Pharmacology lecture
CNS
3
rd
Stage
1
NARCOTIC ANALGESIA :-
These types of analgesia classified into following :-
1- AGONIST. Highly efficacy or strongly agonist .
2- PARTIAL AGONIST. it is of agonist effects or displaced full agonist from their
site-antagonist .
3- ANTAGONIST.
Different sub-type of opioid receptors make an agent to act as agonist at some site &
antagonist or partial agonist at other sites .
Opioid type receptors :-
1- µ (mu) for morphine sub-classified into mu1 & mu2 which is responsible for
analgesia , euphoria , respiratory depression , miosis .
2- Ơ- delta 1& 2 which is responsible for mediation of dysphoria & other delusional
states .
3- K-kappa 1& 2 which is responsible for sedation & analgesia .
4- other like δ & ε their function less certain ,
All are G- protein coupled family type.
OIOID ANALGESIC AGENTS :-
A- strong agonist agents like :-
1-phenanthrenes include morphine , hydroxyl-morphine , oxy-morphine ,
heroin(diacetylmorphine) are a potent & rapid acting agents .
2-phenylheptylamines like a- methadone like morphine but of longer duration of
action , efficacy & potency less than morphine , dependence less than morphine . b-
levomethadyl acetate .
Pharmacology lecture
CNS
3
rd
Stage
2
3-phenylpiperidines like meperidine & fentanyl most widely used one , fentanyl
sub-group include sufentanil , alfentanil , remifentanil .
4-morphinans like levorphanol .
B-mild-moderate agonists .
1-phenanthrenes include codeine , oxycodeine , dihydrocodeine , hydrocodeine
all less common used one , not used alone , combine with aspirin or acetaminophine
2-phenylheptylamines like propoxyphene its potency in120mg + 60 mg of codeine
.
3-phenylpiperidines like a- diphenoxylate & its metabolites like difenoxin , used
only for treatment of diarrhea not for analgesia . b- loperamide .
C-opioid with mixed receptors actions :-
1-phenanthrenes like a- nalbuphine a strong K receptor agonist & mu antagonist
used parenterally . b- buprenorphine potent & long acting agent of such derivatives .
as partial mu receptor agonist .
2-morphinans like butorphanol that produce analgesia like that of phenanthrenes
like nalbuphine & buprenorphine , also produce sedation as K agonist & mu partial
agonist or antagonist .
3-benzomorphans like a-pentazocine as K agonist & weak mu antagonist or partial
agonist , used orally & parenterally , not used SCV cause irritation . b- dezocine highly
affinity to mu receptors & less affinity to K receptors , their efficacy + morphine .
D-miscellaneous include :-
Tramadol as newer agent synthetic one , of weak mu agonist & of some inhibitory
action on NE & serotonine reuptake in CNS . its effects away from opioid receptor
since it partial antagonize by naloxane, it is believe that it act via metabolites of weak
Pharmacology lecture
CNS
3
rd
Stage
3
analgesic effects like propoxyphene . their recommended dose 50-100 mg up to four
times a day .
============================================================
Anti-tussive effects obtain at dose less than that of analgesia & the effects not related
to opioid receptors . commonest used agent for such purpose codeine ,
levopropoxyphene , dextromethorphane , noscapine .
Their clinical uses include anal\gesia , couph , diarrhea , acute pulmonary edema ,
anesthesia .
Pharamacokinetics :-
--he absorption :- most of opioid analgesia well absorbed via IM, SC , mucosal surface
nasal & oral , as nasal insufflations , trans-dermal & oral(rapid one- but undergo first
pass metabolism that make oral dose to be more than that of parenteral route of
administration
--distribution :- all opioid bind to plasma protein with varying affinity , the drug
rapidly leave blood & locate in high perfuse tissues in high concentration like brain ,
liver , kidney , spleen . skeletal muscles of large bulk make it as reservoir. Because of
BBB make brain conc. of opioid low . morphine difficult to access into brain (it is
amphoteric agent of either acidic-C3 or basic group –N17) . while heroin & codeine
readily access in to brain(aromatic hydroxylC3 substituted ) . it cross placenta blood
barrier .
--metabolism :- opioid either
a- conjugated in to polar metabolites to excrete via kidney . morphine &
levorphanol conjugated with glucuronic acid readily , heroin + remifentanil rapidly
hydrolyzed by esterase , heroin(diacetylmorphine) into monoacetylmorphine then into
morphine that conjugated . polar metabolites inactive but some believe that morphine-
6- glucuronides possessing analgesia more than morphine itself .in case of renal
Pharmacology lecture
CNS
3
rd
Stage
4
failuire cause accumulation of inactive metabolites that cause prolong & more
profound analgesia .
b-N-demethylated by CYP3A & O- demethylated by CYP2D6 as minor
pathway in liver .
c-oxidative metabolisam in the liver of phenylpiperidine to fentanyl etc .
--excretion :- in the urine & small amount excrete as unchanged .
Pharamacodynamic :-
Mode of action by binding to the specific receptor in the brain or spinal cord that
involve in pain transmission . analgesia + euphoria + respiratory depression + physical
dependence of morphine due to their effect on mu receptors . while the effects obtain
by action on both K & delta receptors cause analgesic effects only
At cellular level it cause :-
1-closed voltage gated calcium channel on pre-synaptic nerve terminal to cause a
reduce in transmission release via mu , K , delta receptors . or
2-hyperpolaeizatize & inhibit post-synaptic neurons by opening potassium channel
via mu receptor only .
---------------------------------------------------------------------------------------------------
Location of the receptors :-
All present in high conc. in dorsal horn of spinal cord & primary afferent , spinal
action apply opioid in spinal cord cause powerful analgesia + minimal respiratory
depression , nausea , vomiting , & sedation than supra-spinal action .
ORGAN SYSTEM EFFECTRS :-
1-CNS :- analgesia , euphoria , sedation , respiratory depression , , cough suppression
, miosis , truncal rigidity , nausea , vomiting .
Pharmacology lecture
CNS
3
rd
Stage
5
2-peripheral effects on
a - CVS bradycardia .
b -on GIT constipation as CNS effect or local enteric neurons system .
c -biliary system biliary colic via smooth muscle contraction .
d -GUT: of anti-diuretic effects & enhancement renal tubules sodium
re-absorption , increase sphinctors tone causing urinary retention .
e -uterus prolong labor .
f -neuro-endocrine stimulate release of ADH , prolactin , somatotropin
& inhibit release of LH .
g -miscellaneous : flushing , warm skin , sweaty , itching .
effects of drug with both agonist & antagonist action :-
cause sedation & analgesia in therapeutic dose & on high dose cause sweaty ,
dizziness , nauseas .
===========================================================
THE OPIOID ANALGESIA :-
Such available agents include following NALOXONE (older agent) while
NALTREXONE & NALMEFENE both are newer agent .
NALTREXONE :-it is an oral opiate receptor antagonist , it derivative from thebaine
& it structurally similar to oxymorphone , like IV naloxone , it is pure antagonist of
better oral bioavailability & longer duration of action than naloxone , clinically helpful
for maintain an opioid free-state in opioid user patient . it act as competitive antagonist
at opioid receptors subtypes mu , K , delta to prevent or displace opioid from binding
to theses receptors . in case of high conc. of opioid extremely high opioid displace
naltrexone & respiratory depression & death may result. It is twice as potent as
Pharmacology lecture
CNS
3
rd
Stage
6
naloxone . no associated with tolerance of dependence their clinical effect persist for
72 hours . it may also inhibit endogenous endorphins(elevated in various chronic
respiratory disease , naloxone studied in patients with COPD , obesity-
hypoventalation syndrome , pulmonary edema ) , in alcoholism naltrexone may
interrupt a positive feedback mechanism mediated by endogenous opioid . give orall
, rapidly & completely absorbed via GIT undergo extensive first pass metabolism
make only 5-20 % of oral dose reach circulation , widely disterbuted throughout the
body , metabolize to 6-β-naltrexol which is of antagonist activity but less potent than
parent drug , following metabolism both naltrexone & their metabolites conjugated
with glucuronic acid , both unchanged & metabolites may undergo enterohepatic
recirculation , only 2 % excrete as unchanged in the urine.
It is indicated for treatment of opioid agonist dependence(in dose of 25 mg orallyt
repeated after 1 hour if withdrawal sign occur , maintenance dose 50-150 mg orally)
& in treatment of alcoholism(in dose of 50 mg orally /day , or 100 mg every other day
, or150 mg every third day ) . it is contraindicated in case of pregnancy , hepatic
disease . their adverse effects like abdominal pain , anorexia , constipation hepatitis ,
nausea vomitin , agitation , anxiety , dizziness , restlessness , tremor , lethargy ,
lacrimation , insomnia , headache rash , mydriasis , poludipsia .
NALMEFENE:- it is a parenteral opiate receptor antagonist structurally similar to
naloxone but it distinguish itself from nal;oxone by their significant longer metabolic
half-life make its duration of action like that of most opioid agonist , so it is preferable
over naloxone in case of methadone over dose some time need repeating of the dose .
it is pure opioid receptor antagonist with little or no agonist activity , it antagonize mu
,K & delta receptors to a period longer than that of naloxone in 5-10 times .it able to
antagonize both toxic & clini8cal effects of opioid . can be give as IV , IM ,SC .
rapidly disterbuted into about 80% of brain opioid receptors , 54% is their plasma
protein binding , it metabolize in the liver via glucuronide conjugated & trace amount
of N –dealkylated . their excretion via kidney 83% , less than 5% unchanged , 17% in
feces . it may undergo enterohepatic recirculation . indicated for treatment of opioid
agonist toxicity & opioid agonist induce respiratory depression . used in dose of IV in
Pharmacology lecture
CNS
3
rd
Stage
7
non-opioid dependence patient as 0.5 mg /70 kg , if need second dose of 1 mg /70 kg
after 2-5 minutes , while in oipoid dependence patient 0.1 mg /79 kg initially give then
give the recommended dose .as SC as single mg dose of 1 mg or SC their effects
obtain after 5-15 minutes .adult IV dose initially 0.25 microgram/kg followed by
incremental dose of 0.25 microgram at 2-5 minutes interval . it is contraindicated in
case of brain tumor , arrhythmias , cardiac disease , head trauma , seizure . their
adverse effect like dizziness , fever , hypertension , nausea , vomiting , sinus
tachycardia , withdrawal .
NALOXONE :- It is a semi-synthetic opioid receptor antagonist agent , it is the n-
allyl derivatives of oxymorphone . it used to reverse the clinical effects of opioid
analgesia , other uses like to reverse the effect of ethanol & benzodiazepines , to
reverse the hypotension associated with spinal injury , to improve neurologic recover
after ischemic stroke & to treated hypercapnic COPD . it is a pure antagonist agent
act as competitive & short-lived thus repeated dose may need when long-acting opioid
are involved . itself naloxone not produce any physical or psychological dependence
, not worse respiratory depression if administrated for non-opioid overdose . it is
ineffective if give orally unless extremely large dose are administrated , oral dose of
1000-2500 mg to produce clinical effects . oral dose one/fifty as potent as parenteral
dose due to significant first pass metabolism in the liver , their onset of effect within
1-2 minutes after IV & 2-5 after IM or SC , their action delayed in hypotensive patient
, their duration of action more prolong after IM than IV , rapidly distributed .their
metabolism take-place rapidly in liver mainly by conjugated with glucuronic acid ,
the major metabolite is naloxone-3-glucuronide . their excretion via urine within 72
hours . their indication include coma, opioid agonist dependence , opioid agonist
toxicity , pruritus , opioid agonist induce respiratory depression . Their doses like IV
in adult in 0.4 -2 mg every 2-3 minutes children dose 0.01 mg/kg as single IV dose if
no response then 0.1 mg/kg may be give . as IM & SC in the same doses .It is
contraindicated in case of brain tumor , arrhythmias , cardiac disease , head trauma ,
seizure .their adverse effect like diaphoresis , hypertension , hypotension , restlessness
, nausea , vomiting , tremor , ventricular fibrillation & tachycardia .