Treating the Diseases of Central Nervous System | Essay | Medical Science

In this essay we will discuss about the drugs used in treating the diseases of central nervous system.

1. Essay on Anxiolytics:

Anxiolytics (sedatives) relieve anxiety. Anxiety is a normal reaction but when severe and disabling it becomes pathological. Anxiolytics can induce sleep when given at night.

i. Benzodiazepines:

Benzodiazepines also known as minor tranquillizers are the most commonly used anxiolytics and hypnotics; they possess distinct advantages over older drugs such as meprobamate and barbiturates.

a. Benzodiazepines are remarkably free from serious adverse effects and are generally very safe.

b. Specific antagonist (antidote) flumazenil reverses the effects of high doses of benzodiazepines.

c. Dependence (addiction) on benzodiazepines does occur, but the physical withdrawal symptoms are less marked and less severe.

d. Benzodiazepines do not induce hepatic microsomal drug metabolizing enzymes.

Mechanism of action:

Benzodiazepines act on the reticular formation and limbic system in the brain. There are specific receptors for benzodiazepines and they appear to enhance the action of GABA (γ-amminobutyric acid), an inhibitory neurotransmitter.

Pharmacokinetics:

Benzodiazepines differ markedly in pharmacokinetic behaviour which is related to their varying lipid solubility. They are metabolized in liver and some metabolites are themselves sedative which prolong their actions, they cross placenta and are secreted in milk.

Pharmacological actions:

Benzodiazepines mainly act on central nervous system. Their actions are similar, but there are significant differences in duration of action (Table 3.1).

Benzodiazepines cause anxiolytics, sedation, amnesia, and hypnosis. They act as skeletal muscle relaxants by selectively depressing supraspinal polysynaptic reflexes involved in the regulation of muscle tone. They do not possess any analgesic action. Toxic doses produce coma without any specific features and cardiorespiratory depression is usually minimal.

Therapeutic uses:

Benzodiazepines are widely prescribed drugs. Their main uses are:

i. Anxiety:

Benzodiazepines are used for the short-term relief of severe anxiety. The treatment should be usually for a limited period and intermittent, because continuous use leads to a decrease in efficacy and drug dependence. They should not be used for depression, phobic or obsessional states or chronic psychosis.

ii. Insomnia:

Benzodiazepines are the hypnotics of choice. Shorter acting (temazepam and lormetazepam) are the most suitable for transient insomnia where residual effects are undesirable. Longer acting such as nitrazepam is indicated when early morning waking is a problem.

iii. As anticonvulsant:

Diazepam and lorazepam given slowly intravenously are very effective in status epilepticus and febrile convulsions.

iv. Skeletal muscle spasm:

Diazepam is used for the relief of chronic muscle spasm or spasticity. Sedation and occasionally extensor hypotonus are the disadvantages.

v. For premedication:

Diazepam, temazepam, lorazepam and midazolam are used for sedation and amnesia before surgery.

vi. Acute alcohol withdrawal syndrome:

Diazepam and chlordiazepoxide are used as adjuvant.

Adverse effects:

Benzodiazepines are remarkably free from serious adverse effects, although continued use can cause fatigue, memory problem, psychomotor impairment and rarely behaviour disturbances. Benzodiazepines are contraindicated in respiratory depression, severe hepatic impairment, and myasthenia gravis and sleep apnea syndrome. Dependence on benzodiazepines is the main problem. Withdrawal symptoms mainly pertain to CNS and include anxiety, depression, insomnia and depersonalization.

Drug interactions:

Alcohol and benzodiazepines taken concomitantly may result in greater impairment of psychomotor functions than either agent alone. A large number of drugs such as antibacterial, calcium channel blockers, ulcer healing drugs (cimetidine and omeprazole) inhibit metabolism of benzodiazepines resulting in enhanced sedation.

ii. Flumazenil:

Flumazenil is a specific antidote for the reversal of central sedative effects of benzodiazepines, but is rarely required in severe overdose. Its effects last only for about 1 hour, so repeated doses may be required with long-acting bezodiazepines. It can also be used in the differential diagnosis of unclear cases of poisoning due to centrally acting depressant drugs.

iii. Buspirone:

Buspirone has anxiolytic action without possessing any significant hypnotic action. It acts with a group of specific serotonin (5HT_1A) receptors in the brain. As compared to benzodiazepines, buspirone has the advantage of being less sedative, does not cause dependence, does not interact with alcohol and does not impair mental activity.

Buspironeis not very effective in patients who have not responded to benzodiazepines, and its anxiolytic effects are relatively slow to develop. Its only adverse effects are occasional nausea and headache. Buspirone has a limited place in the treatment of anxiety because of its slow onset of action; it requires several weeks to become effective.

iv. β Blockers:

Propranolol and oxprenolol are useful anxiolytics in controlling the autonomic symptoms of anxiety such as palpitations and tremors. They do not reduce non-autonomic symptoms such as mental tension.

v. Antidepressants:

Antidepressants in small doses such as fluoxetine (5-HT reuptake inhibitor) are also helpful in the treatment of anxiety, particularly in the case of panic attacks. Velafaxine, a drug related to 5-HT reuptake inhibitor, is useful for the treatment of general anxiety disorder condition in which the patient feels apprehensive and tense for no particular reason.

2. Essay on Hypnotics:

Hypnotic drugs produce sleep that is comparable to normal sleep. They do not relieve pain. The natural sleep comprises of cycles of deep sleep lasting for about 80 minutes followed by a short phase (about 10 minutes) of rapid eye movement (REM) sleep, which is characterized by dreaming, increased muscle tone, increased heart rate, and rapid eye movements. The cycle of deep and REM sleep lasting for 90 minutes is repeated for about six times per night. Deprivation of REM sleep leads to psychological changes during waking hours. Many centrally acting drugs and alcohol suppress REM sleep and do not produce natural sleep.

i. Benzodiazepines:

Benzodiazepines are the most commonly used hypnotic drugs. They are equally potent and an individual drug mainly differs in its duration of action. The long acting benzodiazepines (nitrazepam, flunitrazepam and flurazepam) may produce a hangover effect the next day. Benzodiazepine toxicity is increased by malnutrition, advanced age, concomitant use of alcohol, other CNS depressants, isoniazid and cimetidine. Benzodiazepines should be given at the lowest recommended doses with intermittent dosing schedule.

ii. Zolpidem:

Zolpidem is a very useful hypnotic drug, with few effects the next morning. It has no withdrawal syndrome, rebound insomnia or tolerance and, because of its rapid onset, is useful for initiating and for maintaining sleep. Side effects include drowsiness, headache and nausea. It should be avoided in patients with obstructive sleep apnea and doses should be reduced in cirrhosis.

iii. Zaleplon:

Zaleplon has a half-life of approximately 1 hour and is mainly indicated for short-term insomnia, which may be due to anxiety, illness etc. It is not recommended for patients under 18 years of age and should not be repeated the same night. Side effects include headache, drowsiness, dizziness and impaired coordination. It causes drug dependence. It is contraindicated in breast feeding and patients suffering from sleep apnea or myasthenia gravis.

iv. Zopiclone:

Zopiclone is a long acting hypnotic providing sleep for 6-8 hours. It may cause some drowsiness the next morning. Tolerance and dependence to zopiclone generally occurs. Side effects include a bitter metallic taste, nausea and psychological symptoms such as hallucinations. It is contraindicated in pregnancy and in children.

v. Promethazine:

Promethazine, an antihistamine, produces sleep by blocking the action of histamine in the brain it is used for insomnia particularly in patients with a history of drug dependence. It is not a good hypnotic drug, because it is not very effective in producing sleep, has a long duration of action with sedation next morning and causes anticholinergic (atropine like) actions.

vi. Barbiturates:

Barbiturates are no longer used as anxiolytics and hypnotics as they are dangerous in over dosage, readily cause psychological and physical dependence, and are potent inducers of liver enzymes.

vii. Chloral Hydrate:

Chloral hydrate is effective and cheap hypnotic. It has an unpleasant taste, is a gastric irritant and can cause rashes. It is rarely used in children where its derivative triclofos is preferred, being less of a gastric irritant. Chloral hydrate should be used with caution in liver or renal failure. Its action is enhanced by heparin.

viii. Paraldehyde:

Paraldehyde, a volatile liquid, is a potent hypnotic, but is not used because of its pungent smell and disagreeable taste. It is metabolized in liver to acetaldehyde, which is exhaled in breath leading to pungent smell and soreness of trachea and larynx. Paraldehyde is mainly used in status epilepticus (given rectally or intramuscularly). It causes little respiratory depression and is therefore useful where facilities for close monitoring and resuscitation (if needed) are not available.

Essay # 3. Analgesics:

Analgesics are drugs which relieve pain without loss of consciousness. Pain is a warning signal of the presence of disease and by its nature may help in the diagnosis of the underlying disease. Analgesics cause symptomatic relief of pain without affecting its cause.

Analgesics belong to two distinct groups:

A. Narcotic (Opioid) Analgesics:

This group consists of opium and synthetic drugs with similar actions. They act on the brain and spinal cord and are used to relieve moderate to severe pain, particularly of visceral origin. These drugs are also called opioids.

Mechanism of action:

Opioids act on specific receptors of several types [µ (mu), κ (kappa) and σ (sigma)] in the nervous system. Stimulation of these receptors, by neurotransmitters or neuromodulators, inhibit the transmission of nerve impulses related to pain and the appreciation of pain is suppressed.

A number of peptides (encephalins and endorphins) occur naturally in the brain and act as neurotransmitter or neuromodulators at these receptors and regulate pain responsiveness at supraspinal and spinal levels, particularly in the midbrain and posterior horn of the spinal cord. Opioid drugs react with these receptors and thus relieve pain. Out of the various opioid receptors, µ receptors are the most important, because its stimulation by opioids accounts for the major effects of opioids, such as analgesia, respiratory depression, euphoria and physical dependence.

Opioid receptor interaction can be of three types:

i. Stimulation of the receptor – agonist

ii. Partial stimulation and partial blockade of receptor  – partial agonist

iii. Blockade of receptors – antagonist

Opium:

Opium is obtained from the unripe poppy (Papaver somniferum) capsule.

Crude opium is a brownish resinous material and contains two types of alkaloids:

(1) Opioid Agonists:

i. Morphine:

Morphine is the most powerful opium alkaloid and serves as the standard against which other opioid analgesics are compared.

Pharmacokinetics:

Morphine is well absorbed orally, but its bioavailability is less than 30% because of extensive hepatic first pass metabolism. It is widely distributed and freely crosses placenta and affects the fetus. It is metabolized in liver; one of its metabolites (morphine-6- glucuronide) has powerful analgesic activity of its own. Metabolites are excreted in urine.

Pharmacological actions:

Central nervous system:

The most important effects of morphine are on CNS, which are both stimulant and depressant.

Depressant effects:

a. Analgesia:

Morphine is the most potent analgesic. Consciousness is not lost and the patient can usually locate the source of pain.

b. Euphoria:

Morphine causes a powerful sense of contentment and wellbeing. This action is an important component of its analgesic action, since the agitation and anxiety associated with a painful illness or injury are thereby reduced.

c. Respiration:

Morphine is a powerful respiratory depressant. It reduces the responsiveness of the respiratory centre to carbon dioxide. Depressed respiration and increased arterial carbon dioxide retention causes cerebral vasodilatation leading to an increase in intracranial pressure.

d. Cough centre:

Morphine is a potent cough depressant.

e. Sedation:

Morphine is a mild hypnotic and may produce drowsiness and sleep.

Stimulant effects:

a. Emesis:

Morphine stimulates the CTZ in the brain stem, producing nausea and vomiting.

b. Miosis:

Morphine produces miosis by stimulating the nucleus of the third nerve. The pinpoint pupils are indicative of morphine poisoning prior to asphyxia.

c. Oliguria:

Morphine stimulates the release of ADH, producing oliguria.

Cardiovascular eystem:

Morphine can cause fall in blood pressure due to vasomotor medullary depression and histamine release.

Gastrointestinal system:

Morphine reduces peristalsis and stomach motility. In addition, spasmodic nonpropulsive contractions of GIT smooth muscle are produced. These actions result in constipation. Biliary pressure is increased due to contraction of sphincter of Oddi.

Other systemic effects:  

Morphine increases detrusor muscle and vesicle sphincter tone leading to urinary retention. It causes histamine release which can cause bronchoconstriction and cutaneous vasodilatation.

Therapeutic uses:

Morphine is still one of the best analgesic for severe pain of a temporary nature such as occurs in surgical emergencies, the postoperative period, following injury, or after myocardial infarction, for not only it relieves pain but also relieves the anxieties and miseries of the patient. It is the drug of choice for the oral treatment of severe pain in terminal cancer on a regular basis.

Morphine is used to control distressing cough in terminal lung cancer. Morphine, by slow intravenous injection (5-10 mg) is very useful for the treatment of acute dyspnea of pulmonary edema due to acute left ventricular failure. The usual dose of morphine is 10-15 mg by subcutaneous injection.

Adverse effects:

(a) CNS effects:

This includes dysphonia, drowsiness and pupillary constriction (pinpoint pupil). Overdose may cause coma.

(b) Respiratory depression:

It is dose related and is especially pronounced after IV administration.

(c) Cardiovascular effects:

This includes peripheral vasodilatation and hypotension.

(d) GI effects:

Nausea and vomiting (particularly in initial stage) and constipation are common.

(e) Urinary retention:

This occurs due to increased bladder, ureter and urethral sphincter tone.

(f) Pruritis:

It occurs most commonly with spinal administration.

(g) Hypersensitivity: 

Patients with respiratory diseases such as chronic bronchitis, asthma and emphysema are very sensitive to opioids and a normal dose may produce signs of overdose.

Tolerance may develop to the analgesia, the euphoria and the respiratory depression and to a lesser extent to miosis and constipation.

Physical dependence (addiction) can develop rapidly when opioids are used in a social context.

The classic symptoms of opioid poisoning are coma, depressed respiration and pinpoint pupils. The patient sweats and is liable to develop hypothermia. The pulse is slow. Pulmonary edema may develop rapidly and is often fatal.

Opioids are contraindicated in acute disease states such as abdominal pain, head injuries, where the pattern and degree of pain are important diagnostic signs. They may also increase intracranial pressure. Opioids are also contraindicated in respiratory depression, acute alcoholism, and chronic rheumatic diseases.

ii. Diamorphine (Heroin):

Diamorphine has a greater analgesic potency than morphine. Its action is more rapid and short lasting. It is not used therapeutically but is more popular among addicts.

iii. Codeine:

Codeine has pharmacological effects similar to morphine, but is much less potent and causes less sedation or respiratory depression or GIT effects than morphine. Addiction liability is rare but may occur. Its main useful action is on cough centre and codeine is widely used in doses of 15-30 mg as a cough suppressant. In combination with aspirin or paracetamol, it is used as a mild analgesic.

iv. Dihydrocodeine:

Dihydrcodeine is similar to codeine and is used as a mild analgesic. It causes constipation and occasionally dizziness, low blood pressure and nausea. It is given orally or by intramuscular injection.

v. Dextropropoxyphene:

Dextropropoxyphene is a very mild analgesic, somewhat less potent than codeine. It is generally used orally in combination with paracetamol (co-proxamol) in painful conditions. It is slightly addictive and like other opioids may cause vomiting. Overdose may result in respiratory depression and acute heart failure due to dextropropoxyphene and hepatic toxicity due to paracetamol.

vi. Methadone:

Methadone is a synthetic opioid. Its analgesic action is as powerful as that of morphine, but is less sedating and euphoric than morphine. It is a drug of dependence. Like morphine, it depresses the cough centre, but the effect on the respiratory centre is not so marked. The principal uses of methadone are in severe pain; cough in terminal disease and as an adjunct in treatment of opioid dependence. The usual dose is 5-10 mg orally or by injection.

vii. Meperidine(Pethidine):

Meperidine is a synthetic opioid, which is chemically related to atropine. It is less potent and short acting analgesic than morphine and is not suitable for severe continuing pain. It has no effect on cough centre, is less depressant to respiratory centre and does not cause constipation.

It does not cause constriction of the pupils and can therefore be used in head injuries where observation of the pupil size may be important. It is no longer used for obstetrical analgesia and has been replaced by epidural analgesia to relieve pain in the later stages of labour. Dependence can develop. It is used for moderate to severe pain in doses of 50-100 mg orally or by subcutaneous injection. Its action lasts for 2 to 3 hours.

viii. Afentanil, Fentanyl and Remifentanil:

These opioids are very potent and are short acting. They are used by injection for intraoperative analgesia to help maintenance of surgical anesthesia. They are liable to cause severe respiratory depression. Fentanyl is available in a transdermal drug delivery system as a self-adhesive patch which allows slow absorption for up to 72 hours in the relief of terminal pain.

ix. Papaveretum (Omnopon):

Papaveretum is a mixture of 253 parts of morphine hydrochloride, 23 parts of papaverine hydrochloride and 20 parts of codeine hydrochloride. Its actions are essentially those of morphine and are hardly used any more.

(2) Opioid Partial Agonists:

These are mixed narcotic agonist antagonist analgesics. They are powerful analgesics but are less addictive, less likely to depress respiration and are less euphoric. They precipitate withdrawal symptoms, including pain in patients dependent on opioid agonists.

i. Pentazocine:

Pentazocine is an effective analgesic, but exerts adverse effects on the heart and central nervous system and has some potential for causing dependence. It causes hallucinations and thought disturbances. It is not recommended and, in particular should be avoided after myocardial infarction as it may increase pulmonary and aortic blood pressure as well as cardiac work.

ii. Buprenorphine:

Buprenorphine is as powerful analgesic as morphine. It seems to be less likely to cause adverse effects, though nausea and vomiting may be troublesome. It has a longer duration of action, but it too seems to have a potential for abuse.

Respiratory depression although not so marked as with morphine, is only partially reversed by naloxone. Buprenorphine is used by injection for postoperative pain in doses of200-600 micrograms, since orally it is metabolized by liver (first pass effect). Sub-lingualis it is given in doses of 200-400 micrograms for various forms of chronic pain. Buprenorphine shows a ‘ceiling effect’ so that increasing the dose above usual range will not improve-its efficacy.

iii. Nalbuphine:

Nalbuphine is as powerful analgesic as morphine and has fewer side effects and less abuse potential. Its action lasts for about 4 hours and has to be given by injection. Nausea and vomiting occurs less than with other opioids but respiration depression is similar to that with morphine. Like buprenorphine, it also shows a ‘ceiling’ effect. It is less suitable than morphine for managing severe pain. Nalbuphine causes fewer psychotomimetic effects and unlike pentazocine does not exert substantial adverse hemodynamic effects and may therefore be of value in treating some patients who have heart disease.

iv. Meptazinol:

Meptazinol is claimed to cause a low incidence of adverse cardiac and respiratory effects. It has a shorter half-life than nalbuphine and has therefore been used to treat obstetric pain where its rapid elimination by both mother and fetus is an advantage. It is also useful for breakthrough pain in the postoperative period.

v. Tramadol:

Tramadol is a weak opioid. It reduces pain by two mechanisms – an opioid effect and by interfering pain pathways through the spinal cord. It is reported to have fewer opioid side effects, notably less respiratory depression, less constipation and less addiction potential. Its analgesic action is as powerful as meperidine and is given intramuscularly for postoperative pain or orally for chronic pain. Side effects include nausea and vomiting, dizziness and dry mouth.

(3) Opioid Antagonists:

These are drugs which occupy the opioid receptors and produce little or no stimulation so that the actions of opioids are reversed. They are used to treat over dosage by opioids.

i. Naloxone:

Naloxone is a pure opioid antagonist having no stimulant action on opioid receptors. It is given in doses of 0.8-2 mg intravenously at intervals of 2-3 minutes to a maximum of 10 mg in opioid poisoning. It can also be used in doses of 100-200 micrograms to terminate the actions of narcotic drugs in postoperative period.

ii. Naltrexone:

Naltrexone is an orally active opioid antagonist used in the treatment of opioid withdrawal as an aid to relapse prevention since it prevents the euphoric action which is linked to addiction.

2. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs):

These drugs act peripherally by reducing the inflammation and are indicated in musculoskeletal conditions accompanied by pain and inflammation.

The NSAIDs belong to following four groups:

A. Salicylates

B. Paracetamol

C. Nonselective COX inhibitor NSAIDs

D. Selective COX inhibitor NSAIDs

Most of the NSAIDs have three therapeutic actions namely- analgesic, antipyretic and anti-inflammatory. Differences in the anti-inflammatory activity between different NSAIDs are small but there is considerable variation in individual patient tolerance and response. About 60% of patients will respond to any NSAID, of the others, those who do not respond to one may well respond to another. A period of 3 weeks is required to achieve ant- inflammatory effect, which if not obtained, requires a substitution of another NSAID. The main differences between NSAIDs lie in the incidence and type of side effects.

Mechanism of action:

Pain and inflammation are due to the production of prostaglandins by the enzyme cyclooxygenase (COX). Prostaglandins are formed by two isoforms of COX the constitutive (constantly) COX 1 and inducible COX 2. COX 1, is responsible for the formation of prostaglandins which are responsible for preserving the homeostatic functions mainly related to the maintenance of physiological functional state of gastric mucosa, renal blood flow, blood platelets and bronchial muscle.

COX 2 is responsible for formation of prostaglandins, responsible for pain and inflammation produced as a result of injury or damage to the cells. Most NSAIDs block both COX 1 and COX 2 and, although they relieve pain and inflammation, may cause adverse effects (particularly peptic ulcer) by interfering with the homeostatic functions of constitutive COX 1 derived prostaglandins.

NSAIDs, which inhibit COX 2 preferentially, may possibly be less likely to cause stomach ulceration.

A. The Salicylates:

Aspirin (acetylsalicylic acid) is the oldest and cheapest NSAID.

Pharmacokinetics:                                                       

Aspirin is rapidly absorbed from both the stomach and the intestinal tract. It is a pro-drug, which is converted in liver into active metabolite salicylate. In large doses, some of the salicylate may combine chemically with plasma protein by acetylation. This changes the nature of the protein so that the immune system regards the altered protein as foreign and forms antibodies against it. The next time aspirin is taken, an allergic response may occur. About 75% of aspirin is metabolized in the liver and the rest is excreted unchanged. Alkalization increases the urinary excretion.

Pharmacological Actions:

i. Antipyretic action:

Aspirin is rapidly effective in febrile patients. It has no effect on normal body temperature. The antipyretic effect is centrally mediated and is believed to be due to inhibition of prostaglandin synthesis in the hypothalamus in response to endogenous pyrogen.

ii. Anti-Inflammatory action:

The anti-inflammatory activity is responsible for the use of aspirin in musculoskeletal disorders, such as rheumatoid arthritis.

iii. Analgesic action:

Aspirin is effective against pain of low intensity through both peripheral and central mechanism. It inhibits the synthesis of prostaglandins peripherally in inflamed tissue and centrally in close proximity to the antipyretic region in the hypothalamus. Analgesia is not associated with mental alterations, such as hypnosis or changes other than pain.

Respiration:

Aspirin simulates respiration directly and indirectly. High doses result in hyperventilation due to stimulation of respiratory centre, leading to respiratory alkalosis. It also interferes with carbohydrate metabolism resulting in accumulation of pyruvic and lactic acid, which may end in metabolic acidosis. Aspirin in very large doses can depress the medulla resulting in metabolic acidosis.

Gastrointestinal tract:

Aspirin can cause dyspepsia, nausea and vomiting by irritating the gastric mucosa and stimulating CTZ in the CNS. It may lead to a dose dependent gastric ulcer and bleeding.

Liver:

Hepatotoxicity associated with encephalopathy (Reye’s syndrome) can occur in children under 15 years of age.

Blood:

Aspirin by binding cyclooxygenase irreversibly inhibits throm­boxane (the prostaglandin produced by platelets) which is responsible for platelet aggregation. The net result is inhibition of platelet ‘stickiness’.

Kidney:

Aspirin may cause renal impairment due to reduced synthesis of vasodilatory prostaglandin in patients with compromised renal function, whose renal blood flow is under ‘prostacyclin tone’.

Therapeutic Uses:

i. Analgesic and antipyretic:

Aspirin in low doses (300-600 mg) is an effective analgesic for headache, transient musculoskeletal pain, and dysmenorrhea but has less useful antipyretic action. Aspirin, for analgesic action is available in a large number of preparations that contain paracetamol, codeine or caffeine.

ii. Anti-Inflammatory:

High doses (3.6-4.2 g a day) are required to achieve a clinical anti-inflammatory effect in rheumatoid arthritis and acute rheumatic fever. However, other NSAIDs may be better tolerated and preferred over aspirin for inflammatory conditions.

iii. Antiplatelet:

Aspirin in low doses (75 or 100 mg daily) inhibits platelet aggregation and has important therapeutic benefit in unstable angina, after myocardial infarction, in transient ischemic attacks, and following bypass surgery. Aspirin is used increasingly for its antiplatelet properties.

Although aspirin is a NSAID for the treatment of pain and inflammation, the greater use of aspirin is in cardiovascular disorders, since in lower doses it is used to inhibit platelet aggregation. Aspirin is generally considered to be more of a cardiovascular drug than a NSAID.

iv. Other uses:

There is evidence that the regular use of aspirin reduces the risk of colon and rectal cancer, and may also reduce the risk of Alzheimer’s disease.

Adverse Effects:

Aspirin, in therapeutic doses, is a gastric irritant and may cause slight bleeding from the stomach. Rarely, it may lead to hematemesis due to loss of the protective action of pro­staglandins on the gastric mucosa. In allergic patients, aspirin may precipitate an attack of asthma, due to reduced production of prostaglandins.

Large doses of aspirin produce side effects like dizziness, tinnitus, deafness and vomiting due to the involvement of eighth cranial nerve. This is associated with hyperventilation alkalosis followed by metabolic acidosis.

Aspirin is contraindicated for fever, myalgia and malaise in children aged under 15 years as it may rarely precipitate Reye’s syndrome with coma and liver damage which can prove fatal. Aspirin should not be used in GIT ulceration, hemophilia and gout. Aspirin increases the effects of warfarin and oral hypoglycemic drugs.

B. Paracetamol (Acetaminophen):

Paracetamol is the most widely used minor analgesic and antipyretic. The COX inhibiting action is so weak in the peripheral tissues that it is devoid of anti-inflammatory action and antiplatelet properties. Its analgesic action is mediated by raising the threshold to pain perception in the CNS. Its main advantage over other NSAIDs lies in the absence of action on other body systems. It does not cause indigestion or gastric bleeding and Reye’s syndrome as seen with aspirin.

Pharmacokinetics:

It is given orally, well absorbed and peak plasma levels are achieved within 60 minutes. It is partly bound to plasma proteins and inactivated by metabolism in the liver.

Therapeutic Uses:

It is the preferred analgesic for many types of pain such as headache, musculoskeletal pain, dysmenorrhea, sore throat, toothache, osteoarthritis, etc. It is not as potent a analgesic as aspirin and not very effective in rheumatoid arthritis because of absence of anti-inflammatory action. It is the ideal drug to be used as antipyretic. The usual dose is 0.5-1.0 g given orally 4-6 hourly (maximum dose, 4 g/day).

Adverse Effects:

Adverse effects are uncommon at normal dosage, but in overdose, it may cause dangerous liver damage. Hepatic toxicity is due to depletion of hepatic glutathione and subsequent accumulation of a toxic intermediate metabolite, N-acetyl-p-benzoquinonimine.

Toxicity usually occurs after ingestion of more than 7.5 g. Paracetamol toxicity also occurs due to chronic ingestion, especially in alcoholics. IV acetylcystine is specific antidote that acts as glutathione substrate. There is also evidence that large doses taken over a long period may damage the kidneys.

C. Nonselective Cox NSAIDs:

This is a large group of drugs, possessing antipyretic, analgesic and anti-inflammatory properties mediated by inhibition of COX. Differences in anti-inflammatory activity between NSAIDs are small and they have a side effect profile similar to that of salicylates. These drugs should be used with caution in patients with impaired hepatic or renal functions.

The main differences between NSAIDs lie in the incidence and type of side effects. Phenylbutazone is a powerful NSAID, but most toxic, causing a number of serious adverse effects, including agranulocytosis, gastric bleeding, salt and water retention and rashes. Its use therefore is restricted to the treatment of ankylosing spondylitis in hospital. Next is azapropazone, which has the highest incidence of adverse effects. Ibuprofen is less likely to produce side-effects than others of this group, but is perhaps less effective. The rest are very similar.

Some of the commonly used NSAIDs include ibuprofen, diclofenac, naproxen, etodolac, indometacin, ketorolac, metoprofen, meloxicam, nabumetone, piroxicam, sulindac. NSAIDs are well absorbed orally, and are highly bound to plasma proteins. They are largely metabolized in liver, are excreted in urine and as well as bile. Nabumetone, meloxicam and piroxicam are long acting and require once daily dosing. Several of these drugs also available as suppositories (e.g. diclofenac, indometacin, ketoprofen) or for injection (diclofenac, ketorolac).

Therapeutic Uses:

It is generally preferable to start with one of least toxic (but also less effective) NSAID such as ibuprofen. For patients, with more pronounced inflammation (especially, if they are young), a drug from the middle of the range (such as diclofenac or naproxen) or the top of the range (such as indometacin) may be the choice.

Rheumatoid arthritis:

NSAIDs relieve the symptoms of pain, stuffiness and swelling of joints, but do not affect cytokines so damage to the joints continues. Diseases modifying anti-rheumatic drugs (DMARDs) are also given early in treatment to protect the joints from damage and minimize deformity.

Gout:

NSAIDs are the preferred drugs for treating acute gout. Azapropazone has uricosuric as well as anti-inflammatory properties and may be used as a single agent in chronic gouty arthritis who requires a NSAID provided that renal function is normal.

Osteoarthritis:

NSAIDs should only be used to supplement a baseline simple analgesic such as paracetamol, if required. Topical application of NSAIDs may provide some pain relief in osteoarthritis.

Soft tissue rheumatism:

NSAIDs provide symptomatic relief in tenosynovitis and soft tissue injuries. Topical application of NSAIDs may be useful and is associated with less systemic toxicity. Local injection of steroids and physiotherapy offer significant relief. Fibromyalgia (fibrositis) responds poorly to NSAIDs.

Non-Rheumatological uses:

Diclofenac is often used for ureteric colic or after trauma in preference to opioids. NSAIDs are particularly useful in dysmenorrhea and have also been used to prevent premature labour. They are given to relieve pain in dentistry, that arising from soft-tissue and bony injuries, associated with bone metastases, and pleurisy and pericarditis. Indometacin and other NSAIDs may also have a role in the treatment of migraine.

Antipletelet action:

The most important non-analgesic role of NSAIDs is the use of low dose aspirin for myocardial or cerebral ischemia.

Adverse Effects:

Inhibition of prostaglandin synthesis results in following side effects:

a. GIT irritation including hemorrhage and peptic ulceration is the most common side effect particularly in elderly patients (exception COX 2 inhibitors). NSAIDs are the single known cause of peptic ulceration.

Concomitant use of prostaglandin analogue misoprostol reduces the incidence of NSAIDs induced peptic ulceration. For optimum healing of peptic ulcers in patients who need to continue treatment with NSAIDs, omeprazole 40 mg is recommended for 4-6 weeks followed by long term treatment with prostaglandin analogue misoprostol.

b. Acute renal failure may occur due to medullary ischemia induced by inhibition of prostaglandin synthesis, which may be the basis for the initial lesion in analgesic nephropathy. Sulindac is relatively less nephrotoxic than other NSAIDs.

c. Bronchospasm, although rare, may occur in susceptible patients due to inhibition of bronchodilatory prostaglandins.                                                             

d. Rapid destruction of the head of femur (“indomethacin hip”) may occur with potent NSAIDs.

e. Rashes are the most common idiosyncratic side effects.

f. Bone marrow depression, fluid retention and stomatitis are common with phenylbutazone.

g. Tinnitus, deafness and dyspnea may be associated with many NSAIDs, particularly with aspirin.

Drug interactions:

NSAIDs may antagonize the actions of diuretics and hypotensive drugs, increase the effects of anticoagulants and decrease the excretion of lithium.

D. Selective COX 2 Inhibitor NSAIDs:

These drugs exhibit selective inhibition of COX 2, thereby inhibiting inflammation while preserving the homeostatic functions of COX 1 derived prostaglandins. Celecoxib, rofecoxib, valdecoxib and etrocoxib are currently available COX 2 inhibitor NSAIDs.

There is lot of controversy about safety of COX 2 inhibitors, because at the dose levels these drugs are effective, they may inhibit COX 1 as well to cause gastric damage. Moreover, COX 2 inhibitors have significantly increased risk of cardiovascular disease, because of their little antiplatelet activity, which may increase the chances of stroke in elderly patients.

Additionally COX 2 inhibitors appear to differ little from nonselective NSAIDs in terms of their effects on the kidney and on blood pressure. Many of COX 2 inhibitors have been withdrawn from the therapy and there does not appear to be any significant justification for their use.

4. Essay on Antiparkinsonian Drugs:

Parkinson’s disease is characterized by rigidity of muscles, by tremors and by inhibition of voluntary movements (hypokinesias). In Parkinson’s disease there is a deficiency of the neurotransmitter dopamine in the basal ganglia, which results in a neurohumoral imbalance between acetylcholine and dopamine. The drug therapy aims to correct this imbalance by the use of dopaminergic or anticholinergic drugs.

A. Dopaminergic Drugs:

i. Levodopa:

Dopamine does not cross the blood brain barrier and hence cannot be used. Levodopa, a precursor of dopamine passes freely into the brain, where it is converted into dopamine. Levodopa is degraded by an enzyme dopa decarboxylase found in the gut wall and the liver.

Benserazide, and carbidopa are extra-cerebral dopa decarboxylase inhibitors that prevent the peripheral degradation of levodopa to dopamine and permit the therapy with lower doses of levodopa. At the same time the reduced peripheral formation of dopamine decreases peripheral side effects such as nausea and vomiting and CVS effects. Two preparations which are widely used are co-beneldopa (levodopa + benserazide) and co- careldopa (levodopa + carbidopa).

Therapeutic uses:

Treatment is usually started with small doses of either with co- careldopa or co-beneldopa to prevent adverse effects. The optimum dose and the intervals between the doses depend on the reactions of individual patient to the drug. The efficacy of the drug falls with time of use. Patients may suffer from the ‘on-off’ effect.

During the ‘on’ period the patient walks normally, but during the ‘off period the patient reverts to the impaired gait of Parkinson’s disease. The duration of benefit of the drug often becomes shortened after prolonged use, necessitating an increase in frequency of dosing, which also increases the adverse effects. This is called the ‘end-of-dose’ effect of levodopa.

Adverse effects:

Nausea and vomiting are the commonest side effects. Domperidone is a useful antiemetic, because it blocks the effects of dopamine on the CTZ, without interfering with the therapeutic action of dopamine on the basal ganglia. Insomnia, postural hypotension, tachycardia and arrhythmias also can occur. Rarely involuntary movements and hypersensitivity and psychiatric symptoms may occur.

Levodopa is contraindicated in close angle glaucoma. Levodopa should not be combined with MAO inhibitors as it may result in hypertensive crisis. Volatile liquid anesthetics such as halothane carry the risk of arrhythmias. Dopaminergic drugs are not indicated in drug induced extrapyramidal symptoms (Parkinsonism).

ii. Amantadine:

Amantadine, an antiviral drug, stimulates the release of dopamine and blocks its re-uptake by dopaminergic nerve terminals in the corpus striatum. This results in an increased concentration of endogenously released dopamine at the receptor site.

It is not as effective as levodopa, but has the advantage of being relatively free from side effects. Adverse effects include nausea, insomnia, convulsions and hallucinations, swelling of the ankles and rarely leucopenia and rashes. Amantadine is contraindicated in epilepsy, renal disease, pregnancy, breast-feeding and peptic ulcer.

iii. Dopamine Receptor Agonists:

Ergot derivatives, bromocriptine, cabergoline, lisuride and pergolide act by direct stimulation of dopamine receptors in the basal ganglia. Though effective, they have no advantage over levodopa and adverse effects limit their use. They are used when treatment with levodopa is ineffective or requires supplementation.

The side effects of these drugs include nausea, postural hypo­tension, abnormal involuntary movements, confessional states, neuropsychiatry effects, pleural effusions and retroperitoneal fibrosis. They are contraindicated in hypersensitivity to ergot alkaloids, toxaemia of pregnancy, and postpartum hypertension.

Dopamine agonists produce their actions by acting on D₁ and D₂ receptors. Lisuride acts mainly on D₂ receptor and has a short duration of action, while pergolide, which acts on both D₁ and D₂ receptors, has the longest duration of action. Ropinirole, a newer D₂ receptor agonist, has been found to be useful in younger patients who may not tolerate levodopa well. Pramipexole is another dopamine receptor agonist which acts on both D₁ and D₂ receptors.

iv. Apomorphine:

Apomorphine is a potent stimulator of dopamine receptors and can be used under specialist supervision in patients to control the ‘off’ period associated with prolonged use of levodopa. The most common side effects of the drug are nausea and vomiting, which can be controlled by domperidone.

B. Dopamine Breakdown Inhibitors:

i. Selegiline:

Selegiline is a monoamine-oxidase inhibitor which prevents the breakdown of levodopa in the brain. Its use along with levodopa permits the use of smaller doses of levodopa as well as prolongation of its action. Nausea and confusion are the common side effects.

ii. Entacapone:

Entacapone blocks the action of the enzyme COMT in the gut wall and liver and thus prevents the breakdown of levodopa. It is used to prevent the ‘end-of-dose’ fluctuations which occur with levodopa. Side effects are mainly GI disorders, dizziness and rarely hepatitis. It is contraindicated in pregnancy and liver diseases.

C. Anticholinergic Drugs:

This group of drugs is less effective than dopaminergic drugs in Parkinson’s disease, although they may supplement their action. These dugs reduce tremors, but have less effect on rigidity. They are useful in reducing excessive salivation often found in Parkinsonism. The anticholinergic drugs, unlike dopaminergic drugs, reduce the symptoms of drug (antipsychotic drugs) induced Parkinsonism. Tardive dyskinesia is not improved and may be made worse.

No important differences exist between many synthetic anticholinergic drugs available, though tolerability to one may be better than another. Those most commonly used are orphenadrine, benzhexol, benzatropine, procyclidine and biperiden. Adverse effects include nausea, constipation, giddiness, dry mouth, urinary retention and glaucoma.

5. Essay on Emetics:

Vomiting occurs due to stimulation of vomiting centre in the medulla. This centre can be stimulated directly involving acetylcholine receptors by vestibular disorders (seasickness, vertigo), by gastric irritation or distension or even by mental activity.

Vomiting centre is also stimulated via chemoreceptor trigger zone (CTZ) involving dopamine and 5 HT receptors. CTZ is stimulated by certain drugs (e.g. apomorphine, opioids, and dopamine), cytotoxics (vagus and gut via 5-HT receptors) and estrogens (pregnancy). Emetics are of very limited value in the treatment of poisoning.

i. Reflex Emetics:

Ipecacuanha is a dried root that contains emetine and induces vomiting reflex by irritating the stomach. It is of very limited value, since there is no evidence that it prevents significant absorption of poison and can even cause mucosal damage and cardiac toxicity. Its use may only be considered if the patient is fully conscious, if the poison ingested is neither corrosive nor a petroleum distillate, if poison is not absorbed by activated charcoal or if gastric lavage is inadvisable or refused.

ii. Central Emetics:

Apomorphine is a semisynthetic derivative of morphine. It stimulates dopamine receptors in the CTZ and has some central depressant action. It is no longer used in poisoning except for patients with resistant Parkinson’s disease.

6. Essay on Antiemetics:

Acetylcholine, histamine, dopamine and 5HT are the neuro­transmitters in the CTZ and vomiting centre. Antiemetics act by blocking the action of these neurotransmitters.

i. Anticholinergics:

Hyoscine is the most effective drug for the prevention of motion sickness. Adverse atropine like effects are not generally prominent at the doses (0.2-0.4 mg) employed. It is also available as a transdermal preparation. Drowsiness and blurring of vision due to paralysis of ocular accommodation can occur.

ii. Antihistamines:

Antihistamines block the action of histamine and have acetyl­choline blocking action. They are slightly less effective in vestibular disorders, but are generally better tolerated. All antihistamines are equally effective, but generally a less sedative such as cyclizine or cinnarizine is preferred for longer journey. Promethazine is the preferred drug for vomiting of pregnancy, which sometimes is combined with pyridoxine.

iii. Dopamine Antagonists:

Phenothiazines are powerful anti-emetics, which act centrally by blocking the action of dopamine in the CTZ. They are used for the prophylaxis and treatment of nausea and vomiting associated with diffuse neoplastic disease, radiation sickness and vomiting caused by drugs such as opioids, general anaesthetics, and cytototoxics.

Chlorpromazine, perphenazine, prochlopromazine and trifluoperazine are commonly used. They may cause sedation. Levomepromazine is used, particularly in terminal case, to control vomiting and to reduce agitation. Domperidone prevents vomiting by blocking dopamine receptors in the CTZ. It penetrates blood brain barrier poorly and as a result is associated with a much lower incidence of extrapyramidal adverse effects.

It also enhances gastric emptying time. Its use is restricted because of its low bioavailability. It is used to suppress the vomiting that accompanies long-term treatment with opioids, levodopa and cytotoxic drugs. Metoclopramide is also a dopamine antagonist that affects gastric motility. It causes stomach to empty more quickly. It is a fairly effective antiemetic in doses of 10 mg thrice daily orally or by intramuscular injection.

It is used in non-ulcer dyspepsia, gastro-esophageal reflex, postoperative and opioid induced vomiting and in migraine. In very large doses it also blocks 5-HT receptors and is used as antiemetic during cancer chemotherapy. Side effects are rare, but metoclopramide may cause drowsiness, diarrhea and spasm of facial and neck muscles. Prolonged administration may lead to Parkinsonism, galactorrhea and tardive dyskinesia.

iv. 5-HT Antagonists:

Ondansetron and granisetron are 5-HT antagonists. They have no dopamine receptor antagonistic action and do not cause extrapyramidal symptoms. Both these drugs act on the gut, reducing gut motility and may cause constipation. They are potent anti-emetics and are used to prevent vomiting in patients receiving highly emetic cytoto-toxic drugs such as cisplatin.

Other Antiemetics:

Nabilone, a synthetic derivative of Cannabis indica, is used for vomiting induced by cytototoxic drugs, unresponsive to conventional anti-emetics. Side effects include dysphoria and dizziness. It is contraindicated in severe hepatic impairment.

Betahistine- The use of betahistine is only confined to Meniere’s disease in which vertigo and vomiting are due to disturbance in the labyrinth of the inner ear. It is believed to lower pressure in the inner ear and thus relieves symptoms. Side effects include GIT disturbances, headache and rashes.

Dexamethasone has proved useful as an antiemetic during cancer chemotherapy.

7. Essay on Local Anesthetics:

Local anesthetics act by causing a reversible inhibition of conduction along nerve fibres of both sensory and motor nerves without loss of consciousness.

Pharmacokinetics:

Local anesthetics vary widely in their solubility in water, ability to penetrate mucous membranes, duration of action, potency and toxicity. These variations determine their suitability for use by various routes, e.g. topical (direct application to skin and mucous membranes), intradermal injection, local infiltration (into subcutaneous tissues or deeper to involve muscles, other soft tissues or periosteum), local nerve blocks, extradural injection (extradural, epidural or caudal), subarachnoid injection (spinal) and intravenous regional anesthesia (Bier’s block).

Local anesthetics used as surface anesthetics (cocaine, lignocaine, prilocaine) are well absorbed from mucous membranes. Absorption can be extremely rapid and has led to deaths from overdose, especially via urethra. Local anesthetics are either hydrolysed by liver and plasma esterases or dealkylated in the liver.

Mechanism of action:

Local anesthetics block the nerve conduction by interfering with cell membrane permeability to sodium by blocking sodium ion channels.

Therapeutic uses:

Most local anesthetics, with the exception of cocaine, cause dilation of blood vessels. The addition of a vasoconstrictor such as adrenaline diminishes local blood flow, slows the rate of absorption of local anesthetics, and prolongs the duration of its action. Adrenaline must never be combined with local anesthetics given intravenously, as in a Bier’s block, because of its obvious dangerous effects on the heart, nor in blocks for digits and appendages as it may produce ischemic necrosis.

An alternative vasoconstrictor is felypressin (synthetic vasopressin), which does not affect the heart rate or blood pressure and may be preferable in patients with cardiovascular diseases.

i. Lingocaine (Lidocaine, Xylocaine):

Lignocaine is the safest and most commonly used local anesthetic. It has a rapid onset of action and duration of action of 1-2 hours. It is a mild vasodilator and is generally combined with adrenaline to prolong its duration of action.

Lignocaine suppresses the excitability of the ventricular muscle with only moderate depression of the heart’s action. It is therefore not likely to cause cardiac arrest or a fall of blood pressure except in overdose. Lignocaine is considered to be the first line drug for treating ventricular arrhythmias after acute myocardial infarction and cardiac operation.

ii. Bupivacaine:

Bupivacaine has a slow onset of action, but has the advantage over other local anesthetics in its longer duration of action. It is particularly suitable for continuous epidural analgesia in labour and spinal anesthesia. It is more toxic to the heart than other local anesthetics and must never be given for intravenous regional anesthesia (Bier’s block).

iii. Prilocaine:

Prilocaine is similar to lignocaine, although less potent and less toxic. In high doses, it may cause cyanosis due to formation of met-hemoglobin, which can be treated with intravenous injection of methylene blue.

iv. Ropivacaine:

Ropivacaine is a recently introduced local anesthetic, which is similar to bupivacaine, but is less cardio toxic.

v. Amethocaine:

Amethocaine is a vasodilator and is very toxic giving rise to hypersensitive reactions. Its use is limited for surface anesthesia.

vi. Mepivacaine and Articaine:

These are local anesthetics commonly used in dentistry.

vii. Benzocaine:

Benzocaine is used as a constituent of proprietary drug mixtures for use in sore throat, mouth ulcers and musculoskeletal conditions.

viii. Cocaine:

Cocaine, an alkaloid, is rarely used because of its potent sympathomimetic actions and its liability to cause euphoria and to increase capacity for physical work (misused as a drug of addiction).

ix. Procaine:

Procaine is an old drug that is now rarely used.

Adverse effects:

All local anesthetics can cause dangerous side effects, if absorbed. CNS toxicity is common and includes confusion, respiratory depression and convulsions. Hypotension and bradycardia leading to cardiac arrest may occur. Hypersensitivity reactions rarely occur. Routine tests for allergy or intolerance have been advocated. Reactions are least with lignocaine.

8. Essay on General Anesthetics:

Several drugs with different actions are used to produce a state of surgical anesthesia with minimal risk of toxic effects.

i. Preanesthetic Medication:

Premedication before surgical anesthesia may be needed to allay anxiety, to reduce oral secretions, to reduce the volume and increase the pH of gastric contents, and to relieve pain and discomfort when present. Drugs used for pre-anesthetic medication include anxiolytics, anti-cholinergic, pro-kinetics and analgesics.

ii. Anxiolytics:

Benzodiazepines possess useful properties for premedication including anxiolysis, sedation and amnesia. They have no analgesic action. Temazepam given orally (10-20 mg) is the usual choice. Its effects last for about 90 minutes.

iii. Anticholinergic:

Anticholinergic are used less commonly as premeditates to dry bronchial and salivary secretions which are increased by intubations, by surgery to the upper airways and by some inhalation anesthetics. Glycopyrronium (0.2-0.4 mg im or iv.) is preferred, because it produces good drying of salivary secretions and produces less tachycardia than atropine. It is widely used with neostigmine for reversal of non-depolarising muscle relaxants.

iv. Prokinetics:

Metoclopramide hastens gastric emptying, thus reduces the risk of vomiting, regurgitation and of subsequent inhalation of gastric contents during general anesthesia. It is commonly used before delivery in obstetric patients or general anesthesia in patients known to have significant gastro-esophageal reflex. Sodium citrate or ranitidine raises the pH of gastric content, which also reduces the risk of vomiting in the obstetric patient or general anesthesia.

v. Analgesics:

Opioid analgesics are now rarely used as premeditates as they cause respiratory depression, CVS depression, nausea and vomiting. NSAIDs do not depress respiration, do not impair GIT motility, do not cause dependence and are useful alternatives to opioids for the relief of pain. Ketorolac is usually preferred and can be given orally or parenterally.

vi. Induction Anesthetics:

Intravenous drugs are usually used to induce anesthesia. Induction is generally smooth and rapid. Intravenous induction drugs act only for a few minutes and anesthesia is then maintained using inhalational anesthetics and other drugs.

vii. Barbiturates:

Thiopental sodium is widely used intravenously for induction but it has no analgesic action. Induction is generally smooth and rapid (within 20 seconds). It cannot be used for maintenance of anesthesia throughout surgery because of its narrow therapeutic margin. Overdose causes cardiorespiratory depression. Accidental intra-arterial injection is dangerous and may result in arterial spasm and permanent ischemic damage to the arm. Awakening from moderate dose of thiopental sodium is rapid due to redistribution of the drug from the brain into other tissues, particularly muscle or fat.

viii. Etomidate:

Etomidate is not a barbiturate. It is metabolized more rapidly and recovery is more rapid without hangover effect. Its use is associated with a high incidence of involuntary muscle movement and pain on injection. It has minimal or no effect on blood pressure and may be preferred for induction in patients with cardiac problems. It is otherwise not commonly used.

ix. Propofol:

Propofol is very rapidly metabolized and is very widely used for induction as well as for maintenance of anesthesia or to sedate patients for hours or days in intensive care wards. Recovery from its effects is more rapid and complete than any of other induction agents. There is sometimes pain on intravenous injection, but significant involuntary muscle movements do not occur. Propofol causes profound bradycardia which can be prevented by atropine. Apnea, convulsions and anaphylaxis have also been reported.

x. Ketamine:

Ketamine differs from other induction drugs, in following respects:

a. It can be given intramuscularly as well as intravenously.

b. It has potent analgesic properties.

c. It increases the muscle tone.

d. It stimulates CVS and causes rise in blood pressure and tachycardia.

e. Recovery is associated with mental symptoms such as night­mares and hallucinations in adults, which restricts its use.

Ketamine is mainly used for paediatric anesthesia.

Maintenance of Anesthesia:

There are three important group of drugs used for maintenance of anesthesia throughout surgery following induction with intravenous anesthetic drug. These are:

A. Inhalation anesthetics

B. Short acting opioids

C. Muscle relaxants.

A. Inhalation Anesthetics:

Inhalation anesthetics may be gases or volatile liquids.

Nitrous Oxide:

Nitrous oxide is a safe anesthetic gas (also called laughing gas because it causes some patients to laugh if used on its own for induction of anesthesia). It is a weak anesthetic and is commonly used in a concentration of 50% to 70% in oxygen, as part of a balanced technique in association with other liquid volatile liquid anesthetics or intravenous drugs.

Unlike the other inhalation anesthetic, it has a powerful analgesic effect in sub-anesthetic concentrations. A mixture of nitrous oxide and oxygen containing 50% of each gas (Entonox) is used for pain relief in labour. Untoward effects of nitrous oxide are due to anoxia (resulting from unskilled use) or megaloblastic anemia due to inhibition of a vitamin B₁₂ co-enzyme necessary for folate metabolism. It may also depress bone marrow leading to leucopenia.

Volatile Liquid Anesthetics:

These are all volatile liquids that require a carrier gas, usually oxygen or nitrous oxide-oxygen mixtures, to deliver them. Unlike nitrous oxide, they have no analgesic properties in sub-anesthetic concentrations.

i. Halothane:

Halothane causes cardiorespiratory depression and severe hepatotoxicity. It produces moderate muscle relaxation and is rarely used.

ii. Enflurane:

Enflurane is less potent than halothane and is a powerful cardiorespiratory depressant. The risk of hepatotoxicity is less than halothane.

iii. Isoflurane:

Isoflurane is more potent than enflurane, does not cause cardiac arrhythmia or organ damage and is most commonly used.

iv. Sevoflurane:

Sevoflurane is the least toxic of the group and is particularly useful for inducing anesthesia in children. It acts extremely rapidly with an immediate recovery.

v. Desflurane:

Desflurane is a newly introduced volatile liquid anesthetic. It may cause cough, apnea, laryngospasm and increased secretions and is not widely used.

vi. Ether:

Ether is no longer used except in rural areas where resources (anesthetic equipment and resuscitation facilities) and skills are limited. It is a fairly safe anesthetic and can be used with simple and portable equipment using room air instead of cylinder oxygen. Ether has a great margin of safety, is an effective analgesic and causes good muscular relaxation due to a curare like action and depression of synaptic pathways in spinal cord.

The disadvantages of ether are that it is highly explosive and cannot be used with diathermy; is highly irritant and can cause copious bronchial secretions, the induction is very slow and recovery from anesthesia is associated with a prolonged hangover with nausea and vomiting.

B. Short Acting Opioids:

Intraoperative opioids in small doses are given before or with induction to adduce the dose requirement of inhalational anesthetics to a minimum. Alfentanil, fentanyl and remifentanil are particularly useful because they act within 1-2 minutes.

Remifentanil:

Remifentanil is of particular interest, because unlike other opioids (which are metabolized in liver), remifentanil is rapidly metabolized by nonspecific blood and tissue esterases and its short duration of action allows prolonged administration at high doses without accumulation, and with little risk of residual postoperative respiratory depression.

Because of its potency, short action and lack of CVS side effects, remifentanil is the drug of choice in the management of general anesthesia for major operations on patients with heart disease. If necessary, as with longer acting opioids, the action of short acting opioids may be easily reversed at the end of anesthesia by naloxone.

C. Muscle Relaxants:

Muscle relaxants used in anesthesia are neuromuscular blocking drugs, which have greatly revolutionized the anesthesia practice by enabling the use of low doses of general anesthetics for major surgery.

Neuromuscular blocking drugs relax the muscles of the abdomen and diaphragm and vocal chords permitting the employment of light levels of surgical anesthesia and intubation. Patients who have received muscle relaxants should always have their respiration assisted or controlled until the drug has been inactivated or antagonized.

a. Non-Depolarising (Competitive) Muscle Relaxants:

These groups of drugs occupy the receptor sites at the neuro­muscular junction and render acetylcholine ineffective that is released following nerve stimulation. The action of competitive muscle relaxants is reversed with anticholinesterases such as neostigmine.

i. Atracurium:

Atracurium is nonenzymatically metabolised which is independent of liver and kidney function, thus allowing its use in patients with hepatic or renal impairment. Cardiovascular effects are associated with some histamine release. Atracurium is one of the most commonly used competitive muscle relaxant.

ii. Vecuronium and Cisatracurium:

These drugs do not produce histamine release and lack cardiovascular effects. The duration of action is 20-30 minutes and is the most commonly used competitive blockers.

iii. Mivacurium:

Mivacurium has the shortest duration of action (10-15 minutes) and rarely requires neostigmine to reverse its action. It causes marked histamine release with cardiovascular effects.

iv. Rocuronium:

Rocuronium has the most rapid action of all non-depolarising muscle relaxants. It is reported to have minimal histamine releasing and cardiovascular effects. High doses produce vagolytic effects. It is excreted unchanged in the urine and is not suitable in patients with poor renal functions.

v. Gallamine and Pancuronium:

These have vagolytic and sympathomimetic properties. They are long acting (45-60 minutes) and are rarely used.

b. Depolarising Muscle Relaxants:

These drugs also occupy receptor sites for acetylcholine. They initially stimulate the muscle to contract and produce a state of persistent depolarisation during which no further stimulation is possible. Neostigmine does not reverse their action, but potentiates the neuromuscular blockade.

Suxamethonium:

Suxamethonium is the only depolarising muscle relaxant which is rarely used. It has rapid onset of action which is short lasting (2-5 minutes). It is mainly used for endotracheal intubation at the beginning of anesthesia and for very short procedures requiring relaxation. Common side effects include post-operative muscle pain, cardiovascular disorders, apnea and respiratory depression. Prolonged paralysis (suxamethonium apnea) may occur in patients with low or atypical plasma cholinesterase.

9. Essay on Centrally Acting Skeletal Muscle Relaxants:

This group of drugs differs in action from the muscle relaxants used in anesthesia which act at the neuromuscular junction. They reduce skeletal muscle tone by a selective action on cerebrospinal axis without affecting consciousness with the exception of dantrolene, which has a peripheral action. Centrally acting muscle relaxants are used for the relief of chronic muscle spasm or spasticity. They are not indicated for spasm associated with minor injuries. These drugs relax spasm without altering normal muscle function by damping down reflexes in the spinal cord.

i. Benzodiazepines:

Diazepam acts by damping down reflexes in the spinal cord. It is the most commonly used skeletal muscle relaxant in anxiolytic doses for the relief of chronic muscle spasm or spasticity of varied etiology including tetanus. Sedation and occasionally, extensor hypo-tonus are the disadvantages.

ii. Baclofen:

Balcofen inhibits transmission at spinal level and also depresses the central nervous system. It is used in chronic severe spasticity resulting from disorders such as multiple sclerosis or traumatic partial section of spinal cord. Sedation, drowsiness and nausea are common. It may occasionally cause respiratory or cardiovascular depression and gastrointestinal and urinary disturbances. Its use is contraindicated in peptic ulcer, and should be used with caution in psychiatric illness, epilepsy and hepatic or renal impairment.

iii. Tizanidine:

Tizanidine, α₂-adrenoceptor agonist, is indicated in spasticity associated with multiple sclerosis or spinal cord injury. It causes drowsiness, nausea and other gastrointestinal disorders, cardiovascular disturbances, hallucinations and insomnia. It is contraindicated in severe hepatic impairment.

iv. Dantrolene:

Dantrolene differs from the others in acting directly on the skeletal muscles at an intracellular level (but not by blocking the neuromuscular junction) and reduces the excessive metabolic activity seen in the muscle cells during malignant hyperpyrexia. It has the advantage of fewer central adverse effects making it a drug of choice.

Dantrolene interferes with calcium efflux in the skeletal muscle cells and thus stops the contractile process. It is used in chronic severe muscle spasticity and in malignant hyperthermia a lethal complication of volatile anesthetics (except nitrous oxide) characterized by a rapid rise in temperature, increase muscle rigidity, tachycardia and acidosis. It causes drowsiness, decrease in muscle power and diarrhea. It is contraindicated in hepatic impairment and in acidic muscle spasm.

10. Essay on Central Nervous System Stimulants:

Central nervous system (CNS) stimulants have very little place in therapy and should not be used to treat depression, obesity, senility, and debility or for relief of fatigue.

a. Amphetamines:

These are sympathomimetic, whose main action is on CNS.

Pharmacological actions:

Amphetamines are potent CNS stimulants, acting probably by releasing noradrenaline and dopamine. They produce euphoria, abolish fatigue, increase activity and reduce appetite. There is considerable psychic dependence but the withdrawal symptoms are not severe. Dexamphetamine has a greater central stimulant and less peripheral sympathomimetic action than amphetamine.

b. Methylphenidate (Ritalin):

Ritalin is a drug related to amphetamine. It is the only CNS stimulant used in narcolepsy and as an adjuvant in the management of refractory hyperkinetic states in children.

c. Cocaine:

Cocaine, a drug of addiction, is a CNS stimulant. It is only used for topical local anesthesia.

d. Caffeine:

Caffeine, one of the naturally occurring methyl-xanthine, has a weak CNS stimulant action. It has no therapeutic use and its combination with analgesics (aspirin) is unfounded.

e. Respiratory Stimulants (Analeptics):

Respiratory stimulants have a limited place in respiratory failure.

f. Nikethamide(coramine):

Nikethamide is an obsolete drug because therapeutic doses are close to toxic doses which may result in convulsions.

g. Doxapram:

Doxapram is the most effective analeptic with greater margin of safety. It stimulates cerebrospinal axis at all levels. Doxapram is used in postoperative respiratory depression and acute respiratory failure. Its use is contraindicated in severe hypertension, status asthmatics, coronary artery disease, thyrotoxicosis, epilepsy and physical obstruction of respiratory tract.

11. Essay on the Drugs of Addiction:

Drug dependence is a condition arising from habitual use of a drug in which the person has a compulsion to continue the use of the drug to have pleasurable psychic effects and feels ill if deprived of it (abstinence or withdrawal syndrome).

Drug dependence has two characteristic components psychological and physical dependence. Psychological dependence on drug leads to euphoria, which is characterized by an exaggerated feeling of physical and mental wellbeing, especially when not justified by external reality and the patient often resorts to antisocial activities.

Physical dependence produces biochemical changes in the patient, which results in very unpleasant signs and symptoms, if the drug is withdrawn. Physical dependence is of a temporary nature and lasts for a varying period, which finally disappears. The serious drugs of addiction are cocaine, opioids, barbiturates, alcohol, Cannabis, LSD, and nicotine.

a. Cocaine:

Cocaine causes intense psychic dependence with a feeling of elation and an increase in physical activity. Physical dependence is practically absent, withdrawal symptoms being depression, sleepiness and increased appetite. Cocaine dependence is quite common and is increasing day by day. It is taken orally, but more often sniffed.

Crack is the free base of cocaine, which is vaporized and the fumes inhaled leading to a rapid and intense effect due to absorption through lungs. More rapid effects are obtained by taking intravenously, when it may be mixed with heroin. The action of cocaine is short-lived and is often taken in repeated doses about every 30 minutes and carries a risk of dangerous overdose.

b. Opioids:

The most potent and frequently opioid of addiction is heroin. Psychological and physical dependence is severe, tolerance develops rapidly and withdrawal symptoms are severe which include nausea, vomiting and muscle cramps. Injections under non-sterile and sharing conditions can give rise to septicemia and risk of being infected with the virus of hepatitis B or C or the HIV causing AIDS.

Lofexidine is used for the alleviation of symptoms in patients undergoing opioid withdrawal. It prevents the rise of noradrenaline in the brain (responsible for many of the unpleasant withdrawal symptoms) which occurs when opioids are withdrawn. It does not lower the blood pressure.

Naltrexone, an opioid antagonist, blocks the euphoric effect of opioids, which is linked to addiction and is given to former opioid addicts as an aid to prevent relapses.

c. Barbiturates:

Barbiturates are still used in epilepsy. They are dangerous drugs of addiction and cause very severe physical dependence. Tolerance is less marked than with opioids, but withdrawal symptoms are more severe.

d. Alcohol:

Psychological dependence on alcohol is very common and its management is a difficult medical and social problem. Chronic use of alcohol leads to physical dependence. Sudden withdrawal from an addict can precipitate an acute psychotic attack (delirium tremens) with agitation, anxiety, excessive sympathetic activity and convulsions.

Chronic alcoholism damages several organs. It may lead to dementia and peripheral neuritis, cirrhosis of the liver and CVS disorders including cardiomyopathy and hypertension. Chronic alcoholics are prone to infection with a high incidence of tuberculosis.

Disulfiram (antabuse) is used as an adjunct to the treatment of alcohol dependence. It inhibits the breakdown of alcohol, leading to accumulation of acetaldehyde which causes flushing, nausea, vomiting and headaches and thus the patient is discouraged from further drinking.

Acamprosate, a centrally acting drug, may be helpful in maintaining abstinence in alcohol-dependent patients. It may cause GIT disorders and occasionally skin rashes. It is contraindicated in renal and severe hepatic impairment.

e. Cannabis (Bhang, Ganja, Charas):

Cannabis is obtained from a plant Cannabis indica. It is the drug of addiction having lowest acute toxicity. Tolerance develops and withdrawal symptoms (anxiety and insomnia) occur. It produces mild excitement with a feeling of relaxation and peace.

Perception of time is altered, concentration is impaired and the subjects feel hungry. It reduces motivation and produces a dreamlike state with disorientation, loss of contact with realities of life and the conjunctivae appear red due to vasodilatation. Rarely, it causes a psychotic state with hallucinations and disorientation. The use of Cannabis may lead a person on to take more serious addictive drugs such as heroin.

f. Lysergic Acid Diethylamide (LSD):

LSD causes hallucinations combined with a variety of mental abnormalities. Its use can lead to severe psychotic states in which life may be at risk.

g. Nicotine:

Nicotine is a constituent of tobacco, which stimulates ANS (rise in BP and pulse rate) and has mild cocaine like action on the brain. It causes both psychological and physical dependence. The use of tobacco is associated with increased incidence of chronic bronchitis, emphysema and lung cancer (in smokers) cancer of lip and tongue, coronary artery and peripheral vascular disease. Withdrawal symptoms include tobacco craving, constipation and increased appetite.