TERBUTALINE MEDICINAL CHEMISTRY.pptx

TERBUTALINE CHEMISTRY AND PHARMACOLOGICAL INTRODUCTION

1. NAME OF DRUG :-TERBUTALINE SYNONYMS:- Brethine , Bricanyl , Brethaire , Brican , IUPAC NAME:- (2-t-butylamino-1-[3,5-dihydroxyphenyl] ethan-1-ol) FORMULA:- C12H19NO3 CHEMICAL STRUCTURE:- Terbutaline has a butyl group on nitrogen atom and a different arrangement of –OH group on the benzene ring. NAME:- MISHA PATEL SUB :-MEDICINAL CHEMISTRY-1 CODE:-BPH5001

2. 2 GENERAL INTRODUCTION:- Terbutaline is synthetic sympathomimetic amine derived from resorcinol . Terbutaline was first synthesized in 1966, and granted FDA approval on 25 March 1974. Terbutaline is beta-2 adrenergic agonist used as a “reliever” inhaler in the management of asthma symptoms and as tocolytic agent to delay preterm labor for up to 48hr. It should not be used more than 48-72hr. In February 2011, the FDA began requiring a black box warning on the drug’s label. Pregnant women should not be given injections/oral dose of the terbutaline for the prevention of preterm labor or for long-term management of preterm labor, due to the potential for serious internal heart problems and death.

3. 3 Physiochemical properties:- S.no Physical and chemical properties 1 Molecular weight 225.28g/ mol 2 Physical appearance Present in solid form 3 Melting point 199-122 ‘C 4 solubility slightly soluble in alcohol and soluble in water 5 Present of ring Benzene ring present 6 Number of chiral center 1

4. Structure activity relationship:- 4 R1-substitution on N the size of R1 β activity α activity t- butyl:- β 2 activity degradation by MAO R3-substitution on Ar –ring. 3’,4’-diOH has poor oral activity and short DOA. 3’,5’-diOH compound orally active and longer DOA. R2-substitution on C2 Et group: oral activity and DOA Additional methyl group: α 2 activity .

5. Structure activity relationship:- Primary or secondary aliphatic amine separated by two carbons from a substituted benzene ring is essential for the high agonist activity. The hydroxyl substituted carbon must be in the R configuration for the maximal direct activity . R1 substitution : When R1 is increased in size, activity of alpha receptors decreases and activity of the beta receptors increases Activity of both alpha and beta receptors is maximum when R1 is methyl group. Alpha agonist activity decreases when R1 is larger than methyl, and went negligible when R1 is isopropyl. Large lipophillic groups can afford compounds with alpha blocking activity. N-substituent provides selectivity for different receptors. 5

6. . R2 substitution : Ethyl group can eliminate the alpha activity of the drug. Erythrostero isomers have maximal activity. The additional methyl group makes the drug more selective for the alpha2 R3 substitution on the aromatic ring : 3’,4’-dihydroxy substituted benzene ring has poor oral activity. 3’, 5’-dihydroxy compounds are orally active. If phenyl group has no phenolic substituent then it may act directly or indirectly 6

7. METHOD OF SYNTHESIS:- i . Bromination of 3,5-dibenzyloxyacetophenone gives 3,5- dibenzyloxybromoacetophenone . ii . It is then reacted with N-benzyl-N- tert - butylamine to give a ketone intermediate . iii. Intermediate undergoes reduction to give terbutaline . 7

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9. Indication:- 1. Relieve bronchospasm associated with asthma ,chronic bronchitis and emphysema. Contraindication:- 1.terbutaline has not been approved and should not be used for tocolysis . Serious ADR occure after administration of terbutaline . In the mother this include increased heart rate , hypokalemia , and myocardial ischemia. 2.Terbutaline, is contraindicated in patient know to be hypersensitive to sympathomimetic amines of this drug product. 9

10. PHARMACOKINETICS:- ABSORPTION:- ORAL: 30-50% and Sub-Q:- Well absorbed. METABOLISM:- Partially metabolized in liver. ELIMINATION:- Approximately 60% of administered terbutaline is excreted unchanged in the urine. DISTRIBUTION:- Crosses placenta and distributes into milk.(see preterm labor .) HALF-LIFE:- Oral dose: 3.hr and Subcutaneous dose: 2.hr. PHARMACODYNAMICS:- Terbutaline is selective beta-2-adrenergic receptor agonist indicated to treat reversibly bronchospasm in asthmatic patients with bronchitis and emphysema. PHARMACOLOGY:-

11. Mechanism of action:- Terbutaline selectively binds to and activates beta-2 adrenergic receptors, leading to intracellular adenyl cyclase activation via trimeric G protein and increase in cAMP production. Increase cAMP levels result in relaxation of bronchial and vascular smooth muscle. Wider air passages allow more air to flow in & out of the lungs. increased airflow reduces shortness of breath. 11

12. PHARMACOLOGICAL ACTION:- Terbutaline is a relatively selective beta 2- adrenergic bronchodilator that has little or no effect on alpha-adrenergic receptor. Terbutaline appears to have a greater stimulating effect on beta-2 receptor of the bronchial, vascular and uterine smooth muscle (beta-2 receptors.) than on the beta-receptors of heart.(beta-1 receptors.) This drug relaxes smooth muscle and inhibits uterine contractions, but may also cause some cardiostimulatory effects and CNS stimulation. 12

13. DRUG-DRUG INTRACTION:- Combining terbutaline with thioridazine may increases the abnormal heart rhythms. The effects of terbutaline are reversed by beta-blockers, conversely terbutaline may reduce the effect of beta-blockers. Therefore, terbutaline and beta-blockers should not be used together. DRUG-FOOD INTRACTION:- There is 1 alcohol/food/lifestyle interaction with terbutaline :- High blood pressure moderate potential hazard 13

14. Therapeutic Uses As a bronchodilator Treatment of asthma As a tocolytic  Side Effects Common side effects of terbutaline are, hypotension, hypokalemia, hyperglycemia, headache, tremors, anxiety and nervousness. 14

15. ADMINISTRATION:- Oral administration:- Administer tablet orally. For patients with difficulty swallowing, the tablets may be crushed. Alternatively an extemporaneous oral liquid may be prepared. Tab:- 2.5mg, 5mg. Injectable administration:- Subcutaneous administration:- inject terbutaline SC. Into the lateral deltoid area. Inj solution:- 1mg/ml Discard unused portion after single patient use; vials or ampoules are for single-use only. 15

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