Analgesic -- These are drugs which produce relief of pain
Antipyretics -- These are drugs which reduces increased body temperature
These drugs relieve pain of lesser intensity like tooth-ache and muscle pain
But they do not relieve severe pain like visceral pain which is relieved by opioid analgesics. These drugs do not produce addiction
All these drugs produce an anti-inflammatory effect, so these are called as non-steroidal anti-inflammatory drugs ( NSAID )
These are weak analgesics as compared to narcotic analgesics and have primary action on peripheral pain mechanism
They act without interacting with opioid receptors, they are called as non- opioid
Analgesics
These drugs have three main function – Analgesics , Anti-pyretic and Anti-inflammatory action
A. Non selective COX inhibitors
1.Salicylates
Acetyl-salicylic acid
Sodium salicylate
Methyl salycilate
Salicylic acid
2.Para- aminophenol derivatives
Paracetamol
Phenacetin
3. Pyrazolon derivatives
Phenyl butazone
Oxyphenbutazone
Aminopyrine
Antipyrine
4. Propionic acid derivatives
Ibuprofen,
Ketoprofen
5. Indole derivatives
Indomethacin
6. Anthranilic acid derivative
Mephenamic acid
7. Aryl acetic acid derivative
Diclofenac
8. Oxicam derivatives
Poroxicam,
Tenoxicam
B. Preferential COX -2 inhibitors
Nimesulide,
Meloxicam
C. Selective COX – 2 inhibitors
Celecoxib,
Rpfecpxon
Mechanism of action
Inflammation is usually regarded as a pathological state however, it is a physiological response of the living tissue to injury
Injury may be due to mechanical , physical, chemical and living agents are also known as bacteria, protozoa’s or fungi
Inflammation may be acute or chronic .
The clinical signs of inflammation are redness, swelling , heat and pain.
Phospholipase A2
Membrane -- Phospholipids --- ------------------------------------- Arachidonic acid
Cyclo- oxygenase
------------------------------------- Prostaglandins --- Inflammation
The arachidonic acid is liberated from damaged cells during an inflammatory reaction
Prostaglandins and other mediators of inflammation are formed from Arachidonic acid with the help of an enzyme Cyclo-oxygenase
The prostaglandin formed are responsible for many of the features of inflammation
I.e. – swelling, redness and pain
The NSAID block the action of enzyme cyclo-oxygenase and thus prevent or reduces the production of prostaglandins and other mediators of inflammation
Salicylates
It includes
Acetyl-salicylic acid or Aspirin
Sodium salicylate
Methyl salycilate
Salicylic acid
Aspirin
It is a acetyl salicylic acid
These are the salts or esters of salicylic acid
Salicylic acid itself is a strong irritant
It is one of the oldest analgesic-anti-inflammatory drugs and is still widely used
It is rapidly converted in the body to salicylic acid which is responsible for most of the actions
Mechanism of action
It inhibits cycloxygenase which is responsible for the synthesis of prostaglandin and thromboxane
It also inhibits platelet aggregation
Pharmacological actions
1. Analgesic action
Asprin is a weaker analgesic than morphine
These are effective only in dull- aching pain of low intensity
They do not relieve severe pain like visceral pain
They act by preventing the integration of pain sensation in the thalamus
But they do not alter the emotional reaction to pain
2. Anti-pyretic effect
Salycylates do not lower normal body temperature
Only the elevated temperature is lowered
Mechanism
- The hypothalamic heat regulating center ( thermostat of the body) is set for a higher temperature in fever
This is reset for a lower temperature by salicylates
B. The salicylates produce sweating which also lowers body temperature
3. Anti- inflammatory action
Asprin exert the anti-inflammatory action at high doses 3- 6 grams /day
Signs of inflammation like pain, tenderness, swelling , vasodilatation and leukocyte infiltration are suppressed
Asprin inhibits cyclo-oxygenase activity, it diminishes the formation of prostaglandins and modulates those aspects of inflammation in which prostaglandins act as mediators
Asprin inhibits inflammation in arthritis
4. on respiration
Salycylates stimulate respiration
The stimulation is depend on the dose
Salicylates stimulates respiration directly by stimulating the respiratory centre
Stimulate the respiration indirectly by through CO2
At anti –inflammatory respiration is stimulated by peripheral (increased CO2 production)
And central (increased sensitivity of respiratory centre to CO2) actions
Hyperventilation is prominent in salicylate poisoning
Further rise in salicylate level causes respiratory depression
Death is due to respiratory failure
5. Cardiovascular system
No effect at normal dose
Large doses increase cardiac output to meet increased peripheral O2 demand and cause direct vasodilatation
Toxic doses produce paralysis of vasomotor centre and BP may fall
6. GI Tract
Salicylates produce nausea and vomiting due to
Direct stimulation
Stimulation of chemoreceptor trigger zone
Salicylates can also cause gastric ulceration and hemorrhage
7. Anti- rheumatic effect
Salicylates have powerful anti-rheumatic effect
T his effect is produced by reducing pain and inflammation of the joints
8. Blood
Salicylates lower the erythrocyte sedimentation rate (ESR) which is high in rheumatic fever
They also decrease prothrombin level of plasma
9. Uricosuric effect
Low doses ( 1 or 2/ g day ) may decrease the urate excretion and increase plasma urea concentration
Intermediate doses ( 2 or 3 g / day ) do not alter urate excretion
Large doses ( over 5 g / day ) induce urocosuric effect and lower plasma urate levels
10. Metabolic effects
Salicylates produce uncoupling of oxidative phosphorylation
They produce hyperglycemia and glycosuria
They inhibit the synthesis but enhance the breakdown of fatty acids
11. Hormones
Salicylates stimulate the release of adrenaline from adrenal medulla
They also stimulate the release of adreno-corticotrophic hormone (ACTH)
They interfere with the binding of thyroxin with plasma proteins
This free thyroxin depresses the secretion of thyroid stimulating hormone (TSH)
12. Local actions
Salicylates , especially salicylic acid and methyl salicylate have antiseptic, fungi static
and keratolytic effects
13. Immunological effects
Salicylates suppress a variety of antigen- antibody reactions, which may be harmful to the body
Pharmaco- kinetics
Salicylates are absorbed from the stomach and small intestine
Sodium salicylate is absorbed more quickly than aspirin
Methyl salicylate is absorbed from the intact skin
50 – 80 % of salicylate binds to plasma proteins
It can displace other drugs – waffarin from the binding sites leading to severe bleeding
They are mainly concentrated in the liver, heart, muscle, and brain
They are metabolized in liver by conjugation with glycine and glucuronic acid
The metabolic products are mainly excreted through urine
Adverse reactions
GI tracts disturbances like nausea, vomiting , diarrhea , ulceration perforation and hemorrhage
Intolerance leading to skin rashes of various types
Bone marrow depression leading to agranulocytosis, thrombocytopenia and a plastic anemia
Fatty infiltration of liver and kidney
Salicylism characterized by headache, difficulty in hearing, drowsiness, lethargy and confusion
Contra- indications
Hypersensivity , peptic ulcer, liver diseases, bleeding tendencies and hemophilia
Contraindicated in children below 12 years , pregnancy and avoided in diabetes
Children suffering from the viral fever
Treatment with NSAID s should be stopped one week before any surgery
Special precautions
Aspirin may precipitate bronchospasm and induce asthmatic attack in susceptible subjects
It may induce gastrointestinal hemorrhage , occasionally major
Use with caution in subjects with gout
During lactation
Preparations
Aspirin Tab
Acetyl- salicylic acid powder
Sodium salicylate as mixture
Methyl salicylate ointment
Salicylic acid ointment
Uses
1. It is used as analgesic for light and moderate pain --- 0.3 - 0.6 g - 3 times
2. Used as anti-pyretic in fever --- 0.3 - 0.6 g - 3 times
3. Used as anti – inflammatory & anti-rheumatic & ---4 – 6 g or 75 – 100mg – 100
mg/kg/day in divided doses
4. Anti- platelet effect - 75 – 300 mg / day
5. Used in the treatment of the gout
6. Local action
Salicylism
Prolonged administration of salicylates in the treatment of rheumatic fever or arthritis may produce mild salicylate intoxication called salicylism
The poisoning may be accidental or suicidal
It is more common in children, 15 – 30 g is the fetal dose of aspirin
Symptoms and signs
Dehydration, fever, gastric irritation, vomiting , acid- base imbalance, restlessness , delirium, hallucinations, metabolic acidosis, tremors, convulsions , coma and death due to respiratory failure and cardiovascular collapse
Treatment
1. Gastric lavage to eliminate unabsorbed drugs
2. IV fluids to correct acid- base imbalance and dehydration
3. Temperature is brought down by external cooling with alcohol or cold water sponges
4. If hemorrhagic complications are seen, blood transfusion and vitamin K are needed
5. The IV fluids should contain sodium, potassium, bicarbonates and glucose .
Blood PH should be monitored
6. In severe cases, forced alkaline dieresis with sodium bicarbonate and a diuretic like
frusemide is given along with IV fluids. Sodium bicarbonate ionizes salicylates making
them water soluble and enhances their excretion through kidneys
Pracetamol
It is a Para-amino phenol derivative
It has analgesic and antipyretic effects like salicylates
Parcetamol , a metabolite of phenacetin is found to be safer and effective
It has analgesic , good antipyretic and weak anti- inflammatory properties
Due to weak PG inhibitory activity in the periphery, it has poor anti-inflammatory actions
Paracetamol is active on cyclo-oxygenase in the brain which accounts for its antipyretic action
In presence of peroxides present at the site of inflammation , it has poor ability too inhibit cyclo-oxygenase
It does not stimulate respiration
It has no action on acid- base balance , cellular metabolism , cardiovascular system and platelet function
It does not produce gastrointestinal irritation and uricosuric effect
It is analgesic and antipyretic of choice especially in patients in whom salicylates or other NSAID are contraindicated
Mechanism of action
Paracetamol exhibits analgesic action by peripheral blockage of pain impulse generation
It produces analgesic and antipyretic action by inhibiting the action of endogenous pyrogen on the hypothalamic heat regulating centers
Its weak anti-inflammatory activity is related to inhibition of prostaglandin synthesis in the CNS
ADME
Rapid absorption on oral administration . 30% protein binding
It is metabolized by the hepatic microtonal enzymes in liver
Plasma half life is 2-3 hrs
Effects after an oral dose last 3-5 hrs
It is mainly excreted I urine as conjugation products of glucuronic and sulphuric acids
The ability of the infant liver for glucuronidation of paracetamol is poor and this results in enhanced toxicity of the drug in neonates
Adverse effects
In antipyretic doses , paracetamol is safe and well – tolerated
Nausea and rashes may occur
Dose
0.5 - 1 g every 4-6 hrs
Chile 6 – 12 yrs – 250 – 500 mg every 4-6 hrs
1– 5 years - 120 – 250 mg every 4 – 6 hrs
Less than 3 months 10 mg / kg body weight every 4 – 6 hrs
Maximum dose for adult – 4 g daily
Maximum dose for child 4 doses in 24 hrs
Acute paracetamol poisoning
when large doses are taken, acute paracetamol poisoning results
Children’s are more susceptible because the ability of their liver to metabolite paracetamol is poor
10 – 15 grams in adults cause serious toxicity
Symptoms
Nausea
Vomiting
Parecetamol is hepatotoxic and causes severe hepatic damage
Hepatic lesions are reversible when promptly treated
Mechanism
Small portion of paracetamol is metabolized to toxic compound – N-acetyl – benzoquinone- imine which is inactivated generally by binding with glutathione in the liver
But when large doses of paracetamol are taken, larger amounts of the toxic compound are fumed and glutathione in the liver is not sufficient to inactivate it
As a result the toxic metabolite now binds to hepatic proteins resulting in hepatic necrosis
Chronic alcoholics and infants are more likely to develop hepatotoxicity
Parecetamol can also cause nephrotoxicity which may result in acute renal failure in some
Treatment
Stomach wash is given
Activated charcoal prevents further absorption
Antidote is N-acetylcysteine more effective when given early
(150 mg/kg IV infusion over 15 min followed by 70 mg/kg every 4 hours -17 doses)
N- acetylcysteine partly replenishes the glutathione stores of the liver and prevents binding of toxic metabolites to the cellular constituents
Uses
Paracetamol is used as an analgesic in painful conditions like toothache, headache and myalgia
As an antipyretic
Ibuprofen
It is was introduced in 1969
It is propionic acid derivatives
It is a better tolerated than aspirin
Its analgesic activity is independent of anti- inflammatory activity and has both central and peripheral effect
Temperature is reduced in febrile patients
It is a potent inhibitor of the enzyme cycloxygenase resulting in t he blockage of prostaglandin synthesis
It also prevents formation of thromboxane A2 by platelet aggregation
It exhibits anti- inflammatory, analgesic and antipyretic activities
All have similar phamacodymamic properties but differ considerably in potency and to some extent in duration of action
Analgesic, antipyretic and anti-inflammatory efficacy is slightly lower than aspirin
It is 99% bound to plasma proteins
Plasma half is 2-3 hours
Adverse effects
Nausea
Vomiting
Gastric discomfort
CNS effects
Hypersensitivity reactions
Dose
400- 800 mg
Uses
1. It has analgesic and antipyretic activity
2. It is used in the treatment of gout
3. Surgical removal of impacted tooth – a combination of ibuprofen with a skeletal
muscle relaxant like chlorzoxaxone is recommended
4. It is a drug of choice in rheumatoid arthritis because of lesser adverse effects
Phenyl- butazone
It inhibits COX and somewhat comparable to corticosteroids
The anti-inflammatory activity of phenylbutazone is better than that of salicylates, antipyrine and aminopyrine
The analgesic and antipyretic activity of phenylbutazone is however much les than that of salicylates
It diminishes the reabsorption of urate by proximal renal tubules and exerts uricosuric effect
Mechanism of action
Like salicylates, it inhibits the biosynthesis of prostaglandins
Pharmacokinetics
The absorption of phebylbutazone on oral administration is rapid and complete, but on intramuscular administration, the drug remains localized at the site of injection for longer time
IM injection is not recommended because its absorption is slow as it binds to local tissue proteins and also causes local tissue damage
It is 98% bound to plasma proteins . Half life is 60 hrs
It is completely metabolized in the liver by hydroxylation and glucuronidation
Chronic phenylbutazone administration results in the stimulation of the liver microsomal enzyme systems producing a faster detoxification of pheylbutazone itself and other compounds like barbiturates
Preparation and Dose
Phenylbutozone tablet contains 100 mg of the drugs in an enteric coated tablet
Dose – 200 – 400 mg daily in divided doses
Small doses may be given 3-4 times a day to avoid gastric irritation
Injection phebylbutazone sodium is available in ampoules containing 200 mg of sodium salt/ml
Dose - 200 – 600 mg by deep intra muscular injection
Adverse effects
Phenyl butazone is more toxic than aspirin and is poorly tolerated
Nausea and vomiting
Peptic ulceration and diarrhea may occur
Hypersensitivity reactions like rashes, hepatitis, nephritis, dermatitis and jaundice can occur
Goiter and hypothyroidism have occurred on long term use
CNS effects like insomnia , optic neuritis, blurring of vision and convulsions may be encountered
Odema as a result of sodium and retention which may precipitate CCF in cardiac patients
Uses
Rheumatoid arthritis
Ankylosing spondylities
Osteoarthritis
Gout
Other musculoskeletal disorders
Oxyphenbutazone
It is a major metabolite of phenylbutazone, similar in pharmacodynamic, pharmacokinetic, toxic and drug interaction profile
Dose
100 – 200 mg
Diclofenac sodium
Diclofenac is an analgesic, antipyretic and anti-inflammatory agent
Its tissue penetrability is good and attains good concentration n synovial fluid which is maintained for a long time
Mechanism if action
Inhibition of the enzyme cycloxygenase in prostaglandin synthesis
Prostaglandins are known to be associated with inflammation
Diclofenac is available as the sodium or potassium salt
The potassium salts are absorbed rapidly and action sets in much earlier
Adverse effects are mild
Dose
50 mg for oral
25 mg /ml inj
2-3 ml 1-2 times a day by deep IM inj
Gel is available for topical application
Ophthalmic preparation is available for use in postoperative pain
Uses
Treatment of chromic inflammatory conditions like rheumatoid arthritis and osteoarthritis
Acute musculo-skeletal pain and sprains and joints pain
Post- operatively for relief of pain and inflammation
Severely painful conditions like acute pulpits
Indomethacin
It has anti-inflammatory, analgesic, antipyretic and antigout actions
It relieves pain and reduces temperature in febrile patients
Reduces pain and joint swelling in rheumatoid arthritis but does not modify progress
Mechanism of action
It is a portent inhibitor of cycloxygenase thus reducing prostaglandin synthesis
Pharmacokinetics
It is well absorbed, 90% bound to plasma proteins & half life is 4 – 6 hours
Adverse effects
Adverse effects are high .
Gastrointestinal irritation with nausea, GI bleeding , vomiting , diarrhea and peptic ulcers can occur
CNS effects include headache, dizziness, confusion, hallucinations, depression and psychosis
Hypersensitivity reactions like skin rashes, leucopenia and asthma in aspirin sensitive individuals
Drug interactions
Indomethacin blunts the diuretic action of furosemide and the anti-hypertensive action of thiazides, beta blockers and ACE inhibitors by causing salt and water retention
Dose
25 -30 mg
Uses
Rheumatoid arthritis
Gout
Nimesulide
It is a sulfonamide compound
The action of nimesulide is somewhat different from that of classic NSAID
Mechanism of action
compound is a weak inhibitor of prostaglandin synthesis with a higher affinity for COX-2 then COX-1
Anti-inflammatory action may be exerted by other mechanisms as well
Ex – Reduced generation of superoxide by neutrophils, inhibition of PAF synthesis and
TNF alpha release and inhibition of metalloproteinase activity in cartilage
Pharmacokinetics
It is completely absorbed orally
99% plasma binding ‘Extensively metabolized and excreted mainly in urine
Half life is 2-5 hours
Pharmacological actions
It has analgesic, antipyretic and anti-inflammatory actions like other ASAID
It inhibits leukocyte function, prevents the release of mediators and in addition has antihistaminic and anti- allergic properties
May also inhibit release of tumor necrosis factor alpha and thus reduce the formation of cytokines
Relief of mild to moderate pain and fever, inflammatory
Dose
50 -100 mg BD
Adverse reaction
Nausea
Diarrhea, Vomiting , Rash , Dizziness and headache
Long term use can cause hepatotoxicity & neprhortoxicity
Uses
It is used as an analgesic, antipyretic and anti- inflammatory agent for short periods as in headache, toothache, , sinusitis, post-operative pain and arthritis
It is beneficial in patients who develop bronchospasm with other NSAID
It has been used primarily for short lasting painful inflammatory conditions like like sports injuries and other ear-nose –throat disorders
Mephenamic acid
An analgesic, antipyretic and anti-inflammatory drug which inhibits COX as will as antagonists certain actions of PGS
Mephenamic acid exerts peripheral as will as central analgesic action
Pharmacokinetics
Oral absorption is slow but almost complete
It is highly bound to plasma proteins- displacement interactions can occur
Plasma half life is 2 – 4 hrs
Adverse effects
Diarrhea is the most important dose related side effect
Epigastria distress is complained, but bleeding is not significant
Skin rashes, dizziness and other CNS manifestations have occurred
Hemolytic anemia is rare but serious complication
Dose
250 – 500 mg
Uses
Mephenamic acid is indicated primarily as analgesic in muscle, joint and soft tissue pain where strong anti-inflammatory action is not needed
It may be useful in some cases of rheumatoid and osteoarthritis but has mo distinct advantage
Opioid analgesics
Analgesics
These are drugs which relieve pain without causing loss of consciousness
Opioid analgesics
These are the natural accruing, semi-synthetic and synthetic drugs which have morphine like action
i.e. relief of pain and depression of CNS
1. According to ring structure
A . Phenanthrene derivatives
Morphine
Codeine
Thebaine
B . Benzo-isoquinoline derivatives
Papaverine
Noscapine
11. According to synthesis
A. Natural opium alkaloids
Morphine
Codeine
B. Semi synthetic opium alkaloids
Heroine
Pholcodeine
C. Synthetic opiods
Pethidine
Methadine
Tramadol
Morphine
Morphine is a natural opium alkaloid
It is a dried extract obtained from the capsules of the poppy plant known as papaver somniferum
Mechanism of action
Opioids exert their major effects by interacting with opioid receptors in the CNS
Opioids activate 7- transmembrane GPCRs located presymaptically and postsymaptically along pain transmission pathways
High densities of opioid receptors known as mu, delta and kappa are found in the dorsal horn of the spinal cord and higher CNS centers
Most currently used opioid analgesics act mainly at mu- opioid receptors
Morphine acts at kappa receptors in lamina 1 and 11 of the substantia Granulose of the spinal cord and decreases the release of substance p, which is modulates pain perception in the spinal cord
Opioids have an onset of action that depends on the route of administration
Opioids causes hyper polarization of nerve cells , inhibition of nerve firing and presynaptic inhibition of transmitter release
Cellular effects of these drugs involve enhancement of neuronal potassium efflux
( hyperpolarizes neurons and makes them less likely to respond to a pain stimulus ) and inhibition of calcium influx ( decreases neuro- transmitter release from neurons located along the pain transmission pathway )
Brainstem opioid receptors mediate respiratory depression produced by opioid analgesics
Constipation results from activation of opoioid receptors in the CNS and in the GIT
Pharmacokinetics
Absorption of morphine from GI T is slow and incomplete
Quick effect is produced on subcutaneous injection
It is partly bound to plasma proteins
It is metabolized by conjugation with glucuronic acid
It is almost completely excreted in urine within 24 hours
Bioavailability is 20 to 40 per cent
Given sc , onset of action is in 15 – 20 min, beak effect in 1 hrs
Duration of action is 3 – 5 hrs
Pharmacological actions
1. Analgesia
Morphine causes analgesia
Morphine relieves severe pain like visceral pain and pain of trauma
Mechanisms
Opioids relieve pain both by raising the pain threshold at the spinal cord level and more importantly by altering the brains perception of pain
It alters the emotional reaction to pain
The analgesic action morphine is primarily due to its effect on endogenous opioid receptors in midbrain and brain stem areas
Inhibitory impulses from these areas to the dorsal horn constitute the gating system
The morphine also acts directly on the dorsal horn where it inhibits the release of substance P
2.CNS
Morphine produces euphoria in presence of pain
But in the absence of pain , it produces dysphoria & restlessness
With an increased dose, it produces sleep
Tolerance is noted to both euphoria (mu receptor ) and dysphoria (kappa receptors)
3. Sedation
Morphine induces sedation in analgesic doses and is useful when pain is accompanied by insomnia
4. Anti-tussive property
Morphine has anti-tussive property
Morphine depress the modularly cough centre , an effect not blocked by naloxone
It is not used clinically and related drugs like codeine, with less respiratory depressant and addictive liability are used
5. Nausea & vomiting
Nausea and vomiting are common features with analgesic doses and induced by stimulation of the chemoreceptor tiger zone (CTZ)
Tolerance develops to vomiting on prolonged use
Higher doses of morphine inhibit the vomiting centre
6. Papillary constriction
Morphine produces constriction of pupil ( miosis)
Miosis is induced by mu and kappa mediated stimulation of the oculomotor nucleus
The effect is blocked by atropine
Morphine addicts have constricted pupil
Tolerance to papillary constriction is not seen in addicts and pinpoint pupils are indicative of morphine abuse and diagnostic in morphine poisoning ( other respiratory depressants induce papillary dilatation)
7. Respiration
The action of morphine on the respiration is dose dependent
Analgesic doses of morphine induce depression of the respiratory centre resulting in increase in plasma carbon dioxide concentrations
Respiratory center depression is mediated by mu receptors and is the cause of death in morphine poisoning
At higher doses it produces respiratory ceases
Respiratory depression is the most common cause of death in acute overdose
8 .Heat regulation
Opioids shift the equilibrium point of heat – regulating centre so that body temperature falls slightly
9 . Gastro-intestinal tract
Morphine decreases peristaltic propulsive movements
It produces spasm of intestinal smooth muscles and sphincters
Gastric emptying is delayed
It also increases absorption of water , So the feces get dried
All these effects leads t o constipation
10 . Billary tract
Morphine increase billiary tract pressure due to contraction of the gallbladder and
constrictor of the biliary sphincter
This produces increase in intrabiliary pressure
Atropine antagonizes this effect
11. Cardiovascular system
Normal dose of morphine produces no effect on heart rate , blood pressure or circulation
But hypo tension and bradycardia may be produced at toxic dose
Hypotension is due to dilation of peripheral veins and arterioles, histamine release and reduced sympathetic activity and in large doses due to depression of modularly vasomotor center’
Brdycardia is due to stimulation of the vagal nucleus
Because of respiratory depression and carbon dioxide retention, cerebral vessels dilate and increase the cerebrospinal fluid pressure
Morphine is usually contraindicated in individuals with severe brain injury
12. Histamine release
Morphine releases histamine from mast cells, causing urticaria, sweating and vasodilatation
Morphine can cause the bronco-constriction , asthmatics should not receive the drug
13. Hormonal actions
Morphine inhibits release of GRH and corticotrophic releasing hormone and it decreases the concentration of luteinizing hormone, FSH & ACTH
It increases prolactin and growth hormone release by diminishing dopaminergic
inhibition
It increases antidiuretic hormone and leads to urinary retention
14. Uterus
No significant effect . May prolog labor in high doses
15. on excretion
Tone and amplitude of contractions of the urters is increased , tone of external sphincter and volume of the bladder are increased
Opioids inhibit urinary voiding reflex
All these result in urinary retention especially in orderly male with prostate hypertrophy
16. Excitory effect
In high doses it produce convulsions. T hey may increases t he excitability of the spinal cord
Adverse reactions
GIT Symptoms – Nausea, vomiting and constipation
Acute morphine poisoning characterized by respiratory depression, pin point pupil cyanosis, reduced body temperature, hypotension , shock and coma
Tolerance and drug dependence
Central effects like dysphoria and mental clouding
Intolerance like tremor, delirium and skin rashes
Depression of fetal respiration
Drug interactions
The depressant actions of morphine are enhanced by phenothiazines, monoamine oxidase inhibitors and tricycle antidepressants
Tolerance and dependence
Repeated use of drug produces tolerance to the respiratory depressant, analgesic, euphoric and sedative effects of morphine
Physical and psychological dependence readily occur with morphine
Withdrawal produce a series of autonomic , motor and psychological responses that incapacitate the individual and cause serious - unbearable symptoms
Preparation & Dose
Tincture opium - 0.3 to 2 ml by mouth
Morphine sulphate - 8 – 20 mg by mouth or by injection
Morphine hydrochloride - 8 – 20 mg by mouth or by injection
Uses
1. It is an analgesic for the relief of severe pain
2. Used as pre-anesthetic medication
3. For producing sleep and sedation
4. Used as anti-tussive
5. For the treatment of diarrhea
6. In the treatment of acute left ventricular failure
Codeine
It is a phenanthrene alkaloid of opium
It is methyl- morphine
Naturally , it appears in opium and is partly converted in the body to morphine
It is less potent than morphine and also less efficacious
It is more selective cough suppressant
Sub-analgesic doses (10 – 30 mg ) suppress cough
It has a predominant anti-tussive effect
It is a less potent analgesic when compared to morphine
Codeine has very low affinity y for opioid receptors
The other action like spasmogenic effect, nausea and vomiting , miosis and addiction are less with codeine
It rarely produces dependence
Codeine produces less euphoria then morphine
Codeine is often used in combination with aspirin or acetaminophen
In most non – prescription cough preparations , codeine has been replaced by drugs such as dextro- methorphan - a synthetic cough depressant that has mo analgesic action and a low potential for abuse
Dose
Codeine has good activity by oral route
Single oral dose acts for 4 – 6 hours
Constipation is a prominent side effect when it is used as analgesic
It has been used to control diarrheas
The abuse liability of codeine is low
Though codeine phosphate is water soluble and can be injected
Parental preparation is not available in India and most other countries
Heroin
It is a diamorphine, or diacetylmorphine
It does not occur naturally
It is produced by di-acetylation of morphine
It is a semi-synthetic derivative of morphine
It is a about 3 times more potent than morphine
It is more lipid soluble
Due to its greater lipid solubility allows it to cross the blood- brain barrier more rapidly than morphine
Heroin is converted to morphine in the body
It enters brain more rapidly but duration of action is similar
It is considered to be more euphorient (specially on iv injection) and highly addicting
The sedative, emetic and hypertensive actions are said to be less prominent
It has mo outstanding therapeutic advantage over morphine and has been banned in most countries except U.K
Pethidine
It is a synthetic compound
It is a opioid structurally unrelated to morphine
It is used for acute pain
Mechanism of action
Pethidine binds to opioid receptors, particularly U receptors
It also binds well to k receptors
Pharmacological actions
Respiratory depression
Sedation and euphoria
Analgesic effect
Spasmogenic effect on smooth muscles and sphincters
It dilates cerebral vessels, increases CSF pressure and contracts smooth muscle
It does not cause pinpoint pupil but rather causes the pupils to dilate because of an atropine like action
It has mo significant cardiovascular action when given orally
On IV administration , it produces a decrease in peripheral resistance and an increase in peripheral blood flow and it may cause an increase in cardiac rate
It does not produces the anti- tussive effects
Pharmacokinetics
It is well absorbed from the GIT when given orally and parental administration
It most often administered IM
It crosses the placental barrier. It also secreted in the milk
T he drug has a duration of action of two to four hours which shorter than that of morphine
It is converted normeperidin the liver and is excreted in the urine
DOSE
Pethidine hydrochloride tablets – 25 –100 mg
Pethidine hydrochloride injection – 25 – 100 mg by subcutaneous or intramuscular injection and 25 to 50 mg by iv injection
Adverse reactions
Euphoria, dysphoria, weakness and palpitation
Depression o fetal respiration
Dry mouth, nausea and vomiting
Local irritation on parenteral administration
Respiratory depression, coma and convulsions
Addiction and tolerance
Uses
It provides analgesia for any type of severe pain
For producing sedation and sleep
As pre-anesthetic medication
Methadone
it is a synthetic, orally effective opioid
it has equal potency to morphine
it produce less euphoria and has a somewhat longer duration of action
It has somewhat longer duration of action than morphine
Mechanism of action
The actions of methadone are mediated by the u receptors
Pharmacological actions
It is chemically dis-similar but pharmacologically very similar to morphine
It has analgesic , respiratory depressant , emetic , anti-tussive , constipating and biliary actions similar to morphine
Pharmaco-kinetic actions
It is readily absorbed following oral administration
It accumulates in tissues, where it remains bound to proteins, from which it is slowly released
The drug is biotransformed in the liver and excreted in the urine
Adverse effects
It can produce physical dependence like that of morphine
Uses
It has been used primarily as substitution therapy opioid dependence
It can also be used as an analgesic for the same conditions as morphine
It is occasionally employed as anti-tussive
Preparation and dose
Methadone Hcl tablets I.P mg tab – dose – 5 – 10 mg
Methadone Hcl inj – 5 mg /ml of salt – dose – 5-10 mg s.c injection
Tramadol
It is a centrally acting analgesic that binds to the u – opioid receptor
It weakly inhibits re-uptake of nor-epinephrine and serotonin
It is used to manage moderate to moderately severe pain
Its respiratory-depressant activity is less than that of morphine
Its analgesic action is only partially reversed by opioid antagonist known as naloxone
Tramadol causes less respiratory depression, sedation, constipation, urinary retention
and rise in intrabiliary pressure than morphine
It is well tolerated
Pharmaco-kinetics
Oral bioavailability is good
The half life is 3-5 hrs and effects last 4-6 hrs
Adverse effects
Dizziness
Nausea
Sleepiness
Dry mouth
Sweating
Drug interaction
Tramadol should also be avoided in patients taking mono amine oxidase inhibitors
Dose
50 mg cap, 100 mg SR tab
50 mg/ml inj in 1 and 2 ml amps
Opioid antagonists
Pure opioid antagonists
1. Naloxone
2. Naltrexone
3. Nalmefene
1. Naloxone
It is N- alyl-nor- oxy- morphine and a competitive antagonist on all types of opioid receptors
It blocks u receptors at much lower doses than those needed to block k or delta receptors
Naloxone is a competitive antagonist at u, k and delta receptors with a ten- fold higher affinity for u receptors than for k
Naloxone produces no pharmacologic effects in normal individuals , but it precipitates withdrawal symptoms in opioid abusers
Naloxone is used to reverse the coma and respiratory depression of opioid overdose
It rapidly displaces all receptor- bound opioid molecules and is able to reverse the effect of a heroin overdose
Within 30 sec of iv injection of naloxone, the respiratory depression and come characteristic of high doses of heroin are reversed, causing the patient to be revived and alert
Naloxone has a half-life o f60 – 100 minutes
No physical or psychological dependence has been observed
Injected intravenously (0.4 – 0.8 mg ) , it promptly antagonizes all actions of morphine
It is inactive orally because of high first pass metabolism in liver
Injected iv , it acts in 2 – 3 min
The primary pathway of metabolism is glucuronidation
Plasma half life is 1 hour in adults and 3 hours in new borns
USES
Naloxine is the drug of choice for morphine poisoning ( 0.4 mg iv every 2 -3 min, maximum 10 mg)
It also partially reverses alcohol intoxication
2. Naltrexone
It is chemically related to naloxone and is anther pure opioid antagonist
It is more potent than naloxone
It has actions similar to those of naloxone
Naltrexone differs from naloxone in being orally active and having a long duration of action (1 – 2 days)
It has a longer duration of action than naloxone and a single oral dose of naltrexone blocks the effect of injected heroin for up to 48 hours
Alcohol craving is also reduced by naltrexone , it is being used to prevent relapse of heavy drinking
Naltrexone in combination with clonidine and sometimes with bruprenorphine is employed for rapid opioid detoxification
It may also be beneficial in treating chronic alcoholism by an unknown mechanism , but benzodiazepines and clonidine are preferred
Naltrexone is hepatotoxic
Dose
50 mg tab
Side effects
Nausea
Headache
Higher doses can causes hepatotoxicity
3. Nalmefene
This is recently developed pure opioid antagonist lacks
No hepatotoxicity
It has higher oral bioavailability and long duration of action
CNS Stimulants
These are brain stimulants which markedly stimulate the respiration and circulation
These in large doses acts as convulsions’.
They are useful in the following conditions
1. Chronic hypoventilation with CO2 retention
2. Respiratory failure in newborns
3. Respiratory failure due to overdose of CNS depressants
4. Post anesthetic respiratory depression
1. Direct CNS stimulants
A. Cortical stimulants
1. Xanthene alkaloids
Caffeine
Theophylline
Theo-bromine
Aminophylline
2. Sympathomimetics
Amphetamine
Methyl phenidate
B. Modularly stimulants
Picrotoxin
Pentylene-tetrazol
Nikethamide
Doxapram
C. Spinal stimulants
Strychnine
11. Reflex CNS Stimulants
Lobeline
Nicotine
Veratrine
Ammonia
Xanthene alkaloids
Methyl xanthenes includes theophyline found in tea and Theo bromine found in cocoa
Caffeine , the most widely consumed stimulant in the world, is found in highest concentration in coffee, but is also present in tea, cola drinks , chocolate candy and cocoa
Mechanism of action
Several mechanisms have been proposed for the actions of methylxanthine
All Xanthene alkaloids inhibit phosphodiesterase and blockade of adenosine receptors
Due to above mechanism there is increase in translocation of extra cellular calcium
Increase in cyclic adenosine monophosphate
Increase in cyclic guanosine monophosphate
Which causes various pharmacological actions including increase in force of contraction of heart and relaxation of vascular and non vascular smooth muscles
Pharmacological actions
On CNS
The caffeine contained in one to two cups of coffee (100 – 200mg) causes a decrease fatigue and increased mental alertness as a result of stimulating the cortex and other areas of the brain
Consumption of 1.5 grams of caffeine ( 12 – 15 cups of coffee ) produces anxiety and tremors
The spinal cord is stimulated only by very high doses (2 -5 g) of caffeine
It also produces stimulation or respiratory , vasomotor and vagal centers
Tolerance can rapidly develop to the stimulating properties of caffeine
Withdrawal consists of feelings of fatigue and sedation
On CVS
A high dose of caffeine has positive heart rate and contraction effects on the heart
Increased contractility can be harmful to patients with angina pectoris
Xanthenes produce a direct stimulant effect on the myocardium, also they produces dilatation of coronary and pulmonary blood vessels due to the stimulation of vagal nerve
On bronchioles
Caffeine and its derivatives relax the smooth muscles of the bronchioles
Decrease in fatigue of smooth muscles
Diuretic action
Caffeine has a mild diuretic action that increases urinary output of sodium, chloride and potassium
GIT
Methylxanthines stimulates secretion of hydrochloric acid from the gastric mucosa
Individuals with peptic ulcers should avoid beverages containing methylxanthines
Pharmacokinetics
The methylxanthines are well absorbed orally
Caffeine distributes throughout the body , including the brain
The drugs cross the placenta to the fetus and are secreted into the mothers milk
All the methylxanthines are metabolized in the liver and the metabolites are then excreted in the urine
Adverse effects
Moderate doses of caffeine cause insomnia , anxiety and agitation
High dosage is produced emesis and convulsions
The lethal dose is about 10 grams of caffeine about 100 cups of coffee which induce cardiac arrhythmias
Lethargy, irritability and headache occur in users who have routinely consumed more than 600 mg of caffeine per day roughly six cups of coffee per day and then suddenly stop
Therapeutic uses
Caffeine and its derivatives relax the smooth muscles of the bronchioles
Antidepressants
Coronary vasodilators
Diuretics
Nicotine
It is the active ingredient in tobacco
The drug is not currently used therapeutically except in smoking
It is mostly widely used CNS stimulant
Nicotine represents a serious risk factor for lung and cardiovascular disease and various cancers
Dependency on the drug is not easily overcome
Mechanism of action
In low doses, nicotine causes gang ionic stimulation by depolarization
At high doses, nicotine causes gang ionic blockade
Nicotine receptors exist in the CNS, where similar actions occurs
Pharmacological actions
On CNS
Nicotine is highly soluble in lipid and readily crosses the blood-brain barrier
Cigarette smoking or administration of doses of nicotine produces some degree of euphoria and arousal as well as relaxation
It improves attention, learning , problem solving and reaction time
High doses of nicotine result in central respiratory paralysis and severe hypotension caused by modularly paralysis
Peripheral effects
The peripheral effects of nicotine are complex
Stimulation of sympathetic ganglia as well as the adrenal medulla increases blood pressure and heart rate
The use of tobacco is particularly harmful in hypertensive patients
Stimulation of parasympathetic ganglia also increases motor activity of the bowel
At higher doses , blood pressure falls and activity ceases in both the GIT and bladder musculature
Pharmacokinetics
Nicotine is highly lipid-soluble
Absorption readily occurs via the oral mucosa, lungs, gastrointestinal mucosa and skin
Nicotine crosses the placental membrane and is secreted in the milk if lactating women
Most cigarettes contain 6-8 mg of nicotine
The acute lethal dose is 60 mg
More than 90% of nicotine inhaled in smoke is absorbed
Clearance if nicotine involves metabolism in the lung and the liver and urinary excretion
Tolerance to the toxic effects of nicotine develops rapidly
Adverse effects
The CNS effects of nicotine include irritability and tremors
Nicotine may also cause intestinal cramps, diarrhea and increased heart rate and blood pressure
Cigarette smoking increases the rate of metabolism for a number of drugs
Withdrawal syndrome
Nicotine is an addictive substance and physical dependence on nicotine develops rapidly and is severe
Withdrawal is characterized by irritability, anxiety, restlessness, difficulty concentrating , headaches and insomnia
Appetite is affected and gastrointestinal pain often occurs
Cocaine
Cocaine is an inexpensive , widely available and highly addictive drug that is currently abused daily by more than three million people in the USA
It is an alkaloid obtained from the leaves of coca plant
It is insoluble in water but its salts are soluble in water
It is poorly absorbed in the intestines but well absorbed by the mucous membrane and it can be given as surface anesthetic
Mechanism of action
The primary mechanism of action of cocaine is blockade of re-uptake of the monoamines ( nor epinephrine, serotonin and dopamine) into t he presymaptic terminals from which these neurotransmitters are released
Pharmacological actions
On CNS
CNS stimulant
Cocaine acutely increases mental awareness and produces a feeling of well being and euphoria similar to that caused by amphetamine
Cocaine can produces hallucinations and delusions
Cocaine increases motor activity and at high doses m it causes tremors and convulsions, followed by respiratory and vasomotor depression
Sympathetic nervous system
Peripherally, cocaine potentates the action of nor-adrenaline and produces the fight or flight syndrome characteristic of adrenergic stimulation
This is associated with tachycardia, hypertension, papillary dilation and peripheral vasoconstriction
Local anesthetic action
Dilates pupil
Raise the body temperature
Rise the BP
Produces euphoria
Pharmacokinetics
Cocaine is often self-administered by chewing intra-nasal snorting, smoking or intravenous injection
The peak effect occurs at fifteen to twenty minutes after intra-nasal intake of cocaine powder
Rapid but short-lived effects are achieved following iv injection of cocaine
Toxic effects
Mental excitement
Confusion
Tremors
Convulsions
Respiratory paralysis
Stimulation followed by depression
Cocaine can induce seizures as well as fatal cardiac arrhythmias
IV administration of diazepam and propranolol may be required to control cocaine – induced seizures and cardiac arrhythmias
Dose
8 – 16 mg by injection
Adrenaline has to be given along with cocaine which produces local vasoconstriction and prolong the local anesthetic effect
Uses
Cocaine has a local anesthetic action
Cocaine is applied topically as a local anesthetic during eye, ear ,nose and throat surgery
The anesthetic action of cocaine is due to a block of voltage – activated sodium channels
An interaction with potassium channels may contribute to the ability of cocaine to cause cardiac arrhythmias
