NonopioidAnalgesics

Ma. Hermie Culeen F. Barapon

PAIN-The means by which the body is made aware of the presence of tissue damage

There are two components of pain:

• Perception is the process by which pain is recognized by the brain• Reaction is any involuntary act occurring in response to a stimulus causing sharp pain

Nonopioid (nonnarcotic) Analgesics• relieve pain with only a minor alteration of consciousness• safer than opioids, produce fewer side effects, and are not addicting• act principally at the peripheral nerve endings• inhibit the synthesis of prostaglandins, which occurs at sites of tissue inflammation and produce their analgesic effects peripherally and their antipyretic effect centrally

CLINICAL CONSIDERATIONS:1. Nonopioid analgesics are more

effective if given before the pain and inflammation associated with prostaglandin synthesis occur.

2. Nonopioid analgesics are not completely effective because they do not affect the formation of primary pain mediators.

Principal Pharmacologic Actions:1. Analgesia2. Antipyresis3. Antiinflammatory action

• Of these actions the salicylates and NSAIAs exhibit all three in therapeutically useful amounts, and acetaminophen exhibits only analgesia and antipyresis.

Salicylates

Salicylates- Came from the extracts of willow bark

containing the bitter glycoside salicin

1. Acetylsalicylic acid (Aspirin, Bayer, A.S.A.)

2. Sodium salicylate (Uracel)3. Magnesium salicylate (Mobidin, Doan’s

pills)4. Salsalate (Disalcid, Monogesic)5. Salicylamide (Uromide)6. Diflunisal (Doloboid)7. Methylsalicylate (oil of wintergreen)8. Salicylic acid (Salacid, Freezone)

Acetysalicylic acid (Aspirin)• most widely employed drug in

medical and dental practice• Described as the prototype salicylateAscriptin EcotrinAspro EntrophenBayer HalfprinBex NovasenBufferin SolprinDisprin Spren

Uses:

1. Treatment of mild to moderate pain2. In control of fever3. Treatment of rheumatic fever and

arthritis4. Treatment of thromboembolic

disorders5. Treatment of transient ischemic

attacks in men6. Treatment in post-MI

Mechanism of Action• The inflammatory stimulus

activates or releases a phospholipase, which cleaves the essential fatty acid (arachidonic acid) from membrane lecithin, thereby making it available for prostaglandin synthesis by the enzyme cyclooxygenase. Aspirin-like drugs inhibit the cyclooxygenase by acytelating a serine at its site of action.

Pharmacologic effects:1. Analgesia

The inhibition of prostaglandin synthesis by aspirin-like drugs leads to analgesia by decreasing the sensitivity of pain fibers to the presence of pain-producing substances.

2. AntipyresisThe antipyretic action of aspirin-like drugs results from inhibition of prostaglandin synthesis in the hypothalamus.

3. Anti-inflammatory effectsThe inhibition of prostaglandin synthesis leads to decreased redness and swelling of the inflamed area.

4. Uricosuric effectLarge doses of aspirin (over 5gm/24 hr) increase uric acid secretion and decrease plasma urate concentrations. Smaller doses of aspirin (1-2gm/24hr) may decrease the secretion of uric acid and elevate the plasma urate concentration.

5. Platelet effectsAt therapeutic doses, aspirin prolongs bleeding time. The mechanism of action is related to acytelation of platelet cyclooxygenase and subsequent reduction in thromboxane A2 (TXA2), a potent aggregating substance. This effect on the platelet is irreversible and lasts for the life of the platelets exposed.

• Aspirin has been shown to be effective in a few selected trials in males, such as in prevention of myocardial infection with unstable angina and prevention of stroke in patients with transient cerebral ischemia.

Adverse effects:1. Gastrointestinal effects

- Dyspepsia- Nausea and vomiting- GIT bleeding- Ulcer

These effects are produced in 2 ways:

- Local irritation- Inhibition of prostaglandin

GIT effects can be reduced through:1. Ingestion with food or with a full

glass of milk or water2. In solution3. Ingestion of liquid antacid

2. Hypoprothrombinemia- can result after long-term use- Aspirin is known to prolong

prothrombin time and inhibit platelet function

3. Thyroid-Stimulating Effect- Results from long-term aspirin

consumption- Elevated free thyroid hormone in the

blood

4. Metabolic Effect- Aspirin uncouples oxidative

phosphorylation and reduces lipogenesis

- Affects CHO metabolism so that the blood sugar may be elevated or lowered

5. Hepatic and Renal Effects- hepatotoxicity- Reye’s syndrome- Papillary necrosis and interstititial

nephritis

6. Effects on Pregnancy- Pregnancy Risk Category: C- Salicylates readily cross placental

barrier and are excreted in breast milk

- Prolonged gestation, delayed parturition, increased risk of hemorrhage in mother and newborn, increased risk of stillbirth or neonatal death, and decreased birthweight

7. Hypersensitivity- Results from inhibition of

cyclooxygenase- SRS-A symptoms include

bronchospasm, angioneurotic edema, rhinitis, urticaria, wheezing, hypotensive shock, abdominal cramps and nasal polyps

8. Glucose-6-Phosphate Dehydrogenase Deficiency- A common inborn error of

metabolism- Symptoms of hemolysis includes

abdominal or back pain, anemia, hemoglobinuria

Toxicity• Salicylism – mild toxic reaction

produced by salicylates• Signs and Symptoms:1. Tinnitus2. Headache3. Nausea and vomiting4. Dizziness5. Dimness of vision

• The lethal adult dose of aspirin is between 10 and 30 gm (30 to 100 of the 5-grain tablets)

Severe acidosis and electrolyte imbalance are usually the causes of death resulting from:1. Depression of the respiratory

center (CO2 accumulation)2. Renal impairment from

dehydration and hypotension (inorganic & metabolic acids accumulate)

3. Impaired CHO metabolism that increases the production of metabolic acids

When aspirin is prescribed for a child, one should ensure that:1. The dosage is accurately

determined2. Adequate fluid intake is

maintained3. The parent is cognizant of the

dangers of poisoning4. The child does not have chicken

pox or flu.

Treatment:1. By inducing emesis, gastric lavage, or

by the administration of activated charcoal.

2. Severe toxic reaction require immediate hospitalization and the use of IV fluids to correct acidosis and electrolyte imbalance

3. Bathing in tepid water and IV fluid must be promptly administered in case of hyperthermia and dehydration.

4. Alkaline diuresis should be maintained by the administration of sodium bicarbonate

5. Hypoglycemia and hypokalemia are treated symptomatically.

DRUG INTERACTIONS1. Warfarin (Coumadin)

- oral anticoagulants- aspirin displaces warfarin from plasma protein binding sites which increases active warfarin in the blood and amplifies its toxic effect- administering salicylates to patients can increase prothrombin time and promote GIT bleeding and hemorrhage

2. Probenecid & Sulfinpyrazone- used in treatment of gout- aspirin has been reported to precipitate an acute attack of gout

3. Sulfonylureas- used in the treatment of adult-onset diabetes mellitus- Aspirins may enhance the hypoglycemic response to sulfonylureas

4. Methotrexate- used as a cancer chemotherapy agent or in the treatment of psoriasis- Methotrexate can be displaced from its plasma protein binding sites, leading to an increased concentration of free methotrexate

Administration, Absorption & Metabolism

- Aspirin is almost always administered orally

- It is rapidly absorbed, partly from the stomach but mainly from the small intestine

- Once absorbed, aspirin is rapidly hydrolyzed in the plasma to salicylic acid which becomes unevenly distributed throughout the body.

Administration, Absorption & Metabolism

- Relatively high concentration are found in the lungs, liver, saliva and kidney; lower levels attained in the muscle and brain

- Salicylates are excreted through urine. Very little salicylate is excreted in the feces

Dosages:

ArthritisAdult: PO 2.6-5.2 g/day in divided doses

q4-6hChild: PO 90-130 mg/kg/day in divided

doses q4-6hPain/feverAdult: PO/REC 325-650 mg q4h prn, not

to exceed 4 g/dayChild: PO/REC 40-100 mg/kg/day in

divided doses q4-6h prn

Dosages:

Thromboembolic disordersAdult: PO 325-650 mg/day or bidPain/feverAdult: PO 650 mg bid or 325 mg qid;

lower daily doses of 160-325 mg have been used as well

Preparations:1. Regular aspirin2. Enteric-coated aspirin3. Sustained-release aspirin4. Combinations

a.With antacid-buffering agentb.With another analgesicc.With sedatives or

antihistaminesd.With caffeine

Diflunisal (Dolobid)- long-acting NSAIA salicylate- Food decrease the rate but not

the extent of absorption- Half-life is 8-12 hours; onset 15-

30 min; peak 2-3 hr- Metabolized by the liver and

excreted via the kidney- Excreted in breast milk, crosses

placenta

Dosage:

Pain/feverAdult: PO loading dose 1 g

then 500-1000 mg/day in 2 divided doses, q12h, not to exceed 1500 mg/day

Adverse effectsGI: Nausea, anorexia, vomiting, bleeding,

diarrhea, heartburn, anorexiaCNS: stimulation, drowsiness, dizziness,

confusion, convulsion, headache, flushing, hallucinations, coma

CV: rapid pulse, pulmonary edemaINTEG: rash, urticaria, bruisingORAL: Dry mouthHEMA: thrombocytopenia,

agranulocytosis, hemolytic anemia, increased pro-time

RESP: wheezing, hyperpneaENDO: Hypoglycemia, hyponatremia,

hypokalemia

Contraindications• Hypersensitivity to salicylates• Bleeding disorders• Children <3 yr• Vit.K deficiencyPrecautions• Anemia, hepatic disease, renal

disease, Hodgkin’s disease, pregnancy category C, lactation

Drug InteractionsGI ulceration, bleeding: aspirin,

steroids, alcohol, indomethacin and other NSAIDs

Hepatotoxicity, Nephrotoxicity: acetaminophen (prolonged use)

NonsteroidAntiinflammatory

Agents

Mechanism of Action• NSAIAs inhibit the enzyme

cyclooxygenase, resulting in a reduction in the formation of prostaglandin precursors and thromboxanes from arachidonic acid.

Chemical classifications:1. Propionic Acid Derivatives

(Ibuprofen, Fenoprofen, Suprofen, Naproxen, Naproxen sodium, Ketoprofen, Benoxaprofen)

2. Acetic Acid Derivatives (Indomethacin, Sulindac, Tolmetin)

3. Fenamic Acid Derivatives (Meclofenemate, Mefenamic acid)

4. Pyrazolones (Phenylbutazone, Oxyphenbutazone)

5. Oxicams (Piroxicam)6. Salicylates (Diflunisal)

Pharmacokinetics:• The NSAIAs peak in usually 1 to 2

hours• They are metabolized in the liver

and excreted by the kidney.• Fecal excretion occurs with

fenamic acids, piroxicam, sulindac, and tolmetin.

• Food can reduce the rate of absorption but oral antacids have minimal or no effect on the rate of absorption

Uses:

• Osteoarthritis, rheumatoid arthritis, gouty arthritis

• Fever• Dysmenorrhea• pain

Pharmacologic effects:

1. Analgesic2. Antipyretic3. Antiinflammatory4. Antigout5. Dysmenorrhea

Adverse effects:

1. GIT effects- pain- bleeding leading to tarry stools- irritation- ulceration

Adverse effects:

2. Renal effects- renal failure- cystitis- increased incidence of UTI- decreased renal blood flow and glomerular filtration rate in patients with kidney disease

Adverse effects:

3. CNS effects- sedation- dizziness- confusion- mental depression- headache- vertigo- convulsions

Adverse effects:4. Blood Clotting

- inhibition of platelet aggregation remains only as long as the drug is present in the blood

5. Other effects- muscle weakness, ringing ears, blurred vision- ulcerative stomatitis, gingival ulceration

Adverse effects:

6. Hypersensitivity- hives or itching- angioneuretic edema- chills and fever- Steven Johnson syndrome- exfoliative dermatitis- anaphylactoid reactions during bronchospasm

Adverse effects:

7. Pregnancy and Nursing- prolonged gestation- delayed parturition- dystocia or premature closure of the ductus arteriosus- most NSAIDs are exreted in breastmilk; piroxicam has been shown to inhibit lactation

Contraindications:• Asthma• Cardiovascular diseases with

fluid retention• Coagulopathies• Peptic ulcer• Ulcerative colitis• Renal function impairment• Hypersensitivity• Geriatric patients

Ibuprofen• The oldest member of the NSAIAs

and has the most clinical experience

• Rapidly absorbed orally, and food decreases absorption, antacids have no effect

• Undergoes hepatic metabolism end excreted by the kidney

• Peak=1-2 hr; Half-life=2-4 hr; Duration=4-6 hr

Uses:• Rheumatoid arthritis,

osteoarthritis• Primary dysmenorrhea• Gout• Mild-to-moderate pain• fever

Adverse effectsOral: Dry mouth, bleeding, stomatitisGI: Nausea, anorexia, vomiting, diarrhea,

jaundice, cholestatic hepatitis, constipation, flatulence, peptic ulcer

CNS: Dizziness, drowsiness, fatigue, tremors, confusion, insomnia, anxiety, depression

CV: tachycardia, peripheral edema, palpitation, dysrhythmias

GU: Nephrotoxicity: dysuria, hematuria, oliguria, azotemia

HEMA: Blood dyscrasias

Contraindications• Hypersensitivity• Asthma• Severe renal disease• Severe hepatic diseasePrecautions• Pregnancy category not

established, lactation, children, bleeding disorders, GI disorders, cardiac disorders, hypersensitivity to other antiinflammatory agents

Drug InteractionsGI ulceration, bleeding: aspirin,

alcohol, corticosteroidsDecreased action of ibuprofen:

salicylatesNephrotoxicity: acetaminophenRisk of increased effects: oral

anticoagulants, oral antidiabetics, lithium, methotrexate

Decreased antihypertensive effects of: diuretics, B-adrenergic blocker, ACE inhibitors

Mefenamic acid• Peak=2 hr; half-life=3-3 ½ hr• Metabolized in liver, excreted in

urine• Excreted in breastmilk• Uses include mild-to-moderate

pain, dysmenorrhea, inflammatory disease

Adverse effectsGI: Nausea, anorexia, vomiting, diarrhea,

jaundice, cholestatic hepatitis, constipation, flatulence, cramps, peptic ulcer

CNS: Dizziness, drowsiness, fatigue, tremors, confusion, insomnia, anxiety, depression

CV: tachycardia, peripheral edema, palpitation, dysrhythmias

INTEG: purpura, rash, pruritus, sweatingGU: Nephrotoxicity: dysuria, hematuria,

oliguria, azotemiaHEMA: Blood dyscrasias

Contraindications• Hypersensitivity• Asthma• Severe renal disease• Severe hepatic diseasePrecautions• Pregnancy category C (avoid

prescribing for dental use in last trimester), lactation, children, bleeding disorders, GI disorders, cardiac disorders, hypersensitivity to other antiinflammatory agents

Drug InteractionsGI ulceration, bleeding: aspirin,

alcohol, corticosteroidsNephrotoxicity: acetaminophenRisk of increased effects: oral

anticoagulants, oral antidiabetics, lithium, methotrexate

Decreased antihypertensive effects of: diuretics

Acetaminophen

Acetaminophen (Paracetamol; N-acetyl paraaminophenol)

• Para-aminophenol derivative from acetanilid

• Metabolized in liver, excreted by the kidneys

• Crosses the placenta and is also found in breast milk

• Rapidly and completely absorbed in the GIT: onset 10-30 min, peak ½-2hr, duration 4-6 hr, half-life 1-3 hr

Uses:

• Mild-to-moderate pain (inhibition of prostaglandin synthesis in the CNS)

• Fever

Advantages:1. Therapeutic doses have no effect

on cardiovascular and respiratory system.

2. It does not produce gastric bleeding.

3. It does not affect platelet adhesiveness or affect uric acid excretion.

4. It enhances water transport in kidney.

Adverse effects:

1. Hepatic necrosis- may occur in adults after ingestion of a single dose of 10-15 gm acetaminophen- symptoms include N & V, anorexia, and abdominal pain

Treatment:

1. Ingestion of gastric lavage2. Administration of activated

charcoal and magnesium or sodium sulfate solution

3. Administration of N-acetylcysteine to reduce or prevent liver damage

4. Hemodialysis or hemoperfusion may be used if oral acetylcysteine does not improve the patient

Adverse effects:

2. Nephrotoxicity- associated with long-term consumption- primary lesion appears to be a papillary necrosis with secondary interstitial nephritis

Contraindications• Hypersensitivity

Precautions• Anemia• Hepatic disease• Renal disease• Chronic alcoholism• Pregnancy category B

Drug InteractionsDecreased effects of

acetaminophen: barbituratesNephrotoxicity: NSAIDs,

salicylates (chronic hig dose concurrent use)

Buffered acetaminophen: decreased absorption of tetracycline

Increased bleeding (Chronic, high doses over 2g/day): oral anticoagulants

References:• Gage, Tommy W. Mosby’s

Dental Drug Reference.Mosby-Year Book, Inc. 1994.

• Holroyd, Sam V. Clinical Pharmacology in Dental Practice.4th ed. The C.V. Mosby Company. 1988.