Non steroidal anti-inflammatory drugs NSAIDs
Cyclooxygenase (COX), the enzyme that converts arachidonic acid to prostaglandins and
related compounds (prostacyclin,thromoxane A2).
Classification of cyclooxygenase inhibitors:
(1) first generation NSAIDs: inhibit COX-1and COX-2 // unable to produce their effects without
posing a risk of serious side effects
(2) second generation NSAIDs: inhibit COX-2 only // can suppress pain and inflammation with
minimal risk of serious adverse effects
First generation NSAIDs
1- Asperin (prototype):
nonselective inhibitor of cyclooxygenase
suppress inflammation , pain , and fever
protection from myocardial infarction
irreversibly inhibits platelet COX ( lasts 8–10 days )
aspirin is absorbed rapidly and completely after oral administration
very short half life ( 15- 20 minutes)
Excretion by the kidney and highly dependent on urinary pH
Therapeutic uses
1-suppression of inflammation (rheumatoid arthritis , osteoarthritis, rheumatic fever , tndinitis)
2-analgesia (joint pain, muscle pain and headache not pain of visceral origin)
3- Reduction of fever (because of Reye syndrome aspirin should never be used to treat fever in
children)
4- Dysmenorrhea
5-Suppression of platelet aggregation (8 days)
Adverse effects
1-GIT effects (gastric distress , heartburn, nausea, Occult blood, ulceration , perforation ,bleeding
)
2- Bleeding
3- Renal impairment
4- Salicylism (tinnitus . sweating , headch and dizziness.)
5- Reye's syndrome (encephalopathy and liver degeneration)
6- Hypersensitivity (rhinorrhea , urticaria, bronchospasm , laryngeal odema, and shock)
2- Ibuprofen:
used to treat fever, mild to moderate pain and arthritis , is superior to most other NSAIDs
for relief of primary dysmenorrhea
effective in closing patent ductus arteriosus in preterm infants
the use of ibuprofen concomitantly with aspirin may decrease the total anti-inflammatory
effect.
3- Diclofenac (voltaren):
Is approved for rheumatoid arthritis , ankylosing spondylitis and primary dysmenorrhea
side effects ( abdominal pain ,dyspepsia ,nausea, fluid retention , exacerbate HT and heart
failure, liver dysfunction ,Gastrointestinal ulceration ,renal adverse effects )
4- Indomethacin:
effective antinflammatory agent , approved for arthritis, bursitis, tendonitis, and for gouty
arthritis . It has been used to accelerate closure of patent ductus arteriosus.
Adverse effects (frontal headache ,, mild GIT reactions, hematological reaction )
not recommended (for infants and children under the age of 14, patient with peptic ulcer,
pregnant and breast feeding women)
5- Mefenamic acid (ponstan):
Is indicated for ( primary dysmnorrhea, and mild to moderate pain )
adverse effect ( diarrhea )
6- Piroxicam(feldene):
Has antinflammatory , analgesic and antipyretic properties .
is approved only for rheumatoid arthritis .
7-Naproxane and Naproxane sodium:
approved for(arthritis, bursitis, tendonitis, primary dysmnorrhea, mild to moderate pain)
Adverse effects(GIT disturbances , compromise renal function )
Second- generation of NSAIDs (COX-2 Inhibitors)
1- Celecoxib:
relief symptoms of arthritis with less GIT ulceration and bleeding
indicated only for rheumatoid arthritis and osteoarthritis
Adverse effects (GIT, dyspepsia ,abdominal pain, allergy)
contraindicated in 3rd trimester of pregnancy
2- Rofecoxib:
approved for treatment rheumatoid arthritis ,osteoarthritis acute pain
Adverse effects ( diarrhea, dyspepsia, abdominal pain, headache , renal toxicity, HT,
anemia , leg edema and upper respiratory tract infection , fetal circulation near term )
contraindicated in pregnancy
Rofecoxib dose not contain sulfur group and hence is safe for Pts allergic to sulfonamide .
Gastric and duodenal ulcer are less common than with traditional NSAIDs.
OPIOID
ANALGESICS
Opioid receptors and and functions
1- u (mu) Supraspinal and spinal analgesia; sedation; inhibition of respiration; slowed GI
transit; modulation of hormone and neurotransmitter release
2- d (delta) Supraspinal and spinal analgesia; modulation of hormone and neurotransmitter
release.
3- k (kappa) Supraspinal and spinal analgesia; psychotomimetic effects; slowed GI transit
1- Morphine (Strong Agonist)
Organ systemic effects:
1. Central nervous system effects:
a. Analgesia
b. Euphoria
c. Sedation
d. Respiratory depression
e. Cough suppression
f. Miosis
g. Truncal rigidity
h. Nausea and vomiting
i. Temperature
2. Peripheral effects
a. Cardiovascular system : Large dose: hypotension and bradycardia + Increase the
cerebrospinal fluid (CSF) pressure
b. Gastrointestinal tract: Constipation
c. Biliary tract: Biliary colic + reflux of biliary and pancreatic secretions
d. Renal: Renal function is depressed by opioids.
e. Uterus: The opioid analgesics may prolong labor.
f. Neuroendocrine: Opioid analgesics stimulate the release of ADH, prolactin, and
somatotropin but inhibit the release of luteinizing hormone.
g. Pruritus: produce flushing and warming of the skin + sweating and itching
h. Miscellaneous: The opioids modulate the immune system by effects on lymphocyte
proliferation, antibody production, and chemotaxis.
Therapeutic uses:
1- Analgesia
2- Treatment of diarrhea
3- Relief of cough: codeine or dextromethorphan are more widely used for this purpose.
4- Treatment of acute pulmonary edema: (reduced anxiety + reduced cardiac preload +
reduced after load)
Infants born of addicted mothers show physical dependence on opiates and exhibit withdrawal
symptoms if opioids are not administered.
Repeated use produces tolerance to the respiratory depressant, analgesic, euphoric, and
sedative effects of morphine.
However, tolerance usually does not develop to the pupil-constricting and constipating effects
of the drug
Adverse effects:
1- Severe respiratory depression.
2- Other effects include vomiting dysphoria, and allergy-enhanced hypotensive effects.
3- The elevation of intracranial pressure .
4- In benign prostatic hyperplasia, morphine may cause acute urinary retention.
5-
Drug interactions: The depressant actions of morphine are enhanced by
phenothiazines
monoamine oxidase inhibitors
tricyclic antidepressants
2- Codeine:
The analgesic actions of codeine are due to its conversion to morphine.
Codeine shows good antitussive activity.
rarely produces dependence.
Codeine produces less euphoria than morphine.
3- Pentazocine:
Pentazocine acts as an agonist on kappa receptors and is a weak antagonist at mu and
kappa receptors.
Pentazocine is used to relieve moderate pain.
Pentazocine produces less euphoria
High doses causes respiratory depression , constipation , increase blood pressure ,
hallucinations, nightmares, dysphoria, tachycardia, and dizziness.
4- Tramadol:
Tramadol is a centrally acting analgesic that binds to the μ-opioid receptor.
It is used to manage moderate to moderately severe pain.
Its respiratory-depressant activity is less than that of morphine.
Side effects ( Anaphylactoid reactions - seizures )
5- Naloxone:
Naloxone is used to reverse the coma and respiratory depression of opioid overdose.
Naloxone is a competitive antagonist at mu, kappa, and delta, receptors, with a 10-fold
higher affinity for mu than for kappa receptors
6- Naltrexone:
Naltrexone has actions similar to those of naloxone
It has a longer duration of action than naloxone
Parkinson Disease
The underlying cause is loss of dopaminergic neurons in the substantia nigra.
disorder of the extrapyramidal system
The symptoms of parkinsonism result from disruption of neurotransmission within the
striatum.
Treatment
1- Agents that directly release dopamine , or indirectly activate dopamine receptors
(dopaminergic drugs).
2- Agents that block actylcholine receptors (anticholinergic drugs)
Dopaminergic Drugs
1. Levodopa:
the drug of choice for parkinsonism.
Mechanism of action : Levodopa reduce symptoms of parkinsonism by promoting synthesis
of dopamine in the striatum
Adverse effects:
1. Nausea and vomiting
2. Dyskinesia
3. Cardiovascular effects (Postural hypotension + dysrhythmias)
4. Psychosis
Drug interactions:
Traditional antipsychotic drugs, block receptors for dopamine in the striatum. As a result
these agents will decrease therapeutic effects of levodopa.
Monoamine oxidase inhibitors. Levodopa can cause a hypertensive crisis if administered to
an individual taking MAO inhibitor.
Pyridoxine. Vitamin B6 stimulates decarboxylase activity. By accelerating decarboxylation of
levodopa in the periphery, pyridoxine can decrease the amount of levodopa that reaches
the CNS. As a result, therapeutic effects of levodopa are reduced.
2- Levodopa Plus Carbidopa (Sinemet):
Carbidopa is used to enhance the effects of levodopa. Carbidopa has no therapeutic effects of its
own
Advantages of Carbidopa
1- in the absence of carbidopa, about 98% of levodopa is lost in the periphery
2- allows the dosage of levodopa to be reduced by about 75%.
3- carbidopa reduces cardiovascular responses to levodopa and also reduces nausea and
vomiting.
4- decreasing the effects of levodopa through inadvertent use of vitamin preparations that
contain pyridoxine
3- Selegiline :
selective inhibitor of type B monoamine oxidase (MAO-B)
selegiline can prolong the effects of levodopa
4- Bromocriptine (Parlodel):
dopamine agonist
the drug is usually employed as an adjunct to levodopa.
Adverse effects (Nausea, Psychotic reactions, dyskinesias and postural hypotension)
5- Amantadine (symmetrel):
antiviral agent
relieves symptoms of parkinsonism by promoting release of dopamine from remaining
dopaminergic terminals in the striatum.
6- Centrally acting Anticholinergic Drugs ( Benztropine ,Procyclidine,Trihexyphenidyl)
The centrally acting agents are just as effective as the older agents (Atropine and related
drugs), and have the advantage of producing fewer anticholinergic effects in the periphery.
These drugs may be employed alone or in combination with levodopa for the treatment of
parkinsonism.
Anticholinergic drugs are generally avoided in the elderly because of the risk of severe CNS
effects.