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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
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
ℎ
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
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
𝐀𝐍𝐒𝐖𝐄𝐑 𝟑
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
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
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
𝑨𝑵𝑺𝑾𝑬𝑹 𝟓
49𝑙∗20𝑚𝑔/𝑙
𝑙𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 𝑎𝑡 𝑡ℎ𝑒 max 𝑐𝑙𝑒𝑎𝑟 = = 1088.88𝑚𝑔
0.9∗1
𝐀𝐍𝐒𝐖𝐄𝐑 𝟔
𝐀𝐍𝐒𝐖𝐄𝐑 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
𝟑𝒎𝒐𝒏𝒕𝒉 𝒍𝒂𝒕𝒆
−𝑪𝒍 𝒕𝒐𝒕𝒂𝒍∗𝑻𝒅
𝑨𝒏𝒔𝒘𝒆𝒓 𝟖𝒃, 𝑫 𝒓𝒆𝒑𝒍𝒂𝒄𝒆𝒎𝒆𝒏𝒕 = 𝑽𝒅 ∗ 𝑪𝒑 ( 𝟏 − 𝒆 ) 𝑽𝒅
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
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
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.
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
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
181.77 0.8774
𝐶𝑝 𝑚𝑎𝑥 = ( ) = 2.515𝑚𝑔/𝑙
126𝑙 0.5033
𝐶𝑝𝑚𝑖𝑛 = 𝐶𝑝𝑚𝑎𝑥𝑒 −𝑘𝑒Ʈ = 2.515𝑒 −0.1166∗6 = 1.25𝑚𝑔/𝑙
130.2 0.8774
𝐶𝑝 𝑚𝑎𝑥 = ( ) = 1.8𝑚𝑔/𝑙
126𝑙 0.5033
𝐶𝑝𝑚𝑖𝑛 = 𝐶𝑝𝑚𝑎𝑥𝑒 −𝑘𝑒Ʈ = 1.8 𝑒 −0.1166∗6 = 0.894𝑚𝑔/𝑙
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
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
𝒍𝒏𝟐−𝒍𝒏𝟏
Ʈ= = 𝟓𝟕. 𝟗𝟔𝒉 𝒅𝒐𝒔𝒊𝒏𝒈 𝒊𝒏𝒕𝒆𝒓𝒗𝒂𝒍 ⇒ 𝟐. 𝟒𝟏𝟓𝒅𝒂𝒚 ≈ 𝟐. 𝟓𝒅𝒂𝒚
𝟎.𝟎𝟏𝟏𝟗𝟓𝟗
LES AMINOGLYCOSIDES
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
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 0.2924
𝐶𝑝 (𝑡) = ( ) ∗ 0.7075
17.5𝑙 0.1588
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