DRUGS EFFECTIVE ON THE RESPIRATORY SYSTEM

Prof. Dr. Esin AKI-YALÇIN CLASIFICATION OF RESPIRATORY SYSTEM DRUGS

1. Antitussive (cough breaker) Drugs 2. Expectorants 3. Mucolytics 4. Bronchodilators 5. Drugs used for the treatment of asthma 6. Bulbar Respiratory Center Stimulators

Prof. Dr. Esin AKI Cough

 A protective physiological reflex.  A weak syndrome  It can also be observed in health status as in the case of disease.  Cough reflexes are stimulated in some disease states or mechanical irritation of the respiratory tract (larynx, trachea, bronchial mucosa,..) or outside the respiratory tract (pleura, external ear canal, middle ear epithelium ..).

Prof. Dr. Esin AKI Cough is accompanied by 2 reflexes.

1. Bronchoconstriction 2. Mucus secretion

Symptomatic (Palliative) Treatment

Antitussives; they reduce the intensity and frequency by suppressing the cough reflex. COUGH STIMULATION

It is initiated by chemoreceptors or mechanoreceptors in the lungs. Stimulus is transmitted to the COUGH CENTER where the afferent nerve fibers in the vagus nerve are located in the brain stem in the Medulla.

Prof. Dr. Esin AKI ANTITUSSIVE DRUGS

Prof. Dr. Esin AKI Mechanisms of Action of Antitussives • Central effect: Inhibition of cough center • Peripheral effect: Depression of nerve endings in the lung and other peripheral areas • Spasmolytic effect: Reducing the sensitivity of cough receptors in the lungs due to spasmolytic effect

Prof. Dr. Esin AKI ANTITUSSIVE DRUGS 1. derivatives

2. Synthetic Antitussives I. Type Antitussives II. Antitussives with Basic Ester Group III. Local Anesthetic Effective Antitussives IV. Other Antitussives Not Classified by Chemical Structures

Prof. Dr. Esin AKI OPIOID DERIVATIVES  Morphine and similar drugs  Inhibitory effect on cough center

Affected Receptors: 1. Opioit receptors 2. Cough inhibitory receptors

Although these compounds are effective, their use is limited due to their intolerance and dependence and toxic effects.

Prof. Dr. Esin AKI OPIOID DERIVATIVES

HO H3CO H3CO

O O O N CH3 N CH3 N CH3

HO HO H3CO

Morphine Thebaine (Narcotic analgesic) (Prototype antitussive) (very toxic) 3,6-dihydroxy-7,8- 7,8-didehydro-4,5-epoxy-3- (Synthesis of starting didehydro-4,5-epoxy-17- methoxy-17-methylmorphinan compound) methylmorphinan -6-ol

Prof. Dr. Esin AKI 2 R1 3 1 Alkaloids and Derivatives: 4 11 O 12 10 13 14 CH 5 9 N 3 15 16 6 8 R2 7 R1 R2 Position of Other Name Salt ethylenic bond 7 CH3O - - OH   Codeine HCI, phosphate

7 C2H5O - - OH   (Dionine) HCI

__ O N CH2CH2O - OH 7 

CH3O - - OH Saturated  (Paracodin) Hydrogen Tartrate

CH3O - O Saturated  (Dicodid) Hydrogen Tartrate

CH3O - O Saturated 14-OH Oxycodone (Eucodal) HCI

6 CH3O - -OCOCH3   Tebacon (Acedicon) HCI CODEINE It is still used today. Phenolic OH —> Ether : analgesic effect decreases, antitussive effect increases, side effect decreases

• The compound inhibits gastrointestinal motility and fluid secretion of the intestinal mucosa. •Side Effects: Sedation, Drowsiness, Constipation (antidiarrheal)

Rarely; Euphoric and addiction

Used as base or sulfate salt Levo and dextro isomer effective Polystyrene salt is long effective. levo = 6 x dekstro

Prof. Dr. Esin AKI CH3 Codeine Metabolism O

O-demethylationO-demetilasyon NN-demetilasyon-demethylation O CH3 N

HO

CodeinKodein CH3 O HO

O O CH3 NH N

HO HO HO Norcodein Norkodein (10-20)(%10-20)

MorphineMorfin (%5(%5-15)-15) O CH3 N

Glu O Glucuronateglukuronat GlucuronateGlukuronat konjugatlariconjugates Idrarlaexcretion atilim conjugateskonjugatlari

6-Glucuronate6-Glukorinat Dihydrocodeine

2 CH3O 3 1 Its antitussive effect is more than codeine. 4 It is addictive like morphine. 11 Therefore it is used only in severe cases. O 12 10 13 14 CH 5 9 N 3 15 16 6 8 HO 7

Prof. Dr. Esin AKI Dihydrocodeinone

2 CH3O 3 1  Potent 4 analgesic 11 O 12 10 13  Antitussive 14 CH 5 9 N 3 15 16  Addictive effect 6 8 is more than O 7 codeine

Prof. Dr. Esin AKI Effect and Usage of General Opioid Derivatives: Reduction of mucosal secretion in the respiratory tract —> sense of dryness

They expose histamine —> It should not be used in bronchial asthma.

Pholcodine —> less addictive than codeine, equally effective Dionine —> less addictive than codeine, equally effective Paracodin —> more addictive than codeine Dicodid —> more addictive than codeine, stronger effect Oxycodone —> more addictive than codeine, stronger effect

7-8 Saturated bond is more addictive HO O N CH2CH2 O ClCH CH N O O 2 2 O N CH3 N CH3 HO HO MORFIN PPHOLCODİNEHOLCODIN + CH3Cl ethylationEtilasyon Metilasyon methylation

H C O H CO 5 2 3 H3CO Red. O O O N CH3 N CH3 N CH3 HO HO KODEIN HO DIONINDIONINE(Et ilmorfin) Codein PARACODINEPARACODIN (Dih i d r o k o dein)

H CO H3CO 3 Red. Oks. 1) Red.

Synthesis O 1) Red. H3CO O N CH3 2) Demetilasyon N CH3 (HBr) H3CO 2) Demetilasyondemethylation O CH TEBAIN N 3 H CO THEBAIN (HBr) 3 O H H HTEOB A/ HIBrN 2 2 DICODID Morphine(H i(%5droliz)-15) Dihidrokodeinon (HYDROCODON) H O / HBr H CO 2 2 3 Asacetylationetilasyon (Hidroliz) H3CO + H2 O OH H3CO O OH N CH3 N CH3 O H3CO O H3CO O OKSIKODON N CH3 Hidroksikodeinon + H Hydroxycodeinone 2 Oxycodone TEBACON CHO3COO O TebakoOn (HACEDICON) OH N CH3 N CH3 O O OKSIKODON Hidroksikodeinon Dekstrometorphan CH3O

N CH 3 * * * N CH3 3-methoxy-N-methylmorphinan It is a synthetic morphinan derivative. The methane derivative of the d-enantiomer of levorphanol, a narcotic analgesic drug, has low affinity for conventional opioid receptors. Does not have any analgesic effect.. Although it effects by inhibiting the cough center in the brain there are no constipation, central depression, and addictive effects. It does not dry mucosa. It should not be used using bronchial asthma. Caution should be exercised in liver patients since demethylation is inactivated in the liver. SYNTHETIC ANTITUSSIVES

 They don’t have side effects of , such as addiction, constipation, drowsiness and sedation .  They inhibit the cough reflex with a peripheral effect.

Prof. Dr. Esin AKI I. METHADONE LIKE ANTITUSSIVES

Methadone (analgesic) (antitussive)

Spasmolytic, bronchodilator, selective effect on the respiratory system

Prof. Dr. Esin AKI Chlophedianol DETIGON

1-o-chlorophenyl-1-phenyl-3-dimethylamino propanol

Selective effects to the respiratory system. It blocks the cough center with partially central and peripheral, spasmolytic and local anesthetic effects. It has local anesthetic, spasmolytic and antihistaminic properties. May perform anticholinergic effects and hallucinations in high doses. Does not cause respiratory depression and drowsiness. Side Effect: Nausea, vomiting Synthesis of Chlophedianol

Cl Cl - + CH O Mg Cl 3 CH C O + ClMgCH CH N C 3 2 2 CH CH N CH3 2 2 CH3

HOH CH3CN/NaNH2 ChlophedianolKlofedianol Cl Cl OH CH2O/HCOOH OH C Red C CH CN 2 CH2CH2NH2

Prof. Dr. Esin AKI SILOMAT

1-(p-chlorophenyl)-2,3-dimethyl-4-dimethylamino-2-butanol

Spasmolytics Local anesthetic Inhibits the cough center Does not cause respiratory depression and drowsiness.

Prof. Dr. Esin AKI Silomat Synthesis

Prof. Dr. Esin AKI C N C CH3 CH CH CH CH 3 2 N ,Sitrik Ac. ISOAMINIL=PEROCAN CH3 CH3 CH3

-isopropyl--(2-dimethylaminopropyl) phenylacetonitril

Supress the center of cough with its bronchodilator effect. There is no suppressive effect on analgesic, sedative or respiratory center.

Prof. Dr. Esin AKI Synthesis of Isoaminyl

H CH2CN CH3 NaNH2 +ClCH C CN CH3 CH H3C CH 3 ClCH2CHN CH3 CH3 CH3 (NaNH2)

CN C CH3 CH CHN H C CH 2 3 CH3 CH3 CH3

Prof. Dr. Esin AKI - NOVRAD

.

(-)4-dimethylamino-1,2-diphenyl-3-methyl-2-butilpropiyonat

The (-) isomer of the compound exhibits much more antitussive activity than both the (+) isomer and the racemic mixture. The analgesic effect is dominant in the (+) isomer of the dextropropoxyphen compound. It acts by inhibiting the cough center. It is used in the upper respiratory tract infections (cold, flu). Used in cases of laryngitis due to smoking. There is also a spasmolytic effect.

Prof. Dr. Esin AKI Synthesis of Levopropoxifene Napsilate :

3-dimethylamino-isobutirophenon

hydrolysis

D-camphorsulfonic acid

2-Naphtalene sulfonic acid . II. BASIC ANTITUSSIVES Carrying ESTER GROUP

Prof. Dr. Esin AKI C H COOCH CH O CH CH N 2 5 2 2 2 2 C H , Sitrik Ac. C 2 5 Carbetapentane Citrate- Pentoxiverine SEDOTUSSIN--GAYABEN 1-phenyl-cyclopentanecarboxylic acid 2-(2- diethylaminoethoxy)ethyl ester

A little more effective than codeine. Suppresses cough caused by upper respiratory tract infection. Spasmolitic. Local anesthetic. Parasympatholytic side effects are seen. It can depress the heart if used in high doses.

Prof. Dr. Esin AKI C2H5 COOCH2CH2 N Ethane, Etan sulphonic disülfonat acid C C2H5 -ALCOPON

1-phenyl cyclopentanecarboxylic acid (2-diethylamino)ethyl ester

Bronchodilator. It affects the cough center. Less powerful than codeine.

Prof. Dr. Esin AKI Okseladin-PECTAMOL

Et , CitricSitrik AcidAsit COO CH2CH2 O CH2CH2 N C Et Et Et ,- Diethylphenylacetic acid-2-(2-diethylaminoethoxy)ethyl ester

Less powerful than codeine, less side effect.

Prof. Dr. Esin AKI General Reaction Scheme

Et Et R COCl + HO CH CH 2 2 N R COOCH2CH2N Et Et Amino Alcohol Division

C2H5 DietilaminoetanolDiethylamino ethanol HO CH2CH2 N C2H5

Et Et + N CH2CH2OH ClCH2CH2OH N CH2CH2O CH2CH2Cl Et Et 2-Diethylamino2-Dietilamino ethoxy etoksi ethyl etil klorürchloride

Prof. Dr. Esin AKI Synthesis C N Na NH C + Br (CH ) Br 2 CH C N 2 4 2 -HBr BenzylBenzil cyanidesiyanür 1-1-siyano-1-fenilsiklopentancyano-1-phenylopentane

HOH/H+

COCl COOH SOCl2 C C 1-1-fenil-1-siklopentanphenyl-1-cylopentane carboxylickarboksilik acid Asit Caramiphane verecek asit klorürü. Carbetapentan }

2C2H5Br/Na NH2 C N HOH/OH- COOH -HBr C H C C2H5 C 5 2 C H H5C2 2 5 22--ethylethyl2-etil-2-fenil-butironitril--22--phenyl--butyronitrile 2-ethyl2-etil-2-fenil-2-phenyl butyric butirik acid asit (okseladin verecek asit) Example Synthesis: Oxeladine citrate

Oxeladine citrate Oxeladine

Prof. Dr. Esin AKI S Dimetoxanate - TUSSIDIN

N Et COO CH CH O CH CH N , HCl 2 2 2 2 Et -Diethylaminoethoxy ethylphenothiazine-10- carboxylate

Prof. Dr. Esin AKI S Pipazetat - SELVIGON

N N

COO CH2CH2 O CH2CH2N

1-Azaphenothiazine-10-carboxylic acid2-(2-piperidino ethoxy) ethyl ester

Less potent than codeine, less side effects.

Prof. Dr. Esin AKI Synthesis of Pipazethate S S + COCI2 N N H N N 1-Azafenotiyazin1-Azaphenotiazin COCI

HO CH2CH2 O CH2CH2N

22(2-piperidino-(2-piperidino ethoxy)ethanol etoksi)etanol S PipazethatePipazetat N N

COO CH2CH2 O CH2CH2N Butamyrate Citrate = SINECOD

C2H5 CH COOCH2CH2OCH2CH2N C H , CitrateSitrat C2H5 2 5 2-2-(diethylamino) ethoxyethyl-2-phenyl butyrate

Used in cases of bronchitis.

Prof. Dr. Esin AKI 3. LOCAL ANESTHETIC EFFECTIVE ANTITUSSIVES

Prof. Dr. Esin AKI - TESSALON n Bu HN COO (CH CH O) CH 2 2 9 3

4-butylamino-benzoic acid-(o-methyl)- nona ethylene glycol ester

A viscous liquid. Both central and peripheral effective. It provides local anesthesia in the lungs, afferent nerve endings and receptors when systemically taken. It blocks the receptors responsible for the cough reflex. Side effects: Nasal obstruction, urticaria, constipation, drowsiness. Oxolamine Phosphate - PEREBRON - FENKO N N C2H5 O CH2CH2N C2H5 5-(2-diethylaminoethyl)-3-phenyl-1,2,4-oxadiazole

Bronchodilator. Local anesthetic. Spasmolitic. Antipyretic, anti-inflammatory. It is used in inflammatory diseases of the respiratory tract.

Prof. Dr. Esin AKI Synthesis of Oxolamine

CONH C NH 2 2 CI CH2CH2COCI + NH OH N OH 2 3(3-kloro-propiyonil-chloro-propionyl chloride klorür) (BenzamidoximeBenzamidoksim)

Et HN Et NH2 OOxolamineksolamin C ISI N O CO CH2CH2CI N N C2H5 O CH2CH2N C2H5

Prof. Dr. Esin AKI 4- OTHER ANTITUSSIVES

Prof. Dr. Esin AKI (1-Narkotin) Isoquinoline derivative alkaloid in opium. Does not create dependency. It is used in cough caused by bronchial asthma and pulmonary emphysema. Slight bronchodilator effect It has no analgesic effect. It is the candidate to be an effective compound as anticancer.

Prof. Dr. Esin AKI BEBEKO - ,BEKANTIL

Sedative effect SO C H SO3Na 3 2 5

(CH ) C C(CH ) (CH3)3C C(CH3)3 3 3 3 3 + SO Na 3 EthyldibunateEtildibunat (CH ) C 3 3 3,6-Di-ter-buthyl3,6-Di-Ter-butil-1-naftalen-1-napthalen sulphonic acid sülfonik ethyl esterac.etil esteri

C(CH3)3

Dibunate Na

3,7-Bis(1,1-dimetil3,7-Bis(1,1-dimethyl ethyl) etil)-1-naftalen-1-napthalen sülfonicsulphonic ac.Naacid sodium tuzu salt

This mixture is found in Turkey.

Prof. Dr. Esin AKI HCl

2-(diphenylmethoxy)-N,N-dimethylethylamine

The classical histamine is the H1-receptor blocker.

It has antitussive effect by inhibiting cough center.

As with classical antihistaminic drugs, side effects: sedation and anticholinergic.

Prof. Dr. Esin AKI OCH3 S O N C C O O CH3 O

(R,S)-2-(2-methoxyphenoxy)-methyl-3-ethoxy-carbonyl-acetyl- 1,3-thiazolidine

It shows effect with peripheral pathway. There is no bronchodilator feature. The antitussive activity of both enantiomers is identical.

Prof. Dr. Esin AKI H Oxatomide N ATOXAN,FLAVORASE O TINSET,TANZOL N

CH2CH2CH2 N N CH

1-[3-(4-(diphenylmethyl)-1-piperazinyl) propyl]-1,3- dihydro-2H-benzimidazole-2-one

It's antiallergic. It can be used in patients with asthma.

Prof. Dr. Esin AKI

N N CH2 CH CH2 OH OH 3-(4-phenyl piperazinyl)-propane-1,2-diol

N N OH H HO Dropropizin's S derivative The –OCH3 coming into the 4nd position of the phenyl ring decreases the effect. -Cl, F increases effect

The –OCH3 at the 2nd position of the phenyl ring increases the side effect. There is not effect difference between the R and S isomers of the substituted and nonsubstituted derivatives.

Prof. Dr. Esin AKI