Inflammation and

Pain
 Inflammation and Pain
Response of the vascularized living tissue to
injury.
Purpose:
To defend against and to eliminate the
injurious agent responsible for injury
Rid the tissue of the consequences of injury
(necrotic cells ) and
To start healing and repair of injured tissue.
 Outcome of acute inflammaton

Four outcomes:
1. Complete resolution with regeneration.

2. Complete resolution with scarring.

3. Abscess (localised collection of pus)

4. Transition to chronic inflammation.

Eicosanoids
The members of this group of structurally related natural hormones, can
lower gastric secretions (PGe2), stimulate uterine contractions, lower blood
pressure, influence blood clotting and induce asthma-like allergic responses.

- metabolism of the essential fatty acid arachadonic acid (5,8,11,14-

eicosatetraenoic acid) they are classified as eicosanoids.
Eicosanoids include prostaglandins, leukotrienes, and thromboxanes.

Prostaglandins were first discovered and isolated from human semen in the
1930s by Ulf von Euler of Sweden, named them prostaglandins.

Prostaglandins, are like hormones in that they act as chemical messengers, but
do not move to other sites, but work right within the cells where they are
synthesized.
 Cell Injury-Mediators

Plasma-
derived
Cell –derived:
Preformed Synthesized

Fact-XII, C3a/C5a
Histamine,
5-HT PGs,LTs,PAF
, IL-1,ROS

Inflammation/Pain
 Pain and Nociception
 Nociception is the mechanism whereby noxious
peripheral stimuli are transmitted to the central
nervous system.

 Pain is a subjective experience, not always associated

with nociception.
Chronic pain: is persistent or intermittent -lasting at least 6 months

Chronic pain produces significant behavioural and psychological

changes
The main changes are:
- depression/sense of hopelessness
- an attempt to keep pain - related behaviour to a minimum
- sleeping disorders
- preoccupation with the pain-results anxiety/irritation
--Mood swing
 Pathophysiology
Nociceptor – receptor preferentially sensitive to a noxious stimulus
or to a stimulus that will become noxious if prolonged.

has a detection threshold potential which must be exceeded before

an impulse travels from the peripheral - to CNS.

 Nociceptors are free nerve endings

 Free nerve endings are distributed everywhere

-both somatic and visceral tissues
-except brain tissue and lung parenchyma
 Nociceptive Pain
Tissue
 Clinically, pain can be labeled Injury Neuron
“nociceptive”
 if it is inferred that the pain is Neuron
due to ongoing activation of the
nociceptive system by tissue Nociceptor
Pain Allodynia
injury.

 Tissue injury activates primary afferent neurons called nociceptors,

which are small diameter afferent neurons
 A-delta and C-fibers
Hyperalgesia
 Nociceptors
Recently, it was found that nerve endings contain transient receptor
potential (TRP) channels that sense and detect damage.
TRP channels, similar to voltage-gated K+ channels, having 6
transmembrane domains

SP

TRP channel
 Nociceptors

Nociceptors are found in

 skin , muscle, joints
 and some visceral tissues
 A-delta and C-fibers

specific to one type of stimulus, such as

- mechanical
- or thermal
but most are polymodal (respond to many stimuli)
the number and size of the receptive fields served by each fiber may
be small or large
 Contd....
nociceptors free nerve endings has capacity to
distinguish between noxious and innocuous stimuli
when exposed to
 mechanical
 thermal
 chemical (toxic substance) stimuli

tissue damage occurs

-subs are released by the damaged
-facilitates the movement of pain impulse to the
spinal cord
 Pain processing
Fast pain Slow pain
– acute – chronic
– pricking type – dull, aching , throbbing type
– well localized – poorly localised
– short duration – long duration

– Thin myelinated nerve fibres – Unmyelinated nerve fibres -c

are involved (A delta) fibres
– Their receptive area is large.
Nociceptive pain: arises from actual or threatened damage to non-neural
tissue

Visceral pain :arising from visceral organs-heart, lungs, kidneys

Different types of stimuli

Chemical stimuli: Exogenous /Endogenous

Thermal
Mechanical
 Types of Pain

Somatic Pain: Both A- delta & C fibers, discretely localizable

Visceral pain: C fibers only, poorly localized.

Silent nociceptors: subtype of C-fibers (recruited - inflammation)

 Physiological Pain: a protective mechanism to causes avoidance,
pain stops once the stimulus is removed

 Pathological Pain: Results from tissue /nerve injury, inflammation

occurs in the area

 Neuropathic pain: occurs as a result of injury to or dysfunction of the

NS itself, peripheral or central NS

- Alcoholism, Amputation, Back, Leg, and Hip problems, Chemotherapy,

-DM, Facial nerve, HIV infection or AIDS Multiple sclerosis.
-NP: Charterstic symptoms
Hyperalgesia: Increased pain from a stimulus
Allodynia : a stimulus that does not normally provoke pain
Paraesthesia: abnormal sensation, whether spontaneous or evoked
 Contd........
 Deaferentation pain/anesthesia dolorosa: -sensory deficit

-malfunctioning sensation of pain is left intact

Phantom pain- pain localizei into non-existing organ (tissue)

Geniculate and Trigeminal Neuralgia: a rare type of nerve pain

that happens when a branch of the facial nerve - nervus intermedius

-or trigeminal nerve becomes damaged or compressed

-Carbamazepine is the drug of choice for nerve pain

 Contd........
Hemiagnosia: loss of ability to identify the source of pain on one side

- produces anxiety, moaning, agitation and distress but no attempt to

withdrawal from or push aside the offending stimulus

-associated with stroke that produces paralysis and hypersensitivity to

painful stimu

Phantom limb pain: - individual feels in amputated limb

Silent MI: Chest pain -a late and inconstant marker of episodes of

transient MI in vasospastic angina and in stable angina
 Nerve pathways carrying pain signals to the brain
 First synapse is present in the dorsal horn of the spinal cord
 Second order neuron travels through the lateral spinothalamic tracts

The brain first perceives the sensation of pain

The thalamus, sensitive cortex :

perceiving
describing of pain
localising

Parts of thalamus, brainstem and reticular formation:

- identify dull longer-lasting, and diffuse pain
 Pain Pathway
The process of nociception: four phases.
Transduction,
 transmission,
perception,
and modulation.
Ist-order neurons synapse with neurons in dorsal horn of the spinal cord
STT is most prominent nociceptive pathway-transmission of 2nd-order
neurons terminates in thalamus.

Modulation-undergo either inhibition or enhancement, at the dorsal horn -

spinal cord or in the brain.

-Perception-a noxious stimulus/pain-3rd-order neurons transmit

information from the thalamus to higher cortical.
Pain Pathway
The Ist order- neuron originates in the periphery and projects to
the spinal cord.
2nd- order neuron ascends the spinal cord.
3rd -order neuron projects into the brain.
The role of the spinal cord in pain processing

• Most afferent pain fibers terminate in the dorsal horn of the spinal
segment that they enter.

A-  fibers, some large A-delta fibers and small C- fibers

terminate in the laminae of dorsal horn and in the substantia
gelatinosa

Laminae than transmit specific information to 2nd afferent neuron

-2nd afferent neurons : transmit the impulse from SG and laminae

through the ventral and lateral horn,
From there the impulse is carried through the STT to the brain.

1. the neospinothalamic tract - it carries information to the mid

brain, thalamus and post central gyrus (A delta fibers)

2. the paleospinothalamic tract - it carries information to the

reticular formation, pons, limbic system, and mid brain
- the multisynaptic paleospinothalamic and
archispinothalamic tracts conduct slow pain (via C fibers)
 Tracts of the Spinal Cord
Tracts that serve to join brain to the spinal cord
 Ascending
 Descending Brain
Pain
x
PAG
C fibre
X
lateral
spinothalamic
substantia tract
gelatinosa
 Pain Pathway

thala thalamus
moco
rtical
tract lateral
s spinothalamic
tract
C fibre
Descending Tracts
 descending tracts involving opioid peptides as neurotransmitter
were discovered
 modify (inhibit) pain impulse transmission at the first synapse at
the SG

first tract was discovered in 1981 by Fields and Basbaum

– it involves enkephalin secreting neurons in the reticular
formation
– starting from the PAG of the midbrain
– ending in the NRM of the medulla
– Raphe magnus/LC
– from their ending in the SG of the dorsal horn
 descending inhibitory tract
substantia

gelatinosa

dorsal horn
c fibre input
substantia gelatinosa cell

in SG-enkephalin secreting neuron - presynaptic inhibition of the pain

impulse by transmission by blocking sub- P release
Presynaptic inhibition

Enkephalin
cannabinoids

substance P
Presynaptic inhibition enkephalin
substance P

blockingof
pain impulse

SP X pain impulse
Glutam
ate
 pain perception depends on
activity of the

Ascending pain impulse

transmitting tracts

Descending pain modulator

–inhibitory tracts
C fibre
 Modulation of Pain Transmission
 Transmission in the dorsal horn is subject to various modulatory
influences, constituting the ‘gate control’ mechanism.

 Descending pathways from the midbrain and brainstem exert a strong

inhibitory effect on dorsal horn transmission.

 Electrical stimulation of the midbrain PAG -causes analgesia

 The descending pain inhibition - mainly by enkephalins, 5-HT,

noradrenaline and adenosine.
-Opioids -activating these descending pathways
-COX -inhibition
Descending pain modulatory system
– stimulus produced analgesia (Reynolds)
– stimulation of certain areas in the brain stem was known
to decrease the neuronal transmission along the
spinothalamic tract

– discovery of morphine receptors

– they were known to be present in the brain stem areas

– discovery of endogenous opioid peptides

-eg. endorphines, enkephalins, dynorphin
 Descending Pain-inhibitory System

Cortex receives descending fibres from the cortex that can influence
transmission :
Four
 Cortical & diencephalic systems.
 Mesencephalic periaqueductal grey matter - rich in enkephalins and
opiate receptors.
 Parts of rostroventral medulla- the nucleus raphe magnus
 The spinal and medullary dorsal horn.
These axons are prominently seratonergic terminating on cells in the laminae I,II & V
and selectively inhibit nociceptive neurons and interneurons.
 Modulation of pain
 changing or inhibiting pain impulses in the descending tract
(brain  spinal cord).

 descending fibers -endogenous opioids or endorphins- inhibiting

the transmission of noxious stimuli.

 also release NA and serotonin-

 cancer /Neuropathic Pain: responds to antidepressant- NA/ 5-

HT availability
 Pain Processes
Transduction:
– Can be blocked by local anesthetics by injection either at the site of
injury/incision or intravenously
– Can be decreased by use of NSAIDs which decrease the -PGs
Transmission:
– Can be prevented by opioids/ Las by inj along peripheral nerves, at
nerve plexus, or in the epidural or subarachnoid spaces
Modulation:
– Can be augmented by inj of LAs or α2-agonists; gabapentin may also
effect modulation
Perception:
– Altered by use of GAs or systemic inj. of opioids and/or α2-agonists
 PCM,
Diclofenac
Celecoxib,
Rofecoxib
 Inflammation and Pain

Steroidal

Methadone- Drug addiction

 Chemical Mediators in Acute inflammation

 Chemical-mediators may be produced locally at the site

of inflammation- PGs and cytokines, LTs

 or they may be circulating in the plasma (synthesized by

the liver) as inactive precursors and activated at the site
of inflammation

Cell-derived mediators are stored in intracellular granules -

secreted on cellular activation (e.g., histamine in mast cells
 Cell Injury-Mediators

Plasma-
derived
Cell –derived:
Preformed Synthesized

Fact-XII, C3a/C5a
Histamine,
5-HT PGs,LTs,PAF
, IL-1,ROS

Inflammation/Pain
 Cyclo-oxygenase (COX)
Exists in the tissue as constitutive isoform (COX-1).
At site of inflammation, cytokines stim the induction of the 2nd isoform
(COX-2).

Inhibition of COX-2 - anti-inflammatory

Inhibition of COX-1 is responsible for their GIT toxicity.

Mostly-NSAIDs used are somewhat selective for -COX-1, but selective

COX-2 inhibitors are also available.

 COX-3 –brain: Acetaminophen/ PCM

-Acetaminophen produces analgesia centrally as a COX-3 inhibitor and
via *activation of descending serotonergic pathways
Cyclo-oxygenase (COX)
COX-1 is found in the gastric mucosa, kidney and platelets.

COX-2 is an inducible form, although to some extent, present

constitutively in the CNS, JG- apparatus of the kidney and placenta
during late gestation.

selective COX-2 inhibitors are of major clinical interest as these have

been related to lower incidence G.I.T

Both COX-1 and 2 inhibitors- cause Na+-retention and reduction of

the GFR (Aspirin –not advised in Renal Failure)

 Fetal COX-2 inhibition can be responsible for neonatal chronic renal

failure and therefore maternal usage should be avoided
Heart- impairments
Act by inhibiting COX => no PG production
– COX-1: Constitutively expressed => house-keeping function
– COX-2: Induced by injury, pro-inflammatory factors (TNFα, IL-1)
– COX-3: Just recently discovered

PGs do not cause pain, but sensitize- nocireceptors, stimulation (e.g.5-HT,

Bradykinine, capsaicin, …)
IL-1 release from activated macrophages (bacteria, etc.) induces COX-2 in the brain
=>PG E produced => affects thermoregulation => fever=> NSAIDs have anti-
pyretic effects- PCM

Classical NSAIDs: => housekeeping PGs reduced => side effects (gastrointestinal,
bronchospasms,…)

2nd generation NSAIDs (COX 2): => only the inflammatory response is inhibited =>
fewer side effects.
 Role of prostaglandins
PGs, LTs -potent eicosanoid lipid mediators- generating from AA
Thromboxane synthase -converts PGH2 to TXA2 while Prostacyclin
synthase- converts PGH2 to PGI2.
 PGE 2 – vasodilation, bronchodilation, stimulation of gastric mucus
secretion, sensitization of pain receptors to chemical and mechanical
stimuli

 PGF2α - uterus contraction, decrease in IOT-eye;- can either induce

labor or cause an abortion
 –while agonist- terbutaline or ritodrine –relax uterus –tocolytic agents

 TXA2: produced by platelets, - induction of platelet aggregation,

vasoconstriction;

 PGI 2 - inhibition of platelet aggregation, potent vasodilation;


 Cell Injury-Phospholipids

LOX-X: Zileuton,
Monterlukast
Arachidonic Acid
X

COX X LOX
Aspirin,PCM

PGG2: PGI2, LTB4, LTC4

PGD2 TXA2 /LTD4

Vaso-
Bronchoco
nsriction
X Inflammation/Pain
 Nonsteroidal anti-inflammatory drugs (NSAIDs)

Nonselective COX inhibitors  5. Antranilic acid

1. Salicylates derivatives -Mephenamic
-Acetylsalicylic acid acid
(Aspirin)  6. Aryl – acetic acid
- Salicylamide derivatives
2. Pyrazolone derivatives -Diclophenac sodium
-Phenylbutazone  7. Oxicam derivatives
-Metamizol (Analginum) -Piroxicam
3. Indole derivatives  8. Dihydropyrrolizine
-Indomethacin carboxylic acid derivative
4. Propionic acid derivatives -Ketorolac
-Naproxen
 Selective COX inhibitors
Preferential COX-2 inhibitors
 Nimesulide
 Meloxicam
Selective COX-2 inhibitors
 Celecoxib
 Parecoxib
 Rofecoxib
-cause little gastric mucosa damage
NSAIDs are used to treat:

-to treat inflammatory diseases

Muscular and Joint Pain- RA, osteoarthritis
and tendonitis and Gout
Muscle and bodyaches.
Dental pain.
Bursitis.
Menstrual cramps in female
 also be used to reduce fever or relieve minor aches
caused by the common cold.
The most frequently reported side effects of NSAIDs:

GIT-upset, PUD-most common pblm

Feeling bloated.
Heartburn.Stomach pain.
Diarrhea and/or constipation.
Blurred vision. Ringing in the ears.
Photosensitivity (greater sensitivity to light).
Unexplained bruising and bleeding.
Wheezing, trouble breathing or unusual cough.

Precaution: NSAIDS- not with Asthma, Antihypertensive

-Children and teenagers with viral infections (Reye's syndrome)
-Known kidney disease and liver disease
- dengue-fever and chikungunya ?
-Rarely, an NSAID -anaphylactic shock.
Low Dose in MI ?
 Contraindications

 Pregnancy
 Haemophilic patients
 Antihypertensive –agents
 Asthma
 Hypersensitivity reactions
 Viral infections mainly in children
 Peptic ulcers
 LOX-pathway

The name leukotriene, introduced by Swedish biochemist Bengt

Samuelsson in 1979

- Cysteinyl leukotrienes -due to the presence of the AA-

cysteine- LTC4, LTD4, LTE4
- Asthama, Anaphylactic shock

LTS- receptor antagonists: Montelukast . zafirlukast

5-lipooxygenase inhibitor- zileuton – also has been reported –

benefeicl effects –in AD

Tepoxalin - dual inhibitor

Steroidal anti-inflammatory drugs

1. Short-acting glucocorticoids 3. Long-acting Betamethasone

(natural)
Hydrocortisone Dexamethasone
Cortisone Paramethasone
2. Intermediate-acting 4.Topically acting glucocorticoids
glucocorticoids Beclomethasone
Prednisone dipropionate
Prednisolone Budesonide
Methylprednisolone Fluocinolone acetonide
Triamcinolone Fluocortolone
Steroidal - MOA

Phospholipid
Glucocorticoids

PLA2

AA-
COX
NSAIDS
LOX
PGs Inflammation
, Pain LTs

Asthma
 Clinical uses
 Arthrities
 Collagen diseases (systemic lupus erhymatosis, scleroderma)
 Bronchial asthma
 Severe allergic reactions
 Autoimmune diseases-RA
 Skin diseases
 IBD: Ulcerative colitis, Crohn’s disease
 Cerebral edema
 Organ transplantation and skin allograft
 Septic shock
 Main side effects
 Susceptibility to infections
 Delayed healing of wounds
 Osteoporosis
 Growth retardation in children
 Peptic ulceration
 Cushing habitus
 Hyperglycaemia
 Muscular weakness
 Psychiatric disorders
 Withdrawal syndrome- adrenal insufficiency
 Corticosteroid Therapy

 Tapering the dosage over 1-2 months or necessary for patients

 Serious ADR, skin thinning, ecchymoses, and Cushingoid appearance
 Significant cause of steroid-induced osteopenia, immunosuppressive – chance-
fungal infection, Covid-19- Black fungus
 Noxious Stimulus
LAs, NSAIDs

Transduction
LAs

Transmission

Opiods, α2-agonists

Modulation
General Anaest, Opiods,
α2-agonists
Perception
Pharmacologic approach
Customized Multimodal Therapy.
1:NSAIDs
2:Opioids – alone or in combination.
 Local Anaesthetics,
 BZDs, tranquilizers & α2 agonists.

Opoids: meperidine—preferred in urinary and biliary colic, less

resp. depression newborns

Morphine/pentazocine

OxyContin/ alfentanil

fentanyl, carfentanil, etorphine and methadone.

 Inflammation and Pain

Steroidal
 Non Pharmacological

Stimulation of touch fibres for pain relief:

– TENS (transcutaneous electrical nerve stimulation)
– Acupuncture
– Massage

Release of natural opioids

– Hypnosis
– Natural childbirth techniques
 Opioid-analgesic
 In 1970-73, endogenous opioid system and opiate binding sites in
the brain through the use of radioligand-binding assays

 In 1975, an endogenous opiate-like factor called enkephalin was

found and shortly after this two more classes of endogenous
opiate peptides

-dynophorins and the endorphins.

Phenanthrene derivatives, structurally related to morphine

 opioid peptides
 endorphin
-Earliest to discover, present in pituitary
enkaphalins - met & leu
-widely distributed
dynorphin
Endomorphine 1 & 2
Pronociceptins

There are four main opioid receptors:

-mu, kappa, delta, recently discovered ORL1 receptor
Opioid Receptors
 μ-receptors: thought to be responsible for most of the analgesic effects of
opioids, (Morphine, Heroine,Pethidine)

-and for some major unwanted effects (e.g. respiratory depression, euphoria,
sedation and dependence

 δ-receptors are probably more important in the periphery, but may also
contribute to analgesia.

 κ-receptors contribute to analgesia: may elicit sedation and dysphoria, but

produce relatively few unwanted effects, and do not contribute to
dependence
-agonists are potently analgesic, and have been employed clinically in the
treatment of pain e.g.butorphanol, nalbuphine, pentazocine/eptazocine

Difelikefalin and CR665 are peripherally restricted KOR agonists lacking

the CNS side effects (hallucinogenic or dissociative effect) under invest.
 Opioid Receptors
 σ-receptors are not true opioid receptors, but are the site of action
of certain psychotomimetic drugs, with which some opioids
interact.
 All opioid receptors - through G-proteins to inhibition of adenylate
cyclase.

 They also facilitate opening of K+ channels (causing

hyperpolarisation), and inhibit opening of Ca2+ channels, decrease
in cAMP formation.

 Difelikefalin and CR665 are peripherally restricted KOR agonists

lacking the CNS side effects of centrally active KOR agonists
 Pharmacological Management
Opioid analgesics
– Potential /strong analgesics-medications
Morphine, Codiene
Meperidine
Methadone
Pethidine

Some narcotic analgesics combine an opioid with aspirin, Percodan

(oxycodone and aspirin), Percocet and Roxicet (oxycodone and
acetaminophen)
 MORPHINE

 Morphine is the golden standard among opioid

analgesics
 isolated in 1806
 Morphine has strong binding affinity for the mu and
delta and some weak affinity for the kappa receptor

 Codeine, Oxycodone and methadone are analogs of

codeine

Fentanyl- 1000 times stronger than morphine.

Side effects of morphine include a depression of cough due to

respiratory depression, nausea caused by increased vestibular
sensitivity, and decreased gastric motility and some constipation
 Morphine
Pharmacological effects and Mechanisms
CNS effects
– Analgesia: increasing tolerance of pain are the
most prominent effects.
– help patients to eliminate dysphoria, anxiety.
– Consciousness is not lost
CNS effects
Respiratory depression and suppression of cough:
 Morphine
Cardiovascular effects:
– Orthostatic hypotention can occur due to vasomotor
medullary depression and histamine release.

Gastrointestinal effect:
– Reduces gastrointestinal motility, causing constipation
– Decreases biliary and pancreatic secretions.
– Constriction at the spincter of Oddi causes an increase in
biliary pressure.

Miosis: pinpoint pupils are indicative of toxic dosage prior

to asphyxia
 Therapeutic uses
 Analgesia, such as the relief of pain from myocardial infaction,
terminal illness, surgery, biliary colic and renal colic
(combined with atropine).

 Dyspnea due to pulmonary edema

 Treating severe diarrhea because of constipating effects.

 Treating cough

 Neuropathic Pain
 Adverse effects
 Respiratory depression is the most important effect.

 Nausea and sometimes dysphoria can occur.

 Increase biliary tract pressure.

 Allergic reactions.

 Bronchoconstrictive action.

 Tolerance and Dependence

 Synthetic analgesic: Pethidine
 very similar to morphine (one-seventh to one-tenth potent) in
pharmacologic effects by μ-receptor agonists.

 Therapeutic uses: analgesic, cardiac asthma, sedation and

artificial hibernation.

 It has no gastrointestinal or antitussive action because of

shorter-acting.

 Adverse effect: also causes respiratory depression and

possesses addiction liability, although withdrawal effects are
less severe than with morphine.
 Opioid Antagonists

NAl NTX

Opioids Poisoing
 Opioid Antagonists
Pure antagonists include : naloxone and naltrexone (long-acting).
-They block μ-, κ- and -δ receptors more-or-less equally.

 Naloxone rapidly reverses opioid-induced analgesia and

respiratory depression, and is used mainly to treat:

 -opioid overdose or to improve breathing in newborn babies

affected by opioids given to the mother.

 Naloxone precipitates withdrawal symptoms in morphine-

dependent patients or animals.
 Opioid Antagonists
Pure antagonists include : naloxone and naltrexone (long-acting).
-They block μ-, κ- and -δ receptors more-or-less equally.

 Naloxone rapidly reverses opioid-induced analgesia and

respiratory depression, and is used mainly to treat:

 -opioid overdose or to improve breathing in newborn babies

affected by opioids given to the mother.

 Naloxone precipitates withdrawal symptoms in morphine-

dependent patients or animals.
 Opioid Antagonists
Naltrexone , is more potent than Naloxone and is used in the
treatment of alcohol addiction, opioids poisoning

The future of Opioid Analgesics seems to be linked to the study of

the k- Receptor.

K- receptor induces analgesia without the dangerous and unwanted

side effects that the mu and delta
 Tolerance and Dependence
Diminished drug effectiveness or potency resulting from repeated
(chronic) use. Tolerance develops rapidly, accompanied by physical
withdrawal syndrome.
Decreased efficacy
-Downward shift
Decreased potency
Rightward shift
may involve adaptive up-regulation of adenylate cyclase.
 Mechanisms of Tolerance

P,cokinetic P,codynamics

Alcohol Beta Receptor

 Mechanisms of Tolerance
Metabolic (dispositional) Tolerance
– e.g., Alcohol and barbiturates increased liver enzyme
activity.
– e.g., Amphetamine alters urine pH, making it more acidic,
which increases excretion of amphetamine.
Physiological (pharmacodynamic) Tolerance
– e.g., receptor affinity or number altered by drug actions
– disruption of homeostatic processes may be critical
Behavioral Tolerance
– Learning to compensate for drug-induced impairments
– respondent or operant conditioning
 Dependence
Withdrawal symptoms
Physiological changes when chronic drug use is
stopped
Particular withdrawal symptoms depend on the drug
Opiate withdrawal: flulike symptoms
Alcohol withdrawal: DTs, possible seizures
Many drugs do not produce dependence but tend to produce
similar withdrawal symptoms
 Cross Dependence: Drugs with similar actions will alleviate
withdrawal symptoms from another drug.
e.g., methadone for heroin dependence, benzodiazepines for
alcohol dependence
 Risk of -Cross Tolerance
When tolerance to one drug diminishes the effects of
another drug
Often observed between members of same drug class
– All opiates display cross-tolerance
– Alcohol may exhibit cross-tolerance with other
substances with similar pharmacological actions,
such as the benzodiazepines (e.g., Valium, Xanax)
 Management
 Heroin -white crystalline form –DAM-
hydrochloride.
 administered through i.v inj. but can
also be administered orally or
vaporized.
-binds most strongly to the mu-R and is
also active in the form of morphine

produces euphoric effects, however, it is thought that these effects are

greater to morphine and more addicting because of extremely rapid effect

 fast action- due to lipid-soluble because of its acetyl groups -immediately

cross BBB
*Naltrexone, Methadone is often used to treat heroin addiction

partial inverse agonist- a sustained course of low-dose naltrexone can

reverse the altered homeostasis
 Contd..Management
Certain opioid analgesics, such as codeine and pentazocine, are much
less likely to cause physical or psychological dependence.

 Methadone is widely used as a means of treating morphine and

diamorphine addiction because of its chronic and insignificant
addiction.
 Nalmefene- opioid antagonist used primarily in the management
of alcohol dependence

 Samidorphan has been investigated for the alcoholism and cocaine

addiction by its developer, Alkermes, showing similar efficacy
to naltrexone but possibly with reduced side effects
 Opioid receptor mixed
agonists/antagonists
Other drugs, such as nalorphine and
pentazocine, produce a mixture of agonist
and antagonist effects.

Buprenorphine: weak partial mu-opioid agonist and a weak

kappa-opioid receptor antagonist

-combination of buprenorphine and naloxone-Suboxone®

Patches for sublingual

Home work cum assignments:
Aspirin is a common NSAIDS-useful in various inflammatory and
pain condition .
Strikingly, it is very useful for cardiac patient and always prefer even
after cardiac attacks.

Why does low dose of aspeirin only (50-110 mg) exert beneficial
effects in MI?

Chronic alcoholism management ?