PHOSPHODIESTERASE INHIBITOR

1. AMINOPHYLLINE
DR.ATHAR

2. INTRODUCTION
Aminophylline is a compound of the
bronchodilator theophylline with ethylenediamine in 2:1
ratio.
Theophylline is one of the three naturally occurring
methylated xanthine alkaloids caffeine,theophylline and
theobromine
The ethylenediamine improves solubility, and the
aminophylline is usually found as a dihydrate
Aminophylline tends to be less potent and shorter acting
than theophylline.

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 more soluble in 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 absorbs carbon dioxide with the liberation of free
theophylline.
• Its solutions are alkaline
• Insoluble in alcohol and in ether.

7. MECHANISM OF ACTION
 Competitive Nonselective Phosphodiesterase
Inhibitor
• Increase tissue concentration of cAMP causes
bronchodilation diuresis, CNSstimulation, cardiac
stimulation, and gastric acid secretion.
• Induces release of epinephrine from adrenal medulla
cells and promotes catecholamine stimulation
of lipolysis, glycogenolysis and gluconeogenesis

8.  Nonselective adenosine
receptor antagonist.
• 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 given parenterally
• 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 t1/2 in adult is 7-12 hours.
It is lesser in children and more in elderly and infant.
• Metabolising enzymes are saturable, t1/2 is prolonged with
higher doses as kinetics changes from first to zero order ,
plasma concentration therefore increase disproportionately.
• Theophyllin has 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 edema and
pulmonary congestion secondary to heart failure.
• Aminophylline is used to reverse dipyridamole or
adenosine based infusions during nuclear cardiology
stress testing.
• Aminophylline has shown some promise as a body fat
reducer when used as a topical cream (sometimes
referred to as "cutting gel").
• Aminophylline is also a treatment option for anaphylactic
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
Theophylline concentration <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
atrial tachycardia and flutter have been reported at
serum theophylline concentrations ≥15 mcg/mL
• Theophylline concentration>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
• Aminophylline has been found to decrease the sedative
effects of propofol and decrease topiramate antiseizure
action.
• Has synergistic toxicity with sympathomimetics such 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