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COLLEGE OF MEDICINE AND HEALTH SCIENCES


SCHOOL OF MEDICINE AND PHARMACY
DEPARTMENT OF PHARMACY

HUYE CAMPUS
CLASS: PHARMACY IV
ACADEMIC YEAR 2018-2019

GROUP 5
PHARM IV
NO REG.NO NAMES Others
1. 215007907 MINANI Theobald
2. 216130735 MUGISHA Carmelle
3. 216074142 NIYIRORA Clementine
4. 215012997 HAGABIMANA Pierre
5. 216163242 MURIISA Moise
6. 216074991 NIYONKURU Emmanuel
7. 216351537 NDEREYIMANA Irene Fischer

EXERCISES/ASSIGNMENT
MODULE : APPLIED PHARMACOKINETICS AND TOXICOLOGY
COMPONENT : APPLIED PHARMACOKINETICS AND BIOPHARMACY
LECTURER : PROF KADIMA NTOKAMUNDA
2

THERAPEUTIC DRUG MONITORING

SECTION I. ANTIEPILEPTIC DRUGS

I.CARBAMAZEPINE

Given
 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
Demand: 1. Da and Dm=?? 2. Dm to adjust from 4mcg/ml to 6mcg/ml

Solution and formula

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

B. 𝑴𝒂𝒊𝒏𝒕𝒂𝒊𝒏𝒆𝒏𝒄𝒆 𝒅𝒐𝒔𝒆 ( 𝑫𝒎)


𝑄𝑜
 𝐶𝐸 = 𝟑. 𝟖𝟒𝒍 𝟔𝒎𝒈
𝑘𝑒𝑉𝑑Ʈ 𝑫𝒎 = 𝑸𝒐 = 𝑪𝒍 ∗ Ʈ ∗ 𝑪𝑬 = ∗ 𝟐𝟒𝒉 ∗
𝒉 𝒍
= 𝟓𝟓𝟐. 𝟗𝟔𝒎 𝒐𝒇 𝒄𝒂𝒓𝒃𝒂𝒎𝒂𝒛𝒆𝒑𝒊𝒏𝒆
3

2.  𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑖𝑛𝑑𝑖𝑣𝑖𝑑𝑢𝑎𝑙 𝑛𝑒𝑤 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 (𝐶𝑙 ′ ) =


𝑑𝑜𝑠𝑒
𝐶𝐸∗Ʈ
=
552.96𝑚𝑔
4∗24
=
𝟓.𝟕𝟔𝒍
𝒊𝒔 𝒗𝒆𝒓𝒚 𝒇𝒂𝒔𝒕𝒆𝒓 , 𝑡ℎ𝑒 𝑟𝑒𝑎𝑠𝑜𝑛 𝑤ℎ𝑦 𝑡ℎ𝑒 𝑑𝑜𝑠𝑒 𝑖𝑠 𝑟𝑒𝑚𝑎𝑖𝑛 𝑏𝑒𝑙𝑜𝑤
𝒉
 𝐶𝑙′ > 𝐶𝑙 ↔ 5.76𝑙/ℎ > 3.84𝑙/ℎ
Cl 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
 𝑛𝑒𝑤 𝐶𝑙 = 4𝑚𝑔 = 5.76𝑙/ℎ
𝑙
∗24ℎ

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

𝟔𝒎𝒈 𝟓. 𝟕𝟔𝒍
𝑸𝒐 = 𝑪𝑬 ∗ 𝑪𝒍 ∗ Ʈ = ∗ ∗ 𝟐𝟒𝒉
𝒍 𝒉
= 𝟖𝟐𝟗. 𝟒𝟒𝒎𝒈 𝒐𝒇 𝒄𝒂𝒓𝒃𝒂𝒎𝒂𝒛𝒆𝒑𝒊𝒏𝒆

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

II. ETHOSUXIMIDE

Given

- 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

Demand

3. expected minimum Cp at the steady state for boy 8 years and 25 kg on


Ethosuximide 250mg two time a day?
4

4. The clinical outcome is not achieved properly, what interpretation If at


this regimen the Cp is 35 mg/L and adjust the dosing.

Solution and formula

3. 𝑇ℎ𝑒 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑤𝑖𝑡ℎ (𝑔𝑖𝑣𝑒𝑛)


 𝑦𝑒𝑎𝑟𝑠 = 8𝑦𝑒𝑎𝑟𝑠 , 𝑤𝑒𝑖𝑔ℎ𝑡 = 25𝑘𝑔 , Ʈ = 12ℎ, 𝐷𝑜𝑠𝑒 =
250𝑚𝑔 , 𝑖𝑑𝑒𝑎𝑙 𝑉𝑑 = ? , 𝑟𝑒𝑎𝑙 𝑉𝑑 =? ? , 𝑖𝑑𝑒𝑎𝑙 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝑖𝑛𝑓𝑎𝑛𝑡 =
0.39𝑙 /𝑑𝑎𝑦 / 𝑘𝑔
 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

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
(Cl′>Cl↔0.595l/h(cp=35mg/l>0.40625l/h(44.5mg/l))
5

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 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝑤ℎ𝑒𝑟𝑒 𝑡ℎ𝑒

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

III.PHENOBARBITAL

Given
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
Demand
Da, Dm, time , D replacement

Solution and formula

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
∗ 49𝑙∗20𝑚𝑔/𝑙 𝟒𝟐𝒍
𝒍
 𝑙𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 𝑎𝑡
𝑳𝒐𝒂𝒅𝒊𝒏𝒈 𝑡ℎ𝑒𝑫𝒂
𝒅𝒐𝒔𝒆 𝑚𝑎𝑥𝒂𝒕𝑐𝑙𝑒𝑎𝑟 =
𝐦𝐢𝐧 𝑪𝒍𝒆𝒂𝒓𝒏𝒄𝒆 = = 1088.88𝑚𝑔= 𝟗𝟑𝟑. 𝟑𝒎𝒈
0.9∗1 𝟎. 𝟗 ∗ 𝟏

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


933.3𝑚𝑔 𝑎𝑛𝑑 𝑘𝑒 =? , Ʈ =?
6

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

𝟕
𝑇ℎ𝑒 𝑡𝑖𝑚𝑒 𝑟𝑒𝑞𝑢𝑖𝑟𝑒 𝑡𝑜 𝑎𝑐ℎ𝑖𝑒𝑣𝑒 𝑡ℎ𝑒 𝑠𝑡𝑒𝑎𝑑𝑦 𝑠𝑡𝑎𝑡𝑒 𝑜𝑓 20𝑚𝑔/𝑙
𝑖𝑓 𝑡ℎ𝑒 𝑙𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 𝑖𝑠 𝑛𝑜𝑡 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑
𝑑𝑜𝑠𝑒 1
 𝐶𝑝 = ( ) 𝑒 𝑘𝑒𝑡
𝑉𝑑 1−𝑒−𝑘𝑒Ʈ
621.78 𝑒 −0.005775𝑡 𝑒 −0.005775𝑡
 20 = ( −0.005775∗190
) ⇒ 20 = 14.785 ( )
42 1−𝑒 0.6662
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
𝟖

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
7

 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 𝒊𝒔 𝒏𝒆𝒆𝒅𝒆𝒅(𝒓𝒆𝒒𝒖𝒊𝒓𝒆𝒅)𝒇𝒐𝒓 𝒕𝒉𝒆 𝒑𝒂𝒕𝒊𝒆𝒏𝒕

−𝐶𝑙 𝑡𝑜𝑡𝑎𝑙∗𝑇𝑑
 𝐴𝑛𝑠𝑤𝑒𝑟 8𝑏, 𝐷 𝑟𝑒𝑝𝑙𝑎𝑐𝑒𝑚𝑒𝑛𝑡 = 𝑉𝑑 ∗ 𝐶𝑝 ( 1 − 𝑒 𝑉𝑑 )
 𝑇𝑜𝑡𝑎𝑙 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 = 𝐶𝑙 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 + 𝐶𝑙 ℎ𝑒𝑚𝑜𝑑𝑖𝑎𝑙𝑦𝑠𝑖𝑠 = 0.28𝑙/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

SECTION II. ANTIARRYTHMIC DRUGS

IV.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
8

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. 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
9

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
𝟓
𝒍𝒏 𝒍𝒏𝟓
𝟏
Ʈ= = = 𝟏𝟖. 𝟓𝟖𝒎𝒊𝒏 (𝒅𝒐𝒔𝒊𝒏𝒈 𝒊𝒏𝒕𝒆𝒓𝒗𝒂𝒍,
𝟎.𝟎𝟖𝟔𝟔𝟐𝟓 𝟎.𝟎𝟖𝟔𝟔𝟐𝟓
𝒕𝒉𝒆 𝒅𝒐𝒔𝒆 𝒘𝒊𝒍𝒍 𝒃𝒆 𝒕𝒂𝒌𝒆𝒏 𝒆𝒗𝒆𝒓𝒚 𝟏𝟖𝒎𝒊𝒏)

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

V.PROCAINAMIDE
Given
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
Demand

11. Da=? , 12. Dm to achieve 6mg/l

𝟏𝟏.
 𝐴 𝑚𝑎𝑙𝑒 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑎𝑔𝑒 62𝑦𝑒𝑎𝑟𝑠, 𝑤𝑒𝑖𝑔ℎ𝑡 =
70𝑘𝑔 𝑑𝑜𝑒𝑠 𝑛𝑜𝑡 𝑟𝑒𝑠𝑝𝑜𝑛𝑑 𝑡𝑜 𝑖𝑑𝑜𝑐𝑎𝑖𝑛𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡
10

 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∗𝒍
𝑫𝒂(𝑳𝒐𝒂𝒅𝒊𝒏𝒈 𝒅𝒐𝒔𝒆 𝑰𝑽) = = = 𝟏𝟐𝟖𝟕. 𝟑𝒎𝒈 ↔ IV(F=1)
𝑺∗𝑭 𝟎.𝟖𝟕∗𝟏

𝟏𝟒𝟎𝒍 ∗ 𝟖𝒎𝒈/𝒍
𝑷𝒓𝒐𝒄𝒂𝒊𝒏𝒂𝒎𝒊𝒅𝒆 𝒐𝒓𝒂𝒍 (𝑫𝒂) = = 𝟏𝟓𝟏𝟒. 𝟓𝒎𝒈
𝟎. 𝟖𝟕 ∗ 𝟎. 𝟖𝟓

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
 . 𝐶𝑙𝐶𝑟𝑠𝑠 = 50𝑚𝑙/𝑚𝑖𝑛
 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
11
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

VI.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.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.
11. Discuss if it is relevant to take a blood sample during the first 24 hours to measure
the Cpss.

𝟏𝟑

𝑸𝑼𝑰𝑵𝑰𝑫𝑰𝑵𝑬 𝑺𝑼𝑳𝑭𝑨𝑻𝑬
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
12

 𝑂𝑢𝑟 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑑𝑟𝑢𝑔 𝑃𝑙𝑎𝑠𝑚𝑎 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑤𝑖𝑙𝑙 𝑏𝑒 𝑎𝑓𝑓𝑒𝑐𝑡𝑒𝑑 𝑏𝑦


14.7𝑙/ℎ
𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 𝑛𝑜𝑡 ℎ𝑎𝑙𝑓𝑙𝑖𝑓𝑒 𝑡ℎ𝑢𝑠 𝑘𝑒 = = 0.1166/ℎ
126𝑙
Ke=0.693/7h= 0.099h-1
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

𝑸𝑼𝑰𝑵𝑰𝑫𝑰𝑵𝑬 𝑮𝑳𝑼𝑪𝑶𝑵𝑨𝑻𝑬
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 = ( ) = ( )
126𝑙 1 − 𝑒 −0.1166∗6 126𝑙 1 − 0.4967

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 𝑄𝑞𝑢𝑖𝑛𝑖𝑑𝑖𝑛𝑒 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
13

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 ≤ ⋯ … … )

SECTION III. CARDIOTONIC DRUGS

VII.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
- Equilibrium between 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 , thus mean Cp=1.5ng/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.

𝐶𝐸∗𝑉𝑑 1.5𝑛𝑔 0.0015𝑚𝑔


𝟏𝟓 𝐿𝑜𝑎𝑑𝑖𝑛𝑔 𝑑𝑜𝑠𝑒 𝐷𝑎 = 𝑂𝑟 𝐶𝐸 = = , 𝑉𝑑 = 70𝑘𝑔 ∗
𝑆∗𝐹 𝑚𝑙 𝑙
7.3𝑙
= 511𝑙, 𝑆 = 1, 𝑎𝑛𝑑 𝐹 = 0.73 (𝑇𝐴𝐵)
𝑘𝑔
14

𝟎. 𝟎𝟎𝟏𝟓𝒎𝒈/𝒍 ∗ 𝟓𝟏𝟏𝒍
𝑫𝒂 = = 𝟏. 𝟎𝟓𝒎𝒈 𝒐𝒇 𝑳𝒐𝒂𝒅𝒊𝒏𝒈 𝒅𝒐𝒔𝒆 𝒐𝒇 𝑫𝒊𝒈𝒐𝒙𝒊𝒏
𝟏 ∗ 𝟎. 𝟕𝟑

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
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

SECTION IV. 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).

Given
Pharmacokinetics
- Poor oral bioavailability ;
Gentamicin et Tobramycin 4 à 8 mg/L (cpmax)< 2 mg/L(cpthrough)
Amikacin 20 – 30 mg/L(cpmax) <10 mg/L(cpthrouh)
- (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
15

- (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.
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.
Answers
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 𝑒𝑞𝑢𝑖𝑣𝑎𝑙𝑒𝑛𝑡 𝑡𝑜 𝑡ℎ𝑒 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 𝑐𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒.
16

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

𝟏𝟖

𝑄𝑜 1−𝑒 −𝑛𝑘𝑒Ʈ 100𝑚𝑔 1−𝑒 −2∗0.346∗0.5


 𝐶𝑝 (𝑚𝑎𝑥 ) = ( −𝑘𝑒Ʈ
)= ( ) = 10.55𝑚𝑔/𝑙
𝑉𝑑 1−𝑒 17.5𝑙 1−𝑒 −0.346∗0.5
 𝐶𝑝 (𝑡) = 𝐶𝑝(𝑚𝑎𝑥)𝑒 −𝑘𝑒𝑡

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


𝟏𝟗
𝑄𝑜 1
 𝐶𝑝 𝑚𝑎𝑥 𝑠𝑠 = ( )
𝑉𝑑 1−𝑒 −𝑘𝑒Ʈ
100𝑚𝑔 1 100𝑚𝑔 1
 𝐶𝑝 (𝑡) = ( )= ( )
17.5𝑙 1−𝑒−0.346∗8 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/𝑚𝑔