Therapeutic Drug Monitoring of Theophylline by mikesanye

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									Therapeutic Drug
 Monitoring of
  Theophylline
           By
  Rodchares Hanrinth
Faculty of Pharmacy and
     Health Science
Mahasarakham University
      Contents
• Theophylline review

• Pharmacokinetics

• Therapeutic drug monitoring
Theophylline Reviews
 • Chemical properties
 • Mechanism of action
 • Pharmacological effects
 • Indication
 • Dosage forms
 • Adverse Drug reactions
Chemical Properties
• 1,3-dimethylxanthine ~ caffeine
• Poorly soluble in water (8 mg/mL at
 25 C)
• Theophylline salts for IV route e.g.
 Aminophylline (ethylene diamine
 salts)
Theophylline
Mechanism of Actions
• Inhibition of the
  translocations of intracellular
  calcium (> 10-20 mg/L)
• Inhibition of
  phosphodiesterase  cAMP
 (>40 mg/L)
Mechanism of Actions
• Potentiation of prostaglandin
  synthesis and reduction of
  uptake of catecholamine
  – limited data support
• Blockade of adenosine receptors
  – The most possible mechanism
   Pharmacological
      Effects
• Many effects in human
1. CNS
2. Cardiovascular system
3. Kidneys
4. GI tract
5. Lungs
6. Miscellaneous
Central Nervous System
  • Anxiety, tremor, insomnia,
    nervousness, headache, nausea,
    and vomiting, (seen even
    therapeutic dose)
  • Respiratory stimulation(apnea
    &COPD)
  • Adverse psychological and
    behavioral performance
  • Seizure (seen ever in
    therapeutic range)
Cardiovascular System
•       heart rate & contractile force

•       pulmonary artery pressure

    –    right and left ventricular
        ejection fraction in pt w/
        COPD
            Kidneys
• Urine production

  –    water and electrolyte
      excretion

• Like thiazide diuretic
Gastrointestinal Tract
•   Gastric acid and pepsin
  secretion
• Block adenosine action (an
  antisecretory action) on the parietal
  cell
• Contraindicate in active peptic
  ulcer
              Lungs
• Improves mucociliary transport
•    diaphragmatic contractility
    – Both effects occur at conc.>
      therapeutic range
• Bronchodilation and dilation of
  pulmonary arteriole and
  pulmonary blood flow
Miscellaneous Effects
•    erythropoetin production
•    liver plasma flow
•    cortisol clearance
•    serum free fatty acid
•    insulin release
“These effects relate to toxic
    effects”
        Indications
• Acute bronchodilator therapy in
  pt w/ acute bronchospasm
  (asthma or COPD)
• Major prophylactic agent in the
  management of chronic
  asthmatic symptoms
• Apnea in premature neonate
        Dosage Forms
1. Rapid-release formulation
 -   Liquid or plain uncoated tabletes
 - Aminophylline (S = 0.85, 0.80)
2. Slow-release formulation
 - Theo-Dur q 8-12 hr
 - Ultraslow: Theo-24
Dosage Forms (cont.)
3. Parenteral formulation
 - LD: IV infusion 30 min
 - MD: Continuous infusion
 - Rapid IV injection may occur
 ADR (cardiac arrest,
 hypotension and death)
 - not usually use in IM or SC
Dosage Forms (cont.)
4. Rectal formulations
 - use in pt that cannot use
 oral or IV
   Adverse Effects
• CVS: AF, hypotension,
  palpitation, syncope, flushing,
  cardiac arrest, ventricular
  tachycardia, supraventricular
  tachycardia
• CNS: seizure, depression,
  anxiety, intracranial
  hemorrhage, headache,
  irritability
     Adverse Effects
         (cont.)
• Endocrine/ metabolic:
  hyperglycemia, hypokalemia,
  hypophosphatemia,
  hypocalemia,
  hypomagnesemia, respiratory
  alkalosis, metabolic acidosis,
  porphyria, lipid abnormality
    Adverse Effects
        (cont.)
• GI system: nausea, vomiting
 diarrhea, ulceration, esophageal
 ulceration, GERD, narcotizing
 enterocolitis
 Adverse Effects (cont.)

• Kidney/ GU: diuresis
• Skin: rash, eczematous
 eruption, exfoliative dermatitis,
 steven johnson syndrom
Pharmacokinetics
    • Absorption

   • Distribution

   • Metabolism

    • Elimination
         Absorption
• Bioavailabilty ~ 100%
• Factor affecting absorption
  1. Dosage forms
    - Salt form: Aminophylline
      - Anhydrous (S = 0.85)
      - Dihydrate (S = 0.80)
    - Ultraslow-relaese (Theo-24),
 enteric coat
        Absorption
2. Food and drug interaction
   -food and antacid (Al-Mg):
 absorption but not consistent
 effect
      Distribution
• 2-compartment PK ;
  ~1-compartment
• Distribution time: 30-45 min
• Protein binding~40%
• Vd = 0.5 L/kg*LBW
Distribution(cont.)
• Pass placenta, BBB, and
  excrete in milk
• Factor affecting distribution
  1. Obesity, BW> 120% of
  IBW use DW
     DW = IBW + 0.4(BW(kg) -
  IBW)
 Distribution(cont.)
• Factor affecting
  distribution(cont.)
 2. Special population (Table 4, p80)
    - Premature newborn: Vd
    - Pregnancy: Vd
    - Elderly: controversial
Distribution (cont.)
3. Disease state
    - Cystic fibrosis(1.2), CHF,
 Cor pulmonale, cirrhosis,
 uncorrected acidemia: Vd
    - COPD, uncorrected
 alkalemia: Vd
  Distribution(cont.)
      Population         Vd (L/kg)
Neonate                  0.69 + 0.95
Children
  1-12 yr                 0.3 – 0.7
Aldolescent (12-16 yr)    0.3 – 0.7
Adult(smoke/non-smoke)    0.3 - 0.7
CHF, Cor pulmonale        0.48 - 1.2
Cirrhosis                0.45 – 0.64
    Metabolism and
      Elimination
• Eliminate mainly at liver (90%):
 hydroxylation; N-demethylation;
 methylation (P450IA2&P4502E1)
• Linear pharmacokinetics
  except: neonate,
• Renal failure(acute&chronic):
 not adjust dose; but dialysis
 affected
Metabolism of Theophylline
     Metabolism and
    Elimination(cont.)
• Factor affecting CL
  - CL:Table 5 (p. 82):        Children,
 obesity, smoking, diet (charcoal broiling,
 high protein, low CHO), hyperthyroidism
 - CL:Table 6 (p. 83): Neonate
 and elderly, heart diseases, Severe
 OPD, Liver diseases, Febrile, viral
 respiratory infection, methylxanthine
 derivative, high CHO, low protein diet,
 hypothyroidism, severe malnutrition
    Metabolism and
   Elimination (cont.)
• Drug interaction
  – Enzyme inhibitors (Table 8,
    p.84)
  – Enzyme inducers (Table 9,
    p.84)
• Correction factors of Drug and
  diseases affect CL(Table 17, p.
 101)
 Correction factors of
Drug and diseases affect
       clearance
• Decrease CL
  – Allopurinol     0.8
  – Caffeine        0.7
  – Cimetidine      0.6
  – Ciprofloxacin   0.7
  – Disulfiram      0.5
  – Enoxacin        0.5
  – Erythromycin    0.8
  – Fluconazole     0.8
 Correction factors of
Drug and diseases affect
    clearance(cont.)
• Decrease CL (cont.)
  – Interferon-alfa      ?
  – Isoniazid            0.8
  – Lansoprazole         0.9
  – Nicotine             0.6
  – Oral contraceptive   0.65
  – Pefloxacin           0.7
  – Propranolol          0.75
  – Thaibendazole        0.5
 Correction factors of
Drug and diseases affect
    clearance(cont.)
• Decrease CL (cont.)
   – Ticlopidine                     0.65
   – Troleandromycin                 0.5
   – Verapramil                      0.9
   – CHF (unstable condition)        0.4
   – Severe OPD(FEV1<1 L; PCO2>45)   0.8
   – Viral pneumonia                 0.5
   – Cirrhosis                       0.4
   – Cor pulmonale                   0.5
   – Geriatric (>60 yr)              0.7
 Correction factors of
Drug and diseases affect
    clearance(cont.)
• Increase CL
   – Carbamazepine           1.5
   – Hydrocortisone          1.2
   – Isoproterenol           1.25
   – Phenobarbital           1.3
   – Phenytoin               1.6
   – Rifampin                1.3
   – Sulfinpyrazone          1.25
   – *Tobacco (1pack/day)    1.6
    • Passive smoker: > 4h/d for 1 d
  – Charcoal broiled meat    -
  – Cystic fibrosis          1.6
    Therapeutic Drug
       Monitoring
• Time to sample
• Therapeutic range
• Dosage calculation base on
  pharmacokinetic parameter
• Dosage adjustment not base on
  pharmacokinetic parameters
• Baseline and follow-up monitoring
  parameters
     Time to sample
• Continuous IV infusion: 2pt:8 hr
  and 20 hr after dosing
• Oral sustained release: any
  time or trough level
• Oral rapid release; 2pt: peak 2
  hr and trough 3-12 hr; or
  trough level
 Therapeutic range
• 10-20 mg/L  usually

• 5-15 mg/L initial use

• Neonate: 5-12 mg/L; if
 progress symptom: 15 mg/L
 Dosage Calculation base
   on Pharmacokinetic
       Parameter
• Step1. Calculate PK parameters
 – CL(L/hr) = 0.04
   L/kg/hr*LBW*factors
 – *Vd(L) = 0.5 L/kg*TBW*factors
 – Ke (hr-1) = CL/Vd
 – T1/2 (hr) = 0.693/Ke
 *if TBW/IBW > 1.2, use DW
 • DW = IBW + 0.4(TBW-IBW)
Step2. Calculate loading
         dose

  C = SFD ;
      Vd
  LD = Cdesired*Vd
          SF
Step3. Calculate maintenance
            dose
 – Selection appropriate model
 1. Bolus model (Abs time or tin <
    1/6 of T1/2)
 2. Short infusion model
    (Abs time or tin >1/6 of T1/2)
 3. Continuous infusion model
    (Abs time – T) < 1/3 of T1/2
Step3 : 1) Bolus model
  – Abs time or tin < 1/6 of T1/2
   Cpeak = SFD;
         Vd*(1-e-KT)
   MD= Cpeak*(1-e-KT)*Vd
              SF
   Ctrough = Cpeak*e-Kt
*Usually use for Aminophylline (Abs
   time = 1 hr)
 Step3:2) Short infusion
             model
• (Abs time or tin >1/6 of
  T1/2)
  Cpeak = (SFD/tin)*(1-e-Ktin)
             CL*(1-e-KT)
  Ctrough = Cpeak*e-Kt
*Not usually use for Theophylline
         Step3: 3)
 Continuous infusion model
• (Abs time ~ T or (T-tin) <
  1/3 of T1/2)
    MD = Cpss*T*CL
           SF
*Usually use for Theo-Dur
(Abs time = 10 hr)
          Case Example
• ผู้ป่วยชาย อายุ 72 ปี น้าหนัก 87 กก. สูง175
  ซม. มีประวัติเป็นโรคหอบหืด ได้รับ ยา Albuterol
  inhaler II qid, Beclomethasone II qid และ Cimetidine
  400 mg po bid เคยสูบบุหรี่ วันละ ½ ซอง มา 40 ปี
  แพทย์สั่ง Theo-Dur จงค้านวณหาขนาดยาที่
  เหมาะสม ในผู้ป่วยรายนี เพื่อให้ได้ความเข้มข้นที่
  Steady state = 10 mg/L
       Case Example(cont.)
• หลังจากผูป่วยได้รับยาไป 3 วัน แพทย์สั่งวัดระดับ
              ้
  ยาในเลือดอีกครังก่อนให้ยา ได้ระดับยา 8 mg/L
  เนื่องจากผู้ป่วยจ้าเป็นต้องใส่ NG tube ยาที่ให้จึง
  จ้าเป็นต้องบด หากบด Theo-Dur จะท้าให้สูญเสีย
  ความเป็นยาออกฤทธิเนิ่น จงค้านวณหาขนาดยา
  ใหม่ ในรูปแบบยา rapid-release เพื่อให้ระดับยาที่
  steady state อยู่ในช่วง 5-15 mg/L
  Dosage adjustment not
 base on pharmacokinetic
       parameters
• General Guideline
  –Loading dose: 5 mg/kg
   of theophylline
  –Maintenance dose: not
   more than400 mg/day
   General Guideline
       (cont.)
– Dose for special population as
  Table 1 and 2 (p.75)
*-if parenteral route: continuous infusion
 - Oral rapid release should be devided q 6-8
 hr
 - Sustained release: q 8-12 hr
 - Switch from continuous infusion to
 sustained release can do at once or after
 stop IV not more than 4 hr
 - Dosage can adjust every 3 days by 25%
 increased dose
  Dosage adjustment not
 base on pharmacokinetic
    parameters (cont.)
• FDA-approved package insert

  (Fig 8, p.97)

• Hendeles method

 (Table 13, p.99)
Baseline parameters
• Age, gender, height, weight,
• Smoking history,
• Concurrent disease list (CHF,
  Pulmonary),
• Out patient theophyylline dosing
  history,
• Liver function tests
    Follow-up monitoring
         parameters
• Concomitant drug therapy (qd)
• Pulmonary function tests (prn)
• Arterial blood gas (prn)
• Signs and symptoms of efficacy
  (qd)
• Signs and symptoms of toxicity
  (qd)

								
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