NARCOTIC ANALGESICS

ANALGESICS ANTIPYRECTICS AND ANTI INFLAMMATORY DRUGS

NARCOTIC ANALGESIC (MORPHINE AND RELATED DRUGS):


Analgesics are agents which relieve the pain with out disturbing consciousness.
Analgesics are divided in to two main classes
1) Narcotic analgesics (Centrally acting drugs)
2) Non Narcotic analgesics (Peripherally acting drugs)

The narcotic analgesics are also called as opiate analgesics. These are mainly obtained from unripe capsules of papaver somniferum (Opium poppy) plant. The important alkaloid is isolated from opium is morphine. The other alkaloids isolated from opium are codeine, Papaverine and thebain.

The opium group of narcotic drugs is most powerfully acting and clinically useful drugs producing depression of CNS. They depress the CNS and relieve the pain and some drugs like morphine induce sleep in presence of pain, diarrhea and suppress sough.
The term opiod is used generally to designate collectively the drugs (natural or synthetic) which bind specifically to any of sub species of receptor of morphine and produce morphine like actions.

The limitations of opiate analgesics are they have addictive property, respiratory depression, decreased gastro intestinal motility leading to constipation, increases biliary tract pressure and pruritis due to histamine release.

Classification
1. Morphine Analogues :
Morphine SO4, Codiene PO4, Ethyl Morphine, Diacetyl morphine(Heroin), Hydro morphoneHCl, Oxy morphone.HCl, Apo morphine.HCl, Hydrocodone, Oxy codone, Dihydromorphine, Dihydro codeine.
2. Morphinan Analogues:
Levorphanol tartarate, Dextro methorphan, Butarphanol,
3. Morphan Analogues:
Metazocin, Cyclazocin, Pentazocin.
4. 4-Phenyl Piperidine Analogues:
Meperidine.HCl(Pethidine.HCl), Di phenoxylate.HCl, Fentanyl citrate, Anileridine.HCl, Phenoperidine, Alphaprodine.HCl, Loperamide.HCl.
5. Phenyl propylamine Analogues:
Methadone.HCl, Dextro propoxyphene.HCl, Metho Trimeprazine.
6. Miscelleneous:
Tramadol, Tilidate, Nexeridine, Sulfentanil.
7. Narcotic Antagonists:
Nalorphine, Naloxone, Levellorphan, Naltrexene, Cyclazocine, Propiram, Profadol

1. Morphine Analogues:

Morphine



Derivatives of morphine





Apo Morphine II. Morphinan Analogues:




III. Morphan Analogues: IV. 4-Phenyl Piperidine Analogues:



V. Phenyl propylamine Analogues:



VI. Narcotic Antagonist
SAR for Morphine like drugs :


General Structure

The structural activity relationship is studied due to the modifications of the following parts of morphine.
1) Modifications on aromatic ring system
2) Modifications on alicyclic ring system
3) Modifications of Tertiary nitrogen
4) Modifications of Ether Bridge

I. Modifications on aromatic ring system :

1. An aromatic phenyl ring is essential for activity.


2. Modifications of C3 phenolic hydroxyl group decreases analgesic activity.


3. Making the phenolic – OH group by etherification to methyl ether (Codeine) and ethyl ether (ethyl morphine) results in about one tenth of analgesic activity of morphine. Because phenolics – OH group binds with opiate receptor by hydrogen bonding easily. But ethers are not easily hydrolysis.


4. Esterification of 3 – OH group gives compounds more active than morphine.


5. Substances other than 3-position in the aromatic ring results in a reduction of opiod actions. But 1-fluoro codeine possess the some analgesic activity as that codeine.

II. Modifications on alicyclic ring system :

1. The C-6-Alpha- OH group is methylated, esterified, oxidized, removed or replaced by halogen in order to get more potent analgesics. But there is also a parallel increase in toxicity. Example : Codeine, heroin, chloro morphone.


2. The saturation of double bond at C - 8 position gives more potent compounds. Example : Dihydromorphine, Dihydrocodeine.


3. Introduction of 14 – OH in dihydro from gives more potent 14 – hydroxy dihydro codeinone and 14 – hydroxy dihydro morphinone.


4. Bridging of C6 and C14 through ethylene linkage gives etorphine which is 200 times more potent than morphine.


5. Introduction of any new substituents at 5th position does not enhance the activity except 5 – methyl dihydro morphine and azidomorphines.

III Modifications of 30 Nitrogens :

1. Replacement of N-CH3 by N-C2H5 results slight fall in analgesic response. More hydrophobic groups such as propyl, pentyl, hexyl and phenylethyl gave an increase in activity.
2. N-allyl and N-cycloalkyl methyl functions give the narcotic antagonistic properties.
3. N-Phenyl ethyl group enhances the analgesic activity in desmorphine, codeine and heterocodeine.

IV Modifications of ether bridge :

1. Breaking of ether bridge and opening of piperidine ring decreases the activity.

SAR for meperidine analogues

1. Replacement of 4-phenyl group by hydrogen, alkyl, aralkyl or heterocyclic groups reduces the activity.


2. The presence of phenyl and ester group at position 4 of 1-methyl piperidine gives optimum activity.


3. The replacement of N-methyl group by various aryl alkyl groups can increase the analgesic property.


4. Introduction of m –hydroxy group in phenyl ring increases the activity similar to C3 – OH of morphine. Example : Bemidone.


5. Replacement of ester moiety by a ketone in bemidone. Example: ketobemidone is equalent to morphine in activity.


6. The reversed ester of meperidine, propionoxy compounds was more active, being 5 times more active than meperidine. Example: Prodine.


7. When a phenyl and acyl group are separated from piperidine ring by a nitrogen atom, it gives a powerful analgesic. Example: Fertanyl.


8. By enlarging the piperidine ring to seven member hexahydro azepine ring. Example: Proteptazine is more active analgesic agent.


9. Contraction of piperidine ring to five member Pyrrolidine ring was also have good activity. Example: Alpha prodine, Prodilidine

SAR for methadone series:

1. The Levo isomer of methadone and Isomethadone are twice active as its racemates.
2. Removal of any one of phenyl rings decreases the activity.
3. Introduction of m – hydroxy group is phenyl ring decreases the activity.
4. Methadone derivatives are generally more potent analgesic than isomethadone series.
5. The replacement of propionyl group by hydrogen, hydroxy or acetyloxy group leads to decrease the analgesic activity.
6. Replacement of propionyl group by amide group (ex. Racemoramide) is more active than methadone.
7. Replacement of dimethylamino group by heterocyclic ring like morpholine and piperidine are potent as methadone with morphine like activity (Racemoramide).
8. An N-methylated derivative of metabolites of methadone analogues retains the analgesic activity.

Mechanism of Action of Opiods :

1. The Pharmacological actions of opiods are mediated by several types of opiate receptors in the CNS.
2. The structural features which are recognized to be essential for the perfect fit of a narcotic analgesic on receptors are represented below.

3. Opiod receptors compared of three major arts. i) A flat portion with holds aromatic part by Vandar-Waal’s force. ii) A cavity or a hallow portion with entraps ethylene bridge. iii) An an ionic site with holds the 30 nitrogen with get ionized at physiological. pH Beckett and Casy model of the analgesic receptor site is in above figure.

4. The fact that these sites do not bind other substances and are saturated by even very low concentrations of opiods explains the highly stereospecific orientation of these three components of opiod receptors.

5. There are three major types of opiod receptors
   i) Mu (m) – op3 receptors – produce analgesia, respiratory depression, Euphoria
   and addiction.
   ii) kappa (K) – op2 receptors – produce dysphoria, Euphoria and addiction.
   iii) Delta (d) – op1 receptors – G – proteins – linked receptors.

6. Morphine binds to m receptor and induce change in shape and open the ion channel in cell membrane. So K+ ion can flow out of the cell, hyperpolarizes membrane potential. Therefore the frequency of action potential firing is decreased, result in a decrease in ion neuron excitability.

7. The increase in permeability decrease the influx of Ca into nerve retinal and reduces neuro transmitter release. Both the effects shut down the nerve and block pain message.

8. Kappa receptor is directly associated with Ca channel. When an agonist binds to K receptors, the Ca channel is closed. Since Ca is necessary for neurotransmitter it cannot pass on pain message.

9. When agonist binds with d(delta) receptors, the receptor changes its shape and triggers a messenger protein (G protein) to carry a message to a neighboring enzyme with catalyses the formation of cyclic adenosine monophosphate. The G protein inactivates the enzyme by preventing the synthesis of cyclic AMP. This act as a second messenger is the transmission of pain signed and stops the pain.