Analgesic drugs

Analgesic drugs:

The ideal analgesic should relive pain with a

minimum of side effects. When formulating a management
plan, it is worth considering what contributes to pain
perception and associated distress.
The International Association of the Study of
Pain defines pain as an unpleasant sensory and emotional
experience associated with actual or potential tissue
damage or described in terms of such damage.
 There is considerable evidence that pt continue to
suffer pain, despite a wide range of available analgesic
drug.
When devising a management plan for both acute
and chronic setting, using balanced or multimodal
analgesia may be helpful.
Effect and repeated assessment of the pt is
essential in determining optimal analgesic management.
Opioids:

Opioids are the most frequently use analgesic for the

treatment of moderate to severe pain.
They may be highly effective in control of dynamic
pain on movement or incident backthrough pain may be
poor and side-effects may be a significant problem.
The term opioids refers to all drugs both systemic
and natural that acts on opioid receptors.
Mechanism of action:

Opioids receptors belong to the G- protein

coupled family of receptors with seven transmembrane
domains, an extracellular N-terminal and intracellular C-
terminal.
Activation results in changes enzyme activity
such as a adenylate cyclase or alteration in calcium and
potassium ion channel permeability.
There are three main receptors – classified as
mu or OP3
Kappa or OP1
delta or OP2
nociception orphanin FQ peptide
receptor

Current International Union of

Pharmacology classification:
MOP
KOP
DOP
NOP
 Opioids receptors are distribute widely in both
central and peripheral nervous systems. The different
effects of currently available opioids are dependent on
complex interactions at various receptors.
There is a range of endogenous neuropeptide
ligands active at these receptors- they function as
neurotransmitters, neuromodulators and neurohormones.
The endomorphins 1and 2 are potent agonist
acting specifically at the MOP receptors. The analgesic
action of morphine and most other opioids is related
mainly to agonist activity at MPO receptor.
Pharmacodynamic effects of opioids:

Analgesic action:
Opioids with agonist activity mainly at
the MOP receptor and to a lesser extend at the KOP
receptor- have analgesic effects.
Analgesic effects have also been demonstrated for
the spinal DOP receptor in certain situations.
Opioids should be titrated against pain. If higher
then necessary dose are given, respiratory depression
and excessive sedation may result.
Opioids exerts their analgesic effect by-

- A peripheral action in inflammatory states,

where MOP receptors on cell of the immune system and
nociceptors are important in regulating peripheral
sensation.
- Inhibitory effects within the dorsal horn of the
spinal cord both pre and post synoptically.
- Supraspinal effects in brainstem, thalamus and
systems in the midbrain periaqueductal grey matter and
ventral medulla.
Central nervous system:

There are several potential central nervous

system effects of opioids-
Sedation and sleep-
Opioids interfere with rapid eye-
movement sleep with changes in the EEG including a
progressive decrease in EEG frequency and production
of delta waves.
Opioids related ventilator depression is
more common during sleep.
Opioids induced sedation may be used
therapeutically- in critical care setting.
Mood:

Significant euphoria is uncommon when

opioids are used to treat pain but it occurs frequently
when they are used inappropriately. ‘
Dysphoria via KOP receptor action and
hallucinations can occur.
Commonly the hallucinations are visual in
nature and may only affect part of the visual field.
Miosis:

This is medicated via a KOP receptor effect on the

Edinger-Westphal nucleus of the ocoulomotor nerve.

Tolerance:

It is clinically impotent because a significant number

of pt are receiving long term opioids therapy for some
malignant and chorionic disease.
 Tolerance may develop much more actually
when opioids are used for pain control before surgery or
when given intrathecally.
After the dose has been titrated initially the
majority of pt on long term opioids are usually
maintained on a stable dose.

At a cellular level, tolerance is caused by a progressive

loss of active receptor sits combined with uncoupling of
the receptor from the Guanosin-triphosphate binding
sub-unit.
Addiction:

This is defined as the compulsive use of opioids

to the detriment of the pt in terms of physical ,
psychological or social function.
Drug seeking behaviors is not a problem if
opioids are used appropriately for pain relief in both
acute and chronic situations.
Respiratory:

Opioids may causes respiratory depression,

particularly in the elderly, neonates and when given
without titrating effect to analgesic response.
Tolerance dose develop to this phenomenon, so
it is less of a problem in chronic use.
Care must be taken if nociceptive input is
reduced or removed- e.g. after a nerve block.
Opioids are effective at suppressing the stress response to
laryngoscopy and airway manipulation.
They may reduce the plasma concentrations of
catecholamine's, cortisol and other stress hormones by
inhibiting the pituitary- adrenal axis, reducing central
sympathetic outflow and influencing central
neuroendocraine responses.
Opioids also suppress cough activity and
mucociliary function. This may cause inadequate clearing
of secretions and hypostatic pneumonia, sedation and
depression.
GIT:

All opioids may causes nausea and vomitting.

This may be medicated both centrally and peripherally with
a direct effect on the CTZ in addition to a delay in gastric
empting.
Opioids increases GIT muscle tone and decrease
motility.
An increase in biliary pressure with gallbladder
contraction may also occur.
Constipation occur commonly via a direct action
on opioids receptors in smooth muscle of the gut.
Cardiovascular:

In normovolaemic pt, the majority of opioids

have no significant cardiovascular depression effect.
If histamine is released then there may be
tachycardia, decrease in systemic vascular resistance and a
reduction in arterial pressure.
Bradycardia may occur in response to some
opioids.
There is no effect on cerebral auto regulation.
If respiratory depression is present then the resultant
increase in PCO2 may increase cerebral blood flow.
 Opioids decrease central sympathetic outflow.
In pt who are relying on increases sympathetic
tone to maintain cardiovascular stability, opioids may
lead to hemodynamic compromise.
This may be severe, particularly if potent opioids
are given by rapid intravenous bolus.
Opioid Structure:

The structures of opioids are usually the

laevorotory stereoisomer –that is the active compound.

Agents are current use include –

Phenanthrenes- -morphine
Phenylpiperidines-- meperidine-pethidine
& Fentanyl
Diphenyl-propylamines- -methadone
Pharmacokinetics of opioids:

Opioids tend to large volume of distribution

because of their high lipid solubility.
A consequence of this can be that redistribution
particularly after a bolus dose or short infusion can have
significant effects on plasma concentrations.
In addition first –pass effects in the lung may
remove significant amounts of drug from the circulation,
reducing the initial peak plasma concentration.
 After prolonged infusion, significant sequestration in
fat stores and other body tissue occurs for highly lipid-
soluble opioids.

Most opioids metabolism occur in the liver with the

hydrophilic metabolites predominantly excreted renally and
small amount may be excreted in the bile or unchanged in
the urine.
Metabolism and excretion of opioids:
Drug Metabolism Faeces Urine

Morphine Glucuronidation Trace 90%

Sulphation N-
dealkylation

Codeine O-demethylation Trace 86%

Dimorphine O-deacetylation Trace 80%

Pethidine N- demethylation -- - -- --- 70%

Fentanyl N-dealkylation 9% 70%

Factors affecting pharmacokinetics :

Age-
Increased CNS sensitivity to opioid effects in
elderly.
Hepatic blood flow may have declined 50%
by age 75 yrs, with reduce clearance of opioids.
Metabolism and volume of distribution
reduce in elderly.
Systemic dose is calculated on body weight.
Hepatic disease-
Hepatic disease has unpredictable effect, there may
be little clinical difference unless there is co-existing
encephalopathy. Reduction of plasma protein concentration
also have effects on plasma concentration of free unbound
drug.

Renal failure:
It may have significant effects for opioids with
renally excreted active metabolites such as morphine,
dimorphine.
Obesity:
Obesity will result in a large volume of
distribution and prolonged elimination.

Hypothermia, Hypotension and hypovolemic may also

result in absorption altered distribution and metabolism.

Routs of administration:
- Oral
- Intrathecal
- Epidural
Morphine:

Morphine is a relatively hydrophilic

phenanthrene derivative. It may be given orally. The
standard parenteral dose for adult is 10mg.
Its oral bioavailability is dependent on first –
pass hepatic metabolism.
Oral morphine is available either as immediate
release or simple or modified release preparation.
Morphine has a plasma half life of
approximately 3 hr, and duration of analgesia of 4-6 hr.
Dimorphine:

It is a pro-drug.
Metabolism is similar to that of morphine.
It is available for parenteral and oral use.

One advantage over morphine is in setting where

high concentration are requires in relatively low volumes
such as palliative care.
Epidural and intrathecal use.
Meperidine(Pethidine):

Pathidine is available as parenteral preparations.

It is fairly short acting in terms of analgesia and
repeated dose can be given.
This is a CNS stimulant and can cause seizures,
especially if there is renal dysfunction. It clearance is
significantly reduced in hepatic disease.
Chronic use may result in enzyme induction and an
increase in normeperidine plasma concentrations.
 Meperidine has other effect related to activity at
non- opioids receptors. It has atropine like action may
causes tachycardia, direct myocardial depression at high
doses.
It can also reduce shivering related hypothermia.
Meperidine also has a local anaesthetic like
membrane stabilizing action.
Fentanyl:
It is available in parenteral, transdermal and
transmucosal administration.
Due to high first pass metabolism it is not given
orally.
t is 100 times more potent then morphine

Fentanyl is very lipophilic with a relatively short

duration of action.
It has a large volume of distribution and rapid
peripheral tissue uptake.
Thanks to all