Analgesic drug

analgesic drug

Analgesics
Medications that relieve pain without causing loss of consciousness

Pain

Is a protective reflex for self preservation due to presence of tissue damage. There are 2 components of pain : Perception and Reaction.

Perception is the physical component of pain that carried of pain through the nerve to the cortex . Reaction is psychological component of pain and involve the patients emotional response to the pain .

Analgesic (Drugs to Treat Pain)

What is pain? Sensory stimuli comes from release of prostaglandins, NO, bradykinins, histamine from damaged tissue Substance P released from sensory nerves, causes spread of pain Stimuli carried by sensory fibres to Thalamus & Cerebrum

Sensory Cortex

Thalamus
Spinothalamic Nerve Tract

Classification of ANALGESICDRUGS

NON OPIO1D OPIOID

Classification of Analgesics

Aspirin
Heroin
Codeine
Opium
Ibuprofen
Acetaminophen
nonopioid Analgesics
(Opioid) Analgesics
Analgesics

Differences between narcotic and non narcotic 

Site of action Mechanism of action Uses for treatment pain Addiction and dependence Side effect Have antiinflammatory effect .

Analgesics

opioid Site of Cortex & thalamusActionAntagonist Naloxone, nalorphine & levallorphan Uses Sever & deep pain e.g. cancer, MI & anginal pianPotency HighSide effect Addiction MOA ‡ of opiates receptors (m, k ,s, d) and relief the pain through the release of endorphines & encephalins Non-opioid(NSAID)Subcortical “thalamus”No antagonistDull pain e.g. headache, toothache & backacheLowNo addiction. ↑in bleeding tendency & ulcerInhibits prostaglandin synthesisby inhibition of cycloxygenaseenzyme


Categories of NSAIDs
There are two major categories for non-steroidal anti-inflammatory drugs The first is non-selective anti-inflammatory drugs. The second is selective anti-inflammatory drugs, COX-2 inhibitors.

The Inflammatory Response

The body’s response to a stimuli which causes pain and/or tissue damage.Physiologically capillaries become “leaky” through vasodilation.The response is initiated by the chemical messengers prostaglandins.

histamine serotonin bradykinin - major contributors to symptoms of inflammationleukotrienes - increase vascular permeability - increase mobilization of endogenous mediators of inflammationprostaglandins PGE2 ‑ promote edema and leukocyte infiltration PGI2 ‑ increase vascular permeability, enhance pain properties of bradykinin Mediators of the inflammatory response

Mediators of inflammation

Inflammation
The classical signs of inflammation are: Redness. Swelling. Heat. Pain. Loss of function.

NSAIDS

A therapeutic agent which relieves pain and fever by inhibiting the inflammatory response. These drugs are available over the counter and by prescription Non-steroidal. anti-inflammatory drugs (NSAIDs) are one of the most common pharmacological treatments prescribed for osteoarthritis

NSAIDs

The NSAIDs are a group of chemically agents that differ in their antipyretic, analgesic, and anti-inflammatory activities. They act primarily by inhibiting the cyclooxygenase enzymes that catalyze the first step in prostanoid biosynthesis. This lead to decreased prostaglandin synthesis with both beneficial and unwanted effects.

Prostaglandins

Prostaglandins were isolated from human semen in 1936. He named them Prostaglandins because he believed they came from the prostate gland.. They are synthesized in the same cell on which they act.

Biosynthesis of Prostaglandins

The goal is to inhibit the biosynthesis of prostaglandins in order to relieve the symptoms caused by the inflammatory response. Prostaglandins are synthesized from arachidonic acid in a pathway mediated by the Cyclooxygenase enzymes.

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Cyclooxygenase

An enzyme involved in prostaglandin synthesis cyclooxygenase-1 (COX-1): beneficial prostaglandins cyclooxygenase-2 (COX-2): harmful prostaglandins

COX Enzyme:Prostaglandin Effects

COX-1: beneficial
COX-2: harmful
Peripheral injury site
Inflammation
Brain
Modulate pain perception Promote fever (hypothalamus)
Stomach
protect mucosa
Platelets
aggregation
Kidney
vasodilation



COX
Expression
Function
Inhibitors
COX-1
constitutively throughout the body
organ pain, platelet function, stomach protection
NSAIDs including aspirin
COX-2
Inducible and constitutively in brain, kidney

NSAIDs, COX 2 inhibitors including celecoxib (Celobrex )

COX-3
Constitutively, high in brain, heart
pain pathways, not inflammation pathways
acetaminophen some NSAIDs


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(NON Opioid Analgesic(non narcotic analgesic 1.NSAIDS(nonselective cox). 2.COX-2 Inhibitors 3.Acetaminophen

Effects of COX Inhibition by Most NSAIDS

COX-1
Gastric ulcers
Bleeding
Acute renal failure
COX-2
Reduce inflammation
Reduce pain
Reduce fever
NSAIDs : anti-platelet—decreases ability of blood to clot

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NON opioid ANALGESIC

NSAID(COX) Salicylate group (Aspirin) Propionic acid derivatives (Ibuprofen) Indoleacetic acid (Indomethacin) Oxicam derivaties (piroxicam) Fenamates (Mefenamic acid) Diclofenac Ketorolac Phenylbutazone

NON opioid ANALGESIC

2.Cox2 inhibitor: Celecoxib Rofecoxib 3.Paraaminophenol group Acetaminophen Phenacetin


Salicylates group
Aspirin(acetylsalicylic acid) Sodium salicylate Coline salicylate Diflunisal Salicylic acid Methyl salicylate

Aspirin

Mechanism of action
Inhibits the enzyme cyclooxygenase(cox1) Irreversibly inactivating enzyme lead to inhibit prostaglandin synthesis. All NSAIDS ,including aspirin have three major therapeutic actions: Analgesic. Anti- inflammatory. Antipyretic.

A Few Word About Prostglandins

Arachidonic Acid
Prostaglandins
Leukotrienes
Lipoxygenase
Cyclooxygenase
Phospholipase A2
Cell Membrane
(What’s the significance? We’ll talk later …)


Pharmacological effect of aspirin
1. Analgesic effect (occur within 1houre).2. Antipyretic effect. The salicylates lower body temperature in patients with fever by impeding PGE2 synthesis and release in hypothalamus, Aspirin resets thermostat‌ toward normal, and it rapidly lowers the body temperature of febrile.

Pharmacological effect ofaspirin

3. Antiinflammatory effect. PGs in inflammation  vasodilation and increase vascular permeability.- Inhibition of PGs by NSAIDs attenuates, not abolish, inflammation.Often the dose 3-6 g/day

4. Antiplatelet effect. .Low doses (60-81 mg daily) of aspirin can irreversibly inhibit thromboxane production in platelets via acetylation of cyclooxygenase. Because platelets lack nuclei, they cannot synthesize new enzyme, and the lack of thromboxane persists for the lifetime of the platelet (3-7days). .


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5.Uricosuric effect 6.Gastrointestinal effect. NSAIDs block PG biosynthesis in the GI tract, they block these cytoprotective processes. primary toxicity seen with the NSAIDs is GI irritation which may lead to the production of ulcers when used in large doses over a long period of time. .

7.Respiratory action. At therapeutic doses, aspirin increases alveolar ventilation., which leads to elevated CO2 and increased respiration.


8. Action on the kidney. Cyclooxygenase inhibitors prevent the synthesis of PGE2 and PGI2 prostaglandins that are responsible for maintaining renal blood flow. Decreased synthesis of prostaglandins can result in retention of sodium and water and may cause edema and hyperkalemia in some patients.

Clinical uses

1.Control mild-moderate pain 2.Control fever 3.Treatment rheumatoid fever and arthritis and gout. 4.Prophylactic in MI(low dose). 5.Chronic use in colorectal cancer 6.Facilitates closure of the patent ductus arteriosus



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Parmacokinetic

Weak organic acid. Completely absorbed from the GIT. Peak blood level 1 hour. Orally, rectally for children. Metabolize in liver and excreted in urine. T1/2 15 minute.

Therapeutic uses:

External applications: Salicylic acid is used topically to treat corns, and warts. Methyl salicylate (oil of wintergreen‌) is used externally as a cutaneous counter irritant in liniments. *

Adverse effects

1.GIT effect.2.Prolong bleeding time..3.Allergic reaction.4. Reye’s syndrome: Salicylates must be avoided in children and teenagers (<15 years old) with varicella (chickenpox) or influenza to prevent Reye's syndrome. Although it occurs rarely there is a 20-30% mortality.

5. Acute renal failure in patient with congestive heart failure or dehydration. Or chronic renal toxicity known as analgesic-associated nephrotoxicity.

6. Higher doses work directly on the respiratory center in the medulla, resulting in hyperventilation and respiratory alkalosis that usually is adequately compensated for by the kidney. At toxic levels, central respiratory paralysis occurs, and respiratory acidosis due to continued production of CO2.

Drug interaction

1- with heparin or oral anticoagulant ------ hemorrhage . 2- antiacid reduce aspirin absorption 3- some Drug increase plasma concentration of aspirin . 4.decrease antihypertensive effect of Bblocker ,ACE inhibitor.

Over dose toxicity (Salicylism)  

More than6-10 g or 200mg/kg Symptoms: Nausea Vomiting Headache Dizziness tinnitus Mental confusion
Electrolyte imbalance Hyperthermia Hyperventilation convulsions Respiratory and metabolic acidosis the end death

Dose-dependent effects of salicylate.

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Treatment

1.Gastric lavage. 2. O2 supply . 3.Activated charcoal 4.I.v Sodium bicarbonate 5. .I.v. fluid. 6. If sever hemodialysis


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Side effect

GIT disturbance CNS effect . Dose and preparation Orally taken with dose of 200 mg every 6 hours(Ibuprofen). naproxen has long half live so is given once daily.t1/2 (15hours) dose 500 mg two times daily.

PROPIONIC ACID DERIVATIVES

Ibuprofen Fenoprofen Ketoprofen Naproxen Oxaprozin All these drugs have anti-inflammatory,Analgesic, antipyretic effects.



* They have gained wide acceptance in the chronic treatment of RA and osteoarthritis, because their GI effects are generally less intense than those of aspirin. (specially Ibuprofen) at therapeutic doses. These drugs are reversible inhibitors of the cyclooxygenases.

PK
* drugs are variably metabolized and conjugated, and they are largely excreted in the urine. Ibuprofen, fenoprofen, and ketoprofen have short plasma half-lives (1 to 4 hours), whereas naproxen has a plasma half life of approximately 15 hours, which allows less frequent dosing. Flurbiprofen has an intermediate half-life of approximately 6 hours; the half-life of oxaprozin is approximately 50 hours.

Therapeutic uses

Chronic treatment of rheumatoid arthritis and osteoarthritis(less GIT effect than aspirin). Dental pain . Ibuprofen oral and IV is effective in closing patent ductus arteriosus in preterm infants, with much the same efficacy and safety as indomethacin. Most used antipyretic in pediatric population. Ketoprofen It is more potent than ibuprofen, with 25 to 50 mg of ketoprofen about equally effective for mild moderate pain as 400 mg of ibuprofen

* Naproxen: Available as both the free acid and as the sodium salt the latter is more rapidly from GIT and is the preferred form for analgesic use. Duration between8-12hours. The most common adverse effects propionic acid drugs are:  GI, ranging from dyspepsia to bleeding. Central nervous system (CNS), such as headache, tinnitus, and dizziness, have also been reported.

Indoleacetic acid

Indomethacin

Indomethacin

Pharmacological effect Potent antiinflammatory(,acute gouty arithritis,osteoarthrits and ankylosing spondylitis). Control of pain. Antipyretic effect.(not use to lower fever) Delay labor. Treatment of patent ductus arteriosus.

Side effect

1.GIT effect including nausea,vomting,diarrhea,anorexia,abdominal pain,ulceration,perforation and hemorrhage . 2.CNS effect. 3.Chronic use decrease antihypertensive drugs such as : Furosamide , Thiazid , B- blocker, ACE inhibitors .

Oxicam derivatives

Piroxicam MELOXICAM (mobic)


Piroxicam, an oxicam is a nonselective COX inhibitor used in Rheumatoid arthritis and osteoarthritis.Side effectincreased incidence of peptic ulcer and bleeding is encountered—as much as 9.5 times higher than with other NSAIDs.GIT disturbances in 20% of patient.

Oxicam derivatives

. Meloxicam(mobic) inhibits both COX-1 and COX-2, with preferential binding It is associated for COX-2, It is not as selective as celecoxib and may be considered “preferentially” selective.rather than “highly” selective. with fewer clinical GI symptoms and complications than piroxicam. long half life 50 hours, given once daily

Fenamates

Mefenamic acid( ponstan) Meclofenamic acid

Mefenamic acid

USES: Dental pain. painful menstruation (dysmenorrhea) No advantage over other NSAIDS.

Side effect

1.Diarrhea 2.Cases of hemolytic can be reported(not used more than one week).

Diclofenac(voltarin)

Semiselective COX2 inhibitor Uses: Rheumatoid arthritis. ankylosing spondilitis. osteoarthritis. Reliefe of pain after third molar extraction(50-100 mg) Dysmenorrhea

Diclofenac

More potent than indomethacin and naproxen. . Side effect: GIT disturbance Rise in liver enzyme level


Pyrrole derivatives
* Ketorolac was the first injectable NSAID approved in the United States. is a potent analgesic but has moderate anti-inflammatory effects. The more than 400-fold selectivity for inhibiting COX-1 over COX-2 probably accounts for ketorolac’s enhanced toxicity

t is available for oral administration, for intramuscular use in the treatment of postoperative pain, an conjunctivitis for topical use for allergic. Not use more than 5 day,

Adverse effects are generally quite similar for all of the NSAIDs: 1. Central nervous system: Headaches, tinnitus, dizziness, and rarely, aseptic meningitis. 2. Cardiovascular: Fluid retention, hypertension, edema, and rarely, myocardial infarction and congestive heart failure. 3. Gastrointestinal: Abdominal pain, dysplasia, nausea, vomiting, and rarely, ulcers or bleeding.
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4. Hematologic: Rare thrombocytopenia, neutropenia, or even aplastic anemia. 5. Hepatic: Abnormal liver function test results and rare liver failure. 6. Pulmonary: Asthma. 7. Skin: Rashes, all types, pruritus. 8. Renal: Renal insufficiency, renal failure, hyperkalemia, and proteinuria.
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2- Paraaminophenol group

Acetaminophen.Phenacetin.
Mechanism of action These drugs act by inhibiting prostaglandin Synthesis in CNS. These drugs have antipyretic and analgesic effect but weak anti-inflammatory effect because they have less effect on Cox in peripheral tissues so their weak anti-inflammatory activity . and no antiplatelet effect and lack many side effect of aspirin.

How Do They Work?

Inhibit prostaglandin synthesis centrally
Anti-inflammatory
Analgesic
Antipyretic
Analgesic
Antipyretic
N S A I D s
A C E T A M I N O P H E N

Acetaminophen

Pharmacological action

1.Antipyretic 2.Analgesic These effects due to inhibition of prostaglandin synthesis. however has no effect on cyclooxygenase in peripheral tissues.

Pharmacokinetic

rapidly absorb from GIT Peak plasma (1-3) hr Dose 500 mg every 6 hr Metabolize in liver and excreted in urine .

Clinical uses

Mild to moderate pain Reduce elevated body tempreture.under 12 years(for children with viral infection). In allergic to aspirin Pregnant women Gout patients

Adverse effect

No side effect with therapeutic dose. Large dose 10-15 g (20-30) tablets causes hepatic necrosis (toxicity). Symptoms: Start in the first 2 days. Nausea,vomting,,anorexia, abdominal pain ,liver toxicity start in third day lead to Encephalopathy coma and death.


With large doses of acetaminophen, the available glutathione in the liver becomes depleted, and N-acetylbenzoiminoquinone reacts with the sulfhydryl groups of hepatic proteins, Hepatic necrosis, a very serious and potentially life-threatening condition, can result.
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Treatment

1.Gastric levage 2.Activated charcoal, sodium or magnesium solution. 3.Oral N-acetylcysten(antidote). Note: Acetaminophen should avoided in alcoholic patient.

3- COX2 Inhibitor

The selective COX-2 inhibitors do not affect platelet function at their usual doses. 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 increase the incidence of edema, hypertension, and possibly, myocardial infarction. .
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Celecoxib, Rofecoxib

Group of drugs that inhibit cox2 which responsible for anti-inflammatory action, : Cox2 is; constitutive in kidney, brain. inducible, in inflamed area

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Celecoxib

USES 1. in patient with rheumatoid and osteoarthritis. 2. used to reduce colerectal polyps. Pharmacokinetic. long half live 11 hours. Side effect: GIT, reduce to 50% (less bleeding and ulcer). Minimal renal & Cardiovascular side effect. No effects on bleeding time(not inhibit platelet).

Contraindication

chronic renal insufficiency Heart disease Allergy to aspirin