Non Steroidal Anti-Inflammatory Drugs NSAIDs
Cyclooxygenase:Cyclooxygenase (COX) is found in all tissues and regulate multiple processes . At side of tissue injury the enzyme converts (catalyzes) arachidonic acid to prostaglandins (prostaglandin E2 (PGE2) and prostaglandin I2) and to related compounds (prostacyclin, thromoxane A2). PGE2 and I2 promote inflammation and sensitize receptors to painful stimuli .
Cyclooxygenase has 2 form : cyclooxygenase -1 (COX-1),and cyclooxygenase-2 (COX-2). Cyclooxygenase-1 present in all tissue, and it is "housekeeping "chores such as protecting the gastric mucosa, supporting renal function, and promote platelet aggregation . In contrast ,COX2 is found mainly at site of tissue injury , and catalyzes the synthesis of prostaglandin E2 (PGE2) and prostaglandin I2 which promote inflammation and sensitize receptors to painful stimuli, therefore the COX-1 has been dubbed the "the good COX and COX-2 the "bad COX".
In stomach, COX promote synthesis of prostaglandin E2 (PGE2) and prostaglandin I2 which protect the gastric mucosa by :reduction of gastric acid secretion, increased secretion of bicarbonate and cytoprotective mucus, and maintenance of submucosal blood flow .
In platlets COX promotes synthesis of thromoxane A2 ,which stimulate platelet aggregation .
In the kidney, COX catalyzes the synthesis PGE2 and prostaglandin I2 which promote vasodilatation and maintain renal blood flow.
In the brain, COX derived prostaglandin mediate fever and contribute to pain perception.
In the uterus COX derived prostaglandin mediate promote contraction .
So inhibition of COX-1 results in harmful effect:
-Gastric erosion and ulceration,bleeding tendency, acute renal failure .
inhibition of COX-1 also has one beneficial effect: protection against myocardial infarction (reduced platelet aggregation.
Inhibition of COX-2 results in beneficial effects : suppression of inflammation. Alleviation of pain .Reduction of fever
Classification of cyclooxygenase inhibitors:
The NSAIDs can be divided in into 2 groups: (1) first generation NSAiDs and (2) second generation NSAIDs. The first generation inhibits COX-1and COX-2., the second generation inhibit COX-2 only. Because the first generation inhibit COX-1and COX-2, they are unable to produce their effects without posing a risk of serious side effects. In contrast, the COX-2 inhibitors can suppress pain and inflammation with minimal risk of serious adverse effects.
Mechanism of action
All of these drugs inhibit cyclooxygenase (COX), the enzyme that converts arachidonic acid to prostaglandins and related compounds (prostacyclin, thromoxane A2).
First generation NSAIDs
Aspirin :
Mechanism of action:
Is a nonselective inhibitor of cyclooxigenase , suppression of inflammation , pain , and fever result from inhibition of COX-2. One beneficial effect protection of myocardial infarction result from inhibition of COX-1.
Major adverse effects gastric ulceration, bleeding, acute renal failure result from inhibition of COX-1. Aspirin is an irreversible inhibitor of cyclooxigenase , this contrast with all other NSAIDs, which are reversible inhibitors , therefore duration of action depends on how quickly specific tissues can synthesize new molecule of COX-1and COX-2 . With other NSAIDs the effect decline as soon as drug levels fall.
Pharmacokinetics
Absorption: aspirin is absorbed rapidly and completely after oral administration in the small intestine, rectal absorption is slower and blood levels are lower than oral therapy.
Metabolism: has very short half life ( 15- 20 minutes) because rapidly converted to salicylic acid , an active metabolite. At low therapeutic level salicylic acid has half life of 2 hours and at high therapeutic level the half life exceeds 20 hours.
Excretion: by the kidney and highly dependent on urinary pH, by raising the pH of the urine from 6 to 8 , we can increase the rate of excretion by a factor of 4.
Therapeutic uses
1-Suppression of inflammation. Aspirin is an initial drug of choice for rheumatoid arthritis, osteoarthritis rheumatic fever, and tendonitis.
The dosages employed to suppress inflammation are higher than doses used for analgesia and reduction of fever .
2-Analgesia ( mild and moderate pain ). Is most effective in joint pain, muscle pain and headache, and inactively against severe pain of visceral origin, in contrast to opioid, aspirin produce neither tolerance nor physical dependence. Aspirin relief pain through action on he periphery. At site of injury, prostaglandin sensitize pain receptor to mechanical and chemical stimulation , by inhibition of COX-2 aspirin can relief pain , in addition aspirin has action on CNS that contribute to relief of pain.
3- Reduction of fever. Aspirin is the drug of choice for reducing temperature in febrile adults, however because or Reye syndrome aspirin should never be used to treat fever in children, aspirin will not lower normal body temperature, nor will it lower temperature that it has become elevated in response to physical activity or a rise in external temperature .the mechanism also by inhibiting COX-2 and thereby inhibit pyrogen- induced synthesis of prostaglandin .
4- Dysmenorrhea : benefit derive from inhibiting prostaglandin synthesis in uterine smooth muscle.
5-Suppression of platelet aggregation : synthesis of TXA2 in platelets promotes aggregation. Aspirin causes irreversible inhibition of COX-1 , the enzyme that make TXA2. since the platelets can not synthesize new COX-1 , the effect of a single dose persist for the life of platelet ( about 8 days ). Aspirin decreases the incidence of transient ischemic attacks,
Unstable angina, coronary artery thrombosis with myocardial Infarction, and thrombosis after coronary artery bypass grafting.
Epidemiologic studies suggest that long-term use of aspirin at low dosage is associated with a lower incidence of colon cancer, possibly related to its COX-inhibiting effects.
Adverse effects
In small doses aspirin rarely cause serious side effects. Toxicity is common when treating inflammatory disorders which require high doses.
1-GIT effects: gastric distress, heartburn, and nausea.
Occult blood occurs which in chronic use can result in anemia .
Long term high-dose can cause ulceration, perforation and bleeding. Ulcers result from (1) increased secretion of acid pepsin, (2) decreased production of cytoprotective mucus and bicarbonate, (3) decreased sub mucosal blood flow , secondary to inhibition of COX-1.,and (4) the direct irritation of gastric mucosa.
2- Bleeding. By inhibiting platelet aggregation.
3- Renal impairment: by inhibiting COX-1 and thereby inhibits synthesis of prostaglandins that cause renal vasodilatation. The resultant vasoconstriction decreases renal blood flow, decrease glomerular filtration rate and promote renal ischemia.( is rare with aspirin).
4- Salicylism: is a syndrome that begins to develop when asirin level climb just slightly above therapeutic. Overt signs include tinnitus . sweating , headache and dizziness.
5- Reyes syndrome: is rare but serious illness of childhood that has mortality rate 20-30%, characteristic symptoms are encephalopathy and liver degeneration , related to use of aspirin in children who have influenza or chickenpox.
6- Hypersensitivity : are uncommon in children and appear in adults with predisposition factors such as asthma, hay fever, urticaria.
The aspirin hypersensitivity reaction begin with profuse watery rhinorrhea , urticaria, bronchospasm , laryngeal odema, and shock.
Other First generation of NSAIDs
Like aspirin all other first generation of NSAIDs are nonselective inhibitors of cyclooxegenase , however in contrast to aspirin which cause irreversible inhibition of cyclooxegenase , the other NSAIDs cause reversible inhibition .
Ibuprofen :
is prototype of propionic acid derivatives , the drug is used to treat fever, mild to moderate pain and arthritis , is superior to most other NSAIDs for relief of primary dysmnorrhea. This property has been attributed to effective inhibition of prostaglandin synthesis in uterine smooth muscle . the incidence of adverse effects is low, and well tolerated. Concomitent use of aspirin may decrease the effect of aspirin. Cross reactive sensitivity occur in patients with aspirin sensitivity. It is not recommended during pregnancy
Naproxane and Naproxane sodium
Have a prolong half life and therefore can be administered less frequently. They are approved for arthritis, bursitis, tendonitis, primary dysmnorrhea, and mild to moderate pain.,
Adverse effects. They are well tolerated, the most common adverse effects are GIT disturbances, and compromise renal function by decreasing renal blood flow. Cross reactive sensitivity occur in patients with aspirin sensitivity
Diclofenac (voltaren)
Is aphenylaceic derivative ,, absorbtion is delayed by food . Peak plasma level occure after 2-3 hrs, half life is 2 hours.. It is metabolizesd in liver ,, and excreted in urine and bile.
Is approved for rheumatoid arthritis , ankylosing spondylitis and primary dysmnorrhea, is well absorbed ,metabolized in the liver and excreted in the urine .The most common side effects are abdominal pain ,dyspepsia and nausea. Can cause fluid retention and this can exacerbate HT and heart failure. The risk of liver dysfunction is greater than with other NSAIDs.
DOSE: adosage of 50-75mg. Twice daily,, may be increased to maximum of 200mg. Per day
Indomethacin:
Is an indolacetic acid,,kidney excret 65%of the metabolized drug. Probencid may increase plasma level of indeomehacin by interfering with excretion. Is an effective antinflammatory agent , approved for arthritis, bursitis, tendonitis, and for gouty arthritis .
Adverse effects :
Is sever frontal headache which occur in 25-50% of patients, GIT reactions(dyspepsia, nausea vomiting and bleeding)occure in 10-40% of patients.
CNS(10- 35%) including headache ,vertigo , dizziness si blurred vision .
hematological reaction . It is not recommended for pregnant and brest feeding women , infants and children under the age of 14, patient with peptic ulcer, pregnant and breast feeding women .
Should be used in caution in patients with coagulation defects or in patents receiving anticoagulat( it inhibit platelet aggregation.
Mefenamic acid (ponstan):
Is indicated for primary dysmnorrhea, and mild to moderate pain. The principal adverse effect is diarrhea.
Piroxicam(feldene)
Is well absorbed after oral adminstration , peak plasma levels are achieved after 3-5 hrs.,,, with variable half life (30-80hrs).excreted through urine and feces. Has antinflammatory , analgesic and antipyretic properties . is approved only for rheumatoid arthritis . Because of its long half life therapeutic effects can be maintained with once-day dosing .
adose of 10-20mg is per day. Higher doses not recommended and may be associated with increased risk of GI side effects.
Meloxicam (Mobic).
Is aderevativef of oxicam and inhibite prosglandin synthesis . it absorption not affected by co administration of food. Peak level after 5 hrs. The mean half life 15-20hrs. Metabolized by the liver, and excreted fecally and renally ..
Adverse effects:
GIT bleeding,, peptic ulceration,,dyspepsia, tinnitus,, dizzines, headch, odema and other reactions generaly associated with NSAIDs may occur.
The dreug is not recommended during pregnancy.
Dose : 7.5- 15mg. Per day.
Second- generation of NSAIDs (COX-2 Inhibitors)
Celecoxib : was the first COX-2 inhibitor , was approved on 1998. the drug can relief symptoms of arthritis with less GIT ulceration and bleeding .
Mechanism of action
Cause selective inhibition of COX-2 the enzyme that mediate inflammation and pain .
Pharmacokinetics:
Celecoxib is well absorbed following oral administration ,not affected by food, peak plasmna level after 3hrs., the effective half life is 11hrs. metabolized in the liver and excreted by the kidney
Therapeutic uses: is indicated only for rheumatoid arthritis and osteoarthritis
Adverse effects :
-GIT : since celecoxib dose not inhibit COX-1, the enzyme that protect the stomach ,a low incidence of GIT ulceration would be expected , the side effects will be limited to dyspepsia and abdominal pain .
-Sulfonamide reaction (allergy). Celecoxib contain a sulfur molecule and can precipitate allergic reaction in patients with sulfonamide allergy . avoid the drug in these patients.
-Celecoxib and other NSADs can cause premature closure of ductus arteriosus , therefore are contraindicated in 3rd trimester of pregnancy .
-High doses are associated with risk of thrombotic events( more than 800mg. , associated with risk of MI) .Hypertension and edema
DOSE: 200- 400mg.
Rofecoxib :
Is the 2nd selective COX-2 inhibitor , it is approved for treatment rheumatoid arthritis ,osteoarthritis acute pain . benefit derived from inhibition COX-2 , the enzyme who promote inflammation and sensitize the receptor to painful stimuli . anti-inflammatory and analgesic effects are equal to those of first generation of NSAIDs, but the GI side effects are less common .
Pharmacokinetics:
Is well absorbed following oral administration , metabolized in the liver and excreted by the kidney .
Adverse effects: the most common side effects are diarrhea, dyspepsia, and abdominal pain. Treatment has also associated with headache , renal toxicity, HT, anemia , leg edema and upper respiratory tract infection . can affect fetal circulation near term , therefore contraindicated in pregnancy . Rofecoxib does not contain sulfur group and hence is safe for Pts allergic to sulfonamide .
Gastric and duodenal ulcer is less common than with traditional NSAIDs.
General consideration
All of NSAIDs display antinflammatory , analgesic and antipyretic properties.All can promote the main side effects, although the intensity of these effects is less with some agents.
All have same effectiveness clinically, however for unknown reason , individual patients may respond better to one agent than other.
The efficacy of COX-2-selective drugs equals that of the older NSAIDs, while GI safety may be improved
On the other hand, selective COX-2 inhibitors may increase the incidence of edema and hypertension.
As of August 2011, celecoxib and the less selective meloxicam were the only COX-2 inhibitors marketed in the USA.
Rofecoxib and valdecoxib, two previously marketed, selective COX-2 inhibitors, were withdrawn from the market because of their association with increased cardiovascular thrombotic events.
Celecoxib has a Food and Drug Administration initiated black box warning concerning cardiovascular risks.
To varying degrees, all newer NSAIDs are analgesic, anti-inflammatory, and antipyretic, and all (except the COX-2-selective agents and the nonacetylated salicylates) inhibit platelet aggregation.
NSAIDs are all gastric irritants and can be associated with GI ulcers and bleeds as well, although as a group the newer agents tend to cause less GI irritation than aspirin.
Nephrotoxicity has been observed for all of the drugs for which extensive experience has been reported. Nephrotoxicity is due, in part, to interference with the autoregulation of renal blood flow, which is modulated by prostaglandins.
Hepatotoxicity can also occur with any NSAID (Abnormal liver function tests and rare liver failure).
Central nervous system: Headaches, tinnitus, and dizziness.
Cardiovascular: Fluid retention, hypertension, edema, and rarely, myocardial infarction, and congestive heart failure
Hematologic: Rare thrombocytopenia, neutropenia, or evenaplastic anemia.
Pulmonary: Asthma.
Skin: Rashes, all types, pruritus.
Gout
Gout is recurrent inflammatory disorder characterized by hyperuricemia and episodes of severe joint pain , typically in the first metatarsial joint. Hyperuricemia occur through two mechanisms: (1)excessive uric acid production and (2) impaired renal excretion of uric acid .
Acute attacks are precipitated by crystallization of sodium urate (the sodium salt of uric acid ) in the synovial space . Deposition of urate crystals promotes inflammatory processes. Feature of inflammatory processes is infiltration of leukocytes inside of synovial cavity , these cells phagocytize urate crystals and then break down, causing release of destructive lysosomal enzymes .
Gout progresses through four stages :
Asymptomatic hyperuricemia.
Attacks of gouty arthritis.
Asymptomatic intercritical period, in which symptoms subside.
Tophaceous gout , is characterized by development of tophi in joints.
Pharmcology of the drugs used for gout .
Colchicine ;
Is an anti-inflammatory agent whose effects are specific for gout. The drug is not active against other inflammatory disorders, is not an analgesic and does not relief pain in conditions other than gout.
Mechanism of action. We dont fully understand the mechanism by which colchicines relieves or prevents episodes of gout, as the drug does not influence either the production or excretion of uric acid. An important contributory action is inhibition of leucocytes infiltration; in the absence of leucocytes, there is no phagocytosis of uric acid and no subsequent release of destructive lysosomsl enzymes . leucocytes migration is inhibited by disruption of microtubules , the structure required for cellular motility , and cell division . Since microtubule required for cell division, colchicines is very toxic for any tissue that has a large percentage of proliferating cells such as (GIT epithelium). Disruption of cell division underlies the GIT toxicity of colchicine.
Pharmacokinetics. Colchicine is rapidly absorbed after oral administration , large amount re-enter the intestine via the bile ( entero-hepatic circulation ). Excreted in the feces .
Therapeutic uses ;
Has 3 distinct applications in gout:
Can be used to: (1) treat acute gouty attacks, (2) reduce the incidence of attacks in chronic gout , and (3) abort an impending attack .
Acute gouty arthritis. Colchicine produces a dramatic relief of acute gouty attacks, within hours; inflammation disappears completely within 2-3 days. Administration either IV or oral, with IV administration, symptoms resolve sooner than with oral or GIT reactions are minimal.
Prophylaxis of gouty attacks. When taken during the asymptomatic intercritical period, small doses of colchicine (0.5 to 1mg.) can decrease the frequency and intensity of acute attacks.
Abortion of an impending attack. Patients may experience prodromal signs of a developing gouty attack , if large doses of colchicines (0.5mg. every 2 hours) are taken immediately , the attack may be prevented .
Preparation, dosage and administration .
Colchicines is dispensed in tablets ( 0.5 or 0.6 mg. and 1mg) for oral administration , and in solution of 1mg for IV administration .
Oral : for an acute gouty attack , the dosage is 0.5 to 1.2 mg. initially followed by 0.5 mg. every 1to 2 hours .administration is repeated until pain relieved or until sign of GI toxicity appear, but should not exceed 8 mg.
The dosage for prophylaxis is 0.5mg. To 1.0mg per day.
The dosage for aborting an impending attack is 0.5mg. every 2 hours.
Intravenous . Intravenous administration can be used to treat an acute gouty attack., relief can be achieved by a single 2mg. injection . Extravasations can cause local necrosis.
Adverse effects. Mostly are nausea, vomiting, diarrhea, result from injury to the rapidly proliferating cells of the GI epithelium .If GIT symptoms develop, the drug must be discontinued immediately. In IV administration ,extravasation can cause local necrosis. Since the drug can cause fetal harm, it should be avoided during pregnancy.
Indomethacin .
Is an NSAID used to treat acute gouty arthritis, the drug efficacy is equivalent to that of colchicine . It does not reduce hyperuricemia, it suppresses inflammation . The adult dose for relief of acute gouty arthritis is 50mg. followed by 25mg. three times daily .
Allopurinol
Is used to reduce blood levels of uric acid. It is indicated for primary hyperuricemia of gout and for hyperuricemia secondary to cancer chemotherapy .
Mechanism of action
Allopurinol and its active metabolite alloxanthine- reduce uric acid production, by inhibition of xanthine oxidase , an enzyme required for uric acid formation.
Xanthine oxidase catalyzes the final two reactions that lead to formation or uric acid from breakdown of DNA.:
DNA ---- hypoxanthine ---------------------- Xanthine-------------- uric acid
Xanthine oxidase xanthine oxidase
Pharmacokinetics . Is well absorbed following oral administration, the drug undergoes rapid conversion to alloxanthine , an active metabolite that have a prolonged half-life ( 25 hours) which permit once daily dosing
Uses :
Chronic tophaceous gout. Allopurinol is the drug of choice for chronic tophaceous gout. By reducing blood levels of uric acid , the drug prevents tophus formation and promotes regression of tophi that have already formed . During the initial months of treatment , allopurinol may increase the incidence of acute gouty attack, therefore colchicines or indomethscin must be co-administered.
Secondary hyperuricemia .
Hyperuricemia may occur secondary to treatment with anticancer drugs. Uric acid levels are elevated due to breakdown of DNA that occur following cell death. Allopurinol should be administered prior to initiation of chemotherapy .
Adverse effects .
The most serious toxicity is a rare but fatal hypersensitivity syndrome characterized by rash, fever , eosinophilia and dysfunction of the liver and kidneys.
Mild side effects seen occasionally include GI reactions ( nausea, vomiting , abdominal discomfort ) and neurological effects (drowsiness , headache, metallic taste).
Prolonged use (more than 3 years) of allopurinol may cause cataracts .
Preparation, dosage and administration .
Allopurinol is dispensed in 100 and 300mg. tablet for oral use .
For treatment of chronic tophaceous gout , the objective is to decrease plasma urate level to less than 7mg. dl. The initial dose is 100mg. daily , the dose is then increased by 100mg. at interval of 1 week until urate has been reduced to acceptable level, usually at doses of 200-300mg.per day .
For secondary hyperuricemia ; in adult dosage ranged from 100-800mg .day. for children aged 6-10 years 300mg. day . children under 6 years the dose is 150mg. per day.
Probenecid. Act on renal tubules to inhibit reabsorption of uric acid , as a result excretion of uric acid is increased and hyperuricemia is reduced. By lowering plasma urate levels, probenecid prevents formation of new tophi and facilitate regression of tophi that have already formed.
The drug may exacerbate acute episodes of gout, therefore treatment should be delayed until the attack has been controlled. During the first months of therapy, may precipitate an acute gouty attack . if an attack occur , colchicines or indometacin sould be added to the regimen.
Adverse effects ; mild GIT effects ( nausea, vomiting, anorexia). Hypersensitivity reactions . Renal injury may occur from deposition of urate in the kidney , this risk can be minimized by consuming 2.5- 3 lit.of fluid daily during the first days of treatment.
Preparation, dosage and administration ;
Probenecid is dispensed in 500mg.tablets. the initial dose is 250mg.twice daily .Therapy should not be initiated during an acute gouty attack
Migraine headache
Migraine headache is characterized by unilateral, throbbing or non throbbing headache, associated with nausea, vomiting, photophobia and photophobia , pain increase gradually and persist for hours or days .
Migraine has two primary forms, called migraine with aura (classic migraine) and migraine without aura (common migraine).
In migraine with aura headache is preceded with by neurological symptoms which are usually visual (e.g. ., flashes of light, a blank area in the field of vision .
Path physiology
Migraine headache result from inflammation and dilatation of intracranial blood vessels , the underlying cause is not completely understood. Available data suggest that 2 compounds Calcitonin Gene Related Peptide (CGRP), and serotonin 5-Hydroxytryptamin ( 5-HT) are involved. The role of (CGRP) is to promote migraine whereas the role of 5-HT is to suppress migraine.
Data that implicate CGRP as a cause of migraine include the following :
1-The plasma level of CGRP rise during a migraine attack.
2-The administration of sumatriptan a drug that relieves migraine, lowers the elevated levels of CGRP.
3- Stimulation of neurons of the trigeminal vascular system promotes release of CGRP, which in turn promotes the release of inflammatory neuropeptides .
Data that support a suppress role for 5-HT include:
1-Plasma level of 5-HT drops by 50% during the migraine attack .
2-Depletion of 5-HT with reserpine can precipitate an attack in migraiene- prone individuals .
3-Administration of 5-HT or sumatriptan , both of which stimulate 5-HT receptors , can abort an ongoing attack.
Treatment :
Drugs for migraine are employed in 2 ways:
To abort an ongoing attack, and to prevent attacks from occurring (prophylaxis ) .
Abortive therapy:
Drug selection depend on intensity of the attack, for mild to moderate symptoms , an aspirin-like drug (e,g asperin , ibuprofen, acetaminophen ) may be sufficient. If these are inadequate, aspirin combined with codeine may be tried .if these analgesic prove insufficient, the second attack should be treated with sumatriptan or an ergot alkaloid ( ergotamine or dihydroergotamine),if these agents fail to relief pain , an opioid analgesic may be needed.
Metoclopramide may be used as an adjunct to other agents for treating an acute migraine attack , this drug suppress nausea and vomiting cased by the attack itself and by the therapy with ergot alkaloid . In addition metoclopamide reverse the gastric stasis caused by the attack, thereby facilitate the absorption of oral medication.
Aspirin-like drugs
Aspirin , acetaminophen , ibuprofen and other can provide adequate relief of mild to moderate migraine attack . When combined with metoclopramide, aspirin can be effective as sumatriptan , and costs less than sumatriptan and causes fewer side effects . Acetaminophen may be used alone or in combination with other drugs. A popular combination consists of acetaminophen and isomethepten (a sympathomimitic drug) and dichloralphenazone (a sedative).
Ergot alkaloids : Ergotamine
Mechanism of antimigraine action .
The actions are complex, and precise mechanism by which the drug aborts migraine attack is unknown. Ergotamine can alter transmission at serotonergic , dopaminergic and alpha adrenergic junctions . Recent evidence suggests that antimigrainic effect related to agonist activity at subtypes of serotonin receptors 5-HT.
Relief related to vascular effect.
By acting directly to promote vasoconstriction of cranial vessel, and reduce the amplitude of pulsations. In addition, the drug can affect blood flow by depressing the vasomotor center and contribute to reduction of migraine pain.
Pharmacokinetics ;
Administration may be oral, sublingual, rectal, or by inhalation. Bioavailability with rectal and inhalation is higher than oral and sublingual. Half life is only 2 hours but effects can still observed for 24 hrs. Metabolized by the liver and excreted in the bile.
Therapeutic uses;
Ergotamine is a drug of choice for stopping an ongoing attack. It is used also for cluster headache.
Adverse effects: is well tolerated at usual therapeutic dosed. The drug stimulates the chemoreceptor trigger zone to cause nausea and vomiting.
Other side effects includes weakness in the legs myalgia , numbness and tingling in fingers and toes, angina-like pain.
Overdose.
Can cause serious toxicity ( ergotism) :symptoms include the adverse effects seen at therapeutic doses plus sign and symptoms of ischemia caused by constriction of peripheral arteries and arterioles : cold and pale extremities , numb , muscle pain and gangrene may result.
Physical dependence.
Daily use of ergotamine can cause physical dependence. The withdrawal symptom is characterized by headache, nausea, vomiting, and restless
( i.e withdrawal resembles a migraine attack ).
Contraindications. Ergotamine is C.I for patients with hepatic and or renal impairment., coronary artery disease , should not taken during pregnancy , since it can promote uterine contraction .
Should not combined with selective serotonin-receptor agonist because a prolonged vasospastic reaction may occur.
Preparations, dosage and administration;
Is available as tablet for sublingual and in aerosol for inhalation.
Ergotamine is dispensed in combination with other drugs for oral and rectal administration
Dihydroergotamine
Pharmacological effects
The actions of dihydroergotamine are similar to those of ergotamine , alters transmission at serotonergic , dopaminergic and alpfa-adrenergic
It causes minimal peripheral vasoconstriction, little nausea and vomiting and no physical dependence. However diarrhea is prominent.
Pharmacokinetic ;
May be administered parenterally (SC.IM. IV) Or intranasal. Because of extensive first-pass metabolism, it is not active orally.
Elimination is by hepatic metabolism.
Parenteral administration :
Intramuscular and subcutaneous
The initial dose is 1mg. after onset of symptoms. Additional 1mg. may be given hourly up to3mg. Per attack.
Intravenous : one mg. is given initially , followed by 1mg. in 1hour if needed.
Intranasal administration:
The nasal spray device delivers 0.5mg. per spray . The dosage is 1 spray in each nostril repeated in 15 min. , for a total of 2mg.pain is relieved in 60% of patients.
Therapeutic uses:
parenteral dihydroergotamine is the drug of choice in terminating migraine and cluster headaches. Administration is by injection and nasal spray .
Contraindications;
Are the same as for ergotamine, and should not be administered within 24hrs. of serotonin agonist .
Selective serotonin 1-receptor agonists ( Triptans):
Selective serotonin 1-receptor agonists also known as triptans , are first line drugs for terminating a migraine attack . They relief pain by constricting intracranial blood vessels and suppressing the release of inflammatory neuropeptides .
Sumatriptan
Is a prototype for the group, can be administered by mouth, nasal inhalation, and subcutaneous.
Mech . of action .
Sumitriptan is an analog of 5-HT, cause selective stimulation of 5-HT1 and no affinity to 5-HT2 or 5-HT3 receptors, nor does it bind to adrenergig, dopaminergic, muscarinic or histaminic receptors .
-Binding to 5-HT1receptor on intracranial blood vessels causes vasoconstriction.
-Binding to 5-HT1 receptors on sensory nerves of the trigeminal vascular system suppresses release of CGRT, a compound that promote the release of inflammatory neuropeptides and thereby diminishes perivascular inflammation. Both actions help relieve migraine attack.
Pharmacokinetics .
With oral and, intranasal admin. , bioavailability is low (15%) whereas SC bioavailability is high (97%). As a result , oral and intranasal doses are higher than SC. Metabolized in the liver and excreted in the urine .
Therapeutic uses:
Is used to abort ongoing attacks. Both headache and associated symptoms are relieved. Beneficial effects begin 15 min. after SC or intranasal administration and 30 min. after oral administration..
In addition is approved for cluster headache.
Adverse effects
Chest symptoms
50% of patients experience heavy arms or chest pressure rather than pain. These symptoms not related to ischemic heart disease. The cause is pulmonary vasoconstriction, esophageal spasm, and bronchoconstriction
Coronary vasospasm.
Sumatriptan cause angina secondary to coronary vasospasm.
Teratogenesis .
Sumatriptan should be avoided in pregnancy, may produce embriolethal effects.
Prophylactic therapy;
Beta adrenergic blocking agents.
Not all beta adrenergic blockers are active against migraine, agents that demonstrated efficacy are, propanolol , atenolol , metoprolol , and timolol. Agents shown to be infective include oxprenolol and pindolol. Because only some beta blockers are effective, whereas all of them block beta adrenergic receptors , it would appear that a mechanism other than beta blockade is responsible for the beneficial effects .
Propanolol : Is the drug of choice for migraine prophylaxis , this agent can reduce the number and intensity of attack in 70% of patients .
Tricyclic Antidepressants .
Tricyclic antidepressants can prevent migraine in some patients, the mechanism is unknown. Amitripyline is the most employed.
Calcium Channel blokers ;
These include verapamil, nifedipine , beneficial effects develop slowly ( 1 to 2 months ).
Although all of these drugs can relieve vasospasm , it is not clear that vasodilatation explain antimigraine effects. A direct effect on neuron is possible
Methysergide
Is an ergot alkaloid, is more effective than propanolol, but is more dangerous , therefore prophylaxis with propanolol is preferred .
The mechanism by which provides prophylaxis is not clear. The drug is able to activate serotonin receptor in the central nervous system.
Side effects
Cause a serious adverse effects , retroperitoneal, pleuropulmonary, and cardiac fibrosis .
Cluster headaches
Cluster headaches occur in a series or (cluster) of attacks , each attack lasts 15 min. to 2 hrs. and is characterized by severe , nonthrobbing , unilateral pain located in or around the eye . A cluster consist of one or more such attacks every day for 4 to 12 weeks .An attack-free interval of months to years separate each cluster.
Treatment
Methysergide was the drug of choice in preventing attacks , other include calcium channel blocker agents (verapamil ), lithium, and glucocorticoids.
Abortive treatment by sumatriptan or an ergot preparation .
An attack may also terminated by inhalation of 100% oxygen for 10 min. is effective in 90% of patients. The mechanism is unknown.
Tension headache.
Is the most common headache. Is characterized by moderate non throbbing pain located in -hat band distribution around the head, with sense of tightness or pressure in the head and neck.
Treatment :
Mild to moderate intensity can be relieved with acetaminophen or nonsteroidal antiinflammatory drugs ( aspirin, ibuprofen, naproxen ).
An analgesic sedative combination may be used.
For prophylaxis , amitriptiline is the drug of choice.