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Drugs Acting On Central Nervous System is among the most commonly used drugs today.
To start with is an important class of drugs known as non-steroidal anti-inflammatory drugs.

Non-steroidal Ant-inflammatory Drugs (NSAIDS).

Analgesics are broadly classified into two categories:

  1. Opioid analgesics and
  2. Non-opioid analgesics

All drugs in this category have analgesic, antipyretic and anti-inflammatory actions in different measures. They are also known as non-narcotic, non-opioid or aspirin-like analgesics.

These drugs comprise of:

  1. Salicylates,
  2. paracetamol,
  3. Non selective COX inhibitor NSAIDS and,
  4. Selective COX2 inhibitor NSAIDS.

Their chief use is to treat minor pain, i.e. headaches etc, and to control the pain and stiffness in rheumatic disorders and osteoarthritis.

Like we have mentioned, NSAIDS have three major therapeutic actions:

  • Analgesic – pain relief,
  • Antipyretic – temperature reduction and,
  • Anti-inflammatory – reduce tissue inflammation.

What is the Mechanism of action of NSAIDS?

Two enzymes are concerned with the formation of prostaglandins: cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). The prostaglandins produced by COX-2 are responsible for pain and inflammation.

NSAIDs block prostaglandin production. COX-1 has a protective effect on the stomach lining.

Most NSAIDs block both COX-1 and COX-2. Although they relieve pain and inflammation, they may cause peptic ulcers. Due to this effect, selective COX2 inhibitors have been developed and are less likely to cause stomach ulceration.

THE SALICYLATES

Aspirin (Acetyl salicylic acid)

This drug has been in used since the year 1899.

Administration and absorption - Asprin is Usually given by mouth and is rapidly given by mouth and is rapidly absorbed from both the stomach and ileum.

Activation and distribution

Once in circulation and tissues, aspirin is converted into the active metabolite salicylate, in the liver; Aspirin is therefore a prodrug.

In higher therapeutic doses, some of the salicylate becomes bound to plasma proteins.

Mechanism of action

Inhibition of prostaglandins. Aspirin is a non-selective inhibitor (it inhibits both COX-1 & COX- 2). It is effective against pain of low intensity and particularly that of rheumatoid arthritis.
Asprin is a weaker analgesic than the morphine type drugs. It produces no sedation, tolerance or physical dependence.

Aspirin is also an antipyretic - It rapidly reduces fever by promoting heat loss (sweating, cutaneous vasodilation). The control of body temperature is regulated by a center in the hypothalamus, which balances heat production, resulting from metabolism against heat loss.

When a patient develops fever the heat regulating mechanism is set at a higher level than normal. Aspirin acts in this centre by inhibiting prostaglandins production in the hypothalamus and reset temperature control to normal levels in the hypothalamus for as long as aspirin therapy is maintained.

Heat loss is achieved by sweating and by dilatation of blood vessels of the skin. Aspirin is used until the body eliminates the cause of pyrexia.

Signs of inflammation (pain, tenderness, swelling, and vasodilation) are suppressed too by asprin.

Therapeutic uses of aspirin

  • Analgesic
  • Antiinflammatory - arthritis
  • Cardiovascular uses – used to inhibit platelet aggregation.

Adverse drug reaction

  1. Side effects – nausea, vomiting, epigastric pain
  2. Hypersensitivity / idiosyncrasy – though infrequent, they can be serious. Reactions include rashes, rhinorrhoea, asthma.
  3. Antinflammatory doses (3-5 g/day) - produces a syndrome called salicylism – dizziness, tinnitus, vertigo, reversible impairment of hearing and vision, mental imbalance and electrolyte imbalance.
  4. Reye’s syndrome – a rare form of hepatic encephalopathy seen in children having viral (varicella, influenza) infection.
  5. Acute salicylate poisoning – more common in children. Fatal dose in adults estimated to be 15 -30 g, but is considerably lower in children.

Signs include:

Vomiting, dehydration, electrolyte imbalance, acidotic breath, haemorrhage, convulsions and death due to respiratory failure and cardiovascular collapse.

Treatment of asprin overdose.

  • The treatment is symptomatic & supportive
  • Most important cooling and iv fluid with Na+, K+, HCO3- and glucose according to need determined by repeated monitoring.
  • Gastric lavage to remove unabsorbed drug.
  • Forced alkaline diuresis.
  • Blood transfusion and vit K should be given if bleeding occurs.

Precautions and contraindications

  • Patients sensitive to aspirin, in peptic ulcer,
  • Bleeding tendencies & patients receiving anticoagulant drugs.
  • Children suffering from chicken pox or influenza.
  • Chronic liver disease
  • Given during pregnancy it may be responsible for low birth weight.

Drug interactions

Increases the effects of : anticoagulants, oral hypoglycaemics by displacing them from protein binding sites.

PARACETAMOL (ACETAMINOPHEN)

Paracetamol is widely used as a minor antipyretic and analgesic. It has some COX inhibiting properties, although, this action is very weak.

It has no anti-inflammatory actions; therefore, it can not be used in the treatment of rheumatoid arthritis.

The main advantage of paracetamol is that it does not cause indigestion, gastric bleeding, hypersensitivity reactions are rare, it does not affect platelet function or clotting factors.

Therapeutic uses

  • The drug is given orally in tablet form. It is well absorbed and the peak plasma concentrations are usually achieved within 60 minutes.
  • Used as a mild analgesic and antipyretic for children under 12 years old as it does not cause Reye’s syndrome.

Adverse drug reactions are uncommon in normal doses.

Acute paracetamol poisoning

Paracetamol overdose causes dangerous liver damage. The margin of safety is relatively low, and doses as low as 2-3 times the maximum therapeutic doses can be harmful to the liver. If large dose > 10 g in an adult; serious toxicity can occur.

Early Treatment

  • If the patient is brought early; induce vomiting or gastric lavage.
  • Activated charcoal administered orally to prevent further absorption.
  • Other supportive measures as needed.
  • Specific antidote: N acetyl cysteine – it replenishes glutathione stores of the liver and prevents binding of the toxic metabolite.

ANALGESIC MIXTURES WITH ASPIRIN OR PARACETAMOL

There are many mixtures in which aspirin or paracetamol is combined with a small dose of weak opiate, thus the risk of dependence is reduced. These combinations are a little stronger than aspirin or paracetamol and are used for more sever pain. They are very common and are available over the counter.

Among those in common uses are:

  • codeine phosphate + paracetamol
  • Codeine phosphate + aspirin

NSAIDS and the uterus

Prostaglandins can cause contraction of the uterus and are important in the initiation of labour. NSAIDS by preventing prostaglandins formation are useful in reducing period pains and have also been used to prevent premature labour.

Older NSAIDS

  1. Indomethacin (indocid)
  2. Phenylbutazone

Both are associated with problematic side effects. Indomethacin has been used in various forms of arthritis and in acute gout.

It is effective but minor adverse effects, particularly the gastrointestinal tract are common.

Phenylbutazone has serious adverse effects, including agranulocytosis, gastric bleeding, salt and water retention.

NON SELECTIVE COX NSAIDS

  1. Diclofenac
  2. Aceclofenac
  • Ibuprofen
  1. Fenbrufen
  2. Ketoprofen
  3. Meloxicam
  • Naproxen
  • Piroxicam
  1. Sulindac

There are now a large number of NSAIDS available for use in rheumatoid arthritis and allied disorders. These drugs are given to reduce pain in dentistry and that arising from soft tissue and bony injuries.

There are certain general principles that can be applied to this group;

  • There is no preferred drug. Patients vary in their preference, and if one drug is ineffective after 2 weeks of treatment, another drug should be substituted.
  • If satisfactory response is obtained; use the lowest dose.
  • All these drugs may cause gastric irritation.
  • Ibuprofen in doses normally recommended is rather less likely to produce side effects than the others in this group.
  • Several of these drugs are available as suppositories (e.g. Diclofenac, indomethacin, ketoprofen) or as injection (Diclofenac).
  • Some NSAIDS are available over the counter (without a prescription) e.g. ibuprofen, ketoprofen etc.

Adverse effects

  • Indigestion
  • Gastric bleeding and perforation are particularly common in the elderly and are believed to be due to the inhibition of the gastric protective action of prostaglandins. They should not be used in patients with peptic ulcers or bleeding disorders, however, if essential they can be combined with omeprazole.
  • Salt and water retention.
  • Rarely bronchospasm; therefore they may worsen asthma.
  • CNS - headache, dizziness, blurring of vision, tinnitus and depression.

SELECTIVE COX-2 INHIBITORS NSAIDS

  1. Celecoxib

These are newer class of drugs that are now prescribed as NSAIDS. They selectively inhibit COX-2; they spare COX-1.

At relatively low concentrations they act predominantly on COX-2, but at the dose levels prescribed, these drugs may be active enough on COX-1 to cause similar levels of gastric damage like the other NSAIDS.

CHOICE OF NSAIDS

NSAIDS have their own spectrum of ADRS. They differ quantitatively among themselves in producing different side effects.

No single drug is superior to all others for every patient.

The cause and nature of pain (mild, moderate or severe); (acute or chronic; ratio of pain: inflammation) along with consideration of risk factors in the given patient govern selection of the analgesic.

Also to be considered are the past experience of the patient, acceptability and individual preference.

Patients differ in their analgesic response.

NSAIDS and the kidney

NSAIDS very rarely damage the kidneys in normal subjects. However, in patients with heart failure, liver cirrhosis, and renal disease or in patients who are taking diuretics, they occasionally precipitate renal failure. This is mainly through the alteration of blood flow through the kidneys, which follows the inhibition of the prostaglandin production. This is usually reversible upon stopping the drug. The renal function should therefore be checked after a short period of treatment.

Some guidelines

  • Mild to moderate pain with little inflammation use paracetamol or low dose ibuprofen.
  • Acute musculoskeletal, osteoarthritis, injury associated pain: paracetamol, Diclofenac
  • Gastric intolerance : Selective COX-2 inhibitor or paracetamol
  • Patients with asthma or history of anaphylactoid reaction to aspirin; Nimesulide, COX-2 inhibitor.
  • Paediatrics: paracetamol, ibuprofen
  • Pregnancy: paracetamol is the safest; followed by low dose aspirin

OPIOID (NARCORTIC) ANALGESICS

All opioids are drugs that potentially cause dependence (addiction).

Opioid and related drugs

Agonists

  1. Morphine
  2. Diamorphine
  • Methadone
  1. Pethidine (meperidine)
  2. Codeine
  3. Dihydrocodeine
  • Dextropropoxyphene

Partial agonist

  1. Buprenorphine
  2. Meptazinol
  • Nalbuphine
  1. tramadol

Antagonist

  1. Naloxone
  2. Naltrexone

THE MECHANISM OF ACTION OF OPIOID ANALGESICS & ANTAGONISTS OF OPIOID ACTION

Norhe body contains chemicals called endorphins and encephalins. These are the body’s own type of opioid. Two of these, β endorphin and metencephalin, act on special opioid receptors in the nervous system, particularly in the midbrain and the posterior horn of the spinal cord.

  • It seems that β endorphin and metencephalin, are part of a system of brain that controls pain appreciation.
  • Opioid drugs also react with these receptors and thus relieve pain. There are several types of opioid receptor in the nervous system, but the most important for pain control by opioids are μ (mu) receptors, they are responsible for analgesia, euphoria and respiratory depression.
  • Other receptors are δ (delta) and κ (kappa).
  1. MORPHINE

This is the principal alkaloid in the opium and is still widely used.

Pharmacological action

  1. CNS

The most important actions of morphine are on the CNS. The effects may be divided into: Depressant and stimulant.

Morphine also causes development of tolerance and dependence.

  1. CNS depressant effects
  • It is a powerful analgesic – depresses the appreciation of pain by the brain.
  • It relieves all types of pain.
  • If the pain is felt at all it seems to have lost all its unpleasant nature.
  • Morphine depresses the emotional aspect of pain (anticipation, fear of pain)
  • It is euphoric and allays anxiety.
  • It is a mild hypnotic and may produce drowsiness and sleep.
  • It depresses the cough centre, relieves cough.
  • It depresses the respiratory centre.
  1. CNS stimulant effects
  • Morphine stimulates the chemoreceptor trigger zone (CTZ) in the brain stem causing nausea and vomiting in about 30% of the patients, particularly if they are mobile.
  • The pupils of the eye are constricted due to the effect on the nucleus of the third nerve.
  • Morphine stimulates the vagus nerve. This action is particularly liable to be troublesome when morphine is used for the pain of coronary thrombosis as it may cause undue slowing of the pulse and lowering of the blood pressure.
  1. Peripheral actions outside the CNS
  2. Constipation – It decreases the peristaltic activity of the bowel and at time increases the tone, leading to constipation. To avoid constipation; it should be administered with senna (a laxative).
  3. Increase in billiary pressure – it causes spasm of the sphinctures, including sphincture of oddi at the lower end of the bile duct and thus produces a rise in the pressure in the billiary system.
  • Urinary retention – It interferes with bladder function, which may cause urinary retention, particularly after an operation.
  1. Histamine release – It causes some histamine release, occasionally leading to bronchoconstriction.

COMMON USES OF MORPHINE

  1. Pain control – morphine is very useful for pain control in:
  • Surgical emergencies
  • The postoperative period
  • Following injury
  • After coronary thrombosis
  • Controlling severe pain in terminal cancer on a regular basis
  • Acute failure of left ventricle with pulmonary oedema.
  1. Cough
  2. Diarrhoea

Administration

Oral

  • Can be given orally as an immediate release tablet that must be given every 4 hours.
  • For long term control of pain there are slow release tablets which are only needed twice daily.
  • When given orally as a single dose, morphine’s effect is greatly reduced because the liver breaks down about 75% of the dose through first pass metabolism before the drug reaches the circulation. With repeated oral dosage, however, it is very effective. This may happen because the metabolite morphine-6-glucuronide is slowly excreted and with repeated dosage accumulates sufficiently to help produce sufficient analgesia.

Injection

  • SC
  • IV
  • Continuous SC infusion – For severe & fluctuating pain.
  • When given as an injection, morphine produces analgesia rapidly. The analgesic effect of morphine usually lasts about 4 hours after injection but depends to some extent on the severity of the pain, sensitivity of the patient to the drug, and on the dose.

Metabolism & excretion

  • After absorption, morphine is converted to form several substances, one of which is (morphine-6-glucuronide) has powerful analgesic properties of its own.
  • The kidney excretes these substances.
  1. DIAMORPHINE (HEROIN)

Its obtained by chemical modification of morphine. When given by injection it enters the nervous system more rapidly than does morphine, so its action starts a little sooner. Thereafter it is converted to morphine in the body.

When given orally, diamorphine is all converted to morphine in the liver before it enters systemic circulation; therefore their actions are similar.

Although diamorphine is more popular than morphine among addicts, it is difficult to see a scientific reason for this and may be for social or mythological reasons.

Adverse effects of morphine and diamorphine

  1. Side effects – Sedation, mental clouding, vomiting constipation, respiratory depression, blurring of vision, urinary retention.
  2. Idiosyncrasy and allergy – Uncommon and anaphylactoid reaction is rare. Urticaria, itching, swelling of lips are the manifestations.
  3. Tolerance and dependence
  • A phenomenon whereby successfully more of a drug is needed to produce the same effect.
  • Tolerance develops only to the CNS actions of morphine, and long term diamorphine (heroin) addicts take doses (as much as 50 times the therapeutic range) that would normally kill the naïve user. The same addicts still develop constipation to a much smaller dose that would not satisfy their craving.
  • High degree of tolerance can be developed to morphine and related opioids if the drug is used repeatedly. It is partly pharmacokinetic (enhanced rate of metabolism), but mainly pharmacodynamic (cellular tolerance).
  • Cross tolerance – among opioids is of high degree. Morphine tolerant subjects are partially cross tolerant to other CNS depressants.
  • Morphine produces pronounced psychological and physical dependence, its abuse liability is rated high.
  • Concern about abuse has been a major limitation in the use of morphine, but appropriate medical use seldom progresses to dependence and abuse.
  • Morphine abuse is higher among medical and paramedical personnel.
  • Withdrawal of morphine is associated with marked drug seeking behavior. Physical manifastations are – lacrimation, sweating, yawning, anxiety, fear, restlessness, tremor, insomnia, rise in blood pressure, palpitation, mydriasis, convulsions.
  • Treatment – consist of the withdrawal of morphine and substitution with oral methadone (long acting, orally effective followed by gradual withdrawal of methadone.

Acute morphine poisoning

  • It is accidental or suicidal or seen in drug abusers.In non tolerant adult 50mg of morphine i.m produces serious toxicity. The human lethal dose is estimated to be about 250mg.

Manifestations

  • Stupor, coma, pinpoint pupils, fall in BP, shock, pulmonary edema at the terminal stages, death due to respiratory failure.

Treatment / management

  • Respiratory support
  • Maintenance of BP with IV fluids and vasoconstrictors
  • Gastric lavage with potassium permanganate to remove unabsorbed drug.
  • Specific antidote – naloxone.

METHADONE

  • A synthetic analgesic that is as powerful as that of morphine, but it has little of morphine, euphoric and tranquilizing effect.
  • It has a depressing effect on the cough centre, but the effect on the respiratory centre is not so marked.
  • It is rapidly and well absorbed after oral administration or SC administration.
  • It has a longer lasting duration of action than morphine. It should not be given more than twice a day to avoid accumulation.

Therapeutic uses

  1. Analgesic – substitute to morphine
  2. Cough suppressant
  3. Heroin withdrawal

PETHIDINE (MEPERIDINE)

  • A synthetic substance that is related to atropine. It is well absorbed after oral / SC administration.
  • It is less powerful than morphine, but has less effect in therapeutic doses on the cough and respiratory centre.
  • It is not constipating.
  • It does not cause pupil constriction; therefore its used in head injuries where observation of the pupil size may be important.

Therapeutic uses

  • Treatment of moderately severe pains.

FENTANYL

  • A pethidine congener, 80-100 times more potent than morphine both in analgesia and respiratory depression. It has a short duration of action; starts wearing off after 30-40 minutes due to redistribution.
  • Transdermal fentanyl is available for use in cancer or other types of chronic pain for patients requiring opioid analgesia.

CODEINE & DIHYDROCODEINE

  • Codeine is obtained from opium. It is given orally as a mild analgesic, having only about 1/7th of the analgesic action of morphine.
  • Its most important action is the depressant action on the cough centre and it has about half as powerful as morphine in this respect.
  • It can also cause constipation.

Therapeutic uses

  1. Mild analgesia – codeine mixed with aspirin / paracetamol.
  2. Diarrhoea
  3. Cough – codeine is widely used in various mixtures.

DEXTROPROPOXYPHENE

  • Is similar to methadone but is a much weaker analgesic.
  • It is combined with paracetamol as the compound tablet co-praxamol (distalgesic) – used for pain that is not relieved by aspirin / paracetamol.

PARTIAL AGONISTS

  • They are powerful analgesic but are less addictive, less likely to depress respiration and are less euphoric.
  1. BUPRENORPHINE
  • Is as powerful as morphine (about 25 times more than morphine).
  • Can be given by injection or sublingually, it is not effective orally as its broken down in the liver in a large first pass action. Its analgesic action lasts 6-8hours.
  • Less likely to depress the respiratory centre and as low risk of dependence.
  • It has a ceiling effect so that increasing the dose above the usual range will not improve its efficacy.

Therapeutic uses

  • Analgesic – for moderate and severe pain. Can be given as an injection for postoperative pain. Can also be given sublingually every 6-8hours for various forms of chronic pain.

Adverse drug reactions

  • Vomiting – This requires the drug to be stopped.
  • Respiratory depression.

MEPTAZINOL

Similar in some respects to buprenophine.

When given by injection, it has a short action (2-3hrs) and is used in obstetrics where its rapidly eliminated by both the mother and fetus.

TRAMADOL

  • It is a weak opioid and in addiction, reduces pain appreciation by interfering with pain pathways through the spinal cord.
  • Its action lasts for about 6 hours.
  • Its as powerful as pethidine.

MORPHINE ANTAGONISTS

  • Several substances antagonize the actions of morphine and other opioids.
  • They resemble morphine in their chemical structure and thus compete with it for their receptor sites. Having occupied the receptor sites, however, they produce little or no stimulation so that the actions of morphine are reversed.
  • They are used to treat overdose by opioids.
  1. NALOXONE

Apure antagonist having no stimulating actions. It reverses the effects of both natural and synthetic opioids.

It has no analgesic actions.
It can be used to terminate the action of narcotic drugs in the postoperative period. It is the drug of choice for morphine poisoning and for reversing neonatal asphyxia due to opioid use during labour.

Its duration of action is relatively short (about 1 hour), therefore, if its used to reverse the effects of longer acting opioids repeated doses might be needed.

2.NALTREXONE

Natrexone is an opioid antagonist used in special clinics for opioid withdrawal.

ANXIETY, SEDATIVE – HYPNOTICS

Another class of drugs Acting On Central Nervous System are drugs to treat anxiety and sedating drugs all in ombination known as hyponotics.

Sedative – a drug that subdues excitement and calms the subject without inducing sleep, though drowsiness may be produced. Sedation refers to decreased responsiveness to any level of stimulation.

Hypnotic – A drug that induces and/ or maintains sleep.

Sedatives and hypnotics are more or less general CNS depressants with somewhat differing time-action and dose-action relationships.

Those with quicker onset, shorter duration and steeper dose relationship are preferred as hypnotics.

Those more slowly acting with a flatter dose-response curve are employed as sedatives.

  1. ANXIETY

Anxiety – term used to describe a condition of generalized, all pervasive fear.

THE NATURE OF ANXIETY

Anxiety is a useful phenomenon and a certain amount is useful to the individual, acting as a stimulant and increasing efficiency. However, when it becomes disproportionate to the stimulus, an anxiety state develops, and this degree of anxiety may interfere seriously with the patients life.

TYPES OF ANXIETY

  1. General anxiety disorder (GAD) – the patient feels apprehensive and tense for no particular reason or as a result of some apparently minor problem.
  2. Panic attacks – Are unexpected attacks of anxiety often with marked physical symptoms such as tremor, palpitation and dry mouth due to the over activity of the sympathetic nervous system.
  3. Obsessive compulsive disorder – Characterized by repetitive, anxiety-driven behavior such as repeated washing of hands or obsessive thoughts and doubts.
  4. Post traumatic stress disorder – anxiety which follows traumatic events such as warfare, rape etc.
  5. Phobic states – in which the patient fears certain situations.

Various methods of treatment may be used including:

  • Counselling
  • Relaxation techniques

ANXIOLYTIC DRUGS COMPRISES:

  1. Benzodiazepines
  2. Buspirone
  • β Blockers
  1. Antidepressants

BENZODIAZEPINES

Mechanism of action

Benzodiazepines act on the reticular formation and limbic system in the brain. There are specific receptor sites for benzodiazepines on the GABA (Gamma-amino butyric acid) receptor and they appear to enhance the action of the neurotransmitter GABA, which is produced by the brain and which depresses brain function.

Therapeutic uses

  • They are widely used for anxiety.
  • Benzodiazepines should only be used for acute agitation, panic attacks and for anxiety if it severe and disabling, the treatment should be at the lowest effective dose for not more than 2 weeks and combined with other treatments.

Although Benzodiazepines are effective in relieving anxiety, they have two serious disadvantages:

  1. They become less effective on prolonged use.
  2. If the drug is stopped suddenly even after a relatively short period of use (e.g. 2-3weeks), about 1/3rd of the patients will develop some withdrawal symptoms; (anxiety, sleeplessness for a few days, but after prolonged and heavy dosage may include seizures, psychotic symptoms, muscle pains and twitchings). They usually occur within a week of stopping the drug and earlier if short acting.

Other uses of benzodiazepines (BZDS)

  1. Diazepam & clonazepam – given IV for treatment of status epilepticus
  2. Diazepam also has some muscle relaxing properties and is used in combination with an analgesic to relieve pain and spasm.
  • Benzodiazepines are metabolized in the liver and often produce further active compounds.
  • Duration is dependent on the dose and to some extent on the individual.

Adverse drug reactions

  1. Side effects of hypnotic doses – dizziness, vertigo, ataxia, disorientation, amnesia, impairment of psychomotor skills – should not drive, weakness, blurring of vision.
  2. Dependence producing liability is low; withdrawal syndrome is generally mild.
  3. Tolerance to the sedative effects develops gradually, but there is little tendency to increase the dose.

Drug interactions

  1. BZDS synergise with alcohol and other CNS depressants leading to excessive impairment.
  2. Concurrent use with sodium valproate has provoked psychotic symptoms.

BENZODIAZEPINE ANTAGONIST

FLUMAZENIL

Is a BZD analogoue which has practically no effect on normal subjects, it compete with BZD agonist as well as.

  1. BUSPIRONE
  • Buspirone is an attempt to produce an anxiolytic drug without side effect. It reacts with a group of 5-HT receptors. It appears to have no sedation or risk of dependence. The only side effects are occasional nausea and headache.
  • The onset of action is delayed until 2 weeks and it appears to be ineffective in the treatment of the symptoms of BZD withdrawal.

iii. β blockers

Propranolol suppresses the physical concomitants of anxiety (tremor and palpitations).

  1. Antidepressants

Both tricyclic antidepressants, and 5-HT re-uptake inhibitors such as fluoxetine are helpful in the treatment of anxiety in small doses particularly in the case of panic attacks.

INSOMNIA

Lack of adequate sleep in a person.

Insomnia can cause feelings of anxiety, inability to concentrate and general debility. Sleep requirements vary with age. Hypnotics are drugs which produce sleep similar to the normal sleep. Before prescribing hypnotics it is important to ascertain whether the patient is not getting enough sleep, since some people exaggerate their insomnia. It is necessary to find out if there is some reason for failing to sleep.

The reasons may include:

  • Anxiety and stress
  • Depression
  • Physical illness e.g. heart failure, chronic lung disease
  • Pain
  • Caffeine, alcohol and steroids taken before retiring
  • If these problems are remedied, sleep should occur naturally.
  • Various simple measures can be tried e.g. a walk, a bath, a rather unexciting book before retiring or a glass of milk at bedtime may be insufficient.
  • Hypnotics may be required in some circumstances, for example during periods of stress or for certain chronic insomniacs, their use should be discouraged.
  • Tolerance to their action often develops in 2-3 weeks with some degree of dependence. Withdrawal as this can lead to increasing wakefulness at night for a few days or longer.

HYPNOTIC DRUGS

  1. Chloral hydrate
  2. Promethazine (an antihistamine)
  • Benzodiazepines
  1. Zaleplon, zopiclone and zolpidem
  2. Ethyl alcohol
  3. Chloral hydrate
  • Chloral hydrate and its derivatives have been used as hypnotics for many years and particularly useful in children.
  • Chloral hydrate is rapidly absorbed and produces sleep in about 30 minutes, by causing interference in the functioning of the brain cells. The drug is conjugated in the liver and excreted via the kidneys.
  • Its hypnotic action lasts about 4 hours.

Therapeutic use

Although it is effective hypnotic, its use has declined and its no longer the hypnotic of choice in children.

Adverse drug reactions

Relatively safe drug but it may cause gastric upset. It should be used with caution in liver or renal failure.

Promethazine (an antihistamine)

It is an antihistamine which by blocking the action of histamine in the brain causes sleep. It is not a particularly good hypnotic, having a rather long hypnotic action thereby causing sedation the next morning. It can also cause dryness of mouth and urinary retention.

  • Benzodiazepines

There is very little to choice between them in efficacy, their main difference being in their duration of action. BZDs with prolonged duration of action may produce a hangover the next day if given in a dose sufficient to produce sleep.

They are easy to use and pleasant to take and are the most commonly prescribed hypnotic drugs.

  1. Nitrazepam

Some sedative effect may persist well into the next day. Good for patients with nocturnal awakening when some daytime sedation is acceptable.

  1. Diazepam

It is usually used as anxiolytic drug, but it is a fairly good hypnotic drug if there is some background anxiety and sedation lasting into the next day is required.

  1. Temazepam

It has a shorter half life and duration of action. It is less liable to cause drowsiness the following day.

Good for sleep onset difficulty. Accumulation occurs on daily ingestion.

  1. Flunitrazepam

Has a fairly prolonged action. It is tasteless; it can be added to drinks etc. It has gained reputation for being used when rape is intended.

Adverse effects of BZDs

  1. Development of dependence – this can occur after 2 weeks or less when they are being used as hypnotic. Withdrawal then results in difficulty to sleep for several days or weeks, and the temptation is to resume using them. Cross tolerance to alcohol and other CNS depressants.
  2. When stopping treatment with BZDs particularly if they have been used for a long time the dose should be reduced in a stepwise manner every 2 weeks, depending on the symptoms and finally withdrawing altogether.
  3. Impairment of psychomotor skills – dizziness, vertigo, disorientation, prolongation of reaction time – therefore the patient should not drive or operate machinery.
  4. Zaleplon, zopiclone and zolpidem

They are short acting hypnotics, differ in structure from the BZDs, they also bind to the BZD receptors and increase the sedating activity of GABA in the brain.

  1. Zaleplon

It is indicated for short time use. It is not recommended for patients under 18 years of age. Patients should be advised not to take a second dose during the same night.

Adverse effects

Headache, dependence, drowsiness and dizziness,

  1. Zopiclone

Rapidly absorbed and produces sleep lasting 6-8hours. There may be some drowsiness the next morning. Tolerance and dependence may develop.

Adverse effects

  • Bitter metallic taste.
  • Should not be used during pregnancy or given to children
  1. Zolpidem

Has low dependence potential & has few after effects the next morning.

None of the above three hypnotics is ideal. It is still not clear whether they are preferred over short acting BZDs. They are more expensive.

  1. Ethyl Alcohol
  • It is occasionally used by the elderly. It is a good hypnotic and although it may help patients to get asleep, they often waken during the night.
  • It is important to note that people who take alcohol regularly may become restless and have difficulty failing asleep.
  1. BARBITURATES

They have been popular hypnotics and sedatives of the last century up to 1960s, but are not now used to induce sleep or calm patients. They are substituted derivatives of barbituric acid.

THE USE AND CHOICE OF HYPNOTICS

Insomnia may be categorized into:

  1. Transient insomnia
  2. Short term insomnia
  3. Chronic insomnia
  4. Transient insomnia

Occurs in people who usually have no sleep problem and is due to altered circumstances, i.e. hospital admission or travel.

A short acting BZD such as temazepam should be used.

  1. Short term insomnia

May be due to anxiety, illness etc, a short acting BZD can be used; but if anxiety is prominent, a drug such as diazepam may be more useful as its action will last well into the next day. The drug should not be given for more than 2 weeks and intermittent dosing is introduced as early as possible. There is risk of dependence development.

  1. Chronic insomnia

Careful assessment is necessary of patients with chronic insomnia. Some will be suffering from psychiatric illness. In others excess coffee & alcohol. A change in lifestyle - exercise and reduction of stress can be tried. Diazepam is the most appropriate drug on intermittent basis for a month.

HYPNOTICS IN SPECIAL CIRCUMSTANCES

  1. Renal failure

Some hypnotics are excreted via the kidneys, so that accumulation occurs in patients with renal failure. Nitrazepam is not excreted via the kidneys; low doses should be used initially.

  1. Liver failure

Temazepam is satisfactory, but should be used with care.

  1. Respiratory disease

All hypnotics produce some depression of respiration so they must be used with great care in patients with respiratory disease /during asthma attacks. Temazepam is as good as any.

  1. In the elderly

Hypnotics should be avoided if possible.

ANTIPSYCHOTIC (NEUROLEPTIC) DRUGS

Another class of Drugs Acting On Central Nervous System are neuroleptics or drugs treating psychosis.

TYPES OF MENTAL ILLNESS

  1. Psychosis

Disorders in which the patient loses contact with the reality. Features of psychosis in paranoia, schizophrenia, manic behavior, severe thought disturbance or poverty of thought. Hallucinations and delusions.

  1. Anxiety

A condition of generalized all pervasive fear.

  1. Depression

A blanket term for several disorders that are characterized by changes in mood rather than in thought or emotional response. Also known as affective disorder.

BRAIN NEUROTRANSMITTERS & PSYCHOTIC DISORDERS

Many of the drugs that have been introduced for treatment of psychotic disorders are known to interfere with the normal action of several of the brain neurotransmitters and their receptors. The major brain neurotransmitters that have been implicated in psychotic disorders are:

  1. Acetylcholine (Ach)
  2. Epinephrine
  3. Noeepinephrine
  4. Dopamine
  5. 5-hydroxytryptamine(5-HT)
  6. GABA (Gamma-aminobutyric acid)
  7. Neuropeptides

CLASSIFICATION OF ANTIPSYCHOTIC DRUGS

Antipsychotic drugs have diverse and wide range of pharmacological actions.

  1. CLASSICAL OR TYPICAL ANTIPSYCHOTICS

THE PHENOTHIAZINES

  1. Chlorpromazine
  2. Promazine
  3. Levomepromazine
  4. Thioridazine
  5. Fluphenazine
  6. Trifluoperazine
  7. THIOXANTHENES
  • Flupenthixol
  1. BUTYROPHENONES
  • Haloperidol
  • Trifliperidol
  • Penfluridol
  1. OTHER NEUROLEPTICS

Pimozide

Loxapine

  1. ATYPICAL ANTIPSYCHOTICS (more recent)
  2. Amisulpride
  3. Clozapine
  • Olanzapine
  1. Risperidone
  2. Quetiapine
  3. Zotepine

MECHANISM OF ACTION OF ANTIPSYCHOTIC DRUGS

Virtually all antipsychotics have so many different pharmacological actions that it is very difficult to relate any one action to their therapeutic effect.

Most antipsychotics have the ability to block dopamine D2 receptors in the brain.

Most of them block the action dopamine on D2 receptors in the mesolimbic system of the brain and this seems important in their sedative and antipsychotic action.

They also block the action of dopamine on the brain CTZ and are thus antiemetic.

THERAPEUTIC USE OF TYPICAL ANTIPSYCHOTIC DRUGS

PHENOTHIAZINES

  • Phenothiazines have an antipsychotic effect. Restlessness, agitation and hallucinations are reduced; this has made them especially useful for treating schizophrenia.
  • They produce some sedation with a feeling of detachment from external worries.
  • Many of them have antiemetic action. Chlopromazine is sometimes used to control persistent hiccup.
  • Phenothiazines are well absorbed after oral administration. They are largely broken down in the liver to numerous breakdown substances.
  • Phenothiazines are used to reduce restlessness, anxiety and agitation in psychotic patients. They are also used to reduce the severity of hallucinations.
  • They are also used as antiemetics and in severe pruritus.
  • The doses of these drugs are very variable and depend on the disorder being treated, and on the response and age of the patient.
  • In treating psychotic patients large doses of phenothiazines are often used nad may have to be continued for many months or even longer; therefore, adverse drug reactions must be checked especially those affecting the nervous system.

Adverse effects of phenothiazines

  • Various disorders of movement – due to directly or indirectly to a dopamine blocking action in the brain. These may occur with all neuroleptics.
  • Akathisia – a feeling of restlessness with an inability to stand still.
  • Dystonia – Uncontrolled movements.
  • Tardive dyskinesia – Abnormal movements of the mouth and tongue and sometimes the upper limbs. It develops in about 20% of the patients on neuroleptics.
  • Depression of leucocyte count.
  • Weight gain and development of gynaecomastia (breast development in men) and male impotence.
  • Dry mouth (can be troublesome).
  • Sedation – which is greatest with chlorpromazine.
  • Skin rashes – including light sensitivity and contact dermatitis when the drug is handled.
  • Thioridazine – has been associated with Cardiotoxicity, in particular an increased incidence of ventricular arrhythmias; it should therefore, not be prescribed for patients with cardiovascular disease.

THIOXANTHENES

  • They are rather similar to the phenothiazines. they are antipsychotic and antiemetic and are largely used in the treatment of schizophrenia
  • They are less sedative than the phenothiazines.
  • Flupentixol is used as an injected depot preparation every 2 weeks or daily as tablets.

BUTYROPHENONES

  • Their actions are rather similar to the phenothiazines.
  • They are less sedative but are liable to produce extrapyramidal (parkinsonsism-like) side effects.
  • Haloperidol is particularly useful in the management of manic and confused patients.
  • Droperidol is similar but acts more rapidly.

OTHER NEUROLEPTICS

PIMOZIDE

  • Is an antipsychotic drug used in the treatment of schizophrenia and manic states. It is longer acting and less sedative than chlorpromazine.
  • It can cause dangerous cardiac arrhythmias and should not be given to those who suffer from them.

SULPIRIDE

  • Has a more specific dopamine-blocking action than the other neuroleptics but with less adverse effects.
  • It can also cause disorders of movement and is associated with hepatitis.

THERAPEUTIC USE OF ATYPICAL ANTIPSYCHOTIC DRUGS

  • Atypical antipsychotics differ from older antipsychotics in their D2 blocking action that may be confined to those areas of the brain believed to be concerned with schizophrenia (the mesolimbic system); In addition they also block serotonin (5-HT) and adrenoreceptors. They seldom cause disorders of posture or movement and they may be effective when older neuroleptics fail.
  • They appear to offer advantages over the older neuroleptics.

CLOZAPINE

  • Used for patients who have proved resistant to the neuroleptic treatment.
  • Because of its adverse effects profile treatment should be started in the hospital under careful supervision.

Adverse effects

  • Neutropenia – about 3% of the patients taking this drug develop this condition within 1 year. Therefore, monitoring of the blood count is mandatory.
  • Seizures, hypotension, excessive salivation and sedation.

RISPERIDONE

  • Blocks several receptors in the brain, including dopamine receptors.
  • More useful in the negative symptoms of schizophrenia, and extrapyramidal side effects seem to be uncommon.

OLANZAPINE

  • Is similar to clozapine,although it does not depress the leucocyte count.
  • It causes drowsiness and weight gain.

DEPOT INJECTIONS

  • Several antipsychotics are given as depot injections, including fluphenazine and flupentixol, because the patients with severe mental disease often fail to take their pills regularly.
  • The depot preparations are given by deep intramuscular injection.

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