𝐻𝑌𝐷𝑅𝑂𝐶𝐻𝐿𝑂𝑅𝐼𝐷𝐸

Ʈ = 3ℎ Ʈ = 4ℎ

𝑜𝑟𝑎𝑙 𝐼𝑉 𝑜𝑟𝑎𝑙 𝐼𝑉

𝐷𝑎 1514.5𝑚𝑔 1287.3𝑚𝑔 1514.5𝑚𝑔 1287.3𝑚𝑔

𝐷𝑚 608.52𝑚𝑔 517.24𝑚𝑔 811.34𝑚𝑔 689.65𝑚𝑔

𝑆 0.87 0.87 0.87 0.87

𝐹 0.85 1 0.85 1

6. Quinidine

Pharmacotherapeutics :
- Antiarrythmic drug for atrial fibrillation and other forms of arrhythmias.
- Usual doses (200 mg to 300 mg per os in 3 - 4 doses/day.

Pharmacokinetics
- Renal Elimination;
- (Cp)=1 –4 mg/L (specific method) ; (F)=0.73 (sulfate), 0.70 (gluconate)
- ( S)=0.82 (sulfate), 0.62 (gluconate)
- patient conditions Normal CHF Cirrhosis
Vd 2.8 L/kg 1.8 L/kg 3.8 L/kg
- Clearance (Cl) 4.7ml/min/kg 3.5ml/min/kg 3.5ml/min/kg
- (T1/2) 7h 7h 7h

Problems
13

13) A male patient 70 kg aged 50 years had heart attack with auricular fibrillation. He is
treated with 300 mg quinidine every 6 hours. Calculate Cpmax and Cpmin reached
after 3 doses are given.
14) Discuss if it is relevant to take a blood sample during the first 24 hours to measure
the Cpss.

𝐀𝐍𝐒𝐖𝐄𝐑 𝟏𝟑

𝑳𝑬𝑻 𝑾𝑶𝑹𝑲 𝑶𝑵 𝑸𝑼𝑰𝑵𝑰𝑫𝑰𝑵𝑬 𝑺𝑼𝑳𝑭𝑨𝑻𝑬 𝑭𝑶𝑹 𝑶𝑼𝑹 𝑪𝑨𝑺𝑬 𝟏


𝑆𝐹𝐷 1−𝑒 −𝑛𝑘𝑒Ʈ
 𝐶𝑝 𝑚𝑎𝑥 = ( ) 𝑡ℎ𝑢𝑠 𝑛 = 3, 𝑄𝑜 = 300𝑚𝑔, Ʈ = 6ℎ, 𝑉𝑑 =
𝑉𝑑 1−𝑒 −𝑘𝑒Ʈ
? 𝑎𝑛𝑑 𝐾𝑒 =? ? . 𝑆 = 0.83 𝑎𝑛𝑑 𝐹 = 0.73
1.8𝑙
 𝑉𝑑 (𝐶𝐻𝐹) = ∗ 70𝑘𝑔 = 126𝑙 , 𝐶𝑙 = 3.5𝑚𝑙/𝑚𝑖𝑛/𝑘𝑔 ∗ 70𝑘𝑔 =
𝑘𝑔
245𝑚𝑙/𝑚𝑖𝑛 ⇒ 𝐶𝑙 = 14.7𝑙/ℎ 𝑡ℎ𝑒𝑛 ℎ𝑎𝑙𝑓 𝑙𝑖𝑣𝑒 ( 𝑡½) = 7ℎ
𝐶𝑙 0.693
 𝐾𝑒 = 𝑎𝑛𝑑 𝑎𝑙𝑠𝑜 𝐾𝑒 =
𝑉𝑑 𝑡½
 𝑂𝑢𝑟 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑑𝑟𝑢𝑔 𝑃𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑤𝑖𝑙𝑙 𝑏𝑒 𝑎𝑓𝑓𝑒𝑐𝑡𝑒𝑑 𝑏𝑦
14.7𝑙/ℎ
𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝑛𝑜𝑡 ℎ𝑎𝑙𝑓𝑙𝑖𝑓𝑒 𝑡ℎ𝑢𝑠 𝑘𝑒 = = 0.1166/ℎ
126𝑙
300𝑚𝑔 ∗ 0.73 ∗ 0.82 1 − 𝑒 −3∗0.1166∗6 300𝑚𝑔 1 − 0.1226
𝐶𝑝 𝑚𝑎𝑥 = ( −0.1166∗6
) = ( )
126𝑙 1−𝑒 126𝑙 1 − 0.4967

181.77 0.8774
𝐶𝑝 𝑚𝑎𝑥 = ( ) = 2.515𝑚𝑔/𝑙
126𝑙 0.5033
 𝐶𝑝𝑚𝑖𝑛 = 𝐶𝑝𝑚𝑎𝑥𝑒 −𝑘𝑒Ʈ = 2.515𝑒 −0.1166∗6 = 1.25𝑚𝑔/𝑙

𝑳𝑬𝑻 𝑾𝑶𝑹𝑲 𝑶𝑵 𝑸𝑼𝑰𝑵𝑰𝑫𝑰𝑵𝑬 𝑮𝑳𝑼𝑪𝑶𝑵𝑨𝑻𝑬 𝑭𝑶𝑹 𝑶𝑼𝑹 𝑪𝑨𝑺𝑬 𝟐


𝑆𝐹𝐷 1−𝑒 −𝑛𝑘𝑒Ʈ
 𝐶𝑝 𝑚𝑎𝑥 = ( ) 𝑡ℎ𝑢𝑠 𝑛 = 3, 𝑄𝑜 = 300𝑚𝑔, Ʈ = 6ℎ, 𝑉𝑑 =
𝑉𝑑 1−𝑒 −𝑘𝑒Ʈ
126𝑙 𝑎𝑛𝑑 𝐾𝑒 = 0.1166/ℎ. 𝑆 = 0.62 𝑎𝑛𝑑 𝐹 = 0.70 𝐶𝑙 = 14.7𝑙/ℎ

300𝑚𝑔 ∗ 0.70 ∗ 0.62 1 − 𝑒 −3∗0.1166∗6 300𝑚𝑔 1 − 0.1226


𝐶𝑝 𝑚𝑎𝑥 = ( −0.1166∗6
) = ( )
126𝑙 1−𝑒 126𝑙 1 − 0.4967
14

130.2 0.8774
𝐶𝑝 𝑚𝑎𝑥 = ( ) = 1.8𝑚𝑔/𝑙
126𝑙 0.5033
𝐶𝑝𝑚𝑖𝑛 = 𝐶𝑝𝑚𝑎𝑥𝑒 −𝑘𝑒Ʈ = 1.8 𝑒 −0.1166∗6 = 0.894𝑚𝑔/𝑙

𝑄𝑢𝑖𝑛𝑖𝑑𝑖𝑛𝑒 𝑠𝑢𝑙𝑓𝑎𝑡𝑒 𝑄𝑢𝑖𝑛𝑖𝑑𝑖𝑛𝑒 𝐺𝑙𝑢𝑐𝑜𝑛𝑎𝑡𝑒

𝐶𝑝𝑚𝑎𝑥 2.515𝑚𝑔/𝑙 1.8𝑚𝑔/𝑙

𝐶𝑝𝑚𝑖𝑛 1.25𝑚𝑔/𝑙 0.894𝑚𝑔/𝑙

𝐂𝐎𝐌𝐌𝐄𝐍𝐓: 𝑄𝑢𝑖𝑛𝑖𝑑𝑖𝑛𝑒 𝐺𝑙𝑢𝑐𝑜𝑛𝑎𝑡𝑒 𝑖𝑠 𝑛𝑜𝑡 𝑡ℎ𝑒 𝑟𝑖𝑔ℎ𝑡 𝑚𝑒𝑑𝑖𝑐𝑖𝑛𝑒 𝑡𝑜 𝑡ℎ𝑖𝑠 𝑝𝑎𝑡𝑖𝑒𝑛𝑡


𝑓𝑜𝑟 𝑤𝑒𝑙𝑙 𝑚𝑜𝑛𝑖𝑡𝑜𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑡ℎ𝑒𝑟𝑎𝑝𝑒𝑢𝑡𝑖𝑐 𝐶𝑝 𝑓𝑜𝑟 𝑡ℎ𝑖𝑠 𝑑𝑜𝑠𝑒 , 𝑄. 𝑆𝑈𝐿𝐹𝐴𝑇𝐸 𝐼𝑆 𝑇𝐻𝐸
𝐵𝑒𝑠𝑡 𝑜𝑟 𝑐ℎ𝑜𝑜𝑠𝑒 𝑡ℎ𝑒 𝑔𝑙𝑢𝑐𝑜𝑛𝑎𝑡𝑒 𝑤𝑖𝑡ℎ 𝑑𝑜𝑠𝑒 𝑎𝑑𝑗𝑢𝑠𝑡𝑖𝑛𝑔

𝐀𝐍𝐒𝐖𝐄𝐑 𝟏𝟒
 𝐼𝑡 𝑖𝑠 𝑛𝑜𝑡 𝑟𝑒𝑙𝑒𝑣𝑒𝑛𝑡 𝑡𝑜 𝑡𝑎𝑘𝑒 𝑡𝑜 𝑡𝑎𝑘𝑒 𝑏𝑙𝑜𝑜𝑑 𝑡ℎ𝑒 𝑠𝑎𝑚𝑝𝑙𝑒 𝑡𝑜 𝑚𝑒𝑎𝑠𝑢𝑟𝑒
 𝑡ℎ𝑒 𝑝𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑎𝑡 𝑠𝑡𝑒𝑎𝑑𝑦 𝑠𝑡𝑎𝑡𝑒 𝑏𝑒𝑐𝑎𝑢𝑠𝑒 , 𝑡ℎ𝑒 𝑐ℎ𝑎𝑛𝑔𝑒𝑠
 𝑃𝐾 𝑝𝑎𝑟𝑎𝑚𝑒𝑡𝑒𝑟, 𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝑑𝑒𝑐𝑟𝑒𝑎𝑠𝑒 𝑎𝑛𝑑 ℎ𝑎𝑙𝑓 𝑙𝑖𝑓𝑒 𝑟𝑒𝑚𝑎𝑖𝑛 𝑐𝑜𝑛𝑠𝑡𝑎𝑛𝑡
𝐶𝑙
 𝐴𝑛𝑑 𝑉𝑑 𝑑𝑒𝑐𝑟𝑒𝑎𝑠𝑒 , 𝑎𝑛𝑑 𝐾𝑒 = , 𝑡ℎ𝑖𝑠 𝑚𝑎𝑘𝑒 𝑚𝑎𝑘𝑒 𝑎𝑙𝑡𝑒𝑟𝑛𝑎𝑡𝑖𝑣𝑒𝑙𝑦
𝑉𝑑
 𝑎𝑓𝑓𝑒𝑐𝑡𝑒𝑑 𝑡ℎ𝑒 𝑑𝑟𝑢𝑔 𝑒𝑙𝑖𝑚𝑖𝑛𝑎𝑡𝑖𝑜𝑛 ℎ𝑒𝑛𝑐𝑒 𝑠𝑡𝑒𝑎𝑑𝑦 𝑠𝑡𝑎𝑡𝑒 𝑚𝑎𝑦 𝑟𝑒𝑎𝑐ℎ
 𝑒𝑖𝑡ℎ𝑒𝑟 𝑏𝑒𝑓𝑜𝑟𝑒 24ℎ 𝑜𝑟 𝑎𝑓𝑡𝑒𝑟 24ℎ𝑜𝑢𝑟𝑠(… … . . ≥ 24ℎ ≤ ⋯ … … )

CARDIOTONIC DRUGS

7. Digoxin

Pharmacotherapeutics:
- Digitalis chemical indicated in Chronic heart failure and for auricular
fibrillation; Usual Doses (load=1 - 1.5 mg/70kg ; maintenance= 0.25
mg/day) per os.

Pharmacokinetics
15

- Equilibrium between Type equation here.plasma and myocardium is achieved


at 3 to 4 hrs after administration. The myocardium is in the peripheral
compartment (two compartment model)
- (Cp)=1 –2 ng/ml
- (F)=0.73 (tablet),0.80 (elixir),1 (capsule), (S)=1, Vd=7.3 L/kg
- Clearance (Cl) with CHF =0.33ml/min/kg+ 0.9Clcreatinine
- Clearance (Cl) without CHF 0.80 ml/min/kg + Clcreatinine
- (T1/2) β=2 h

Problems

15) Mr JOHN 70 kg and 50 years old in CHF condition is digitalised with digoxin
tablets. His Scrss is 1 mg/dL. Calculate the loading dose to achieve the
therapeutic concentration.
16) Find the maintenance dose to achieve that Cpss.

𝐀𝐍𝐒𝐖𝐄𝐑 𝟏𝟓
𝐶𝐸∗𝑉𝑑 1.5𝑛𝑔 0.0015𝑚𝑔
 𝐿𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 𝐷𝑎 = 𝑂𝑟 𝐶𝐸 = = , 𝑉𝑑 =
𝑆∗𝐹 𝑚𝑙 𝑙
7.3𝑙
70𝑘𝑔 ∗ = 511𝑙, 𝑆 = 1, 𝑎𝑛𝑑 𝐹 = 0.73 (𝑇𝐴𝐵)
𝑘𝑔

0.0015𝑚𝑔/𝑙 ∗ 511𝑙
𝐷𝑎 = = 1.05𝑚𝑔 𝑜𝑓 𝐿𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 𝑜𝑓 𝐷𝑖𝑔𝑜𝑥𝑖𝑛
1 ∗ 0.73

𝐀𝐍𝐒𝐖𝐄𝐑 𝟏𝟔

 𝒄𝒍𝒆𝒂𝒓𝒂𝒏𝒄𝒆 (𝑪𝑳)𝒘𝒊𝒕𝒉 𝑪𝑯𝑭 = 𝟎. 𝟑𝟑𝒎𝒍/𝒎𝒊𝒏/𝒌𝒈 + 𝟎. 𝟗𝑪𝒍 𝒄𝒓


𝒘𝒆𝒊𝒈𝒉𝒕(𝟏𝟒𝟎−𝒂𝒈𝒆) 𝟕𝟎𝒌𝒈 (𝟏𝟒𝟎−𝟓𝟎)
 𝑪𝒍(𝑪𝒓𝒆𝒂𝒕𝒊𝒏𝒊𝒏𝒆) = = = 𝟖𝟕. 𝟓𝒎𝒍/𝒎𝒊𝒏
𝟕𝟐𝑺𝒓𝑪𝒓 𝟕𝟐∗𝟏𝒎𝒈/𝒅𝒍

 𝑪𝒍 (𝑪𝑯𝑭) = (𝟎. 𝟑𝟑𝒎𝒍/𝒎𝒊𝒏/𝒌𝒈 ∗ 𝟕𝟎𝒌𝒈) + (𝟎. 𝟗 ∗ 𝟖𝟕. 𝟓𝒎𝒍/𝒎𝒊𝒏)


 𝑪𝒍 (𝑪𝑯𝑭) = 𝟏𝟎𝟏. 𝟖𝟓𝒎𝒍/𝒎𝒊𝒏
𝒍𝒏 𝑪𝒎𝒂𝒙 − 𝒍𝒏 𝑪𝒎𝒊𝒏 𝑪𝒍 𝟔. 𝟏𝟏𝟏𝒍/𝒉
Ʈ= , , 𝒌𝒆 = = = 𝟎. 𝟎𝟏𝟏𝟗𝟓𝟗/𝒉
𝒌𝒆 𝑽𝒅 𝟓𝟏𝟏𝒍

 𝑫𝒎 = 𝑫𝒂(𝟏 − 𝒆𝒌𝒆Ʈ ) = 𝟏. 𝟎𝟓𝒈(𝟏 − 𝒆−𝟎.𝟎𝟏𝟏𝟗𝟓𝟗∗𝟓𝟕.𝟗𝟔 )


16

 𝑫𝒎 = 𝟏. 𝟎𝟓 ∗ 𝟎. 𝟓 = 𝟎. 𝟓𝟐𝟓𝒎𝒈 𝟐. 𝟓𝒅𝒂𝒚 𝒐𝒇 𝒅𝒊𝒈𝒐𝒙𝒊𝒏


 𝑫𝒂𝒊𝒍𝒚 𝑫𝒎 = 𝟎. 𝟓𝟐𝟓𝒎𝒈/𝟐. 𝟓𝒅𝒂𝒚 = 𝟎. 𝟐𝟏𝒎𝒈/𝒅𝒂𝒚 𝒐𝒇 𝒅𝒊𝒈𝒐𝒙𝒊𝒏

𝒍𝒏𝟐−𝒍𝒏𝟏
 Ʈ= = 𝟓𝟕. 𝟗𝟔𝒉 𝒅𝒐𝒔𝒊𝒏𝒈 𝒊𝒏𝒕𝒆𝒓𝒗𝒂𝒍 ⇒ 𝟐. 𝟒𝟏𝟓𝒅𝒂𝒚 ≈ 𝟐. 𝟓𝒅𝒂𝒚
𝟎.𝟎𝟏𝟏𝟗𝟓𝟗

𝟎.𝟔𝟗𝟑 𝟎.𝟔𝟗𝟑 𝒍𝒏𝟐−𝒍𝒏𝟏


 𝑲𝒆 = = = 𝟎. 𝟑𝟒𝟔𝟓/𝒉 ⇒ 𝑻𝒉𝒆𝒏 Ʈ = = 𝟐𝒉
𝒕½ 𝟐𝒉 𝟎.𝟑𝟒𝟔𝟓
𝑪𝒍∗Ʈ∗𝒄𝒑 𝟔.𝟏𝟏𝟏𝒍/𝒉∗𝟐𝒉∗𝟎.𝟎𝟎𝟏𝟓𝒎𝒈/𝒍
 𝑫𝒎 = = 𝟎. 𝟎𝟐𝟓𝒎𝒈
𝑺∗𝑭 𝟏∗𝟎.𝟕𝟑

LES AMINOGLYCOSIDES

8. Gentamicin, tobramycin, amikacin

Pharmacotherapeutics:
- Antibiotics against gram negative infections;
- Doses (infusion 50 to 120 mg in 30 to 60 min every 8 hours for gentamicin
and tobramycin; 200 to 500 mg for amikacin).

Pharmacokinetics
- Poor oral bioavailability ;
- (Cp) Cpmax Cpthrough
Gentamicin et Tobramycin 4 à 8 mg/L < 2 mg/L
Amikacin 20 – 30 mg/L <10 mg/L
- (F) < 0.3, ( S)=1, Vd=7.3 L/kg
- Clearance (Cl) in non renal failure=Cl=Clcr
- Clearance (Cl) moderate renal failure =Cl=0.0043 L/h/kg
- Clearance (Cl) in severe renal failure =Cl=0.0021 L/h/kg
- Clearance hemodialysis=Cl= 1.8 L/h
- (T1/2) in non renal failure =2- 3 hrs
- (T1/2) in renal failure =30 - 60 hrs

Problems

17) Mss BETY 30 years old and 70 kg carrying infections received a first dose of
gentamicin 100 mg in infusion during 30 min. Her Scrss is 0.9 mg/dL. Calculate
the concentration Cp achieved one hour after starting infusion.
17

18) Considering the infusion as rapid intravenous injection, re-calculate the


concentration achieved one hour after injection taking CL-6.06 L/h, Vd=17.5 L
and ke=0.346 h-1.
19) Calculate Cpssmax and Cpssmin if the infusion is given every 8 hours.

𝑨𝑵𝑺𝑾𝑬𝑹 𝟏𝟕

𝐾
 𝐶𝑝 (𝑡 − 𝑇) = (1 − 𝑒 −𝑘𝑒Ʈ )𝑒 −𝑘𝑒(𝑡−𝑇)
𝑉𝑑∗𝑘𝑒
𝐷𝑂𝑆𝐸 100𝑚𝑔
 𝑅𝑎𝑡𝑒 𝑜𝑓 𝑖𝑛𝑓𝑢𝑠𝑖𝑛 (𝐾 ) = = = 200𝑚𝑔/ℎ
𝐼𝑛𝑓𝑢𝑠𝑖𝑜𝑛 𝑡𝑖𝑚𝑒 0.5ℎ
7.3𝑙
 𝑉𝑑 = ∗ 70𝑘𝑔 = 511𝑙
𝑘𝑔
 𝑡 − 𝑇 = 1ℎ − 0.5ℎ = 0.5ℎ
0.693 0.693
 𝑘𝑒 = = = 0.2772/ℎ or
𝑡½ 2.5ℎ
𝐶𝑙 𝑤𝑒𝑖𝑔ℎ(140−𝑎𝑔𝑒) 70𝑘𝑔(140−30)
 𝐾𝑒 = ⇒ 𝑐𝑙 = ( ) ∗ 0.85 = ( ) ∗ 0.85
𝑉𝑑 72𝑆𝑟𝐶𝑟𝑠𝑠 72∗0.9
 ⇒ 𝐶𝑙 = 101𝑚𝑙/ min = 6.06𝑙/ℎ
6.06𝑙/ℎ
 𝐾𝑒 = = 0.011859/ℎ ,
511𝑙
𝑓𝑜𝑟 𝑜𝑢𝑟 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 , 𝑡ℎ𝑒𝑟𝑒 𝑖𝑠 𝑛𝑜 𝑖𝑛𝑑𝑖𝑐𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑟𝑒𝑛𝑎𝑙 𝑓𝑎𝑖𝑙𝑢𝑟𝑒 ↔
𝑑𝑟𝑢𝑔 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝑖𝑠 𝑒𝑞𝑢𝑎𝑙 𝑡𝑜 𝑡ℎ𝑒 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒.

200𝑚𝑔/ℎ
 𝐶𝑝 (𝑡 − 𝑇) = (1 − 𝑒 −0.011859∗0.5)𝑒 −0.011859∗0.5
6.06𝑙/ℎ
200𝑚𝑔/ℎ
 𝐶𝑝 (𝑡 − 𝑇) = (0.00591) ∗ 0.00591 = 0.1949𝑚𝑔/𝑙
6.06𝑙/ℎ

𝑨𝑵𝑺𝑾𝑬𝑹 𝟏𝟖
18

𝑄𝑜 1−𝑒 −𝑛𝑘𝑒Ʈ
 𝐶𝑝 (𝑡) = ( ) 𝑒 −𝑘𝑒𝑡
𝑉𝑑 1−𝑒 −𝑘𝑒Ʈ

100𝑚𝑔 1−𝑒 −2∗0.346∗0.5


 𝐶𝑝 (𝑡) = ( ) 𝑒 −0.346∗1
17.5𝑙 1−𝑒 −0.346∗0.5

100𝑚𝑔 0.2924
 𝐶𝑝 (𝑡) = ( ) ∗ 0.7075
17.5𝑙 0.1588

 ⇒ 𝐶𝑝 (𝑡) = 10.52 ∗ 0.7075 = 7.44𝑚𝑔/𝑙

𝑨𝑵𝑺𝑾𝑬𝑹 𝟏𝟗 … … … … 𝑳𝑨𝑺𝑻

𝑄𝑜 1
 𝐶𝑝 max 𝑠𝑠 = ( )
𝑉𝑑 1−𝑒 −𝑘𝑒Ʈ
100𝑚𝑔 1 100𝑚𝑔 1
 𝐶𝑝 (𝑡) = ( −0.346∗8 )= ( )
17.5𝑙 1−𝑒 17.5𝑙 1−𝑒 −0.346∗8
100𝑚𝑔 1
 𝐶𝑝 max 𝑠𝑠 = ( ) = 6.09𝑚𝑔/𝑙
17.5𝑙 0.9372

𝑄𝑜 1
 𝐶𝑝 min 𝑠𝑠 = ( ) 𝑒 𝑘𝑒Ʈ = 𝑐𝑝𝑚𝑎𝑥𝑠𝑠𝑒 𝑘𝑒Ʈ
𝑉𝑑 1−𝑒 −𝑘𝑒Ʈ

 𝐶𝑝 min 𝑠𝑠 = 𝑐𝑝𝑚𝑎𝑥𝑠𝑠𝑒 𝑘𝑒Ʈ = 6.097𝑚𝑔/𝑙𝑒 −0.346∗8


 𝐶𝑝𝑚𝑖𝑛𝑠𝑠 = 0.3828𝑚𝑔/