An Overview on Analgesics Drugs | Pharmacology

This article provides an overview on analgesics drugs.

Introduction to Analgesic Drugs:

The control of pain is one of the most important uses to which drugs are put.

Analgesic drugs are divided into four main categories:

(i) Narcotic analgesic

(ii) Non-steroidal anti-inflammatory drugs, also known as non-narcotic analgesics.

(iii) Local anesthetics

(iv) Various centrally acting non-opioid drugs.

Out of the above categories – (i) and (iv) produce analgesia by acting on CNS, whereas (ii) and (iii) act peripherally.

Physiology of Pain and Historical Background:

Pain is a protective mechanism for body; it occurs whenever any tissue is being damaged and it causes the individual to react to remove the pain stimulus. Pain has been classified into two different major types: fast pain and slow pain.

Fast pain occurs within about 0.1 second after application of stimulus, whereas slow pain begins after a second or more and increases slowly. Fast, sharp pain is not felt in most of the deeper tissues of the body, whereas slow, throbbing pain can occur both in the skin and in almost any deep tissue or organ. The pain receptors in the skin and other tissues are all free nerve endings.

These are classified as mechanical, thermal and chemical pain receptors depending on the input stimuli. Some of the chemicals that excite the chemical type of pain receptors include: bradykinin, serotonin, histamine, potassium ions, acids, acetylcholine and proteolytic enzymes. In addition, prostaglandins enhance the sensitivity of pain endings, but do not directly excite them.

Muscle spasms also cause pain, by directly stimulating the mechanosensitive pain recectors and by indirectly compressing the blood vessels leading to ischemia and production of lactic acid. The fast-sharp pain signals are transmitted from the peripheral nerves to the spinal cord by small diameter myelinated.

A fibers at velocities of 6-30 m/s whereas, the slow-chronic pain signals are transmitted by large diameter non-myelinated C fibers at velocities of 0.5-2 m/s. There is thus a double system of pain innervation: a fast-sharp pain followed by a second slow-burning pain.

The degree to which each animal reacts to pain varies tremendously. This is due to the capability of brain to control the degree of input of pain signals to the nervous system by activation of a pain control system, called an analgesia system.

This system consists of three major components:

1. The periaqueductal gray area-surrounding the aqueduct of sylvius

2. The raphe magnus nucleus-located in lower pon and upper medulla

3. The presynaptic pain inhibitory complex-located in the dorsal horn of the spinal cord.

The tansmitter substance involved in the analgesia system are enkephalins, endorphins and serotonin. Dynorphin is also found in minute quantities, but it is a extremely powerful pain killer, having 200 times more potency than morphine.

A few visceral areas are almost entirely insensitive to pain of any type. These include the parenchyma of the liver and the alveoli of the lungs. The brain itself is also totally insensitive to pain, and the headaches are actually referred pain to the surface of head from the deep structures like meninges, cranium, sinuses etc.

In most case the stimulation of pain receptors in the periphery is of chemical origin. Though mechanical or thermal stimuli cause acute pain, but the persistence of such pain is due to chemical substances. A simple method for measuring the pain -producing effect of various substance has been developed by Keele and Armstrong (1964).

In this cantharidin is applied to the skin of the forearm of human subjects, and a small blister is produced. The test substance is then injected into the blister which gains access to nerve endings in the dermis. The pain so produced is recorded subjectively and is able to achieve reproducible responses.

Out of the various neurotransmitters that produce pain, 5-HT and bradykinin is the most active. Bradykinin partly acts through production of prostaglandins. Histamine is less active and tends to cause itching rather than actual pain.

Prostaglandins do not themselves cause pain, but strongly enhances the pain producing effect of other agents. PGE and PGF are known to be involved in it. Animal tests of analgesic drugs measure the nociception and involve measuring the reaction of an animal to a mildly painful stimulus.

The two tests usually employed are:

(i) Tail flick test (thermal)-In this the time taken for a rat to withdraw its tail when standard radiant heat stimulus is applied is measured.

(ii) Paw pressure test (mechanical)-In this the paw is pinched with increasing force and the withdrawal threshold of paw is measured.

There is often a poor correlation between the activity of analgesic drugs in animal tests and their clinical effectiveness.

Narcotic Analgesics:

Opium and opioid alkaloids are prototype drugs included in this group. Opioids have been used since time immemorial. It was recommended for relief of pain in the Ebers Papyros 1500 BC. The opioid alkaloids have a capability of causing addiction in humans, but it is of little significance in animal medicine because the animals are generally not given the chance to develop drug dependence.

Opium is the air-dried milky exudate obtained from the incised unripe seed capsules of the poppy plant, Papaver somniferum, Opium contains about 24 alkaloids out of which only morphine and codeine have clinical value. Opium also contains other alkaloids with different activities, like thebaine which has convulsant activity similar to strychnine and papaverine, a smooth muscle relaxant.

Morphine is named after Morpheus, the Greek god of dreams. Morphine was crystallized from crude opium by F.W.A. Serturner in 1805. Morphine sulphate is the principal salt of morphine.

The morphine molecule consists of an partially hydrogenated phenanthrene nucleus, an oxide link and nitrogen containing structure. In addition two hydroxy groups, alcoholic and phenolic are important in maintaining the pharmacologic integrity of the morphine molecule (Fig. 11.1).

The pharmacodynamics properties of morphine can be altered when substitutions are made in place of one or both hydrogen atoms at phenolic or alcoholic hydroxy groups.

If substitutions are made at phenolic group; there is reduction in analgesic potency, respiratory depression and constipation effect, while a stimulant effect upon the CNS is noted, e.g. codeine.

If substitution is made at the alcoholic hydroxy group; there is enhanced narcotic and respiratory depression. Substitution in either of the hydroxy position lessens emetic activity of the parent molecule.

Hydromorphone is more potent as an analgesic agent than morphine.

Other semisynthetic derivatives of morphine are apomorphine, a potent emetic agent and naloxone, an anatagonist of opiate-type drugs.

Terminology:

Opiates:

These are drugs derived from opium and include morphine, codeine and semi- synthetic congeners derived from them.

Opioid:

This is more wide term, including all agonists and antagonists with morphine like activity.

Narcotic:

This term is derived from Greek word for stupor. It is referred to any drug that induce sleep. More often it is used in legal context for abused drugs.

Endorphin:

It is a generic term referring to the three families of endogenous opioid peptides: the enkephalins, the dynorphins and β-endorphins.

Endogenous Opioid Peptides:

There are three distinct families of peptides under this category – the enkephalins, the endorphins and the dynorphines. Each family is derived from a distinct precursor polypeptide and has a characteristic anatomical distribution.

These precursors are designated as:

(i) Proenkephain-yields met-enkephalin.

(ii) Prodynorphin-yields Iev-enkephalin, dynorphin (A, B)

(iii) Proopiomelanocortin-yields melanocyte stimulating hormone, adrenocorticotrophin, and β-lipotropin. β-LPH in turn yields β-endorphin and β-MSH.

Opioid Receptors:

The opioid peptides are not confined to the CNS, since specific opiate receptors have been identified within the brain, spinal cord, ANS and myenteric plexus of the G.I tract, heart, Kidney, vas deferens, pancreas, fat cells, lymphocytes and adrenal glands.

Based upon studies in the chronic spinal dog, W.R. Martin and co- workers in 1976 proposed the existence of three different types of opiate receptors and named according to the drugs that have high binding affinity for them. Such as µ (mu : morphine), K (Kappa : Ketocyclazocines) and σ (sigma: SKF 10047).

A year later, J.A.H. Lord and colleagues identified a fourth opiate receptor, δ (delta) through which the endogenous opioids are considered to mediate their effects, σ (sigma) receptors are now considered to be true opioid receptors, since many other types of psychotropic drugs also interact with them. The opioid receptors are G-protein coupled receptors.

It is believed that there are two subtypes of µ receptors – µ₁ and µ₂.µ₁ mediates the analgesia whereas µ₂ mediates other effects like respiratory depression, emesis etc. The δ (delta) receptors have the greatest binding affinity for enkephalins. They mediate cardiovascular depressant, respiratory depressant and behavioural effects.

The enteric neurons contain both µ and δ receptors, and if either of this receptor is activated, peristalsis of the GI tract is inhibited. The characteristic constriction of pupil is also produced through µ and δ receptors. The physical dependence of morphine and the euphoric effect is also mediated through µ and δ receptors.

The K receptor stimulation produces sedation like µ and δ- receptors but with dysphoria. Recent investigations have proposed three subtypes of K receptors viz. K₁, K₂, K₃. K₁ receptors produce analgesia spinally, while K₃ produce supraspinal analgesia, pharmacological properties of K₂ are not known.

The σ receptors mediate mania and other psychotomimetic effects. It also causes pupillary dilatation, increased respiratory and pulse rates and triggers abstinence in morphine dependent animals. These properties differ from those elicited by µ, δ & K receptors.

Agonists and Antagonists:

1. Pure agonists:

Includes most of the typical morphine like drugs having high affinity for µ receptors and varying affinity for δ and K sites. Some drugs like codeine, methadone and dextro propoxyphene are, sometimes referred to as weak agonists since their maximal effects of analgesia are much less than those of morphine and do not cause dependence.

2. Partial agonists and mixed agonists-antagonists:

Drugs like nalorphine and pentazocine exhibit a degree of agonist and antagonist activity on different receptors. Pentazocine and cyclazocine are antagonists at µ receptors, but partial agonists on µ and K receptors. Most of the drugs in this group cause dysphoria due to interaction with the a-receptor possibly.

3. Antagonists:

These drugs block the µ, K & δ receptors; e.g. naloxone and naltrexone

β-endorphin is thought to be the most potent amnestic substance known. Naloxone given soon after administration of β-endorphin reverses the amnestic effect.

The finding that acupunture analgesia is partially blocked by naloxone in humans and animals implies that acupunture triggers release of an endorphin at the opiate receptor in pain pathways, β-endorphin may be considered to be a natural antidote for the pain and stress of parturition and other conditions. Nitrous oxide, a general anesthetic also in someway enhances the release of an endorphin and/or enkephalins

Cellular Mechanism of Action:

All opioid receptors are linked through G proteins for inhibition of adenylate cyclase. They also facilitate opening of K⁺ channels causing hyper-polarisation and inhibit opening of Ca²⁺ channels, inhibiting transmitter release.

Pharmacological Actions:

The main pharmacological effects are:

(i) Analgesia:

Morphine is effective in most kinds of acute and chronic pain. It not only reduces the sensation of pain, but also strongly reduces the distress component.

(ii) Euphoria and Sedation:

Euphoria appears to be mediated through µ receptors.

(iii) Respiratory Depression:

Morphine decreases the sensitivity of respiratory centre to PCO₂ causing respiratory depression.

(iv) Suppression of Cough:

Codeine and pholcodine which have substituent group at phenolic-OH group of morphine, causes suppression of cough through central mechanism.

(v) Eye:

Morphine produces a variable effect upon the size of the pupil in animals. The pupillary size of the monkey, cat, sheep and horse increases after morphine administration and this is mediated through σ receptors on accotomotor nucleus.

It causes pinpoint pupils in dogs, rats, rabbits and humans and this is mediated through µ & K receptors. The iris of the bird is not affected because it contains non-responsive skeletal muscles.

(vi) Pupillary Constriction:

This is a centrally mediated effect, caused by µ and K receptor pin point pupils are an important diagnostic feature in over dosage with morphine.

(vii) Reduced gastrointestinal motility and causing constipation. There is also contraction of gall bladder and constriction of the biliary sphinctor which makes morphine a unfavourable drug to treat biliary colic.

(viii) Morphine releases histamine from mast cells and causes bronchoconstriction and hypotension.

(ix) Straub Tail Reaction:

It is one of the diagnostic phenomenon of morphine. It consists of raising and stiffening of the tail of rats or mice given opioid drugs and is due to spasm of a muscle at the base of the tail.

(x) Immunosuppressant effect.

(xi) Nausea and vomiting- morphine by acting on chemo-sensitive trigger zone (CTZ) causes vomiting and nausea. This effect disappears on repeated administration. Horses and ruminants do not vomit following administration of central or local acting emetics.

(xii) Thermoregulation:

Hypothermia is the prominent response to morphine in rabbits, dogs and monkeys, whereas hyperthermia usually occurs in cats, goats cattle and horses. In guinea pigs, rats and mice, low dosage of morphine elicit a hyperthermic effect, while higher dosage induce hypothermia.

(xiii) Urinary Tract:

As the effect of morphine progresses, there is decrease in urine secretion by 10% or less due to liberation of an excess of the ADH from the pituitary gland. Morphine increases the muscular tone of the bladder, resulting in the spasm of the sphincter which may make urination difficult. This is more pronounced in humans than in animals. Morphine readily develops tolerance and psychological dependence in the animals.

New Approaches:

(i) Enkephalinase inhibitors, e.g., Thiorphan, act by inhibiting the metabolic degradation of endogenous opioid peptides and have been shown to produce analgesia, without causing dependence.

(ii) Neuropeptides such as somatostatin and calcitonin produce powerful analgesia when applied intrathecally. They may have similar effects when used systemically.

(iii) Non-peptide antagonists of substance P.

Non Narotic Analgesics:

These are also termed as non-steroidal anti-inflammatory drugs (NSAID’s) and are among the most widely used of all therapeutic agents.

Most of the NSAID’s have three major types of effects:

(a) Anti inflammatory effect

(b) Analgesic effect

(c) Antipyretic effect

In general, all of these effects are related to the primary action of the drugs- inhibition of arachidonate cyclo-oxygenase and thus inhibition of the production of prostaglandins and thromboxanes, In 1982, John Vane received the Nobel prize in physiology and medicine for his discovery in the early 1970’s that aspirin blocks or inhibits the enzymatic conversion of arachidonic acid to prostaglandins.

There are two types of cyclo-oxygenase (cox) viz. cox-1 and cox-2. Cox-1 is a constitutive enzyme expressed in most tissues, including blood platelet, and is involved in cell-cell signalling and in tissue homeostasis. Cox-2 is induced in inflammatory cells when they are activated and is believed to be the enzyme that produces the prostanoid mediators of inflammation.

Most NSAID’s in current use are inhibitors of both isoenzymes, varying in the degree of inhibition of each. Clearly the anti- inflammatory action of NASID’s is related to their inhibition of cox-2 and their unwanted effects are due largely to their inhibition of cox-1.

A. Analgesic Effect:

Prostaglandins sensitize the nociceptive afferent nerve terminals to mediators of pain.

In the presence of PGE₁, or PGE₂, pain will be felt even with concentrations of inflammatory mediators such as 5-HT or bradykinin, that are too low to cause pain on their own.

NSAID’s are mainly effective against those types of pain in which prostaglandins act to sensitise nociceptors, viz. pain associated with inflammation or tissue damage. For e.g. arthritis, bursitis, pain of muscular an vascular origin, toothache, dysmenorrhea, the pain of post portum states, cancer metastases in bone etc.

NSAID’s also relieve headache by counteracting the vasodilator effect of PG’s on the cerebral vasculature.

B. Antipyretic Effect:

Normal body temperature is regulated by a centre in the hypothalamus which ensures a balance between heat loss and heat production. During an inflammatory reaction, bacterial endotoxins, cause the release from macrophages of a pyrogen- inter-teukin-1 and this II-1 stimulates the generation of PGE’s in the hypothalamus and these in turn elevates the set point of the hypothalamic thermostat. NSAID’s by the virtue of its inhibitory action on the production of PG’s reset the thermostat. Normal body temperature is not affected by NSAID’s.

C. Ant-inflammatory Effect:

Inflammation is characterised by responses such as vasodilation, increased vascular permeability leading to edema and swelling, pain etc., which are mainly mediated through cox-2 products like PGE₂, and PGI₂. NSAID’s by blocking the cyclooxygenase pathway reduce many of the local signs and symptoms of inflammation.

In fact, prostaglandins in chronic inflammatory conditions, decrease lysosomal enzyme release, reduce the generation of toxic O₂ products and inhibit Lymphocyte activation. Hence inhibitors of PG synthesis may actually enhance the tissue damage in the long term.

D. Other Actions of NSAID’s:

(i) Aspirin can reduce the diarrhea that occurs after radiation therapy and is thought to be due to PG production in the intestinal wall.

(ii) Aspirin is also known to reduce fluid loss in experimental cholera.

(iii) Sulindac, is a potent inhibitor of aldose reductase in the lens of the eye. Aldose reductase reduces glucose to sorbitol and involved in development of cataract and peripheral neuropathy in diabetes.

(iv) Aspirin is also used as anti-platelet aggregatory agent and thereby used in prophylaxis against thrombosis, myocardial infarction.

Classification of NSAID’s:

All the NSAID’s do not exhibit all the three actions mentioned above to same extent. A comparative classification of NSAID’s is given in Table 11.2

A. Mechanism of Action:

The main action of NSAID’s; is inhibition of arachidonate cyclooxygenase. But this enzyme is modulated in a very complex manner. The products of this enzyme PGG₂ have a positive feedback mechanism on its own synthesis, whereas very high concentrations of this peroxide PGG₂ inactivate the enzyme.

Inhibition of this enzyme can occur by different mechanisms:

(a) An irreversible inactivation of the enzyme for e.g. Aspirin, indomethacin. Aspirin does-so by acetylating the active site of enzyme, hence further synthesis of prostaglandins depends on the synthesis of new enzyme.

(b) A rapid, reversible competitive inhibition for e.g. ibuprofen, piroxicam etc. They compete with the natural substrate, arachidonic acid and block further synthesis.

(c) A rapid, reversible non-competitive inhibition for e.g. paracetamol. This action is due to interference with the positive feedback of PGG2 on its own synthesis by antioxidant or free radical trapping mechanism.

B. Side effects of NSAID’s:

There are certain side effects which are common to all NSAID’s.

(a) Gastrointestinal Disturbance:

Prostaglandins have a protective effect on gastric mucosa by modulating its blood flow, increasing mucus secretion and inhibition of acid secretion.

Hence NSAID’s when used for analgesic, antipyretic or anti-inflammatory effect, also non specifically inhibit gastric prostaglandin synthesis causing unwanted effects like dyspepsia, diarrhea, nausea, vomiting and serious hemorrhages or perforation. This can be counteracted by oral administration of prostaglandins or analogues such as misoprostol.

(b) Renal Disturbances:

Prostanoids particularly PGE₂ mediates a compensatory vasodilation in response to the action of noradrenaline and angiotensin II. Hence inhibition of these prostanoids by NSAID’s lead to disturbed blood dynamics and a condition called “analgesic nephropathy” comprising of chronic nephritis and renal papillary necrosis.

(c) Skin reactions such as rashes, urticaria and photosensitivity.

C. Some commonly used NSAID’s and their salient features:

1. Salicylates:

These were some of the earliest drugs introduced. Sodium salicylate was introduced in 1875 by Buss and acetylsalicylic acid (aspirin) in 1899 by Dresser. The willow bark contains a glycoside, salicin, which is a precursor of salicylic acid. Oil of wintergreen which contains methyl salicylate has been used since long for rheumatic conditions.

Salicylates are weak organic acids with PK_a of 3.5. They are largely uninioised in the acid environment of stomach, facilitating its absorption. But this is not so in the case of herbivorous ruminants.

Aspirin inhibits platelet aggregation and interferes with coagulation process. It also displaces warfarin from plasma proteins leading to hemorrhages. Salicylates do not lower the normal temperature in the cat or rabbit, but in rat, it induces hypothermia.

Aspirin is a derivative of phenol which is known to be especially toxic to cats as cats lack the enzyme glycuronyl transferase. Hence the biologic half life of aspirin is exceedingly long and dose dependent. Aspirin administered during pregnancy results in teratogenic effects such as cleft palate stillborns or resorption in mice and rats. Salicylates appears to cross placenta quite rapidly.

Toxic doses of aspirin causes centrally mediated hyperpnoea and alkalosis followed by respiratory depression, acidosis, circulatory collapse, hyperpyrexia, convulsions, coma and death. Treatment of aspirin toxicity is done by initially giving a gastric lavage, followed by oral administration of activated charcoal. The renal elimination is increased by alkalinization of urine with IV sodium bicarbonate.

As a precaution, aspirin should not be administered simultaneously with aminoglycoside antibiotics because the incidence of nephrotoxicity is increased.

Aspirin has been used to treat radiation induced diarrhea.

2. Paracetamol:

It is also called acetaminophen in USA. and paracetamol in UK. It has analgesic, antipyretic, but no anti-inflammatory activity. In cats paracetamol is not recommended at any dose.

Paracetamol is a potential hepatotoxic agent on over-dosage or continued therapy, hence it is not recommended to administer this analgesic in the post operative period. Benorylate is an aspirin + paracetamol ester. After metabolism in the liver it releases both the active constituents.

3. Phenylbutazone:

This drug is highly plasma protein bound i.e. about 99%. It is beneficial in the treatment of soft-tissue or non-articular rheumatism like tendonitis, acute tenosynovitis, capsulitis and bursitis. Phenylbutazone has been used to extend the useful breeding life of aged stallions suffering from osteoarthritic or other painful conditions of the limb.

Phenylbutazone also has a property of O₂ radical scavenging and so it decreases the tissue damage due to inflammatory conditions. Phenylabutazone stimulates hepatic microsomal enzyme activity reducing its own biologic half life. Phenylbutazone has a uricosuric effect in animals whereby uric acid reabsorption is reduced.

Toxicity of phenylbutazone results in protein losing enteropathy, resulting in a decrease in blood volume, hemoconcentration, hypovolemic shock, circulatory collapse and death. Phenylbutazone is metabolized in the body to give oxyphenbutazone which is equally active as parent compound hence the biologic half life is extended.

D. Other Non-Narcotic analgesics:

1. Xylazine:

It is an analgesic as well as sedative and skeletal muscle relaxant. It is a potent α₂ adrenergic agonist and by stimulating central α₂ adrenoceptors it produces a potent antinociceptive or analgesic effect. Xylazine has synergestic properties when used along with etorphine or fentanyl or ketamine. Xylazine also produces skeletal muscle relaxation through central mechanism.

Giraffes are extremely sensitive to xylazine.

2. Detomidine and Medetomidine:

Both of these drugs are selective α₂ – agonist and 360 to 17225 times more potent than xylazine. Along with their analgesic effect they are also used as anesthetics.

E. Dosages:

1. Sodium salicylates – large animals 15-120 gm orally.

2. Aspirin – Cat-10 mg/kg at 2 day interval

Dog-10 mg/kg at 12 hr interval

3. Phenylbutazone – Dog-20 mg/kg orally

Horse – 2g twice daily for 4 days then 2g/day for 4 days

4. Meclofenamic acid-horse – 2.2 mg/kg orally

5. Flunixin – Horse-1.1 mg/kg im or iv

cattle-2.2 mg/kg iv

6. Naproxen – Horse 10 mg/kg orally twice daily.

Clinical use of Analgesic Drugs:

The choice and route of administration of analgesic drugs depends on the nature and duration of the pain. Often a progressive approach is used i.e. start with NSAID; supplement it with weak opioid analgesic and then by strong opioids if need be.

In general, severe acute pain (e.g. trauma, burns, post operative pain) is treated with strong opioid drugs such as morphine, fentenyl etc. Mild inflammatory pain (e.g. arthritis) is treated with NSAID such as aspirin supplemented by weak opioid drugs such as codeine, dextropropoxyphene, pentazocine etc.

For analgesia in painful conditions (e.g. headache, dysmenorrhea, backache, cancer, postoperative pain) the drugs of choice for short term analgesia are aspirin, paracetamol and ibuprofen., for chronic pain, drugs like diflunisal, naproxen, piroxicam which are longer acting are useful. To lower temperature, paracetamol is preferred because it lacks gastrointestinal side effects.

Local Anesthetics:

These are agents when applied locally to nerve tissue, provide relief from pain by blocking conduction of a sensory nerve impulse from the receptor to the cortex of the brain.

They have no effect on consciousness. Many substances can cause local analgesia, but the term “local anesthetics” is applied only to those agents whose action is reversible and does not damage the nervous tissue. Cocaine was first such drug to be isolated from coca leaves in 1860.

Local anesthetics produce analgesic effect by blocking the initiation and propagation of action potentials in the sensory nerves carrying pain impulse by virtue of its blocking action on Na⁺ channels on the nerve membrane. Local anesthetics block conduction in small diameter nerve fibers more readily than in large fibers. Nociceptive and sympathetic transmission is thus first to be blocked.

Examples:

Benzocaine, procaine, Butacaine, Amethocaine, proxymetacaine, mepivacaine, lignocaine, prilocaine, cocaine etc. Out of these lignocaine penetrates tissues readily and is suitable for surface application. Bupivacaine has particularly long duration of action. Benzocaine is unusual as it has very low solubility and is used as a dry powder to dress painful skin ulcers, providing long lasting surface anesthesia.

Physical Analgesics:

These are agents which bring about analgesia and anesthesia by their physical effect of freezing the local area.

ex. Ethyl chloride:

It is a volatile liquid stored under pressure and can be released as a spray. This takes away the latent heat of vaporization from the skin and results in intense local cooling

Carbon monoxide:

It is also stored under pressure in cylinder and sprayed as a jet. It forms “Dry ice” crystals causing intense local cooling. It is used to cauterize warts.

Various Centrally Acting Non-Opioid Drugs:

This is a separate category of analgesic drugs which are able to block certain effective disorders and secondarily bring about analgesia.

For ex. Carbamazepine is used for a painful condition called as trigeminal neuralgia and ergotamine is used in another painful condition like migraine in humans. Antidepressants such as amitriptyline have shown to be analgesic in patients who are not suffering from depression.

Anti-Inflammatory Agents:

These agents can be classified as follows:

(i) Non-steroidal anti-inflammatory agents.

(ii) Steroidal anti-inflammatory agents, and

(iii) Miscellaneous agents

The NSAID’s have already been considered earlier. Here we will consider steroidal drugs used to control inflammatory process. Corticosteroids are steroidal agents secreted by adrenal cortex of adrenal glands.

Cortisol and corticosterone are the principal corticosteroids of the adrenal cortex. Cortisol predominates in the human, pig and dog.; but corticosterone predominates in the rabbit, mouse and rat. Ruminants secrete both steroids in sizeable amounts.

Corticosteroids besides possessing anti-inflammatory effect also have following variety of action:

(a) Effects on metabolism of carbohydrate, protein and fat.

(b) Water and electrolyte balance

(c) Immunosuppressive effects

(d) Musculoskeletal effects, and

(e) Endocrine feedback effects on pituitary and hypothalamus.

Corticosteroids suppress the connective tissue response to injuries like chemical, thermal, traumatic, anaphylactic or infective. They inhibit not only the early phenomenon of the inflammatory process such as edema, fibrin deposition, capillary dialatation, migration of leukocytes into the inflamed area, but also the later manifestations like proliferation of capillaries and fibroblasts, deposition of collagen and scar formation.

Corticosteroids bring about all the above anti-inflammatory effects through following mechanisms:

1. In the inflammed area, corticosteroids inhibit the ability of leukocytes and other inflammatory cells to release various chemotactic factors for e.g. interleukins 1 and 2, platelet activating factor etc. Hence further accumulation of inflammatory cells at the site is inhibited.

2. Corticosteroids stabilize lysosomes in damaged tissue and leukocytes, thereby preventing lysosomal proteolytic enzymes from escaping to damaged surrounding tissue.

3. Corticosteroids induce formation of a class of proteins known as lipocortins which inhibit the activity of enzyme phospholipase A₂ which is responsible for formation of eicosanoids (Prostaglandins and PAF). Corticosteroids thus have a effect similar to NSAID’s but at a higher level in controlling the inflammatory mediators.

4. On vascular tissue, they reduce vasodilation, due to direct action on small blood vessels and there is diminished plasma exudation into tissues.

5. Corticosteroids also inhibit the formation of plasminogen activator by neutrophils. This enzyme converts plasminogen to plasmin which is thought to facilitate the migration of leukocytes into sites of inflammation by hydrolyzing fibrin and other proteins.

6. Formation of scar tissue is inhibited by depressing the synthesis of fibroblasts and collagen. This would adversely affect the healing of surgical operations.

The exact mechanism of action of corticosteroids is unclear; but following mechanisms are known to participate in its action:

1. Induction and synthesis of lipocortins which control prostaglandin synthesis.

2. Interaction with a transcription factor activator protein termed “AP-1”. AP-1 is involved in the induction of several genes for ex. collagenase, IL-2, Cox-2. The corticosteroid- receptor complex can bind to AP-1 and inhibit its function.

3. They also have an immunosuppressive effect.

Free Radicals in Inflammation:

The inflammatory process involves a series of events in response to numerous stimuli like ischemia, infection, Ag-Ab reaction, trauma etc. The ability to mount an inflammatory response is essential for survival although sometimes this response may get exaggerated and serve no benefits.

Leucocytes play an essential role in inflammation, when polymorphonulear leucocytes are activated during inflammation, there is rise in oxygen consumption by the cells, generating toxic oxygen metabolites such as superoxide anions, H₂O₂ and hypochlorous acid. Although oxygen radicals normally defend the host against invading pathogens, an excessive or inappropriate leucocyte response can result in acute tissue damage at the site of inflammation.

Oxygen radicals are suggested to be involved in the pathogenesis of variety of disorders like rheumatoid arthritis, adult respiratory distress syndrome, damage to myocardium and brain due to ischemia etc. The hypochlorous acid generated is capable of reacting with many biological molecules and responsible for much of the tissue injury.

A. Free Radical Scavenger:

1. Nimesulide:

This is a NSAID of sulfonanilide class. The drug reduces superoxide generation by activated neutrophils without influencing their phagocytic or chemotactic responsiveness and inhibits leucocyte oxygen demand. In addition, it also directly scavenges the hypochlorous acid so generated. The main metabolite of nimesulide, 4-hydroxy-nimesulide possess anti-lipoper-oxidant activity.

Other mechanisms of action are selective inhibition of PGF. PAF synthesis, inhibition of proteases (e.g. elastase, collagenase), inhibition of histamine release from human basophils & mast cells, reduced degradation of cartilage matrix through inhibition of metalloprotease synthesis making nimesulide as one of the newer approach towards treating inflammation.

The normal day-to-day level of Cortisol produced by the body is not enough to inhibit wound healing. So, large doses are administered and possibly local or topical therapy is preferred as systemic administration gives rise to number of metabolic effects which are unwanted.

Metabolic actions of corticosteroids which are considered to be unwanted effects:

1. on carbohydrates-decreased uptake and utilisation of glucose and increased gluconeogenesis, tendency for hyperglycemia

2. on proteins-increased catabolism, reduced anabolism.

3. on fat-effect on lipolytic hormones and redistribution of fat.

4. Reduced function of osteoblasts and increased activity of osteoclasts and tendency to develop osteoporosis.

Miscellaneous Agents: (Free Radicals in Inflammation):

1. Free Radical Scavengers:

(a) Orgotein:

It is a superoxide dismutase of boving liver origin. This enzyme converts superoxide free radicals into molecular oxygen and hydrogen peroxide. The H₂O₂ is later converted by endogenous catalase into molecular oxygen and water. It has been used to treat inflammatory problems of joint and soft tissue in horse and dog but without any consistent satisfactory results.

(b) Dimethyl Sulphoxide (DMSO):

This is an organic solvent and is very rapidly absorbed following dermal application. DMSO is also a scavenger of hydroxyl free radicals of oxygen and used to bring early relief from pain and swelling in limb injuries of horses and dogs. By interfering with transmission in peripheral nerves, it also produce analgesic effect.

2. Hyaluronic Acid:

This glycosaminoglycan is present normally in synovial fluid, produced by synovioytes, and it provides characteristic viscous lubricating property to the joint. During inflammation this substance is lacking in the joint hence intra-acrticular injection of sodium hyluronate under aseptic conditions will reinstate, the protective effect of synovial fluid. Following just single injection, horses have shown good response and return to normal function.

3. Poly-sulphated Glycosaminoglycan:

This agent resembles, the ground substance of cartilage and is known to inhibit enzymes capable of degrading proteoglycans of articular surfaces eg. stromelysin and improve the characteristics of synovial fluid. It is also claimed to stimulate the metabolism of chondrocytes and synovial cells, hence it is contraindicated in actively inflammed or infected joints.

Anti-Rheumatoid Drugs:

These are agents which arrest and alleviate the pain and immobility associated with long term progressive diseases of joints.

The therapeutic approach to such rheumatoid conditions include:

1. NSAID’s

2. Gold compounds

3. Pencillamine

4. Chloroquine

5. Sulphasalazine

6. Glucocorticoids

NSAID’s and Glucocorticoids have already been considered earlier:

1. Gold Compounds:

In 1890 Robert Koch observed that Gold compounds inhibit Mycobacterium tuberculosis in vitro. Clinical trials on arthritis were started and in 1929 it was first used in rheumatoid arthritis. The preparations used are aurothioglucose, sodium aurothiomalate and auranofin. Gold compounds are effective in stopping the progression of bone and joint damage in rheumatoid arthritis but cannot cure them.

The onset of action is slow and may take up to 3 to 4 month. Pain and joint swelling subside and the concentration of rheumatoid factor falls. The mechanism of action of gold compounds is to inhibit mitogen induced lymphocyte proliferation, reduce the release & activity of lysosomal enzymes, decrease the production of toxic O₂ metabolites from phagocytes, inhibit infiltration of neutrophils and reduce the release of mast cell mediators.

Sodium aurothiomalate is given by deep IM injection and auranofin is given orally. The compounds get concentrated in almost every tissue of body and the half life is 7 days in initial stages, but increases with treatment. So it must be given with increasing intervals between doses.

Gold compounds can suppress or prevent, but do not cure experimental arthritis and synovitis and have minimal anti-inflammatory effect

2. Penicillamine:

Penicillin on hydrolysis yields di-methyl-cysteine which was named as penicillamine by Abraham and coworkers. It has an important role in Wilsons disease and cystinuria. The D-isomer is used in the therapy of rheumatoid arthritis.

The drug is known to have metal-chelating properties and has a highly reactive thiol group which can substitute for cysteine. But the exact mechanism underlying its antirheumatoid effect is still unknown. It has a high response rate and the main response may take months to be seen.

The swelling of joints gradually subsides and nodules disappear. The plasma concentration of rheumatoid factor falls. (The rheumatoid factor is an IgM antibody against host IgG factor) Penicillamine is given orally and shows many unpleasant side effects like anorexia, vomiting, nausea, disturbance of taste, bone marrow disorders etc.

3. Chloroquine:

Chloroquine is a 4-aminoquinoline drug used to treat malaria mainly. The drug inhibits mitogen induced lymphocyte proliferation, decreases leucocyte infiltration, lysosomal enzyme release is decreased and generation of toxic oxygen metabolite is reduced. It also reduces the generation of IL-1 and inhibits phospholipase A₂ thereby reducing the formation of prostaglandins and PAF.

It may also inhibit DNA & RNA synthesis, as it does in microorganisms. The drug is given orally. Side effects are nausea vomiting, dizzineses & blurring of vision, urticarial symptoms, large doses result in retinopathy, hypotension and dysrhythmias.

4. Sulphasalazine:

This drug is a combination of a sulphonamide (sulphapyridine) and a salicylate (5-amino salicylic acid). The saliciylate is a free radical scavenger of toxic oxygen metabolites produced by neutrophils. It is used mainly for chronic inflammatory bowel disease and the enteric coated capsules and licensed for use in rheumatioid arthritis. The side effects are usually not serious.

Drugs Used in Gout:

Gout is a genetically determined metabolic disease in which there is over production of purines. The products of purine metabolism, urate, gets deposited in synovial tissue of joints.

An inflammatory response is evoked and the neutrophils engulf the crystals of sodium urate causing generation of tissue damaging toxic oxygen metabolites. There is subsequent lysis of the cells and release of proteolytic enzymes. There are intermittent attacks of acute arthritis.

Drugs used to treat gout can be classified according to their mechanism of action, as follows:

1. Drugs inhibiting the uric acid synthesis ex. allopurinol

2. Drugs increasing uric acid excretion or uricosuric agents ex. probenecid, sulphinpryrazone.

3. Drugs inhibiting leukocyte migration into the joints ex. colchicine

4. Drugs having general anti-inflammatory and analgesic actions ex. NSAIDS.

1. Allopurinol:

Allopurinol is converted in the body to alloxanthine by xanthine oxidase. This alloxanthine is an analogue of hypoxanthine and inhibits the enzyme required for purine synthesis. Thus allopurinol reduces the synthesis of uric acid by inhibiting xanthine oxidase.

The concentration of insoluble urate and uric acid in tissues, plasma and urine decreases. The deposition of urate crystals in tissue is reversed and formation of renal stones is inhibited.

Allopurinol is a drug of choice in long-term treatment of gout but contraindicated in acute attacks. Allopurinol is given orally and the drug is not bound to plasma proteins. The side effects of allopurinol are gastrointestinal disturbances and allergic reactions sometimes.

2. Colchicine:

Colchicine is a specific drug for gouty arthritis and can be used to prevent as well as relieve acute attacks of arthritis due to gout. Colchicine’s main effect is to prevent the migration of neutrophils into the joint and thereby avoid further production of tissue damaging factors in the joint.

Colchicine is thought to bind to tubulin, the protein of microtubules, resulting in their de-polymerisation. This effect interfers with motility of neutrophils colchicine treated cells have a sluggish motility in vitro.

Colchine may further inhibit the production of inflammatory glycoprotein by neutrophils that have phagocytosed urate crystals. Colchicine is administered orally and the unwanted effects are largely gastrointestinal, sometimes hemorrhages and kidney damage also. Chronic treatment may cause blood dyscrasias.

3. Uricosuric Agents:

These are drugs that increase uric acid excretion by direct action on the renal tubules ex. probenecid and sulphinpyrazone and a newer class of uricosuric diuretic derived from ethacrynic acid ; namely indacrinone. The write up has been compiled from following literature.