TITLE:- Pharmacology

CLASS:- BDS 2nd Year

MODULE:- CNS (Central Nervous System)

TOPIC:- Opioid Analgesics

LECTURE DATE:- 25th August & 26th August 2020

PRESENTER:- Dr. Ahmed Fawad

 OPIOID ANALGESICS

1) NATURAL OPIUM ALKALOIDS:-

(a) PhenanThrene Group:-
Morphine – Codeine – Thebaine
(b) Benzyl Iso Quinoline Group:-
PapaVerine – Noscapine.
2) Semi Synthetic Opium Derivatives:-
(a) Morphine Derivatives:-
Hydro Morphone,Oxy Morphone, Herion ( Diacetyl Morphine)
(b) Codeine Decivatives:-
Hydro – codone, Oxy – codone , Phol codeine and Dihydro
Codeine.
3) Synthetic Opium Subsitutes:-
(a) Phenyl Piperidines :-
Mepridine (Pethidine), Fentanyl,Sufentanil,Diphenoxylate –
loperamide.
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b) Phenyl Heptylamines:-
Methadone – Propoxyphene.

c) Morphinans:-
Levorphanol, Dextro Methorphan

d) Benzomorphan:-
Pentazocine – Phenazocine.

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PAIN:- Un-pleasant sensory & emotional experience associated
with actual or potential tissue damage. Pain is a complex
phenomena that involves both the generation of specific
neuronal activity& response of patient to that activity. The
physiological process by which pain is perceived is known as
NOICEPTION. Stimuli that produce tissue damage , initiate
activity in the nervous system.
Pain is the subjective sensation that result from the
perception of these impulses. Pain can arise from somatic or
visceral structures.
OPIOD ANALGESICS:- Opioid is a Term used for Both Naturally
Occurring and Synthetic molecules that produce their Effects by
combining with Opioid Receptors. In CNS
Opioid Receptors (OR)
Mu(u) Analgesia , Euphoria,Sedation,Miosis,Respiratory
Depression and Physical Dependence.
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Kappa (K) :-Analgesia Tolerance respiratory depression
Delta:-Analgesia tolerance respiratory depression.
Opioids peptide released from nerve endings modulate
transmission In brain and spinal cord. Brain produces several
neuropeptides known as “ ENDORPHIN” (Enkephalins Dynorphin
and Beta endorphin) which act as Neuro-transmitters Via specific
Opioid Receptors. Morphine and related analgesics produce their
effects by acting at specific “ Opioid Receptors” in CNS. Certain
Opioid Receptors located on primary afferents and spinal cord pain
transmission neurons ( ascending path ways ) and on neurons in Mid
Brain and Medulla ( descending path ways ) that function in Pain
Modulation.
Pharmacokinetics:- Most drugs are well absorbed from GIT. Morphine
and Hydro Morphone under go first Pass metabolism. They are also
given parentally and are widely distributed to body tissues. Cross
Palcental Barrier and can result in Respiratory Depression.
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M.O.A.:- Opioid analgesic inhibit synaptic activity partly through direct
activation of Opioid Receptors and partly through release of
Endogenous Opioid peptides, which are themselves inhibitory to
Neurons. All three Major Opioid Receptors are coupled to their
effectors by G-Proteins and activate phospho lipase “C” or inhibit
Adenylyl cyclase leading to decrease intra-cellular generation of
cAMP by adenylyl cyclase. The G-Proteins are also directly coupled
to Potassium (K+) channels.

At Pre Synaptic Level:- Opioid Receptors activation can close Voltage-

gated Calcium Ion Channels to inhibit neuro–transmitters release. Pre
synaptic actions result in inhibition of Acetylcholine,NorEpinephrine,
Serotnin , Glutamte and substance “P” release.

At Post Synaptic Level:- Activation of Receptors can open Potassium Ion

channels to cause membrane Hyper Polarization.(Neurons in the pain
pathways become hyper polarized)

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Effects Of Opioids:-
Acute:- Analgesia , Euphoria , Sedation , Respiratory Depression , Anti –
tussive, Nausea , vomiting , Smooth Muscles , Eyes (Miosis) , release of
ADH and Prolactin.
Chronic:- Tolerance and Dependence.

PHARMACOLOGICAL EFFECTS:-
1) Analgesia :- The Paleo Spinothalamic pathway and limbic system are rich
in opioid receptors. Therefore analgesia produced by morphine is most
effective for chronic visceral pain. Analgesia is associated with an elevated
sense of well being (Euphoria) mediated by Mu-receptors.
2) Respiratory depression:- Sensitivity of the Respiratory center to stimulation
by CO2 is reduced by Morphine which decreases respiratory drive and leads
to respiratory paralysis (common cause of death). Increased concentration
of CO2 may cause cerebro-vascular dilatation , resulting in increased blood
flow and increased intra-cranial pressure. OPD- analgesics are contra
indicated in patients with head injuries.
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3) Sedation and Euphoria:- Effects occur in doses below for maximum
analgesia. Some people experience dysphoric effects. High doses
may cause mental clouding & result in a stuporous or comatose state.
4) Nausea and Vomiting:- are caused by activation of chemo-trigger
zone (CTZ).
5) Anti Tussive:- Supression of Cough reflex.
6) Gastro Intestinal Effects:- There is increase in resting tone of the gut
wall and sphincters but a decrease in propulsive activity.
Constipation occurs through a decrease intestinal peristalisis. An
increase in biliary pressure is caused by spasm of sphincter of ODDI.
This can exacerbate biliary colic. Used mainly as antidiarrheal agent.
7) Miosis:- Stimulation of third nerve nucleus results in pupillary
constriction.
8) Miscellaneous :- Flushing and pruritis ( histamine release ) . Also
cause release of ADH and prolactin.
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9) Tolerance and Dependence:- Are inter-related phenomena probably resulting
from changes in functioning of opioid receptors during continuous opioid
administration. In response to Inhibitory Effects of Morphine on cyclic
AMP generation, there is increased synthesis of stimulatory ‘G’- proteins
and adenylate cyclase, in an attempt to restore homeostasis. As a
consequence more drug is necessary to produce the same effect (Tolerance)
and with drawl of the drug produces adverse physiological effect until the
compensatory changes are reset (Dependence).
Tolerance:- Develops rapidly during chronic OPD administration. Tolerance
develops to Analgesia, Euphoria, Respiratory depression and emesis but
much less to constipation or miosis.
Dependence:- Manifests it self as a with drawl syndrome, which can be
precipitated when patients who are taking long term opioid therapy (or
individuals who are abusing) have their intake stopped or given opioid
antagonist. With drawl affects during the first 12 hrs produce following
symptoms; Rhinorrhea , lacrimation , chills , gooseflesh , muscle aches ,
nervousness , sweating , diarrhea , depression , insomnia , pyrexia ,
increased respiratory rate , yawning , anxiety , anorexia and weakness.
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CLINICAL USES :-

1- Analgesia : Treatment of moderate to severe pain.(angina , myocardial

infarction , fractured bone).
2- Cough Suppression : Anti-tussive / dry cough.
3- Treatment of Diarrhea : Diphenoxylate and Loperamide.
4- Treatment of Acute Pulmonary Edema : Because of its hemodynamic
actions. Decrease venous return and produce calming effects.
5- Anesthesia : Opioids used as pre-operative medications and Intra-operative
adjunctive agents in balanced anesthesia.
6- Opioid Dependence : Methadone , one of longer acting opioids used for with
drawl and maintenance programs for addicts in rehabilitation centres.

SIDE-EFFECTS :- Nausea, Constipation , Respiratory Depression, Tolerance

and Dependence , Over dose leads to Miosis and Comatose state.

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BUPRENORPHINE:- Partial Agonist at “Mu Receptors”. It has less
liability to induce dependence and respiratory depression than pure
agonists. It is 30 times more potent than Morphine & Dissociates
very slowly from receptors.Therepeutic level after parenteral
administration may last for 10 hrs. It has an extensive first pass
metabolism given by sub-lingual , I/M or slow I/V. It is suitable for
transdermal patch because of long ½ life and high lipid solubility.

PETHIDINE:- (MEPERIDINE) Discovered in 1939 during a search for

atropine like compounds. It is primarily a “Mu Receptors” agonist.
Its effects are reversed by NALOXONE. 75mg to 100mg dose given
parenterally is approximately equal to 10 mg of Morphine. It is meta-
bolized in liver and excreted in urine.
NOR PETHIDINE:- Is pharmacologically active metabolite. It can cause
central excitation , convulsions. Accumulates after prolonged I/V
administration or in Renal impairment.
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SIDE EFFECTS:-Dry mouth , blurred vision, Euphoria and high
incidence of dependence.

TRAMADOL:- Is centrally acting analgesic with relatively weak “Mu

Receptors” activity.
M.O.A.:- It inhibits neuronal re-uptake of Nor-adrenaline and enhances
serotonin release. This action account for analgesic action.
Rapidly absorbed from GIT. 20% of an oral dose under goes first pass
metabolism. It is less likely to depress respiration and has a lower
incidence of constipation. But has a high incidence of nausea and
dizziness.

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OPIOID ANALGESICS:- COMPARATIVE TABLE (13)
COMPOUND (13ANAGESIC TOLERANCE & CLINICAL
POTENCY DEPENDENCE USES

Morphine + + + + + + Pain moderate to

Severe. Myocardial
infraction.
Heroin (Diamorphine) + + + + + + + + Use restricted because
of high abuse potential.
Buprenorphine + + + + + + Alternate to Morphine for
analgesia.
Methadone + + + + + With drawl from
Morphine / Heroin.
Pethidine + + + Pain ( Angina ,
Myocardial infraction.)
Fentanyl ++ + Transdermal patch for
Intractable pain.
Tramadol + + Obstetric anesthesia.

Codeine + + Anti-tussive / Anti-

diarrheal.
OPIOID ANTAGONISTS:- Naloxone , Naltrexone and Nalmefene are
pure opioid antagonists ( receptors). These drugs have greater
affinity for “Mu Receptors”

Uses:- Management of acute opioid over dose. Naloxone given I/V and
has short duration of action ( 1 – 2 hrs ). Naltrexone has a long
elimination half life up to 48 hrs.

DRUG INTER ACTIONS:- Opioid analgesics are additive to CNS

depression with Ethanol , Sedative Hypnotics , Anesthetics , Anti –
Psychotic drugs , Tri-cyclic Anti-depressants and Anti-Histamines.

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