Aminophylline

PHOSPHODIESTERASE INHIBITOR

1. AMINOPHYLLINE
DR.ATHAR

2. INTRODUCTION
Aminophylline isa compound of the
bronchodilatortheophyllinewithethylenediaminein2:1
ratio.
Theophyllineisoneofthethreenaturallyoccurring
methylatedxanthinealkaloidscaffeine,theophyllineand
theobromine
Theethylenediamineimprovessolubility,andthe
aminophyllineisusuallyfoundasadihydrate
Aminophyllinetendstobelesspotentandshorteracting
thantheophylline.

3. STRUCTURE
•1,3-dimethyl-7H-purine-2,6-dione; ethane-1,2-
diamine

4. PREPARATIONS
Injectable: 25 mg/mL (theophylline equivalent = 19.7
mg/mL)

5. Tablets: 100 mg (theophylline equivalent =
78.9 mg ), and 200 mg (theophylline
equivalent=158 mg)
225 mg controlled released tablets
Oral liquid: 105 mg/5ml (theophylline
equivalent = 90 mg/5ml )

6. PHYSICAL PROPERTIES
•It is moresolublein water than theophylline.
•White or slightly yellowish granules or powder, having a
slight ammoniacal odor and a bitter taste.
•Upon exposure to air, it gradually loses ethylenediamine
and absorbscarbon dioxide with the liberation of free
theophylline.
•Its solutions arealkaline
•Insoluble in alcohol and in ether.

7. MECHANISM OF ACTION
Competitive NonselectivePhosphodiesterase
Inhibitor
•Increase tissue concentration of cAMP causes
bronchodilationdiuresis,CNSstimulation, cardiac
stimulation, and gastric acid secretion.
•Induces release ofepinephrinefrom adrenal medulla
cells andpromotescatecholaminestimulation
oflipolysis,glycogenolysis andgluconeogenesis

8. Nonselective adenosine
receptorantagonist.
•Adenosine is an endogenous extracellular
messenger that regulate myocardial oxygen
needs.
•It increases coronary artery blood flow, slows
heart rate, block atrioventricular node
conduction, suppress cardiac automaticity, and
decrease β-adrenergic effects on contractility

9. •Adenosine also antagonizes chronotropic and
ionotropic effects of circulating catecholamines.
•Adenosine’s receptors are competitively
antagonized by methylxanthines such as
aminophylline
•Aminophylline competitively antagonizes the
cardiac actions of adenosine at the cell surface
receptors. Thus, it increases heart rate and
contractility

10. •At high concentration it stimulate the
Release of Ca
+2
from sarcoplasmic
reticulum, specially in skeletal and cardiac
muscle
•Inhibits release of histamine and other
mediators from mast cells and activated
inflammatory cells.

11. PHARMACOLOGICAL ACTIONS
CNS -Stimulation of higher centre.
-also stimulate vagal,respiratory and vasomoter
centre
Heart -stimulation
heart rate-increased
BP-systolic-increased ,diastolic-decreased
Blood vessel-relaxation
Bronchi -dilation
Kidney -diuresis

12. PHARMACOLOGICAL ACTIONS
Skeletal.muscle -increased contractility
Gastric mucosa -irritation
-increased secretion of acid pepsin
BMR -increased

13. PHARMOKOKINETICS
•These drugs can be given orally, although
absorption may be slow and not as
effective as when givenparenterally
•Distributed in all tissues-crosses placenta
and is secreted in milk.
•Extensively metabolised in liver by
demetylation and oxidation.

14. PHARMOKOKINETICS
•Metabolism:Children >1 year and Adults:
Hepatic; involves CYP1A2, 2E1 and 3A4;
forms active metabolites (caffeine and 3-
methylxanthine).
•Only 10% is excreted unchanged in urine

15. •Protein binding Only 60%
•Half-life elimination: Highly variable and dependent upon
age, liver function, cardiac function, lung disease, and smoking
history
At therapeutic concentration t
1/2in adult is 7-12 hours.
It is lesser in children and more in elderly and infant.
•Metabolising enzymes are saturable,t
1/2is prolonged with
higher doses as kinetics changes from first to zero order ,
plasma concentration therefore increase disproportionately.
•Theophyllinhas a narrow margin of safety: therapeutic
concentration range is 10-20 mcg/ml.

16. DOSE
Loading dose:
6 mg/kg in 100 to 200 mL of IV fluid intravenously once over 20
to 30 minutes.
Maintenance dose (following loading dose):
Otherwise healthy nonsmoking adult: 0.7 mg/kg/hr continuous
intravenous infusion.
Young adult smoker: 0.9 mg/kg/hr continuous intravenous
infusion.
Patient with cor pulmonale or congestive heart failure: 0.25
mg/kg/hr continuous intravenous infusion.

17. Oral:
Loading dose: 6.3 mg/kg orally once
Maintenance dose (following loading dose):
Otherwise healthy nonsmoking adult: 12.5 mg/kg/day in
divided doses. Do not exceed 1,125 mg/day.
•Young adult smoker: 19 mg/kg/day in divided doses.
•Patient with cor pulmonale or congestive heart failure:
6.25 mg/kg/day in divided doses. Do not exceed 500
mg/day.

18. PEDIATRIC DOSE FOR
APNEA OF PREMATURITY
<= 4 weeks: (IV or oral, all dosages based on
aminophylline):
Loading dose: 5 to 6 mg/kg once -if IV, dilute in IV fluid
and give intravenously once over 20 to 30 minutes.
Maintenance dose: 3 to 8 mg/kg/day divided every 6 to
12 hours.

19. LIVER DOSE ADJUSTMENT
Loading dose: 6 mg/kg (patient not receiving
aminophylline or theophylline) diluted in IV fluid at a rate
not more than 25 mg/min.
Maintenance dose: 0.25 mg/kg/hr continuous
intravenous infusion.

20. CLINICAL USES
•Used as a bronchodilator in reversible airway
obstruction.
•May be used in cases of Pulmonary edemaand
pulmonary congestion secondary to heart failure.
•Aminophyllineis used to reversedipyridamoleor
adenosine based infusions during nuclear cardiology
stress testing.
•Aminophyllinehas shown some promise as a body fat
reducer when used as a topical cream (sometimes
referred to as "cutting gel").
•Aminophyllineis also a treatment option foranaphylactic
shock

21. SPECIAL INDICATIONS
•PREGNANCY -category C by the FDA
-evidence of embryolethality and teratogenicity in
animals.
-use during pregnancy when there are no alternatives
and benefit outweighs risk.
•LACTATION–excreted in human milk and may cause
irritability or other signs of mild toxicity.
•PEDIATRIC USE -safe and effective for the approved
indications in children.

22. SIDE EFFECTS
Theophyllineconcentration <20 mcg/mL
•nausea
•vomiting
•headach
•insomnia
•diarrhea,
•irritability,
•restlessness
•fine skeletal muscle tremors,
•transient diuresis.

23. •In patients with hypoxia secondary to COPD, multifocal
atrialtachycardia and flutter have been reported at
serum theophyllineconcentrations ≥15 mcg/mL
•Theophyllineconcentration>20 mcg/mL
persistent vomiting,
cardiac arrhythmias,
intractable seizures which can be lethal.

24. CONTRAINDICATIONS
•Hypersensitivity to theophylline or
ethylenediamine

25. Special Precautions
Neonates,
Elderly,
Lactation,
Pregnancy,
Cardiac/hepatic diseases,
Peptic ulceration,
Hyperthyroidism,
Hypertension,

26. Special Precautions
epilepsy,
heart failure,
chronic alcoholism,
acute febrile illness

27. DRUG INTERACTIONS
•Aminophyllinehas been found to decrease the sedative
effects of propofoland decrease topiramateantiseizure
action.
•Has synergistic toxicity with sympathomimeticssuch as
ephedrine.
•Halothane-the risk of side effects such as irregular
heartbeat may be increased.
•Ketamine-risk of seizures may be increased.

28. •Adenosine, benzodiazepines (eg, diazepam, lorazepam
midazolam), lithium,or nondepolarizing muscle relaxants
(eg, pancuronium) -effectiveness may be decreased by
Aminophylline.
•Allopurinol, cimetidine, disulfiram, interferon alpha,
macrolide antibiotics (eg, clarithromycin, erythromycin),
methotrexate, oral contraceptives, quinolone antibiotics
(eg, ciprofloxacin), verapamil -risk of side effects of
Aminophylline may be increased

29. •Aminoglutethimide, barbiturates (eg,
phenobarbital),
beta-blockers (eg, propranolol),
carbamazepine,
hydantoins (eg, phenytoin), rifampin, or
sulfinpyrazone –
effectiveness of Aminophylline may be
decreased

30. OVERDOSE
•Symptoms of overdose can occur at usual prescribed
dosages of aminophylline.
•Symptoms: agitation, nausea, frequent vomiting, unusual
thirst,fever, ringing in the ears (tinnitus), fast/irregular
heartbeat, seizures, confusion,chest pain,agitated
maniacal behavior, palpitation and arrhythmias.
•Treatment is usually supportive and withdrawal of the
drug.
•Restoration of fluid and electrolyte balance is necessary.

31. THANK YOU