Download Narcotic analgesics

Lecture 7
Narcotic analgesics
Analgesics:
Analgesia: relieve of pain or control of pain
Analgesics: are drugs that relieve pain without significantly altering consciousness. They relieve pain
without affecting its cause (pain killer).
Analgesic drugs are divided into four main categories:
i)-narcotic analgesic. As morphine and morphine like drugs
ii)-non-steroidal anti-inflammatory drugs also known as non-narcotic analgesics. As aspirin
iii)-local anaesthetics as lidocaine
iv)-various centrally acting non-opioid drugs.
Out of the above categories narcotic analgesic & various centrally acting non-opioid drugs produce analgesia
by acting on CNS, whereas NSIADs and local anaesthetic act peripherally.
Primary differences at glance:
1
2
3
4
5
Narcotic analgesics
Act centrally
Addiction , dependence , tolerance
Notable adverse effects :sedation,respiratory
depression ,constipation.
No-antiinflammatory effect
No ceiling effect
Non-narcotic analgesics
Act peripherally
Not habit forming
Notable adverse effects: gastric irritation, bleeding
problems ,renal toxicity
Anti-inflammatory effect
Ceiling effect: increase in dose does not increase
analgesia but increases side effects.
Narcotic analgesics :
Opium and opioid alkaloids are prototype drugs including in this group.
Opioids have been used since time immemorial . it was recommended for relief of pain in the ebers papyrus
1500 BC. The opioid alkaloids have a capability of causing addiction in humans , but it is of little significance in
animal medicine because the animals are generally not given the chance to develop drug dependence.
Opium is the air-dried milky exudates obtained from the incised unripe seed capsules of the poppy
plant,papaver somniferum , opium contains about 24 alkaloids out of which only morphine and codeine have
clinical value.
Lecture 7
Narcotic analgesics
Opium also contains other alkaloids with different activities,like thebaine which has convulsant activity similar
to strychnine and papaverine , a smooth muscle relaxant.
Morphine is named after Morpheus , the Greek god of dreams.
Morphine was crystallized from crude opium by F.W.A serturner in 1805. Morphine sulphate is the principal
salt of morphine.
The morphine molecule consists of an partially hydrogenated phenanthrene nucleus, an oxide link and
nitrogen containing structure .
In addition two hydroxygrroups , alcoholic and phenolic are important in maintaining the pharmacologic
integrity of the morphine molecule.
The pharmacodynamic properties of morphine can be altered when substitutions are made in place of one or
both hydrogen atoms at phenolic or alcoholic hydroxyl groups.
If substitutions are made at phenolic group, there ia reduction in analgesic potency , respiratory depression
and constipation effects, while a stimulant effect upon the CNS is noted e.g codeine
If substitution is made at the alcoholic hydroxyl group ; there is enhanced narcotic and respiratory depression.
Substitution in either of the hydroxyl position lessens emetic activity of the parent molecule.
drug
Morphine
Methylmorphine (codeine)
Hydromorphone
diacetylmorphine
Phenolic position
OH
OCH3
OH
OCOCH3
Alcoholic position
OH
OH
O
OCOCH3
Hydromorphone is more potent as an analgesic agent than morphine
Other semisynthetic derivatives of morphine are apomorphine , a potent emetic agent and naloxone , an
antagonist of opiate-type drugs.,
Terminology :
Narcotics : are the drugs that relieve pain by depressing CNS pain transmitter also cause dependence this
term derived from greek word for stupor.
Opium : a dark brown , resinous material obtained from poppy ( papaver somniferum) capsule or((dried
juice obtained from the capsules of poppy)) . It contains two types of alkaloids :
Lecture 7
Narcotic analgesics
Phenanthrene derivatives : morphine ( 10% in opium) codeine ( 0.5% in opium ) thebaine (0.2% in opium ,
nonanalgesic)
Benzoisoquinoline derivatives : papaverine (1%) noscapine (6%) nonanalgesic
The term Opiates : refers to drugs ( like morphine or codeine ) that obtained from opium poppy.
Opioids : any substance (naturally or synthetic ) produce morphine like effects.
Narcotic : this term is derived from greek word for stupor. It is referred to any drug that induce sleep. More
often it is used in legal context for abused drugs.
Endorphin : it is a generic term referring to the three families of endogenous opioid peptides : the enkephalins
, the dynorphins and B-endorphins.
Endogenous opioid peptides (opiopeptins) : there are three distinct families of peptides under this category :
the enkephalins , the endorphins and the dynorphines.
Each family is derived from a distinct precursor polypeptide and has a characteristic anatomical distribution.
These precursors are designated as :::::::::::::::::::::::::::
i)-proenkephalin-yields met-enkaphalin
ii)prodynorphin yields lev-enkephalin,dynorphin (A,B)
iii)-proopiomelanocortin –yields melanocyte stimulating hormone,adrenocoticotrophin, and
B-lipotropin B-LPH in turn yields B-endorphin and B-MSH.
Opioid receptors :
The opioid peptides are not confined to the CNS ,since specific opiate receptors have been identified within
the brain,spinal cord,ANS and myenteric plexus of the GIT ,heart,kidney,vas deferens,pancreas,fat
cells,lymphocytes and adrenal glands.
Based upon studies in the chronic spinal dog, W.Martin and co-workers in 1976 proposed the existence of
three different types of opiate receptors and named according to the drugs that have highly affinity for them.
Such as µ(mu : morphine) , K (Kappa : ketocyclazocines) and (sigma : SKF 10047) . a year later J.lord and his
colleagues identified a fourth opiate receptor (delta) through which the endogenous opioids are considered to
mediate their effects . sigma receptors are not considered to be true opioid receptors , since many other types
of psychotropic drugs also interact with them.
The opioid receptors are G-protein coupled receptors.
Lecture 7
Narcotic analgesics
It is believed that there are two subtypes of µ receptors : µ1 and µ2 . µ1 mediates the analgesia whereas µ2
mediates other effects like respiratory depression , emesis …etc.
The delta receptors have the greatest binding affinity for enkephalins.
They mediate cardiovascular depressant , respiratory depressant and behavioural effects.
The enteric neurons contain both µ and delta receptors and if either of this receptor is activated , peristalsis of
the GIT is inhibition.
The characteristic constriction of pupil is also produced through µ and delta receptors . the physical
dependence of morphine and the euphoric effect is also mediated through µ and delta receptors
The K receptor stimulation produces sedation like µ and delta receptors but with dysphoria.
Recent investigations have proposed three subtypes of K receptors viz K1,K2,K3 : K1 receptors produce
analgesia spinally , while K3 produce supraspinal analgesia,pharmacological properties of K2 are not known.
The delta receptors mediate mania and other psychotomimetic effects. It also causes papillary dilatation ,
increased respiratory and pulse rates and triggers abstinence in morphine dependence animals. These
properties differ from those elicited by µ and delta and K receptors
Agonist and antagonists :
1)- pure agonists : includes most of the typical morphine like drugs having high affinity for µ receptors and
varying affinity for delta and K receptors sites. Some drugs like codeine ,methadone and dextropropoxyphene
are sometimes referred to a weak agonists since their maximal effects of analgesia are much less than those of
morphine and do not cause dependence.
2)- partial agonists and mixed agonists –antagonists : drugs like nalorphine and pentazocine exhibits a degree
of agonist and antagonist activity on different receptors. Pentazocine and cyclazocine are antagonists at µ
receptors,but partial agonists on delta and K receptors . most of the drugs in this group cause dysphoria due to
interaction with the delta receptor possibly.
3)- antagonists : these drugs block µ , delta and K receptors as naloxane and naltrexone.
B-endorphin is thought to be the most potent amnestic substance known. Naloxane given soon after
administration of B-endorphin reverses the amnestic effect.
The finding that acupuncture analgesia is partially block by naloxane in humans and animals implies that
acupuncture triggers release of an endorphin at the opiate receptor in pain pathways .
B-endorphin may be considered to be a natural antidote for pain and stress of parturition and other
conditions.
Lecture 7
Narcotic analgesics
Nitrous oxide , a general anaesthetic also in someway enhances the release of an endorphin and/or
enkephalins.
Cellular mechanism of action : all opioid receptors are linked through G proteins for inhibition od adenylate
cyclase. They also facilitate opening of K+ channels causing hyperpolarization and inhibit opening of ca++
channels, inhibiting transmitter release.
Pharmacological actions:
The main pharmacological effects are :
i)-analgesia : morphine is effective in most kinds of acute and chronic pain,it not only reduces the sensation of
pain, but also strongly reduces the distress component.
ii)-euphoria and sedation : euphoria appears to be mediated through µ receptors.
iii)-respiratory depression : morphine decreases the sensitivity of respiratory centre to PCO2 causing
respiratory depression.
iv)-suppression of cough: codeine and pholcodine which have substituent group at phenolic-OH group of
morphine ,cause suppression of cough through central mechanism.
v)-eye: morphine produces a variable effect upon the size of the pupil in animals.the pupillary size of the
monkey , cat , sheep and horses increases after morphine administration and there is mediated through delta
receptors on accotomotor nucleus.
It causes pinpoint pupils in dogs, rats,rabbits and humans and this is mediated through µ & K receptors.
The iris of bird is not affected because it contains non-responsive skeletal muscles.
vi)-pupillary constriction : this is a centrally mediated effect,caused by µ & K receptors pin point pupils are an
important diagnostic feature in overdosage with morphine.
vii)-reduced gastrointestinal motility and causing constipation.
There is also contraction of gall bladder and constriction of the biliary sphincter which makes morphine a
unfavourable drug to treat biliary colic.
viii)-morphine releases histamine from mast cells and causes bronchoconstriction and hypotension.
x)-immunosuppressant effect.
xi)-nausea and vomiting : morphine by acting on chemoreceptor trigger zone (CTZ) causes vomiting and
nausea.
Narcotic analgesics
Lecture 7
This effect disappears on repeated administration.horses and ruminants do not vomit following administration
OF central or local acting emetics
xii) thermoregulation : hypothermia is the prominent response to morphine in rabbits, dogs, and monkeys,
whereas hyperthermia usually occur in cats, goats, cattle,and horses. In guinea pigs , rats and mice , low
dosage of morphine elicit a hyperthermic effect,while higher dosage induce hypothermia
xiii)-urinary tract : as the effect of morphine progresses , there is decrease in urine secretion by 10% or less
due to liberation of an excess of the ADH from pituitary gland
morphine increases the muscular tone of bladder , resulting in the spasm of the sphincter which may make
urination difficult.
This is more pronounced in humans than in animals.
Morphine readily develops tolerance and psychological dependence in the animals.
New approaches :
i)
ii)
iii)
enkephalinase inhibitors : as thiorphan act by inhibiting the metabolic degradation of endogenous
opioid peptides and have been shown tp produce analgesia. Without causing dependence.
Neuropeptides as somatostatin and calcitonin produce powerful analgesia when applied
intrathecally . they may have similar effects when used systemically.
Non-peptide antagonists of substance P.