Analgesics

Drugs that relief pain without loss of

conciousness.

Opioid or Narcotic analgesics

Non-opioid or NSAIDS

Basic Pharmacology of Opoid

Analgesic

Source

Opium (Morphine Source) is obtained from Poppy, Papaver somniferum and P album.

Poppy seed pod exudes white substance that turns into brown gum i.e crude opium

Morphine is present in high concentration (10%).

Codeine is commercially synthesized from Morphine

Classification

Action

Full agonists

Partial Agonists

Antagonists

Receptors

Mu-opoid receptor

Delta-opoid receptor

Kappa-opoid receptor

Morphine Full mu-receptor agonist

Codeine Partial mu-receptor agonist

Nalbuphine Mixed Agonist-Antagonist and Partial

Agonist

Chemistry

Substitution of allyl group on the nitrogen of

morphine and addition of single hydroxyl group

Form naloxone(strong mu-

receptor antagonist)

Certain opoid analgesics modified in liver

form compounds with greater analgesic action

Most of the synthetic opoids are simpler

molecules

Endogenous Opoid Peptides

Opoid receptors are having drifferent affinities for endogenous peptides

Opoid receptors Endogenous peptides

Mu-receptor Endorphins>Enkephalins>Dynorphins

Delta-receptor Enkephalins>Endorphins and dynorphins

Kappa-receptor Dynorphins>>Endorphins and enkephalins

Families of Endogenous opoids

Endorphins

Enkephalins

Dynorphins

Opoid alkaloidProduce analgesia through

action at CNS receptors

Respond to endogenous peptides with opoid like

pharmacological properties

Endogenous peptides are derived from three

precursor proteins:

Prepro-opiomelanocortin(POMC)

Preproenkephalin(Proenkephalin A)

Preprodynorphin(Proenkeohalin B)

POMC contains Preproenkephalin contains Preprodynorphin contains

Met-enkephalin sequence Six copies of met enkephalin active opoid peptides containg

leu-enkephalin sequence

Beta-endorphin one copy of leu-enkephalin Active peptides are dynorphin

A, dynirohin B and alpha and

beta-nonendorphins

nonopoind peptides including

adenocorticotropic hormone,

Beta-lipotropin, melanocyte

stimulating hormone

met and leu have slightly high

affinity for delta then mu

receptor

Dynorphin A found in dorsal horn of

spinal cord play role in sensitization of

nociceptive neurotransmission.

Increased dynorphin causing increase pain and

long lasting hyperalgesia due to tissue injury and

inflammation

Endogenous opoid precursor molecule and

endopmorphins are present at CNS sites that have been

implicated with pain modulation

Pronociceptive action of dynorphin

independent of opoid receptor…..but dependent on

bradykinin receptor activation

Endogenous peptides, endomorphin-1 and endomorphin-

2 selectively activate central and peripheral mu-opoid

receptors

Pharmacokinetics

Absorption Opioid agonist are well absorbed when given by

subcutaneous,intramuscular and oral route.

Oral route needs high dose as compared to parenteralroute

Certain analgesics such as codeine and oxycodoneare effective orally because they have reduced first-pass metabolism.

Other routes includes oral mucosa via lozenges and transdermal via transdermal patches.

Recently an iontophoretics transdermal system has been introduced.

Distribution

All opioids bind to plasma proteins with varying

affinity.

The drugs rapidly leave the blood compartment

and localize in highest concentrations in tissues.

Drug concentrations in skeletal muscle may be

much lower, but this tissue serves as the main

reservoir because of its greater bulk.

Metabolism

The opioids are converted in large part to polar

metabolites (mostly glucuronides).

Morphine is metabolized to M3G and M6G.

M3G, a compound with neuroexcitatory property

and M36, a compound with analgesic property.

Esters are rapidly hydrolyzed by tissue esterases

e.g remifentanil.

Heroin (diacetylmorphine) is hydrolyzed to

monoacetylmorphine and finally to morphine,

which is then conjugated with glucuronic acid.

Cont…

Hepatic oxidative metabolism is the primary route of

degradation of the phenylpiperidine opioids.

The P450 isozyme CYP3A4 metabolizes fentanyl by

N-dealkylation in the liver.

Codeine, oxycodone, and hydrocodone undergo

metabolism in the liver by P450 isozyme CYP2D6.

Metabolic disposition of naloxone is chiefly by

glucronides conjugation like that of the agonist .

Excretion

Polar metabolites, including glucuronide

conjugates of opioid analgesics, are excreted

mainly in the urine.

Small amounts of unchanged drug may also be

found in the urine.

Glucuronide conjugates are also found in the bile.

Enterohepatic circulation represents only a small

portion of the excretory process.

Pharmacodynamics

Mechanism of Action• Opioid agonists produce analgesia by binding to

specific G protein-coupled receptors

• Receptors located primarily in brain and spinalcord regions (transmission and modulation of pain).

Receptor Types

• Multiple receptor subtypes have been proposedbased on pharmacologic criteria, including

o µ1,µ2

o δ1,δ2

o κ1,κ2,κ3

Pharmacodynamics

Opioid receptors form a family of proteins that physically couple to G-proteins

This interaction affect ion channel gating

1. They close voltage-gated Ca2+ channels on presynaptic nerve terminals and thereby reduce transmitter release

2. They hyperpolarize and thus inhibit postsynaptic neurons by opening K+ channels.

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Mu, delta, and kappa agonists reduce transmitter release from

presynaptic terminals. Mu-agonists also hyperpolarize second-order

pain transmission neurons by increasing K+ conductance, evoking an

inhibitory postsynaptic potential.

Tolerance and Physical Dependence

Tolerance

With frequently repeated administration of therapeutic doses of morphine there is a gradual loss in effectiveness

Physical dependence

Occurrence of a characteristic withdrawal when the drug is stopped or an antagonist is administered.

Organ System Effects

Central Nervous System Effects

Analgesia:

Opioids reduce both sensory and affective aspects

of pain.

Specially affective aspects.

Euphoria:

IV morphine – euphoria…reduce anxiety and

distress

Sedation:

Drowsiness

Clouding of mentation

Induce more sleep in elders than youngs

Morphine + sedative-hypnotics = Deep sleep

Phenanthrene derivatives > synthetic agents

Morphine disrupts REM and Non-REM sleep

patterns

Repiratory Depression:

Direct action on brain stem respiratory centre

Increases alveolar CO2

Respiratory rate = 3-4 beats/min

Cough supression:

Cough treatment

Ventilation via endotracheal tube – codiene

Secretion Airway obstruction

Miosis:

Induce pupillary constriction in awake state

Block pupillary reflex dilation during anasthesia

Nausea and Vomiting:

Opioids activates CTZ in area prostema of

medulla

Temperature:

Endogenous opioids – maintain body temperature

Morphine – hyperthermia

K- agonists - hypothermia

Peripheral Effects CVS:

No direct effect on heart (cardiac rhythm)

Morphine – release of histamines – peripheral

vasodilation- preload, ionotropy & chronotropy

– cardioprotective

GIT:

Stomach- motility tone HCL secretion

Intestine- resting tone with spasm – constipation

Biliary tract:

Contracts biliary smooth muscles – biliary colic

Renal:

Depress renal function – renal plasma flow –

ADH release – Na+ reabsorbtion – urinary

retention

Uterus:

uterine tone –prolong labour

Neuroendocrine:

+ release of ADH, prolactin and somatotropins

- release of LH

Skin:

Histamine release – dilation of cutaneous blood

vessels – flushing, warming of skin

Miscellaneous:

Opioids modulate immune system

Lymphocyte proliferation

Antibody production

Chemotaxis

Leucocyte migration- opioid peptides –

inflammatory pain.

CLINICAL PHARMACOLOGY

ANALGESIA:

• Relieve constant pain.

• In cancer, terminal illness, labor, renal and biliary colic

pain.

• Sustained release dosage forms MSContin and

OXYContin.

• In GIT disturbances we use fentanyl transdermal or

transmucosal patches.

• Amphetamine.

• Morphine and mepridine in labor.

• Strong opiod agonist for renal and biliary pain.

• Nalaxone – antagonist

ACUTE PULMONARY EDEMA:

Morpine and furosemide are used.

Furosemide when only pulmonary edema.

Morphine (IV) when pulmonary edema with myocardial

ischemia as decreases anxiety, cardiac preload and

afterload.

COUGH:

Low dose like 15mg codeine.

Diminished use.

DIARRHEA:

Paregoric, diphenoxylate and loperamide.

Not used when infection is there..

SHIVERING:

Mepridine - more pronounced effect.

Alpha-2 adrenoreceptor.

ANESTHESIA:

Along with analgesic opiods have sedative and anxiolytic

property.

Direct action on superficial nerves of dorsal horn of spinal

cord through epidural and subarachanoid route.

Epidural route is preferred – morphine.

Nalaxone – Antagonist.

CVS surgery.

Thoracic and upper abdominal surgery

local anesthetic + fentanyl

thoracic epidural catheter

Continuous infusion.

ADVERSE EFFECTS OF OPIOD ANALESICS:

Respiratory depression

Nausea

Vomiting

Constipation

Itching around nose

Postural hypotention

Hypovolemia

Restlessness

Tremulousness

Hyperactivity

Increased intracranial pressure

Urinary retention

Urticaria (spinal and parenteral administration)

TREATMENT:

Antagonist – nalaxone (IV).

Reverse coma due to opiods only.

CONTRAINDICATIONS:USE OF PURE AGONIST WITH WEAK PARTIAL

AGONIST

Morphine + pentazocine.

Diminished analgesia and withdrawl effects.

USE IN PATIENTS WITH HEAD INJURY:

Respiratory depression – CO2 retention – cerebral vasodilation – brain function alters.

USE DURING PREGNANCY:

Physical dependence and withdrawl effects with 6mg heroin daily.

Irritability, shrill crying, diarrhea, seizure with 12mg heroin.

Treated with diazepam, methadone & camphorated tincture of opium.

USE IN PATIENTS WITH IMPAIRED PULMONARY

FUNCTION:

Respiratory failure.

USE IN PATIENTS WITH IMPAIRED HEPATIC

FUNCTION:

Effects drug metabolism.

USE IN PATIENTS WITH IMPAIRED RENAL

FUNCTION:

Increased half life and accumulation of active

glucoronide metabolites.

USE IN PATIENTS WITH ENDOCRINE DISEASES:

Prolonged and exaggerated response to opiods.

DRUG INTERACTIONS:SEDATIVE – HYPNOTICS:

Increased CNS depression

Increased respiratory depression

ANTIPSYCHOTICS TRANQUILIZERS:

Increased sedation

Respiratory depression

Anti-muscarinic CVS effects

Alpha blocking CVS effects

MAO INHIBITORS:

Hyperpyrexic coma

Hypertension

SPECIFIC AGENTS

Strong agonists

Phenanthrenes

Phenyl

Heptyl

amines

Morphinans

Phenyl

piperidines

PhenanthrenesThis class includes drugs as Morphine,

hydromorphone and oxymorphone.

Strong mu-R agonist although shows

binding affinity to other opioid receptors.

Heroin:

It is also called diamorphine ,

diacetylmorphine.

It is potent and fast acting.

More effective than morphine in relieving

pain by IM route.

PhenylheptylaminesThis class includes agents such as Methadone.

Potent mu-R agonist.

Exists as racemic mixture i.e. in form of D

and L isomers of methadone.

Can block NMDA and Monoaminergic

reuptake transporter thus helpful in

treatment of neuropathic pain.

Methadone-Clinical uses Used in treatment of opioid abuse. Treatment of mild to severe pain. For detoxification of heroin dependent

addict it is given 5-10 mg orally two to three times a day for 2-3 days.

Its use as analgesic has increased due to less effect on CNS functions compared to Morphine.

Phenylpiperidines This class include Fentanyl and its subgroup

includes agents like sufentanil, alfentanil, remifentanil.

Sufentanil is 5 to 7 times more potent than fentanyl.

Alfentanil is less potent than fentanyl but rapidly acting and with shorter duration of action.

Remifentanil is rapidly metabolized by blood and tissue esterases thus exhibiting shorter half life.

Meperidine:

Shows anti-Muscarinic effects which can

be a contraindication in case of

tachycardia.

Negative inotropic action on heart.

Can produce seizures

Due to increased side effect profile its

rarely used as an analgesic.

MILD TO MODERATE OPIOID AGONISTS

Phenantherenes Phenylpiperidines Phenantherenes

Phenantherenes

CODIENE, DIHYDROCODEINE,

HYDROCODONE:

Are less efficious than morphine.

OXYCODONE:

Semisynthetic derivative of codeine that acts as

a narcotic analgesic’ more potent.

COMBINATION:

Hydrocodone/oxycodone with acetaminophen=> for

treatment of mild to moderate pain, used orally

Phenylheptylamines

PROPOXYPHENE:

Chemically related to methadone

Low analgesic properties

Low efficiancy

Phenylpiperidines

Diphenoxylate

loperamide

Used as Anti-diarrheal agents.

Diphenoxylate is used in combination with

atropine.

DOSE: two tablets to start and then one

tablet after each diarrheal stole.

OPIODS WITH MIXED RECEPTOR FUNCTIONS

Phenantherenes Benzomorphans Morphinans

PhenantherenesNALBUPHINE:

K-receptor agonist

u-receptor antagonist

Given parenterally

Causes such

respiratory

depression which cannot

Be reversed by naloxone.

BUPRENORPHINE:

• Partial u agonist

• K-antgonist

• Slow dissociation

from u-receptorslong

duration of action

• Used for

detoxification

• Maintaince of heroin

abuse

Morphinans

BUTORPHANOL:

K-receptor agonist

Partial u-receptor

agonist/antagonist.

Produces analgesia

equivalent to nalbuphine

and buprinorphine.

PENTAZOCIN:

• K-receptor agonist

u- antagonist/ partial

antagonist.

• Orally or parenterally.

• No sub cutaneous

injection becaucse of

irritant properties.

Benzomorphans

AntagonistsNaloxone

Naltrexone

Nalmefene

They are receptor antagonist that acts on opioid receptors (µ, ,k).

These agents in the treatment of opioid overdose

Clinical Uses

NALOXONE Initial dose: 0.1 to 0.4mg IV

for life threatning CNS and

respiratory depression

NALTREXONEUsed in maintainence

programs

Blocks heroin effects

upto 48hours

FDA approved for

alcohol abuse

Used to prevent relapse

of alcohol drinking

Effective for weight lose

When you do not succeed in taking giant steps on the road to your goal, be satisfied with little steps,

and wait patiently till the time that you are able to run, or better still, to fly.

Be satisfied to be a little bee in the hive who will soon become a big bee capable of making

honey…

Thank you …

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