• Using your textbooks, draw up a classification of the drugs that are used as antidepressants.
  • • • • Tricyclic antidepressants
        • Monoamine oxidase inhibitors
        • Serotonin Noradrenaline Re-uptake Inhibitors
        • Serotonin receptor modulators
        • Noradrenaline Receptor Inhibitors
        • Tetracyclic and unicyclic antidepressants
        • Circadian rhythm regulators
        • Selective Serotonin Re-uptake Inhibitors.

• What do the existing drugs all have in common regarding their mechanisms of action?

They all influence serotonin and noradrenaline levels.

• How long does it take for the antidepressive effects of these drugs to appear? What is the reason for this?

3-5 weeks. It takes a while to establish a new homeostasis.

• How do the TADs and the selective serotonin reuptake inhibitors (SSRI’s) differ in respect of:
  • • Efficacy: individuals have different responses, but the efficacy is the same for both.
    • Side effects: TAD has anti-cholinergic, alpha-lytic and quinidine-like effects. SSRI’s have insomnia, non-sedating, GIT disturbances.
    • Safety: SSRI’s are safe and have fewer side effects than TAD. SSRI’s may cause serotonin syndrome.

• What is the action of mirtazapine?

It blocks alpha1, alpha2, H1, 5-HT2a and 5-HT3 receptors. It also indirectly stimulates 5-HT1a receptors.

• What is the action of venlafaxine?

It blocks both serotonin and noradrenaline re-uptake. It also moderately blocks SERT and NET.

• What is the action of agomelatine?

It is an antagonist on the 5-HT2c receptors and an agonist on the melatonergic receptors (MT1 and MT2). It adjusts melatonin levels.

• Discuss the possible mechanisms of action of lithium.

Lithium inhibits several enzymes involved in the recycling of neuronal membrane phospholipids. This results in the depletion of 2^nd messengers (PIP2, IP3 and DAG). It also inhibits glycogen synthase kinase-3.

• What is the therapeutic index of lithium and what is its clinical significance?

Its target plasma concentration levels are between 0.6 and 1.4mEq/L. Its clinical significance is for the treatment of bipolar disorder, recurrent depression and schizoaffective disorder.

• When is lithium used as single drug and in which cases and with which type of drugs is lithium combined?

Lithium is used as monotherapy for bipolar disorder and acute manic episodes and rapid cycling. Lithium should be used in combination with antidepressants or benzodiazepines for severe depressant episodes. The initial treatment with SSRI can cause manic episode. Lithium and valproate may be used in combination when there is no or partial response to lithium monotherapy.

• Name 3 clinically significant interactions lithium may have with other drugs. Illustrate your answer with suitable examples of drugs.

Interaction with diuretics (thiazides), NSAID’s (ibuprofen), ACE Inhibitors and fluoxetine – increase lithium levels that may be toxic.

Interaction with typical anti-psychotic drugs (chlorpromazine) lead to increased severity of EPS.

Interaction with anti-convulsants (carbamazepine), calcium channel blockers (amlodipine) and anti-histamines (losartan) may lead to lithium toxicity.

• Name the major side effects of lithium.

Tremors, sedation, ataxia, aphasia, muscle weakness, fatigue, polydipsia, polyuria, nocturia, nephrogenic diabetes insipidus, thyroid enlargement, leucocytosis, oedema, acne, alopecia, sexual dysfunction and bradycardia-tachycardia.

• What is the status of the use of lithium during pregnancy and lactation?

Category D: evidence that it causes fetal birth defects.

• Name three other important indications for lithium.

Depression, mania and schizophrenia.

Evaluate the following case and fully motivate your recommendations:

Ms B. Polar (21 years, 60 kg) is a student and used the following medication for the past two months:

Camcolith 600mg bd. The plasma levels after two weeks were 0.8mmol/l. She sustained a muscle injury and has been using Indocid® 75mg nocte for the past 10 days. On questioning she reveals that “she had picked up a lot of weight” and is now using some of her mother’s “water pills” in the hope of losing a few of the extra kilos. However, she complains of fatigue, that she has difficulty in keeping her eyes open in class, remains thirsty and constantly feels shaky and nauseous.

Camcolith is a form of slow-release lithium. There is an interaction between the lithium and the NSAID and lithium and the diuretic (water pill), that increases lithium plasma level and could lead to lithium toxicity. This could be the result of her dehydration (excessive thirst), fatigue and sedation (struggle to keep eyes open), weight gain and tremors. The recommendation would be to immediately stop the use of the NSAID and the diuretic. Because she is still so young, it would be advisable for her to switch over to fluoxetine.

• Name an example of each of the three phenothiazine sub-families and state how they differ from one another in terms of potency and side effects.

Aliphatic side chain, eg chlorpromazine – low potency, little EPS, severe sedation, strong anti-cholinergic effects, strong alpha-lytic effects, cardiotoxic.

Piperidine side chain, eg thioridazine – low potency, little EPS, severe sedation, strong anti-cholinergic effects, strong alpha-lytic effects, cardiotoxic.

Piperazine side chain, eg fluphenazine – high potency, strong EPS, less anti-cholinergic effects, less sedation, less alpha-lytic effects, less cardiotoxic.

• Which receptors in particular are blocked by the typical antipsychotic drugs?

D2 receptors in the mesolimbic pathway

• How does the mechanism of action of the atypical drugs differ from that of the typical drugs?

It has a higher affinity for 5-HT2a receptors (blocks more) than D2 receptors.

• Which of the receptors blocked by the older drugs reduce the risk of extrapyramidal side effects?

Low affinity for D2 receptors

• Which of the older drugs have a high incidence of extrapyramidal side effects? What is the reason for this?

Piperazine side chain phenothiazines – its high affinity for D2 receptors.

• Because of which receptor(s) blockade do the aliphatic group ofdrugs have a high incidence of autonomic side effects?

Muscarinic and alpha receptors.

• Which two main groups of drugs are important in the treatment of Parkinsonism?

Drugs that increase dopamine and Anti-cholinergic drugs (decrease cholinergic activity).

• In what way does amantadine act as an antiparkinsonism drug?

It increases the activity of dopamine (Increases its release, synthesis and blocks its reuptake). It also is a NMDA antagonist (antidyskinetic effects) and is a adenosine A2a antagonist (block adenosine to improve D2 function).

• Discuss the mechanisms of action of the antiparkinsonism drugs that indirectly increase dopamine concentration.

MAOI – Inhibits MAO-B and -A, which increases dopamine as MAO breakdown dopamine.

COMT inhibitors – Inhibit COMT, which metabolises L-dopa to 3OMD peripherally and 3MT centrally. It therefore increases L-dopa, which is converted to dopamine.

Metaffinoid potentiator of Dopamine – increase dopamine release, increase dopamine synthesis, block dopamine reuptake.

• Which of the dopamine agonists are ergot derivatives and which are not?

Ergot derivatives: Bromocriptine, Pergolide

Non-ergot derivatives: Pramipexole, Ropinirole, Rotigotine

• List the specific dopamine receptors that are stimulated by each agonist.

Pramipexole: D3 receptors

Ropinirole D2 receptors

Rotigotine: DA receptors

Bromocriptine: D2 receptors

Pergolide: D1 and D2 receptors

• Which of these drugs are classified as neuron protecting drugs? What does this mean?

Pramipexole. It protects neurons.

• What is the importance of monoamine oxidase B (MAO-B) selective drugs in the treatment of Parkinsonism?

It does not inhibit the breakdown of the other important MAO’s like adrenaline, noradrenaline and serotonin (which is broken down by MAO-A). It is selective for MAO-B, to inhibit the breakdown of Dopamine and Tyramine

• How do the COMT-inhibitors act in Parkinsonism?

It blocks COMT peripherally and some centrally. COMT metabolises L-Dopa to 3OMD (peripherally) and 3MT (centrally). COMT-inhibitors prevent this and in turn increase the dopamine concentrations.

• How does istradephyline act?

It is an Adenosine A2a antagonist – blocks adenosine (which inhibits D2 function), which in turn promotes D2 function.

• Discuss the MOA of safinamide

Safinamide is a novel dual MOAI. It increases dopamine activity, by potently inhibiting MOA-B (reversible) and inhibiting dopamine reuptake. It also decreases glutamate release.

Methylphenidate is the active found in Concerta and Ritalin. They are both central nervous system stimulants and have the potential for patients to become addicted. It has a similar chemical composition to cocaine and amphetamine; therefore, it may be highly addictive.

It disturbs the sleep-wake cycle, by promoting sleeplessness. Often students and learners make use of Concerta or Ritalin when studying for a big test, as it improves their attention and promotes wakefulness. Many of the students do not have prescriptions for it and will then buy tablets from a friend or sibling. The use of using stimulants like methylphenidate, without a prescription, can therefore be very dangerous – as the students do not always realise the side effects and dangers thereof if they have not been prescribed with it. The dosages are individualized by the prescribing medical practitioner and therefore unprescribed use could also possibly lead to unintentional overdose.

Patients may also start experiencing withdrawal symptoms (like fatigue, paranoia and depression), if they stop using methylphenidate. Tolerance may also develop, leading to students taking or needing higher doses to feel the effects thereof, which could lead to possible overdose. It may also lead to students having to find ways to obtain the drug, whether it be legal or illegal. This may result into serious trouble for the student.

Methylphenidate also has an appetite suppressing effect and leads to the abuse and addiction of the drug. Many people abuse methylphenidate to lose weight. This could be potentially dangerous if it is not monitored by a medical practitioner and could have serious negative consequences for the abuser.

Some people also use methylphenidate by crushing it and snorting it, for the “high effect” it produces. Methylphenidate activates the reward system in the brain by increasing dopamine levels in the brain, much like amphetamine-like drugs.

Often students go out clubbing and drinking, with the intention of getting drunk or the good feeling they get when consuming large amounts of alcohol. Methylphenidate is a CNS stimulant, which opposed the CNS suppressive effects of alcohol, which therefore, encourages people to drink more, as they feel “fine”. They might drink a tablet before they go out, so that they can stay awake all night to party. This results in increased blood alcohol levels and could potentially be fatal.

References:

1. Brand, L. 2021. ADHD. Study Unit 13.2 [pptx document]. Unpublished lecture notes on eFundi. FKLG312. Potchefstroom: NWU.
2. Juergens, J. 2021. Concerta Addiction. https://www.addictioncenter.com/stimulants/concerta/ Date accessed: 18 June 2021.

Good day, all ladies.

Thank you for this opportunity to speak to you all regarding the use of sedatives and sleeping tablets.

Is it dangerous to use sedatives and sleeping drugs?

Sedative-hypnotic drugs are psycho-active drug. This means that it has an effect on the central nervous system and brain activity, which may be the result of changes in behaviour and mood.

It may at first seem as if though it is helping you cope with whatever midlife crisis you are faced with, whether it be a divorce, a rebellious teenager’s behaviour and mood at home, or month end coming and you are worried about how you are going to manage to pay all the bills. You may feel as if the only thing going to help with your insomnia is sedatives and sleeping tablets.

The truth is, they are going you improve your sleeping patterns, but at the same time they have such a high dependence potential if used chronically and many side effects that may end up being fatal. Therefore, it is so important to not use sedative-hypnotics for longer than 2 weeks. Sedative-hypnotics are used for treatment of anxiety, induce calmness, sedation or sleep. Some of the commonly found sedative-hypnotics under the benzodiazepine class, include alprazolam sold under the name “Xanax”, zolpidem as “Stilnox”, diazepam as “Valium” or lorazepam as “Ativan”. All these drugs have a calming effect, decreases anxiety and induces sleep. They also have central nervous system suppressing effects. Sedative-Hypnotics are therefore sleeping drugs. Other sleeping tablets include doxylamine succinate sold under the name “Somnil”, which may be bought over the counter for sleeping difficulties.

Suppose you have been prescribed Xanax for anxiety, and you still feel that you have trouble sleeping, so you go to the local pharmacy and get Somnil for your insomnia. Both of these drugs will have additive central nervous system depressant effects. This may result in a decreased breathing rate, which may slow down too much leading to an oxygen shortage and eventually a coma or death. They also decrease your heart rate; may induce seizures and you may lose consciousness. Some people may experience allergic reactions to the drugs and my present with symptoms such as difficulty breathing, chest pains, nausea and swelling.

If you were to involve alcohol with the use of sleeping tablets, it may have severe central nervous system suppressive effects. The total effects may cause respiratory and cardiovascular suppression and may lead to death.

Common side effects that may be seen with sedative-hypnotics include, but are not limited to: Constipation or diarrhoea, change in appetite, dry mouth or throat, dizziness, next day sleepiness, headache, heartburn, cognitive impairments, weakness, gastric pain and heartburn.

Sedative-hypnotic drugs combine with alcohol are also used these days as “date rape”. Commonly used drugs are flunitrazepam sold as “Rophynol”, and it causes muscle relaxation, amnesia and can incapacitate victims and prevents them from resisting sexual assault. Rophynol is very similar to Valium, but 10 times more potent. Some of the common names for the “date rape” drug is “rophies”, “roofies” or “rope”.

After 2 weeks of use, a person may become dependent on the sedative-hypnotic. This means that you may find it impossible or very difficult to sleep without taking a pill. Also, abrupt discontinuation of the drug may lead to withdrawal syndrome, which may be characterized by central nervous system stimulation, anxiety, tremors, nausea, vomiting, insomnia, depression, muscle cramps, delirium, hallucinations, and convulsions. It may even result in death.

Withdrawal syndrome can be treated by replacing the drug with a longer acting or slow release drug, like diazepam, with the tradename of "Valium". Thereafter, gradually decrease the dosage after 2 weeks. Clonidine, known as "Catapres" or propranolol, known as "Inderal" may be given to decrease sympathetic activity like cramps, nausea, vomiting, increased heart rate, sweating and hyperthermia (fever).

It is also important to know that if you are a chronic drinker and have developed a dependency for sleeping pills, not to abruptly discontinue the use of alcohol and sleeping pills at the same time. Deciding to stop both at the same time, instead of gradually decreasing the dose, may also cause withdrawal syndrome and can even be fatal.

In an acute overdose of sedative-hypnotics, treatment involves supportive treatment like oxygen, and a dose of flumazenil sold as "Romazicon". Romazicon reverses the effects of the sedative-hypnotic.

Thank you for your time. I hope that this has been a valuable message to you.

Type of kinetics for alcohol in the body:

Alcohol is a small water-soluble molecule that has fast absorption and distribution in the body. Peak levels in the blood can be seen within 30minutes after consumption of alcohol, during a fasting blood test. 90% of alcohol is metabolised by the liver and the rest is metabolised by the lungs and kidneys. Alcohol can be metabolised in 3 ways, namely alcohol dehydrogenase system, microsomal ethanol-oxidizing system and acetaldehyde metabolism.

Summary of the metabolic pathways:

Alcohol can follow any of the 3 paths. The first pathway is alcohol dehydrogenase pathway and it involves alcohol dehydrogenase (ADH), which is a cytosolic enzyme that catalyses the conversion of alcohol to acetaldehyde. These enzymes are mainly located in the liver and small amounts in other organs. Some metabolism occurs in the stomach already, but only in people whom have lower levels of gastric enzymes. H+ is transferred from the ethanol to co-factor NAD+ (nicotinamide adenine dinucleotide).

The next pathway is the microsomal Ethanol-Oxidising System (MEOS), which is also known as the mixed function oxidase system. It makes use of NADPH as a cofactor in the metabolism of ethanol and consists primarily of cytochrome P450 2E1,1A2 and 3A4. During alcohol consumption, MEOS activity is induced. Ethanol metabolism is induced and the clearance of other drugs by the liver.

The third pathway is the acetaldehyde metabolism. Much of the acetaldehyde formed is oxidised in the liver and this reaction is catalysed by mitochondrial NAD-dependent aldehyde dehydrogenase. The products of this reaction is acetate, which is further metabolised to carbon dioxide and water, or it is used to form acetyl-CoA

Drugs that affect metabolism and the effect thereof:

Most drugs have reactions with alcohol; therefore, it is better to actually not consume alcohol while using medications. Fomepizole inhibits alcohol dehydrogenase. This inhibits the conversion of alcohol to acetaldehyde, consequently increase the alcohol levels.

Disulfiram inhibits the oxidation of acetaldehyde, which result in the accumulation of acetaldehyde which causes flushed skin, nausea, vomiting, dizziness and headaches. Metronidazole, Cephalosporins and Hypoglycaemic drugs inhibit aldehyde dehydrogenase which cause effects similar to those of Disulfiram.

Alternative medicines in treating anxiety and insomnia.

Extracts of valerian and valerenic acid are often used in the treatment of insomnia, as it activates 5-HT5a receptors. This is related to the release of melatonin, which controls the sleep-wake cycles of a person.

In China, Japan, Korea and other countries Semen Ziziphi Spinosae (SZS) – which is a safe sedative-hypnotic - is used to promote sleep quality, extend duration of sleep and increase NREM sleep. In Egypt, Lactuca sativa – also known as garden lettuce -has been used for centuries to promote sleep.

Kava-kava, a botanical, has the intended use to treat anxiety. However, it causes hepatotoxicity and should be avoided completely, especially by patients whom already suffer from liver impairment or liver failure.

Ginkgo, extracted from Ginkgo biloba was always used to treat many central nervous system insufficiencies, but mainly for dementia of the Alzheimer type. Recent studies show that ginkgo is effective for treatment of dementia, but anxiety and insomnia have been reported as adverse effects of the use thereof. Therefore, ginkgo should be avoided in the treatment of insomnia and anxiety.

Patients that use ginseng, derived from Panax, to increase central levels of acetylcholine, serotonin, norepinephrine and dopamine can expect insomnia, irritability and nervousness as adverse effects. Patients that are already suffering from insomnia and anxiety should therefore not use ginseng.

St. John’s wort is very effective in treating anxiety. There is however, very little evidence and too few cases to draw a conclusion regarding the efficacy of St. John’s wort as effective treatment for anxiety and other mood-related conditions. St. John’s wort causes sedation and restlessness as adverse effects in rare cases – which can lead to the relief of anxiety.

Morinda citrifolia fruit have shown to be GABAᴀ receptor agonists. Low central levels of GABA are linked to many disorders such as anxiety, hyperactivity (which in turn could be the cause of sleeplessness) and depression. Therefore, having increased central levels of GABAᴀ or GABAᴀ receptor agonists may reduce anxiety and promote sleep.

More herbal drugs used to treat insomnia:

• Chamomile
• Passionflower
• Hops
• Lemon balm
• Lavender oil

More herbal drugs to treat anxiety:

• Chamomile
• Lavender (in many forms)
• Galphimia glauca
• Green tea

There are also other alternative methods to treat insomnia and anxiety:

• Yoga
• Exercise
• Take relaxing bath
• Meditation
• Massage
• Accupuncture

References:

1. Barnett, R.A. 2019. 19 Natural Remedies for Anxiety. https://www.health.com/ condition/anxiety/19-natural-remedies-for-anxiety Date accessed: 4 March 2021.
2. Bingiin, L., Changhong, L., Lui, L., Pu, W., Yicun, W. & Yuxin, L. 2015. Herbal Medicine for Anxiety, Depression and Insomnia. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790408/#:~:text=Extracts%20of%20valerian%20(Valeriana%20officinalis,and%20promotes%20falling%20into%20sleep. Date accessed: 4 March 2021.
3. Cronkleton, E. 2018. 8 Home remedies for insomnia. https://www.healthline.com/ health/healthy-sleep/insomnia-home-remedies  Date accessed: 4 March 2021.
4. Katzung, B.G.  2018.  Basic & Clinical Pharmacology.  14^th ed. 
5. Pathak, N. 2020. Alternative Treatments for Insomnia. https://www.webmd.com/sleep-disorders/alternative-treatments-for-insomnia Date accessed: 4 March 2021.
6. Richards, L. 2020. 9 herbs for anxiety. https://www.medicalnewstoday.com/ articles/herbs-for-anxiety Date accessed: 4 March 2021.

Factors that affect the absorption and distribution of sedative-hypnotic drugs:

The rate of oral absorption is dependent on the lipophilicity of the drugs. The more lipophilic they are, the more rapidly they are absorbed and distributed in the brain. For example, triazolam is very lipophilic and is absorbed very rapidly. Diazepam and active metabolite of clorazepate are absorbed faster than other benzodiazepines. Some drugs are converted to the active form by acid hydrolysis in the stomach, which are then absorbed much quicker. Barbiturates, older sedative-hypnotic and newer sedative-hypnotic drugs are absorbed very quickly into the blood stream after oral administration. All sedative-hypnotic drugs cross the placental barrier during pregnancy and may be found in breast milk of nursing mothers. This is clinically significant as this factor is responsible for the rapid onset of effects caused by these drugs. It suppresses the central nervous system and may contribute to depression of neonatal vital functions.

Redistribution of drugs and the significance thereof:

Drug redistribution refers to drugs that are distributed to the brain, heart, kidney, etc. directly followed by distribution into muscle and fatty tissue and stored there. Once plasma concentration starts decreasing, the drugs are redistributed from the muscle and fatty tissue into the blood so that it can prolong the drugs effect and prevent the plasma concentration from decreasing rapidly.

Benzodiazepine metabolism:

Benzodiazepines are metabolised step-by-step by the hepatic microsomal enzymes. The various steps in the process are:

1. Dealkylation: converting the benzodiazepines to active metabolites.
2. Oxidation: of the active metabolites by the cytochrome P450 enzymes.
3. Conjugation: (Phase 2) of the oxidised metabolites with glucuronic acid (endogenous substance) to form inactive metabolites.

However, some benzodiazepines, like oxazepam, lorazepam, temazepam and lormetazepam do not undergo dealkylation and oxidation. These drugs are immediately converted to glucuronide conjugates. All the glucuronide conjugates are hydrophilic and are excreted in the urine.

Benzodiazepines converted to active metabolites:

Diazepam, clorazepate, prazepam, chlordiazepoxide and ketazolam are the more lipophilic drugs and they are converted to active metabolites then oxidised and conjugates. The active metabolites contribute to the prolonged duration of action of the drug and cumulative effects occur with multiple doses (as their elimination half-lives are very long).

Benzodiazepines not dependent on cytochrome P450 oxidative enzymes:

Oxazepam, lorazepam, temazepam and lormetazepam are the benzodiazepines that do not undergo metabolism by the cytochrome P450 oxidative enzymes. They are the drug of choice in patients that are elderly, neonates, suffer from liver cirrhosis, are using therapy with cytochrome P450 inhibitors. This is advantageous as the metabolism of the drugs will not be affected. For example, if diazepam were to be used, there would be prolonged duration of action and drug accumulation would occur, which could be toxic.

Enzyme induction and the significance thereof:

An increase in the number of enzymes as a result of stimulation. Barbiturates increase biotransformation of other pharmacological agents as a result of enzyme induction. This is the potential mechanism underlying drug interaction of barbiturates and other drugs.

What is anterograde amnesia and drugs that may cause it?

Anterograde amnesia refers to the inability of a person to remember events that happened in the time that the drug was in its duration of action. Drugs that cause this are benzodiazepines, for example diazepam, midazolam, lorazepam, etc.

Effects of sedative-hypnotic drugs on normal sleeping pattern and the significance thereof.

Sedative-hypnotics drugs decrease the (latency of sleep onset) time to fall asleep and the patient suffering from insomnia or any sleeping disorder will be able to fall asleep faster if they make use of benzodiazepines or older sedative-hypnotics.

These drugs also increasing the total sleep duration (duration of stage 2 NREM is increased), if the patient is only used to receiving less than 6 hours of sleep per night. Therefore, if the patient struggles to sleep for more than 6 hours per night, the use of sedative-hypnotic drug will increase the total sleep duration.

Benzodiazepines decrease REM (Rapid Eye Movement) sleep if given in high doses. Thus, if the patient uses benzodiazepines, he/she may experience less dreaming, but also it affects the brain area responsible for learning and memory.

A decrease in stage 4 NREM (Non-Rapid Eye Movement) slow-wave sleep can be expected as a result of the use of sedative-hypnotics. During this stage the patient will be in a deep sleep and possibly dreaming. Using sedative-hypnotics will make it easier for the patient to wake up as the period of stage 4 NREM is shortened.

Sedative-hypnotic drugs that are used as a supplementary therapy in anesthesia and why?

Barbiturates, thiopental and methohexital are used solely as anesthesia because they are very lipophilic and are able to penetrate brain tissue and distribute rapidly after intravenous administration. However, benzodiazepines (like midazolam, diazepam and lorazepam) in high doses are used as supplementary agents as adjuncts to general anesthesia. They are used as supplementary agents because they have relatively long half-lives, form active metabolites and slow onset of action. This effect lasts long and persists to post anesthesia.

Sedative-hypnotic drugs are used as anticonvulsants?

Benzodiazepines, like diazepam, lorazepam. Are used to treat seizures and status epilepticus. They show selective anticonvulsive effects with phenobarbitone, clonazepam and clobazam. If barbiturates, phenobarbital and metharbital are given in high doses, they are effective to treat generalized tonic-clonic seizures and they produce anticonvulsive effects (although it is not a first line treatment).

What is the mechanism of the muscle-relaxing effects of the carbamates and the benzodiazepines?

These drugs exert an inhibitory effect on the polysynaptic reflexes and internuncial transmission. At high doses they depress transmission at the skeletal neuromuscular junction, which leads to muscle relaxation. In this way, muscles that are in spasms can also be relaxed after the use of carbamates and benzodiazepines.

Effects of the sedative-hypnotic drugs on the respiratory and cardiovascular systems.

At hypnotic doses in healthy patients, effects on respiration change during natural sleep. At therapeutic doses, respiratory depression is produced in patients that have pulmonary diseases. The effects thereof are dose-related and the depression of the medullary respiratory centre is usually the cause of death – due to overdosing.

Doses of sedative-hypnotics that cause hypnosis have no significant cardiovascular effects on healthy patients. Whereas, in patients with cardiovascular diseases and impairments, normal doses lead to cardiovascular depression, as a result of its action on the medullary vasomotor centre in the brain. At toxic doses0, circulatory collapse can be expected, as the drugs depress centrally and peripherally via facilitation of adenosine.

Cardiovascular and respiratory depression becomes more intensified when the sedative-hypnotic drugs are given intravenously.