Category: 1. Drug acting as analgesics

Rheumatoid arthritis is an autoimmune disorder. IgG antibodies are formed which start cross-reacting against body tissues, mainly synovial membranes and joints. The disease is not confined here and can effect heart, lungs, kidneys, spleen, eye, or any other tissue.

It affects more females than males in a ratio or 3:1. Peak incidence starts within 20s, can occur between 20-40 years of age.

Disease has waxing and waning character and the person has to live with it for the rest of his life. Life span is shortened by 10-15 years.

It is treated aggressively if diagnosed early.

Signs and Symptoms

1. Morning stiffness of joints

2. As person moves about, stiffness progressively decreases. This is one sign looked into. If stiffness increases, disease is severer, if decreases it is going into remission.

If the disease is not treated well in time, joint deformity may occur.

Osteoarthritis

Wear and tear arthritis, bones appose each other at joints. They are swollen, inflamed, joint erosions and deformities are seen.

Ulnar deviation of metacarpophalangeal joints is most prominent in rheumatoid arthritis.

Boutonniere deformity is the flexion of proximal interphalageal joint and hyperextension of distal interphalangeal joint.

Swan neck deformity includes hyper-extension of proximal and flexion of distal interphalangeal joint.

Objectives Of Treatment

1. Reduction of inflammation & pain (acute relief, NSAIDS mainly)
2. Preservation of functions (disease modifying anti-rheumatic drugs)
3. Prevention of deformity
4. Prevention of extra-articular manifestations

Management

1. Patient education

Due to nature of disease, one has to live with it. One has to adhere to the instructions for normal life.

2. Rest

Initially at least. Progressively mobility is encouraged.

3. Exercise

Passive at first, gradually little harder

4. Weight reduction

5. NSAIDs
6. DMARDs
7. Combination therapies
8. Surgery –plastic joints, repair

Drug Treatment of Rheumatoid Arthritis

First Line Drugs

Non steroidal anti-inflammatory drugs

Non-selective Cox I inhibitors

	Naproxen		Fenoprofen
	Flurbiprofen		Sulindac
	Nabumetone		Etodolac
	Diclofenac		Piroxicam
	Aspirin (high dose)		Diflunisal
	Ibuprofen

Selective Cox-2 inhibitors

Celecoxib

Lumiracoxib

Roxecoxib

2nd Line Drugs or Disease Modifying Anti – rheumatic Drugs (DMARDS)

Immunosuppressive drugs

Methotrexate

Cyclophosphamide

Azathioprine

Anti Malarial drugs

Chloroquine

Hydroxychloroquine

Gold Salts (not used as toxic)

Aurothiomalate

Aurothioglucose

Auranofin

Glucocorticoids

Prednisolone

Triamcinolone

TNF Alpha Blocking Agents

Adalimumab

Infliximab

Etanercept

Miscellaneous

Sulphasalazine

Pencillamine

Levamizole

Leflunomide

Abatacept

Rituximab

Methotrexate

Much lower dose is required on weekly basis. Starting dose is 7.5 mg/week. It is gradually increased depending upon the response up to 300 mg/week.

Effects are slow to appear for all DMARDs taking about 6 weeks to 6 months to appear.

Mechanism Of Action

a. At low dose, blockage of two enzymes occurs:

1. Amino imidazole carboxamide ribonucleotide (AICAR) transformylase

2. Thymidylate synthetase

These enzymes are required for DNA and RNA synthesis. Their blockage causes blockage of neutrophil chemotaxis which is important for inflammation.

b. Dihydrofolate reductase is inhibited at slightly higher dose. It is also required for DNA and RNA synthesis and blockage of  lymphocyte and macrophage functions and chemotaxis occurs.

c. Apart from this, there is evidence that methotrexate also blocks proinflammatory cytokines like interleukins, which are proinflammatory.

d. Decreases proliferation of immune inflammatory cells

e. Apoptosis of immune inflammatory cells.

Side – Effects

1. Nausea
2. Stomatitis
3. Mucosal ulcers
4. Hepatotoxicity, chances of cirrhosis are minimal
5. Bone marrow suppression (thrombocytopenia, neutropenia)
6. Hypersensitivity lung reaction leading to shortness of breath, managed by withdrawing the drug.
7. Pseudolymphomatous reactions.

GI and liver function abnormalities can be decreased by:

1. Using leucovorin -24 hours after weekly dose
2. Using folic acid daily, but may also decrease efficacy of methotrexate

Uses

50-70% of patients diagnosed with rheumatoid arthritis –main stay

Not only for these, but also for other connective tissue disorders like:

1.  SLE,
2. Wegener granulomatosis
3. Psoriatic arthritis

Gold Salts

Two parenteral preparations are available:

1. Aurothiomalate
2. Aurothioglucose, contains 50% elemental content of gold.

Oral auranofin contains 29% elemental gold.

Gold combines with sulfhydryl groups, its affinity may be responsible for actions. It is also present in the tissues.

Mechanism Of Action

Various steps in inflammatory cascade are blocked by gold preparations.

1. Alteration of morphology and function of neutrophils and macrophages
2.   Lysozomal enzyme inhibition
3.   Inhibition of release of histamine
4.   Inactivation of complement system
5.   Inhibit release of PGE₂ and leukotriene b₄

Various aspects of inflammatory chemical mediators are blocked by gold salts.

Pharmacokinetics

Can be given I/M or orally (auranofin).

Tend to adhere to body tissues and get deposited in:

1. Synovial membranes of joints
2. Liver
3. Spleen
4. Kidneys
5. Lymph nodes

Because of this terminal half life is increased to one year.

Two-thirds of these gold preparations are excreted through kidneys

One-third through faeces (liver).

Side – Effects

Most patients exhibit some side effects. These include:

1. Skin rashes
2. Hematological (bone marrow) suppression
3. Proteinuria
4. Stomatitis
5. Mouth ulcers
6. metallic taste
7. corneal gold deposits
8. Nitritoid reaction, like nitrates, flushing because of vasodilatation of blood vessels of face, dizziness and hypotension. This is not because of gold, but because of the additives in preparation.

Auranofin causes dermatitis and diarrhea.

Sulfasalazine

Mechanism Of Action

Sulfapyridine and Sulfasalazine 5- amino salicylic acid combination splits in colon by bacteria, 5-amino salicylic acid exerts local inflammatory reaction in gut, used in inflammatory bowel disease.

In rheumatoid arthritis, both exert their effects. They do so by suppression of T and B cell function. One evidence is that when sulfasalazine is used, the antibodies levels decrease.

Decreased I_gA and I_gM.

Side Effects

1. GI symptoms -Nausea vomiting
2. Skin rashes
3. Hematological suppression (aplastic anemia, thrombocytopenia, leucopoenia)
4. Hypersensitivity (with drugs having sulfa moiety)
5. Reversible infertility in males

Chloroquine And Hydroxychloroquine

Antimalarial drugs.

Mechanism Of Action

Quite different from antimalarial actions:

1. Decrease T cell responses (T lymphocytes)
2. Decrease chemotaxis (neutrophils, macrophages)
3. Stabilization of lysosomal membranes
4. Inhibition of DNA and RNA synthesis
5. Trapping of free toxic radicals

Used orally in arthritis.

Protein binding is low (about 50-60%).

Volume of distribution is very large, about 13000 liters because have special affinity for melanin containing tissues, where they get deposited.

Long term use, because of this effect, leads to retinopathy.

Antimalarials are used for short time.

Side effects

1. GI symptoms –nausea, vomiting, diarrhea
2. Ocular examination is recommended every 6-12 months, because of retinopathy.

Glucocorticoids

Used parentally, orally and locally (intra-articular injections) depending upon conditions.

Mechanism of Action

Have lot of anti-inflammatory actions, main are:

1. Block phospholipase A2

When disruption of cell membrane occurs, arachidonic acid is formed, utilized in lipo-oxygenase or cyclooxygenase pathways. Both are blocked.

Cyclooxygenase II isoform is not constitutive in most body tissues. It needs to be  induced by stimuli.

2. Block expression of cyclooxygenase II.
3. Prevent antigen antibody reaction
4. Inhibit release of histamine by mast cells
5. Stabilize lysosomal membrane
6. Lymphoid tissues regress under action of glucocorticoids (involution)

Side effects

Effect every tissue.

Cushing syndrome (moon like face)

TNF-alpha inhibitors

Etanercept- TNF inhibition- suppression of T-cell & macrophage function

Infliximab- chimeric antibodies

TNF alpha is one of the most important cytokine of chronic inflammation, modulates monocyte macrophage functions. As these drugs block this cytokine, they are very important for severe rheumatoid arthritis.

They can be given alone or in combination with methotrexate.

Inhibition leads to suppression of T cells (as activation requires antigen presenting cells, which are macrophages, so stimulation blocked) and macrophage functions.

Infliximab is also used subcutaneously (monoclonal)

Infliximab has 75% human and 25% mouse origin, thus consists of three chimeric monoclonal antibodies. It gets bound to both soluble and membrane bound TNF-alpha. Varied genetic origin, given slow I/V. It causes demyelinated syndrome and also infusion site reactions (due to anti-infliximab antibodies)

The problem is that TNF is very important cytokine involved in immune response to chronic inflammation. Bacterial infection (T.B) is aggravated by these agents. If there is a need to use one of these, person is thoroughly scanned for tuberculosis.

Chances of malignancy, lymphopoenia are enhanced by use of these agents.

These agents are recommended if all other drugs fail to bring remission. They are then given alone, or in combination with methotrexate.

Leflunomide

Prodrug, converted to active metabolite in liver. It inhibits dihydroorotate dehydrogenase. When inhibited, DNA and RNA synthesis is blocked.

T and B cell functions are also blocked.

Adverse effects

1. GI symptoms
2. Hepatotoxicity
3. Hypertension
4. Mild alopecia
5. Weight gain
6. Increased blood pressure

Cholestyramine increases excretion and clearance.

Abatacept

It decreases the activation of T cells by binding to CD 80 and CD 86 inhibiting CD 28 binding. Its dose depends on body weight:

1. Less than 60 kg -500 mg
2. 60-100 kg -750 mg
3. Above 100 mg -1000 mg

Adverse Drug Reactions

Increased risk of infections esp. URTI

Infusion site reactions

Anaphylaxis

Anti-abatacept antibody

Increased chances of lymphomas

Azathioprine

Its metabolite is 6-thioguanine which:

1. Decreases ionisinic acid synthesis
2. Decreases B cell and T cell functions
3. Decreases Ig production
4. Decreases IL-2 secretion

Pharmacokinetics

In presence of thiopurine methyltransferrase it is converted to active metabolite.

Uses

1. Rheumatoid arthritis.
2. Psoriatic arthritis
3. Reactive arthritis
4. SLE
5. Polymyositis
6. Behcet’s disease

Adverse effects

1. Bone marrow suppression
2. GI upset
3. Increased infection risk
4. Increased lymphomas

Cyclosporine

It regulates gene transcription and decreases IL-1 and 2 production, this inhibits macrophage T cell interaction, decreases T cells responsiveness and T cell dependent B cell functions

Pharmacokinetics

Incomplete and erratic absorption

Microemusion -20-30% bioavailability

Grapefruit juice increased bioavailability up to 62%

Metabolized by CYP3A.

Uses

1. Rheumatoid arthritis
2. SLE
3. Polymyositis
4. Dermatomyositis
5. Wegener’s granulomatosis

Gout is a disease of purine metabolism, necessary for DNA and RNA synthesis, characterized by:

1. Hyperuricemia
2. Recurrent attacks of acute arthritis
3. Deposition of monosodium urate crystals in subcutaneous tissues, known as tophi

If remains untreated, there are chances of joint deformity.

Difference between rheumatoid arthritis and gout

Rheumatoid arthritis	Gout
Incidence is more common in females	more common in males
Post menopausal	30 years peak age

Signs and symptoms

• Involvement of singe joint, usually 1^st metacarpopharyngeal joint, big toe
• Pedegra (excruciating pain, swelling)
• Red and tender in acute phase, it becomes difficult to differentiate gout and cellulitis.
• Definitive when monosodium urate crystals from aspiration for gout.
• Subsides after some time, person becomes normal, then comes again.

On average, 5g purines are synthesized by body, 0.5 g are excreted and 4.5 g are recycled.

One enzyme is HGPRT (hypoxanthine guanine phosphoribosyl transferrase). In some deficiency of this enzyme leads to syndrome known as Lesch Nyhan syndrome. There are neurological problems as well.

People having primary gout have either relative or absolute deficiency or over activity of enzymes.

People with secondary gout also have some hereditary component.

Famous sufferers include Isaac Newton, Martin Luthar, Benjamin Franklin (introduced colchicine)

Drug Treatment of Gout

Causes of Hyperuricemia

Hyperuricemia is associated with gout, but every sufferer of hyperuricemia does not have gout.

Secondary causes

1. Decreased renal excretion
2. Drugs like diuretics are actively secreted at proximal tubule (thiazide, furosemide) 80% uric acid is actively secreted and most is reabsorbed.
3. Low dose aspirin
4. Pyrazinamide
5. Cyclosporine
6. Niacin

Lactic acidosis

1. Alcohol
2. Exercise
3. Vomiting
4. Starvation

Increased production of uric acid

Myeloproliferative disorders e.g. polycythemia

Lymphoproliferative disorders like CLL, psoriasis

Pathogenesis

Hyperuricemia causes increase in monosodium urate crystals, which are phagocytosed by synovial sites, producing prostaglandins and interleukins (inflammation). Chemotaxis of polymorphs makes the environment more acidic, which further enhances the precipitation. Further mediators of inflammation are released causing:

1. Activation of chemotactic factors
2. Production of lactic acid
3. Release of lysosomal enzymes
4. Glycoprotein synthesis

Treatment

Acute Gout

Specific

Colchicine

Non-specific

Indomethacin

Phenyl butazone

Ibuprofen

Piroxicam

Corticosteroids

Triamsinolone –orally, if not infective intra-articular injection

1. Aspirin in low doses inhibits uric acid excretion.
2. In higher doses decreases reabsorption -uricosuric effect

Both are undesirable.

Paracetamol is not used

Tolmetin is not used

Oxprozen is not used

Drugs used for Chronic Gout

Allopurinol

Febuxostat –newer drug

Uricosuric agents

Probenecid

Sulphin pyrazone

Benzbromarone

IL-1 inhibitor

Anakinra

Colchicine

Specifically meant for acute attack of gout. It is not analgesic and relieves pain by controlling inflammation.

1. Very narrow therapeutic index so fallen out of favor
2. Hardly available

Source alkaloid obtained from Colchicum autumnale

Mechanism of Action

In acute inflammation for migration and macrophage functions.

Microtubules are required, polymerization of tubulin occurs. When colchicine binds tubulin, it prevents polymerization. Both chemotactic and phagocytic functions of macrophages are lost, thus

1.  Controls inflammation and
2. Rapid proliferation of these inflammatory cells

For cell division, microtubules are required, as are inhibited, thus cell proliferation does not take place.

3. Also inhibit leukotrines B4 by unknown mechanism.

Thus used for treatment of acute gout.

Pharmacokinetics

Well absorbed orally. Also used I/V.

Dose 0.6 mg initially. 0.6 mg after every two hours, till acute attack subsides. As little as 8 mg can be fatal.

Metabolites are partly excreted through liver, and partly through kidneys.

Side effects

1. GIT intolerance –where cells are rapidly dividing, nausea, vomiting, diarrhea, abdominal pain -1^st sign of acute toxicity.
2. Bone marrow suppression
3. Hair loss
4. Peripheral neuritis

Acute toxicity

1. Burning throat pain
2. Hypotension
3. Shock
4. Oliguria leading to hematuria
5. Ascending CNS paralysis occurs because of respiratory paralysis

Treatment

Only supportive

Probenecid and Sulfinpyrazone

Weak acids having similar mechanism of action.

Mechanism of action

Uric acid is freely filtered partly at glomerular membrane. 80% is actively secreted and reabsorbed at PCT. These drugs block the reabsorption of uric acid. More uric acid is lost in urine. So known as uricosuric agents. They are very useful in individuals who are underexcretors of uric acid. If less than 800 mg/24 hours uric acid is excreted in urine, then known as underexcretors.

For determination, have to take 24 hour urinary sample.

Adverse effects

1. GIT irritation
2. Allergic dermatitis
3. Uric acid stones –as greater uric acid may precipitate. Before starting treatment it is checked whether person does not have problem already. There are two remedies to counter this side effect:

• Increased urinary volume (increased water intake)
• pH of urine is kept above 6.

4. Aplastic anemia

Allopurinol

Inhibits uric acid production. Itself is acted upon by xanthine oxidase, converted into alloxanthine, which is active metabolite with a half life of 18-30 hours. Drug is needed to be given once a day. Alloxanthine inhibits xanthine oxidase

Once inhibited, relative increase in hypoxanthine and xanthine occurs, which are soluble and easily excreted through kidneys.

Indications

Chronic tophaceous gout

Severe disease characterized by monosodium urate crystals and tophi. If uric acid production is decreased, tophi resolve. As urate pool goes down, it enters plasma, thus in high uric acid excretors (more than 800mg/day) allopurinol is very effective.

In those individuals in whom uricosuric agents are contraindicated or have recurrent renal stones or impaired renal functions, sulphinpyrazzoles cannot be used.

There is gross elevation of uric acid levels.

Dose

100 mg/day, may be increased to 300 mg/once a day.

Side effects

1. Precipitation of acute gout

Fluctuating levels in plasma are more dangerous than simple hyperuricemia. Phagocytosis by synovial sites is increased. Allopurinol use decreases plasma uric acid levels, fluctuation in levels occurs, resulting in chances of precipitation of acute gout.

Whenever allopurinol is given in chronic case, initially it is combined with Indomethacin or Colchicine, to guard against this.

2. GI intolerance

a. nausea

b. vomiting

c. diarrhea

3. Allergic reactions

4. Bone marrow suppression

5. hepatic/renal toxicity

Drug interactions

Especially with anticancer drugs. In all types of cancers, there is increase in uric acid as well as increase in cell turnover, thus allopurinol has to be used. Mercaptopurine and Azathioprine are themselves metabolized by xanthine oxidase. Dose has to be reduced.

The dose of cyclophosphamide has to be reduced when allopurinol is given along with it.

Febuxostat

Non-purine inhibitor of xanthine oxidase. Similar mechanism of action to allopurinol, but is more selective and lower dose is required.

Dose 80-120 mg/day.

Adverse effects

1. Nausea
2. Diarrhea
3. Impaired liver functions (transient rise in ALT, AST)
4. Headache

Anakinra

It is under investigation and is interleukin 1 inhibitor. Interleukin 1 is released at start of gout, it is thought that it might be fruitful to use it in gout.

Apart from Aspirin and Paracetamol, already discussed, following are the important non-steroidal anti-inflammatory drugs:

Diflunisal

Difluoro phenyl derivative. Because of chain structure cannot cross blood brain barrier. So cannot be used as anti-pyretic.

It can be used as anti-inflammatory and analgesic peripherally.

As cannot cross BBB, so CNS effects like salicylism, auditory effects are not present.

Uses

1. Rheumatoid arthritis
2. Ankylosing spondylitis
3. Osteomyelitis

Chances of GI bleeding are much less.

Ibuprofen

Actions are also dose related (400mg tablet). Anti-inflammatory effects at 2400 mg/day (2 tablets 3 times a day).

Below this dose, used as anti-pyretic and analgesic.

GI bleeding from use of aspirin

Used in treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis and acute gout.

Also available as ointment and cream and applied for muscle sprains.

Adverse effects

If used over prolonged periods, there are chances of renal failure, interstitial nephritis.

Indomethacin

Slightly different, as is selective for COX-1, slightly more than the other.

Mechanism of action is same like the others.

Therapeutic uses

Can be used as analgesic, anti-pyretic and anti-inflammatory.

It cannot be used for longer durations due to fear of toxicity which occurs in 35-50% of the patients on prolonged use.

Indications

Patent ductus arteriosus

When fetal lungs are not functional and liver is only partially, placenta provides oxygen and nutrition and helps in excretion of wastes. Certain changes take place when born. Closure of patent ductus arteriosus occurs, during fetal life prostaglandins keep it patent under COX-1 influence. In some individuals, even after birth, closure does not occur. If detected earlier, this drug can help in closure. Later on surgery is indicated.

Adverse effects

1. 25% of patients suffer from headache –frontal, on prolonged use

2. psychosis, hallucinations

3. chances of agranulocytosis

4. pancytopenia

5. thrombocytopenia

6. GI bleeding

7. Gastropathy

Probenecid prolongs the half life of Indomethacin because it decreases its renal and biliary clearance.

Piroxicam

Available as injections, capsules, tablets, gel for local application.

Most important is that it has a very long half life about 46-72 hours. Can be used once a day.

Uses

1. Post op pain
2. Renal colic
3. Other indications are anti-inflammatory effects

Diclofenac Sodium 

Available as potassium or sodium salt. Potassium salts are better absorbed. Preparations are available as tablets, injectables, gels for topical use, eye drops.

Uses

1. Post op pain
2. Renal colic
3. Rheumatoid arthritis, acute gout, ankylosing spondylitis
4. Eye drops for post op inflammation of eye
5. Gel (topical) for solarkeratoses and musculoskeletal pain
6. Rectal suppositories for post op nausea and pre-emptive analgesia
7. Another preparation is available in combination with misoprostol, used for prevention of gastropathy. In combination, the drug is tolerable for patients of GI ulcers.

Fenoprofen

Causes interstitial nephritis

Flurbiprofen

Propionic acid derivative.

Uses include:

1. Dose of 200-400 mg with aspirin and other in clinical trials for rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, gout.
2. In topical eye drops, prevents intra op miosis
3. For peri op analgesia in nose, ear and neck surgeries (I/V)
4. In lozenge form for sore throat

Adverse Drug Reactions

Cog wheel rigidity

Sulindac

Sulfoxide. Prodrug.

Metabolism:

Metabolized to active sulfide metabolite, undergoes enterohepatic circulation and prolongation of half life.

Uses

1. Rheumatoid arthritis
2. Suppress familial intestinal polyposis
3. May decrease the development of colon, breast and prostate cancers.

Adverse Drug Reactions

1. Stevens Johnson epidermal necrolysis syndrome
2. Thrombocytopenia
3. Agranulocytosis
4. Nephrotic syndrome
5. Increased ALT and AST levels
6. Cholestatic jaundice

Tolmetin

Efficacy is similar to other NSAIDS except that it is ineffective in treatment of gout. Adverse drug reactions include thrombocytopenic purpura.

Tiaprofen

Racemic propionic acid derivative

Half life is 1-2 hours (however in elderly it is 2-4 hours)

It decreases renal uric acid reabsorption leading to hypouricemia

Selective COX-2 inhibitors

COX-2 is constitutive at two places:

1. Brain
2. Kidneys

Not in stomach.

Within therapeutic range, as more selective, chances of GI problems are far less. Benefits are lost at higher dose, as selectivity is lost.

As COX-2 is constitutive in kidneys, chances of renal toxicity in renal compromised or CCF or cirrhosis of liver, as blood flow is then maintained by prostaglandins mediated COX-2. When blocked, there are increased chances.

Uses

Only for anti-inflammatory use, rheumatoid arthritis, ankylosing spondylitis, etc.

No anti-platelet or anti-pyretic actions, chances of stroke and thrombotic events are increased. This is one reason why drugs like Valdecoxib and Roficoxib have been withdrawn.

Celecoxib

10-20 times more selective for COX-2 than COX-1. Adverse drug reactions include:

1. Edema
2. Hypertension
3. Rashes

Celecoxib and warfarin are both metabolized by cyp2c9.

Valdecoxib

Diaryl substituted isoxazole. Used in rheumatoid arthritis and as analgesic (20 mg, twice daily).

Adverse drug reactions include:

1. Increased CVS risks
2. Stevens Johnson syndrome

So withdrawn.

Etoricoxib

Structurally similar to diclofenac, so hepatic functions should be monitored.

Recent drug, use started in 1949. Derivative of phenacitin, use of which has been discontinued because of nephrotoxicity. This drug is relatively free of toxicity.

Chemically it is acetaminophen.

1. Acetyl,
2. amino radical and
3. benzene rings are present.

Antipyretic action is present because of anime benzene ring.

Mechanism of Action

It is a good antipyretic and analgesic. Mechanisms are same, it blocks prostaglandins synthesis.

1. Anti-inflammatory action is very weak. The reason is that at site of inflammation super oxides, hydrogen peroxide and oxidative radicals are present, in presence of which actions of paracetamol are absent or very weak due to:

• Inability to inhibit COX
• Does not suppress phagocytes directly (immunologic process)
• More effective COX-3 inhibitor

2. All other additional effects like suppression of neutrophils and interleukin production are not present.
3. Antipyretic due to amino benzene ring
4. Inhibition of COX-3, a splice variant of COX-1 found in CNS
5. Analgesic

Thus cannot be used for treatment of rheumatoid arthritis, ankylosing spondylitis, also cannot be used for gout.

Pharmacological Actions

1. No effect on respiration
2. No adverse effect on cardiovascular system
3. GIT- less chances of GIT damage
4. Paracetamol can be used preferentially in cases of GI ulceration
5. No effect on uric acid excretion
6. All metabolic actions seen with aspirin are not present.
7. CNS –devoid of salicylism

It is thus a very safe drug, this being the reason for popularity.

Pharmacokinetics

Well absorbed orally (as opposed to aspirin)

Plasma protein binding is low 50%

Main importance is of metabolism, which may take place in liver,

1. about 60% drug glucuronide conjugation
2. 30% sulphate conjugation
3. 3% cysteine conjugation
4. 1-2% N-hydroxylation (phase I reaction)

As a result of N-hydroxylation, converted into N-acetyl benzoquinoneimine

Normal range of 4-5 g/day dose is handled by hepatic glutathione, which converts it into mercapturic acid, which is non-toxic and easily excreted.

When person ingests toxic amounts of 10-15 g/day (1 tablet 500 mg, more than 20 tablets) this 1-2% N-hydroxylation production of toxic radical is increased. Sulfhydryl groups of glutathione are overwhelmed, leading to reaction with sulfhydryl groups, producing damage and centrilobular hepatic necrosis.

Reports indicate that in some individuals, esp. chronic alcohol intake, can be toxic even at 4-5 g/day.

Signs and symptoms of hepatotoxicity

If the person does not give history, the diagnosis becomes difficult.

1. Nausea
2. Vomiting
3. Anorexio abdominal pain (acute gastroenteritis symptoms)
4. After 24-48 hrs hepatocellular damage, jaundice, increased ALT, AST, increased prothrombin time

Biochemical markers start rising within 4-15 hours.

Treatment

1. If person is received within 4 hours, gastric lavage
2. Specific antidote for paracetamol poisoning is N-acetyl cysteine which has sulfhydryl groups in structure, which alternate the suphydral groups for detoxification. Liver enzymes regenerate glutathione, within 8-12 hours.
3. Other supportive measures include acid base balance, cardiac and respiratory support, etc.

Therapeutic Uses

Very good drug when used for anti-pyretic actions and as analgesic.

It is the drug of choice in children as no Reye’s syndrome is associated.

Adverse effects

Very safe drug, until toxic doses are taken (hepatotoxic).

	Aspirin	Paracetamol
Chemistry	Salicylate	P-amino phenol derivative
Anti-inflammatory	Yes	No
Anti-platelet	Yes	No
COX-1 inhibition	Peripherally	Centrally
COX-3 inhibition	No	Yes (in CNS)
Kinetics	Above 600mg- 0 orderBelow 600mg -1st order	1st order
Metabolism
Half life	15 minutes	2-3 hours
Tablet weight	300 mg	500 mg
Toxic metabolite	No	N-acetyl benzoquinonimum
Centrilobular hepatocellular damage	No	Yes
Reye’s syndrome	Yes	No
Salicylism and cinchonism	Yes	No
GI bleeding	More risk	Less risk

Aspirin is a prototypical drug. Although so many newer drug are available, but it is still the most commonly used drug as analgesic and anti-platelet.

Glamour is not associated with aspirin, as is easily available and has been in use for such a long time.

Chemistry

Derivative of salicylic acid. Acetyl radical is attached. Salicylic acid itself is very irritant. Acetyl radical increases the oral use is improved. They have actions by virtue of salicylic acid, which inhibits COX. Acetyl radical gives extra properties:

1. Acetyl radical acetylates certain sites on COX enzyme. Other members reversibly inhibit the enzyme while aspirin does it irreversible. Every tissue will have to resynthesize enzyme before activity returns. Every tissue resynthesizes at different rates, depending on protein synthesis.
2. Platelets are anucleated and have no ability to synthesize proteins, thus proteins of the whole batch cannot aggregate

Aspirin is the only drug of this group used as anti-platelet.

Paracetamol etc. only reversibly inhibit the COX enzyme.

Mechanism of Action

1. Anti-inflammatory

Anti-inflammatory effect is seen only at very high doses, at 4-5 g/day. Ordinary tablet only contains 300 mg, thus if 15 tablets are taken.

It inhibits cyco-oxygenase, prostaglandins and prostacyclines and also directly:

• Interferes with kinin system
• Cause direct immunological suppression
• Inhibits movement of neutrophils
• Causes modification of ground substance of connective tissue, thus infection cannot spread.

2. Anti-pyretic action

At dose of 300-600 mg, every 4-6 hours (1-2 tablets).

3. Analgesic action

300-600 mg –same as anti-pyretic, enough to alleviate mild to moderate pain.

Therapeutic uses

1. Respiration

a. At normal dose

Produces direct and indirect effect on respiration:

1. Direct action –crosses BBB and stimulates respiratory center in medulla
2. Indirect action –produces uncoupling of oxidative phosphorylation, process which yields ATP (1g glucose yields 38 ATP), thus oxidative phosphorylation stops. Lot of carbon dioxide is produced, which stimulates the respiratory center.

This leads to an increase in rate and depth of respiration, leading to hyperventilation, which increases carbon dioxide washout from lungs, leading to respiratory alkalosis.

This is initially partially compensated by increase in bicarbonates loss along with sodium and potassium, thus electrolyte imbalance occurs.

b.    When drug is consumed in toxic dose

Suppression of respiratory and vasomotor center occurs, leading to respiratory acidosis and circulatory collapse.

2. CVS

In normal doses (300-600 mg 4-6 hours) hardly affect CVS.

At high doses, produce direct vasodilatation due to relaxation of smooth muscles.

At toxic doses, suppression of vasomotor center occurs, leading to circulatory collapse and shock due to: a. vasomotor center action b. vasodilatation

At low doses

75-150 mg/day are given for prevention of IHD. At this dose, platelet aggregation is inhibited, but has no effect on prostaglandins and prostacyclines.

• One one hand, low dose is less irritant to stomach mucosa
• Beneficial effects of prostaglandins and prostacyclines are not lost as we want to produce vasodilatation.
• Only thromboxane A2 is inhibited.

TIA (Transient ischemic attack)

Micro thrombi arise in heart, and enter brain, where they cause stroke for only few moments, then the person recovers. Low dose aspirin is also used because:

1. Irreversibly inhibits
2. High dose also inhibits prostaglandins and prostacyclines

3. GIT

Aspirin induced gastropathy

Aspirin is acidic and irritant to gastric mucosa, producing nausea, vomiting at low to normal doses.

At higher doses also stimulates the CTZ, leading to more vomiting.

The symptoms start from

1. nausea and vomiting
2. abdominal discomfort
3. abdominal pain
4. dyspepsia
5. feeling of indigestion
6. ulceration (frank ulcers
7. perforation and hemorrhage of GIT)
8. Decrease production of prostaglandins and prostacyclines under COX 1, which is constitutive in stomach, leading to decrease in production of mucous rich in bicarbonates, increasing acid production and decreasing blood flow.
9. Also inhibit platelet aggregation

Thus chances of gastropathy increases.

Prevention

• Not to take aspirin on empty stomach
• Avoid NSAIDS which are notorious, use paracetamol, which is safer
• Combine NSAIDS with PG analogs like misoprostol, thus useful effects are not lost; as NSAIDS inhibit production of PG, or give already prepared PG.
• Proton pump inhibitors can be combined with aspirin.

4. Effects on liver

At normal dose has minimal effect. High dose if used for longer time leads to hepatocellular damage, leading to increased levels of transaminases (ALT and AST).

It should not be used in children below 20 years of age. There has been increased incidence of Reye’s syndrome, leading to hepatic encephalopathy, damage, coma and death, when used in viral infections (measles, mumps, rubella, etc.)

Thus should refrain in every case.

Paracetamol and ibuprofen are safer.

Till 1986, aspirin was available as baby aspirin, but lots of deaths occurred, and has now been withdrawn.

5. Effects on kidneys

Normally aspirin has no effect. In certain conditions auto regulation of blood occurs under prostaglandins influence. This auto regulation is seen in cases of hypovolemia (either blood loss or third space hypovolemia).

In CCF, cirrhosis of liver, nephrotic syndrome, where auto regulation of blood flow is protective for the kidneys under prostaglandins influence, can lead to kidney failure due to inhibition.

Uricosuric effect

Effects vary in low and high doses.

1. Acid which is synthesized due to purine metabolism is excreted in kidneys at proximal convoluted tubules in S2 by active transport. This transporter also transports all other acids as well.
2. Also reabsorbed in proximal convoluted tubules.

At low doses

Secretion is inhibited by competitive inhibition. This decreases uric acid excretion, leading to hyperuricemia and precipitation of gout.

At high doses

Reabsorption is blocked, leading to increased excretion, known as uricosuric effect, which promotes uric acid excretion.

Aspirin is not used in treatment of gout.

6. Metabolic effects

Effects are dose related. At higher doses for longer periods, uncoupling of oxidative phosphorylation occurs, thus ATP is produced by anaerobic glycolysis. Accumulation of acetic acid, pyruvic acid and lactic acid occurs.

1. Aspirin is itself acidic
2. Increased accumulation of these acids can lead to metabolic acidosis

These reactions in which ATP is produced are not energy efficient, thus lot of heat is produced.

Aspirin causes increased sweating at higher doses, and can lead to hyperpyrexia.

Effect on carbohydrate metabolism

Higher doses cause increased epinephrine, increased glycogenolysis in muscles, leading to hyperglycemia.

Effects on protein metabolisms

High doses increase cortisol, which increases the metabolism of proteins, leading to aminoacid urea.

Effects on fat metabolism

Increase release of free fatty acids.

7. Effects on pregnancy

• Inhibition of prostaglandin synthesis can lead to increased period of gestation
• Anti-platelet action promotes antepartum and post partum hemorrhage
• Mother taking normal doses of aspirin over prolonged periods during pregnancy has low birth weight babies.
• No teratogenicity is known.

8. Effects on CNS

CNS effects are seen only in very high doses, also known as Salicylism. Symptoms include:

1. Nausea
2. Vomiting
3. Tinnitus
4. Vertigo
5. Blurred vision
6. Hearing deficiency
7. Confusion

By virtue of high doses of aspirin.

Similar symptoms also occur with quinine, known as cinchonism.

Pharmacokinetics

Absorption occurs from stomach as is acidic. Quantitatively greater is absorbed from upper part of small intestine, due to greater absorptive area.

Distribution is wide and is excessively plasma protein bound, thus can displace oral anticoagulents, etc.

Metabolism is dose related.

1. Below 600 mg/day aspirin shows 1^st order kinetics.
2. Above 600 mg/day rate of metabolism shows zero order kinetics.

Some is metabolized by glucuronidation.

Mostly is conjugated to glycine, producing salicyl uric acid.

1% of drug is converted to gentisic acid.

Excretion

1. Some is excreted as glucuronide conjugates
2. 75% as salicyl acid urea
3. 10% is excreted unchanged
4. 1% as gentisic acid.

Clinical Uses

Therapeutic uses are dose related.

1. Use as analgesic

Analgesic dose is 300-600 mg (1 to 2 tablets) every 4-6 hours. Used for:

1. Mild to moderate pain
2. Myalgia
3. Arthralgia
4. Neuralgia
5. Tooth ache
6. Head ache

The treatment is symptomatic

2. Anti pyretic

At dose of 300-600 mg, every 4-6 hours (1-2 tablets). Although out of favor as paracetamol is used, but still used as easily available.

3. Arthritis

Given in a dose of 4-5 g/day (acids accumulate adding to metabolic acidosis). Also used for:

1. Non-inflammatory arthritis
2. Osteoarthritis

It is also used in rheumatic fever. Aspirin is not usually given to children (Reye’s syndrome) but still used as drug of choice in children of rheumatic fever.

4. Anti platelet use

Dose is 75-150 mg/day. At this dose irreversibly blocks the cyclooxygenase enzyme. Thus they are knocked out for 8-11 days.

• This is used for treatment of heart diseases (TIA).
• Also used as anti platelet after bypass surgery
• Angioplasty
• Angiography

5. Primary dysmenorrhea

As blocks synthesis of prostaglandins

6. Bartter’s syndrome

Exact etiology is not known. There is hypokalemia, hyperrenninemia, hyperaldosteronism, despite normotension.

It is a congenital disease normally diagnosed early, and results from defect in ascending thick limb. The reabsorption of sodium cannot take place. More reaches the distal portion, increased loss of potassium occurs, leading to alkalosis. One of the effects is prostaglandin mediated, the hyperplasia of JG apparatus.

Aspirin is part of treatment, along with spironolactone, ACE inhibitors and potassium.

Aspirin can reverse the hyperplasia of JG cells.

Why normotension?

No vasoconstriction occurs, although increase in angiotensin I and II occurs, but prostaglandins produce vasodilatation. The disease is characterized by:

1. Polyuria
2. Polydipsia
3. Retardation of growth both neurological and physical

Minor Uses

1. In low dose used for prevention of colonic cancer
2. In low dose, used for prevention of eclampsia and pre-eclampsia.
3. Can be combined with a sulpha drug (sulpha salizine) for inflammatory bowel disease and ulcerative colitis.
4. Niacin therapy; given to hyperlipidemics causing decreased cholesterol, preventing IHD. But it causes PGD2 synthesis, resulting in vasodilatation of skin vessels, causing intense flushing. So aspirin is used, which decreases PG synthesis

Adverse effects and toxicity

These are dose related.

Normal dose

Produces antiplatelet, analgesic and anti pyretic actions.

1. Gastric intolerance
2. GI bleeding
3. Hypersensitivity
4. Impaired homeostasis –antiplatelet action
5. Reye’s syndrome esp. in measles, chicken pox

Mild toxic dose

1. Effects CNS –Salicylism

2. Tinnitus, vertigo, impaired hearing, psychosis

It is thought to be because of pressure on cochlear cells by constriction of labyrinthine vessels in ear

3. Hyperventilation –direct and indirect stimulation

4. Respiratory alkalosis

Moderate toxic dose

1. Leads to uncoupling of oxidative phosphorylation
2. Accumulation of acids –pyruvic, lactic
3. Metabolic acidosis

Excessively toxic dose

Vasomotor and respiratory collapse.

1. Toxic itself, causes fever, uncoupling of phosphorylation which is met by processes producing excessive heat.
2. Dehydration, leading to fever

Severe toxic dose

1. Comma
2. Vasomotor collapse

Lethal

1. Renal failure
2. Respiratory failure

150-175 mg/kg body weight can be fatal. Has no specific antidote, only supportive measures like

a. gastric lavage

b. treating dehydration

c. monitoring acid base balance

d. sponging, to reduce fever

e. alkalization of urine

f. enhance excretion of aspirin

There has been purposeful effort to differentiate these from glucocorticoids, as glucocorticoids are the ultimate answer but with huge side effects, as each and every cell is affected.

These drugs are differentiated because they are also anti-inflammatory, but lack some of the side effects of glucocorticoids.

NSAIDS are also known as non-opioid analgesics. Pain is the most common symptom for which a person comes to the doctor, fever being the second. Both can be treated by this group, so referred to as the non-opioid analgesics.

They are also anti-pyretic, also known as non-narcotic analgesics, due to the fact that dependence may occur with other analgesics.

They are also known as aspirin like drugs, as aspirin is the first drug in the group discovered.

History

Aspirin was the first drug discovered. Willow tree bark was used for pain relieving effect from the time of Hippocrates, but in 1753 a British clergyman, Raven Admin Steve first wrote about powdered form of bark of Willow tree used for pain, fever and arthritic pain.

Salicylic acid is irritant and difficult to take orally. Hoffmann, a German in 1899, manufactured acetyl salicylic acid (aspirin –a from acetyl and spiria is a plant). Ever since it is being used continuously. Newer uses are being discovered every few years, thus“aspirin a hundred years young”. Every new drug discovered is compared with aspirin.

Cyclo-oxygenase enzyme-isoforms

Classification is based on the mechanism of action. It is known that this group inhibits cyclo-oxygenase enzyme. There are three isoforms:

1. COX-1
2. COX-2
3. COX-3
4. COX-1 

• homeostatic enzyme which tries to keep internal conditions constant
• constitutive –present in active form in blood, stomach and kidneys, performing important functions

I. Blood

Under influence of prostaglandins, prostacyclines and thromboxanes (most powerful substance to cause platelet aggregation, which is the first step in injury to micro vessels to control bleeding).

II. Stomach

Helps in formation of prostaglandins and prostacyclines, which:

i.            On one hand inhibit acid production
ii.            Increase mucous production rich in bicarbonates, which is protective
iii.            Increase blood flow to stomach mucosa and epithelial cells to speed up reconstitution process.

III. Kidneys

In certain cases, auto regulation of blood in kidneys takes place under influence of prostaglandins, which themselves are under influence of cyclo-oxygenase 1.

2. COX-2  inducible (constitutive in kidneys and brain)

Not present in active form but in inducible form. There are two places where it is constitutive (brain and kidneys). Otherwise induced by

1) Oxidative stress

2) Injury

3) Ischemia

4) Seizures

5) Neuro-degenerative disorders

COX-2 is responsible mainly for inflammation.

3. COX-3

Only present within brain.

Classification

Classification is based on inhibition of COX, either non-selectively or selectively.

Drugs are chemically different, but have the same mechanism of action.

Non selective cyclo-oxygenase inhibitors

Salicylates

• Aspirin
• Sodium salicylate
• Diflunisal,
• Choline magnesium trisalicylate

Para amino phenol derivatives

• Paracetamol (acetaminophen)

Propionic acid derivatives

• Ibuprofen
• Ketoprofen
• Flurbiprofen
• Naproxen,
• Fenoprofen

Phenyl acetic acid derivatives

• Diclofenac
• Tolmetin
• Ketorolac

Fenamates (anthranilic acid derivatives)

• Mefenamic acid
• Meclofenamic acid

Indole derivatives

• Indomethacin
• Sulindac

Enolic acid derivatives

• Piroxicam
• Tenoxican

Alkanone derivatives

• Nabumetone

 Pyrazolone derivatives

• Azapropazone
• Phenylbutazone

Cyclo-oxygenase-2 selective inhibitors

• Celecoxib
• Etoricoxib
• Parecoxib
• Lumaricoxib
• Meloxicam
• Etodolac
• Nimesulide
• Valdecoxib – ? Is associated with increased risk of cardiovascular thrombotic events and stroke so is withdrawn from market.

Inflammation

Definition?

Inflammation is the response of vascular and supporting tissue to injury. There are three phases:

1. Acute inflammation

Increased permeability leads to outpouring from vessels, leading to edema and release of various mediators:

• Histamine
• serotonin
• bradykinin
• prostaglandins
• leukotrines

In an effort to control foreign body (offending agent) to wall it off.

2. Immune response

Neutrophils and lymphocytes try to control the infection, if controlled inflammation is over.

• Prostaglandins
• Leukotrines
• Complement system c5a are involved

3. Chronic inflammation

If infection cannot be controlled, it leads to chronic inflammation. Residual damage takes place e.g. rheumatoid arthritis-damage to joints, synovial membranes. Mediators are different:

• interleukins
• granulocyte-macrophage
  stimulating factor (GM-CSF)
• tumor necrosis factors (TNF)
• interferons
• platelet derived factors

During inflammation, lot more mediators are released apart from prostaglandins and prostacyclines. Even if they are inhibited, others act as well. Drug has to do more than just inhibiting prostaglandins and prostacyclines.

Whenever disruption of cell membrane occurs, phospholipids are exposed, which are acted upon by phospholipase A2. This converts them to arachidonic acid, which can be processed by:

1. Cyclo-oxygenase pathway, producing prostaglandins, prostacyclines and thromboxanes.
2. Lipo-oxygenase pathway, producing leukotrines

Mechanism of action

1. Anti – inflammatory action

NSAIDS block enzyme cyclo-oxygenase, thus no thromboxanes, prostacyclines or prostaglandins are produced.

Had this been the only mechanism, anti-inflammatory effect would be incomplete. Inside into other mechanisms is rather patchy.

• NSAIDS directly suppress phagocytic system and neutrophils.
• NSAIDS directly suppress migration of neutrophils
• NSAIDS directly suppress production of interleukins
• NSAIDS inhibit the production of superoxides, peroxides and radicles involved in cell damage.

2. Anti – pyretic action

Hypothalamus controls temperature in the body. There are two areas:

• Heat promoting area or the posterior hypothalamus
• Heat losing center or the anterior hypothalamus

Mechanism of heat regulation

Antipyretic Action

NSAIDS block the production of prostaglandins, which are responsible for resetting the hypothalamus at a higher level. Thus they reset the hypothalamus back to normal, promoting heat losing mechanisms.

3. Analgesic action

Shared uses of NSAIDS

1. Analgesics

Helpful in controlling mild to moderate pain including

1. Myalgia
2. Headache
3. Dental pain
4. Arthralgia
5. Neuralgia
6. Muscle spasm or sprains.

Severe pain is controlled by opioids

2. Anti – pyretics

All members do have anti-pyretic actions. Few are used including:

• Paracetamol
• Mefenamic acid
• Ibuprofen

3. Anti – inflammatory

Used in conditions like:

• Rheumatoid arthritis
• Osteoarthritis
• Acute gout
• Ankylosing spondylitiss

4. Dysmenorrhea

Painful menstruation is due to prostaglandin production, which can be inhibited by this group.

Side – effects

1. GIT bleeding

Stomach has important protective mechanism controlled by prostaglandins and prostacyclines:

1. Production of mucous rich in bicarbonates.
2. Decrease in acid production
3. Increase in blood flow to stomach mucosa, helping in repair under control of prostaglandins and prostacyclines, as block production so protective mechanisms are lost.

Wide range of symptoms occur which used chronically including:

• Dyspepsia –mildest form
• GI ulcers –severest form, may bleed and become life threatening.

2. Prolonged gestation

Can prolong gestation, especially in last trimester of pregnancy. At time of parturition, there is role of prostaglandins, prostacyclines, as their production is blocked, so there is no parturition.

Also increase the incidence of post maturity.

3. Inhibition of PG mediated renal blood flow

in normal role of PG is not that important, but in certain conditions, like chronic renal failure, cirrhosis of liver, CCF, when blood flow is compromised, PG play important role in auto regulation of renal blood flow.

As PG are inhibited, result is worsening of renal functions.

4. Blockage of platelet aggregation

Thromboxane A2 is inhibited by COX, so aggregation does not take place. This is made use of in the use of low dose aspirin in ischemic heart disease. This can promote bleeding (e.g. from stomach ulcers). Here the side effect is used as therapeutic use.

5. Hypersensitivity reactions

Arachidonic acid has two pathways. When COX is inhibited, lipo-oxygenases and leukotrines are responsible for allergic reactions.

These include:

1. simple articaria
2. angioedema
3. bronchoconstriction
4. asthma
5. anaphylactic reaction –rarely

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Aspirin

Paracetamol

Important Non Steroidal Anti Inflammatory Drugs

Opioid antagonists have no effect when administered alone. When given after a dose of agonist they promptly reverse all of the action of the agonist.
Mu receptor antagonist predominantly but affect all receptors.
Naloxone is the drug of choice for opioid overdose.
In addicts antagonist rapidly reverses the effect of agonists such as heroin & precipitate the symptoms of withdrawal

Alvimopam is modified analogue of Naloxone, given orally or parentally.

It selectively inhibits peripheral mu receptors, with minimum CNS penetration

Used in post op (bowel resection surgery problem of paralytic ileus). It is used because has no CNS action, only localized mu receptors. Selectively GIT peripheral receptors are blocked.

Naloxone

• Reverses the coma& respiratory depression of opioid overdose, within 5 minute of I/V administration respiratory depression is reversed, patients is revived.
• Competitive antagonist at µ, K,d receptors. High affinity for  µ receptors

Methyl naltrexone bromide

Is effective orally and is long acting. It is a selective analog devoid of side effects, esp. constipation in terminally ill, seriously advanced diseases.

It is used in addicts’ maintenance programmes, decreasing craving for drug. Baseline beta endorphins increase also decreases alcohol craving.

Uses of Opioid Antagonists

1. Opioid induced toxicity
2. Diagnose physical dependence in those on opioids. If denial or not apparent, precipitation of severe withdrawal syndrome by giving.
3. Treatment of compulsive opioid users

Therapeutically:

1. Neonatal respiratory depression, to overcome if morphine, pethidine used. Although does not cause but may lead to respiratory depression.
2. Patients of septic shock –naloxone is especially used where opioid peptides are released due to stress causing hypotension.

Meperidine (Pethidine)

Common name is pethidine. It is a synthetic drug.

Is less potent than morphine, binds to kappa receptor.

Given parentally, hepatic oxidation converts it into active metabolite, normepridine, which may cause seizures.

Less spasmogenic has no cough suppressive ability.

Meperidine is used in obstetrics. Unlike morphine, meperidine produces no respiratory depression in the fetus.

It does not release histamine, thus hypotension is less.

Side effects                                                                                 

Related to morphine sedation.

1. Antimuscarinic/vagolytic actions
2. Nausea and vomiting
3. Atropine like effects (stimulant action initially) less, less miosis and constipation. Causes tachycardia.
4. Mydriasis occurs in over dosage
5. Excitation, hallucinations, tremors, delirium, seizures.
6. Dryness of mouth, myoclonus because of excitation, unpleasant dreams

Contraindications

Morphine is contraindicated in pregnancy but pethidine can be given.

Contraindicated in patients of tachycardia

	Morphine	Pethidine
Source	Natural	Synthetic
Chemistry	Phenanthrene	Phenyl piperidine
MAO	µ agonist	µ agonist and anticholinergic
Potency	10 times potent	Less potent
Pharmacological actions	Powerful analgesicMiosisCough suppression	Less powerfulMydriasisNo cough suppression
Respiratory effects	Severe depressionbronchoconstriction	LessBrochodilation
Anticholinergic actions	No anticholinergic effectSpasmogenicUrinary retentionAntidiarrheal/constipation	Possesses effectsSpasmolyticNoneNone
Uses	Severe visceral pain, MIAntidiarrheal	Moderate visceral pain, not MIRenal/biliary colicObstetrics
Dose	10-20 mg	25-100 mg
ADRs	ToleranceReleases histaminesPostpartum hemorrhage	Less toleranceLess releaseNone
Pharmacokinetics	I/M	I/M or I/V

Fentanyl:

Is highly lipid soluble and 80 times more potent than morphine, has short duration of action. It is used in anesthesia or as transdermal patch.

It also undergoes hepatic oxidation. 1^st pass metabolism occurs in intestinal walls.

Drawback

Trunkal rigidity may occur –remifentanil, sufentanil even morphine

Increase in tone of large muscles, mediated at supraspinal level.

If drug is used in surgical anesthesia, thoracic compliance is reduced, interfering with ventilation.

Naloxone is not given, as have to maintain analgesia. Give cortical acting agent as we want to maintain analgesia.

Sufentanil and alfentanil are metabolized in liver.

Ramifentanil is metabolized by tissue esterases, also heroin (diacetyl morphine)

Partial agonists

Nalbuphine is given I/V and is very potent.

Pentazocine is commonly used along with others.

Buterphenol is weak partial agonist.

Pentazocine

Pentazocine is psychomimetic on kappa receptors, producing dysphoria. Although has very low dependence, but has potential. Effective potency is 20 times less. When combined with NSAIDS, hemodynamic actions occur leading to increased arterial blood pressure and heart load, with chances of tachycardia.

Not used for left ventricular failure. Other actions are less nausea and vomiting, less constipation and less miosis.

Adverse effects

If used continuously:

1. Psychomimetic effects –hallucinations, unpleasant dreams
2. No euphoria but dysphoria
3. Can precipitate acute withdrawal symptoms in addicts

Nalbuphine

More potent than pentazocine with similar actions. Side effects are less. Hemodynamic effects are negligible. Analgesia occurs within 15 minutes.

Methadone

Weak long acting drug.

Is used in the treatment of patients addicted to opioids (heroin).

• The idea behind methadone treatment is to replace the addict’s heroin with an orally active agonist that has a long duration of action.
• This reduces drug craving & prevents symptoms of withdrawal.

Introduction

• Analgesia means insensibility to pain. Drugs used in management of pain are known as analgesics.
• Pain serves the useful function of alerting an individual that some component of physiological system has gone awry.
• Pain is most effectively treated by removal of underlying cause.
• Physician is often faced with the necessity for treating pain as a symptom
• Pain can be divided into acute & chronic

1. Chronic pain can endure long after healing.
2. Acute pain is directly related to  a noxious stimulus

• Pain is due to the release of prostaglandins, substance P and bradykinin, which contribute to pain.
• Acute pain has two components:

1. Phasic
2. Tonic components

Phasic pain is produced by the presence of a noxious stimulus

It is superficial pain and involves skin Produces intense sharp sensation. It is transmitted through, fast conducting myelinated A-delta fibers

Tonic pain is evoked by tissue damage occurring in the skin or in the viscera, gradual onset than phasic pain, dull throbbing aching pain. It is conducted through the unmyelinated slow conducting C-fiber pathways.

• Drugs can alter pain experienced in several ways. Pain is sensation, perception and has emotional aspect as well.
• Pain is not a single entity; it is pain of the entire inflammatory process and one of the clinical signs of inflammation.
• Pain can be described as Acute or chronic and associated with malignant disease or chronic and not associated with malignant disease.
• The duration of acute pain is usually hours to days while the chronic pain can last for months to years and have associated problems of depression and anxiety.

• Drugs may act as analgesics by altering either sensational or emotional aspects of pain. Adjuvant drugs are also used like hypnotics, antidepressants to reduce anxiety and depression.
• Oral pain is associated with pulpitis, periodontitis, abscesses, temporomandibular disorders (TMDs) and masticatory muscle disorder. Dental procedure also can have pain.
• Pain inducing substances can be produced and released from cell membranes by trauma, (e.g. mechanical trauma to the soft tissues and bone during periodontal surgery), infection and allergenic reactions.
• The majority of dental pain is an acute response to inflammation, usually managed pharmacologically.
• For moderate pain that is not relieved by NSAIDs, opioid analgesics are the agents of choice. Opioids alter the patients perception of the pain in the brain.
• Combined use of a NSAIDs with an opioid produces a synergistic effect so that a lower dose of opioid can be used.
• Opioids alone are not prescribed for the management of acute dental pain because to high a dose would be needed. The adverse side effects would not be acceptable.
• Analgesics are divided as those

1. Acting on the CNS i.e. Opioids.
2. Acting peripherally – NSAIDs

Nociceptors: are specialized sensory nerve endings, which when stimulated may lead to the sensation of pain

Pain may be of visceral or somatic type:

Visceral pain arises from viscera is dull and less localized. It is treated by opioid analgesic

Somatic pain arises from musculoskeletal organs, skin and muscle, it is localized & sharp & is treated by NSAIDS

Opioids act at CNS and alter the patient’s perception. They are used in severe types of pain. They alter perception, intensity and have emotional effects as well. They are obtained from natural source, opium poppy.

Opium has two series of alkaloids:

1. Phenanthrene
2. Benzyl isoquinaline

Opioid drugs mimic the actions of 03 peptide families in the brain, known as:

1. Endorphins
2. Enkephalins
3. Dynorphins

The peptides along with non-opioids peptides are cleaved from the protein precursors

– Pro-opiomelanocortin (POMC)

– Proenkephalin

– Prodynorphins

Papaverine is a vasodilator

Noscapine is cough suppressant and does not has analgesic property.

Types of receptors

1. Mu (µ)-most actions mediated
2. Kappa
3. Sigma
4. Delta
5. Epsilon
6. Mu receptors

These are responsible for pharmacological actions of morphine.

• Respiratory depression, sedation is produced, slowed GI+  transit
• Modulation of hormone and neurotransmitter release.
• Supraspinal and spinal analgesia.

2. Kappa receptors

• Produce supraspinal and spinal analgesia
• Contribute to psychomimetic action
• Slowed GI Transit time

3. Delta receptors

• Supraspinal and spinal analgesia
• Modulation of hormone and neurotransmitter release.

ORI-I

Orphanin opioid-receptor like subtype-I, which is an endogenous receptor.

Mechanism of action

1. Opioid receptors are located on primary afferents and spinal cord pain transmission neurons (Ascending pathways).
2. On neurons in the mid brain and medulla (descending pathway) that function in pain modulation.
3. Opioid receptors involved in altering reactivity to pain are located on neurons in the basal ganglia, the hypothalamus, limbic structures and the cerebral cortex.
4. Opioid analgesic inhibit synaptic activity through direct activation of opioid receptors and partly through release of the endogenous opioid peptides.
5. Opioid receptor are coupled to their effectors by G proteins and activate phospholipase C or inhibit adenyl cyclase
6. At the postsynaptic level, activation of these receptors can open K+ ion  channels to cause membrane hyperpolarization (inhibitory postsynaptic potential)
7. At the presynaptic level, opioid receptor activation can close voltage gated Ca++ ion channels  to inhibit neurotransmitter release
8. Presynaptic actions result in the inhibition of release of multiple neurotransmitter (Ach, NE, 5HT, glutamate & substance-P)

Chemical classification

Phenanthrene Alkaloids of Opium

• Morphine,
• Codeine

Semisynthetic Alkaloids of Opium

• Hydrocodone,
• Oxycodone,
• Buprenorphine

Totally Synthetic

Phenanthrene Derivatives

• Tramadol (dependence, tolerance not seen as with others)

Phenylpiperidines

• Meperidine (Pethidine)
• Fentanyl,
• Sufentanil,
• Alfentanil
• Remifentanil

Morphinan Derivatives

• Levorphanol,
• Butorphanol

Phenylheptylamine Derivatives

• Methadone,
• Levomethadyl Acetate,
• Propoxyphene

Benzoprophan Derivatives,

• Pentazocine

Opioid Agonists

• Morphine
• Codeine
• Hydrocodone
• Oxycodone
• Levorphanol
• Meperidine
• Methadone
• Levomethadyl Acetate
• Fentanyl
• Sufentanil
• Alfentanil
• Remifentanil

Partial Agonist (Mixed Agonist/Antagonist)

• Buprenorphine
• Butorphanol
• Pentazocine

Antagonists

• Naloxone (parenteral)
• Naltrexone (oral, parenteral)
• Nalmefene

Pharmacological Actions Of Opioids

Morphine is the prototype agonist.

Predominantly act on CNS and GIT. Alter pain perception in CNS.

1. CNS

Both depression and stimulation of CNS occurs.
– Analgesia/sedation (improve perception to pain, pain not felt both at spinal and supraspinal level, reduce substance P from afferent neurons
– Euphoria with rapid I/V injection
– Respiratory depression –decrease rate and depth of tidal volume, hypoxic drive is depressed
– Depression of Cough reflex

Calming effect, mental clouding, unable to concentrate

Vasomotor center is depressed, leading to bradycardia

Usual dose is 10 mg subcutaneous or I/M.

I/V 3-4 mg

Oral absorption is erratic.

2. Eye

Miosis by a direct action in the brain nucleus of the oculomotor nerve (edinger-westphal). Classic pinpoint pupil is important diagnostically.

Morphine if applied locally produces no mitotic effect. No tolerance develops to mitotic effect of opioids.

3. Emesis

Morphine directly stimulates CTZ in the area postrema that causes vomiting..

4. CVS

– Morphine has no effect at therapeutic doses. Large doses cause hypotension bradycardia.(because of histamine and vagal stimulation)

– Because of respiratory depression and Co₂ retention, cerebral vessels dilate and increase (CSF) pressure.

Not administered to those with head injury because of CO2 retention.

5. GIT

Morphine increases the resting tone of the smooth muscle of the entire GI tract.

This result in a decrease in the movement of stomach and intestinal contents increase tone of the anal sphincter.

Spasm and constipation

Spasm of the smooth muscle of the biliary tract increases pressure, which may lead to biliary colic. Other drugs are used in biliary colic due to increased tone of sphincter of Odii and increase in pressure

6. Genitourinary System

In elderly, increase in tone and spasm of the smooth muscle. This can lead to urinary retention.

Hyperglycemia is due to central sympathetic stimulation in increased doses.

7. Histamine Release

Morphine releases histamine from mast-cell causing urticaria, sweating and vasodilatation. May lead to bronchoconstriction as well.

8. Temperature

µ receptor agonists act on anterior hypothalamus, producing hyperthermia.

Action on kappa receptors causes hypothermia.

In over dosage, there is always subnormal temperature, due to:

1. Increased sweating
2. Kappa activation

Clinical Uses

1. Analgesia

          Morphine, Fentanyl

In cardiac and asthmatic patients.

• Cancer pains
• Pain of MI
• Obstetric labour
• Renal and biliary colic
• Post operative pain

2. Cough suppression

Codeine, Dextromethorphan

3. Treatment of diarrhoea

Diphenoxylate, loperamide

Diphenoxylate is given with atropine, not as anti-spasmodic, but in small quantity to prevent abuse liability.

However, opioid analgesics are not used in bacterial diarrhoea, because diphenoxylate decrease GI mobility, stopping diarrhoea but increasing the absorption of toxins.

Also not used in children, producing post diarrheal dilation ileus.

4. Management of acute pulmonary edema

Morphine given along with furosemides and oxygen.

Mechanism is:

1. Anxiolytic effect –decreases perception of shortness of breath
2. Decreases preload and after load, it directs pulmonary blood to periphery.

5. Anaesthesia

Morphine, Fentanyl (preanesthetic)

• Preanesthetic medication
• Intra op in combination with other aesthetic agents
• Mostly used in cardiovascular surgeries and those in which minimum CVS suppression is required
• As regional anaesthesia in epidural and subarachnoid spaces.

6. Shivering

Meperidine causes alpha 2 activation in CNS, decreasing shivering.

Opioid dependence

Main problem is development of tolerance and dependence. Tolerance does not develop in therapeutic dose, but only when withdrawn abruptly. Reason being adaptive changes at cellular levels.

Methadone is weak long acting agonist; chances of withdrawal symptoms are less.

Routes of Administration

1. Rectal suppositories- Morphine, Hydromorphone
2. Transdermal patch– Fentanyl
3. Intranasal————  Butorphanol
4. Buccal—————– Fentanyl citrate, Buprenorphine (mixed agonist and antagonist, cannot be antagonized by naloxone so not used)

Morphine and hydromorphine are given orally or parentally, rectal suppositories are also available.

Respiratory depression is the most serious complication of opioids, mediated through mu receptors, antagonized by naloxone 2-4 mg I/V.

Oral route is not preferred. Subcutaneous or I/V mostly used.

Adverse effects

1. Behavioural restlessness, tremulousness
2. Dysphoria when administered with no pain
3. Muscle rigidity, convulsions
4. Cortical areas/hippocampal stimulation leading to convulsions in over dosage
5. Respiratory depression -emphysema
6. Nausea and vomiting
7. Increased intracranial pressure, leading to respiratory depression and CO2 retention
8. Postural hypotension, bradycardia, vagal stimulation
9. Constipation
10. Urinary retention in elderly males due to actions on urethra
11. Itching around the nose
12. Idiosyncratic allergic reactions because of histamine release.
13. Tolerance (physical, physiological) and dependence.
14. Withdrawal syndrome
15. Hypothermia in higher doses.
16. Drug is avoided during pregnancy or labour. I/V or I/M may cause foetal distress, alternatives are used. Can be used intrathecally at labour, as there is no respiratory depression, constipation or dependence.

Avoided as routine analgesic. Immediate tolerance develops to CNS actions, some to bradycardia, but some actions do not develop tolerance:

• Miosis –route is different so no tolerance
• Constipation
• Convulsions due to cortical and hippocampal cells
• Some antagonist actions do not develop tolerance.

Dose has to be increased against tolerance.

Withdrawal is prevented by long acting opioid agonist.

Contraindications

1. Use of pure agonist with weak partial agonist
2. Use in patients with head injuries
3. Use during pregnancy
4. Use in patients with impaired hepatic or renal function
5. Use in patients with impaired pulmonary function
6. Use in patients with endocrine diseases like Addison’s disease & Hypothyroidism show exaggerated responses to opioids.

3 and 6 morphine glucuronide are the metabolites. 6 morphine glucuronide is the active metabolite, more active than parent drug. It undergoes enterohepatic circulation and is avoided in impaired hepatic and renal functions.

Pharmacokinetics

1. Absorption of morphine from GIT is slow and erratic
2. Significant first pass metabolism in the liver
3. Rapidly distributed to all body tissues
4. Morphine is least lipophilic, as compared with other opioids
5. Only a small amount crosses blood brain barrier
6. Metabolized to  morphine-6-glucuronide and active metabolite is potent analgesic
7. Excreted in urine and bile duration of action is 4-6 hrs.
8. 3 morphine glucuronide is a neuroexcitator in the GABA glycinergic pathway. It does not act through the mu pathway. On prolonged use, it may lead to seizures. This does not occur in therapeutic doses.
9. Increased sensitization to morphine occurs on continuous use, hypersensitivity is at spinal cord level.
10. Codeine is another natural opioid agonist, on administration it is converted to morphine; itself has less affinity for mu receptors, so used as cough suppressant. It has least abuse liability and is non-addictive. But is often misused. Draw back in cough suppressant can lead to accumulation of secretions, resulting in obstruction of airways. Thus, atelectasis may occur.

Acute morphine poisoning

Signs and symptoms

1. Coma
2. Pinpoint pupil
3. Respiratory depression (chyene stokes breathing)
4. Bradycardia
5. Hypothermia
6. Decreased urine
7. Decreased bowel sounds
8. Pulmonary edema
9. Cyanosis

Management

1. Oxygen inhalation
2. Intravenous fluid
3. Decontamination (gastric lavage)
4. Potassium permanganate administration, oxidizes the opioids
5. Naloxone
6. Steroids to counter histamine release
7. Naltrexone
8. Obscure the patient from withdrawal symptoms

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Common Opioid Analgesics

Opioid Antagonists