Paracetamol, Tylenol (p-Aminophenol Derivatives.)

Acetaminophen = paracetamol= Tylenol= para-Aminophenol derivative:

Acetaminophen (Tylenol) has fewer toxic effects than either precursor. Phenacetin and acetanilide are no longer used therapeutically because they have been linked to methemoglobinemia.

Acetaminophen is less plasma protein bound than the salicylates.A minor toxic metabolite
is generated by the metabolism of acetaminophen. This toxic metabolite is normally conjugated to glutathione (small protein) in the liver and excreted via the kidney. However, with the depletion of glutathione in certain disease states, such as liver cirrhosis and necrosis, and following chronic use of high doses of acetaminophen, this toxic reactive metabolite can accumulate and induce liver damage.


Mechanism of Action

Acetaminophen is a weak inhibitor of peripheral COX (so it is not anti inflammatory). Its analgesic effects may arise from inhibition of prostanoid synthesis in the CNS. The antipyretic effects of acetaminophen are similar to those of aspirin in that it acts at the level of the hypothalamus to reduce pyrogen-initiated alterations in body temperature by inhibiting
prostaglandin synthesis.

Pharmacological Effects and Clinical Uses Acetaminophen is similar to salicylates in that it is a
useful analgesic for mild to moderate pain, with equal efficacy to aspirin, and like aspirin, it is antipyretic. However, acetaminophen not effective in platelet aggregation and is not antiinflammatory. Thus, it is not useful for patients with arthritis or other inflammatory
diseases. It is also not useful as an antithrombotic agent in the prevention of myocardial infarction or transient ischemic attacks.

Acetaminophen does not produce the gastric ulceration that can occur with aspirin and is
useful in patients who are salicylate sensitive or who have a history of ulcers or other gastric ulcerations.

Adverse Effects, Contraindications, and Drug Interactions:

The onset (time till the symptoms occur) of toxicity may not occur for several days, and the predominant damage is to the liver.The initial signs of toxicity occur within 12 to 24 hours and include nausea and vomiting. Signs of hepatotoxicity occur within 72 hours. In addition to hepatotoxic effects, renal necrosis and myocardial damage may occur.

Acetaminophen is contraindicated in late-stage alcoholism, In addition, barbiturates and phenytoin induce the metabolism so decrease the effectiveness of acetaminophen. Acetaminophen crosses the placenta but is nonetheless used in pregnant women with few side
effects for the mother or the fetus.

Asprin, The most famous analgesic.

Each drug have a family and friends, the family of asprin is called salicylates which are the chemical group, that contain salicylic acid as a part of its structure.

Aspirin is a weak organic acid (a cause of peptic ulcer) and is one of the oldest known drugs for the relief of fever and pain. Aspirin remains the standard to which most NSAIDs are compared
for efficacy.

Aspirin and related salicylates are rapidly absorbed upon oral administration,
with most absorption occurring in the small intestine. The pH of the stomach (a secondary site of drug absorption) along with the gastric emptying time of the
stomach (which depend on the food eaten), determines the rate of absorption of the drug (and so, the time till effect appears). Thus, food, which alters gastric emptying time and possibly the pH of the stomach, will alter absorption of the drug.

Salicylic acid is highly plasma protein bound, an effect that alters the pharmacokinetics of other drugs taken in combination with aspirin. Most of drugs bounds to the proteins in the plasma of our blood, this complex act as reservoir for the drug in the body, the drug is released from this binding at a specific rate, and exert its action on the body. So asprin if taken with another drug will increase the concentration of the free drug in blood and so may cause toxicity.

Salicylates passively diffuse to all tissues, including breast milk, fetal tissues, and the CNS.They tend to accumulate, since increases in dose decrease renal clearance and prolong the half-life of the drug. The higher the pH of the urine, the greater the clearance of the drug. So when some one intake a lot of asprin to suicide or by accident, we give him (under medical supervision) sodium bicarbonate (alkalinization of urine) as a step in the treatment to eliminate the drug out of the body.

Aspirin and related salicylates produce their pharmacological effects predominantly by inhibiting the synthesis of prostaglandins and to a lesser extent synthesis of the thromboxanes (role in platelet aggregation). The prostanoids are mediators of inflammatory responses in many cell types. COX-2 is induced during inflammation and is therefore considered to mediate most inflammatory responses. New enzyme must be synthesized to overcome the effects of aspirin, which in the case of platelets can take as long as 11 days.


Clinical Uses

Aspirin and related salicylates are the primary treatment for mild to moderate pain, such as that associated with headache, joint and muscle pain, and dysmenorrhea.

At higher doses aspirin is an effective analgesic in rheumatoid arthritis. The salicylates are also potent antipyretic agents, with the exception of diflunisal, which is only weakly active.
Other uses of aspirin include inhibition of platelet aggregation.

Overdose and Other Adverse Effects

The major consequence of aspirin overdose, Salicylate-induced stimulation of respiration leads to hyperventilation. In addition, increased carbon dioxide production and metabolic acidosis. The onset of acidosis, if not treated less than 1 hour after ingestion of aspirin, will lead to loss of rhythmicity of respiration and eventually loss of breathing.

Treatments include alkalinization of the urine, fluid replacement, gastric lavage with activated charcoal, dialysis, and artificial ventilation.

Some patients exhibit hypersensitivity to aspirin in the form of salicylism, which is accompanied by ringing in the ears (tinnitus), vertigo, and bronchospasm (especially in asthmatics). The use of salicylate-containing preparations is not the only source of this drug. Those sensitive to salicylates should be aware of salicylates in a number of foods, such as curry powder, licorice, prunes, raisins, and paprika.

The use of aspirin in children and teenagers with either chickenpox or influenza is contraindicated, since there is evidence linking the use of the salicylates in such diseases to Reye’s syndrome, a potentially fatal disease accompanied by liver damage and encephalopathy.

Other potential adverse effects of the drugs include the use of aspirin by patients who anticipate surgery or dental procedures. Such patients should be closely monitored and the salicylate stopped at least 1 week prior to surgery because of the possibility of increased clotting time and excessive bleeding. Similarly, the use of salicylates in pregnant women may increase bleeding upon delivery and prolong delivery. In addition, adverse fetal effects have been documented, such as low birth weight, fetal intracranial bleeding, and possible teratogenic effects.
Due to the ulcerogenic effects of the drugs, patients with a history of ulcers or other GI disturbances should be carefully monitored for increased blood in the feces while taking salicylates.

Drug Interactions

The salicylates displace a number of drugs from plasma protein binding sites.

Anticoagulants are potentiated by aspirin by:
(1) displacement of the anticoagulants from plasma proteins
(2) the intrinsic anticoagulant effect of aspirin.
Thus, the dosage of drugs such as coumarin and heparin should be reduced in patients taking aspirin.

Oral sulfonylureas (Orinase, DiaBeta):
for non–insulin-dependent diabetes or phenytoin (Dilantin) for seizures. Displacement of the sulfonylureas or phenytoin from plasma binding necessitates a decrease in dosage to prevent an acute hypoglycemic event or sedation, respectively.

Aspirin enhances the effects of insulin (leading to hypoglycemia), penicillins and sulfonamides (increasing acute toxicity), and corticosteroids.

Aspirin increases the hypotensive effects of the cardiac drug nitroglycerin but decreases the effectiveness of the loop diuretics.

In patients taking methotrexate for cancer chemotherapy, aspirin may increase retention of the drug, and severe toxicity may result.

Certain drugs modify the effectiveness or side effects of aspirin.

Phenobarbital, occasionally used for seizures, induces liver enzymes that increase the
metabolism and excretion of aspirin,

Adrenoceptor– blocking drugs, such as propranolol, and decrease the anti-inflammatory effects of aspirin, whereas reserpine decreases its analgesic effects.

Antacids decrease the absorption of aspirin. Alcohol consumption in combination with aspirin increases the latter’s ulcerogenic effects.


ِAs i always say, don't consider any drug as a candy, but it is a toxin, which we use in a small dose.
Aspirin is OTC (over the counter) but it is still a drug (toxin) so be careful during the use of it.

NSAIDs, Non addictive analgesics

Nonopioid Analgesics

Non Steroidal Anti Inflammatory Drugs
NSAIDs

When we read NSAIDs, the first thing which comes to our minds is aspirin, but they are a huge class of analgesics, with many uses in different types of pain !!

In general, pain is first treated with the nonopioid analgesics (Non Steroidal Anti Inflamatory Drugs). These drugs are useful for treatment of pain, fever, and inflammation and for reduction of platelet aggregation. Although the NSAIDs are less effective than the opioids in providing pain relief, they do not produce tolerance and physical dependence, as do the opioids.

The mechanism of action of traditional NSAIDs involves blockade of the production of prostaglandins (The cause of inflammation and pain) by inhibition of the enzyme cyclooxygenase (COX) at the site of injury, thus decreasing the formation of mediators of pain in the peripheral nervous system.


The enzyme COX is have two types, the first one COX-1 is existing in the body, and the second one COX-2 is induced during the bruise, or abnormal enjury conditions.In addition to a role in inflammatory processes, COX-2 seems to play a role in colon cancer and Alzheimer’s disease, providing potential additional uses for COX-2-selective drugs.

We may think of prostaglandins as the (black cat), or the bad guy in the body, as it is responsible for our pain and suffer, but it has a major role in keep us alive.

It keeps the gastric mucosal lining (which is responsible of protecting our stomach from the gastric acid) and certain renal functions.Thus, inhibition of COX by the NSAIDs may be accompanied by ulceration of the stomach lining and renal damage. So we have to be careful during the use of analgesics or any drug, its not candy.

COX, non selective inhibitors:

Aspirin
Etodolac Indomethacin Sulindac
Meclofenamate Mefanamic acid
Fenoprofen Flurbiprofen Ibuprofen Ketoprofen Naproxen
Phenylbutazone Oxyphenbutazone
Piroxicam Ketorolac
Diclofenac Tolmetin
Oxaprozin Nabumetone


COX-2, selective Inhibitors:

Acetaminophen (Panadol)
Celecoxib(Celebrex) Rofecoxib (Vioxx)