Using your textbooks, draw up a classification of the drugs that are used as antidepressants.

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

• They increase noradrenaline and serotonin at central synapses.

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

• 14 to 21 days or more, the drugs have a slow onset of action.

How do the TADs and the selective serotonin reuptake inhibitors (SSRI’s) differ in respect of:

Efficacy

• TADs have  a mixed and variable blockage of Norepinephrine Transporter (NET)  and Serotonin Transporter (SERT) while SSRIs have a highly selective blockage of SERT and little effect on NET.

Side effects

• TCAs -anticholinergic effects, alpha-blocking effects, sedation and weight gain

      SSRIs-Sexual dysfunction

Safety

• TCAs interact with CYP inducers and inhibitors, while SSRIs are CYP inhibitors.

What is the action of mirtazapine?

• Blockage of serotonin 2A and 3 receptors and Histamine 1 and alpha 1 receprors

What is the action of venlafaxine?

• Blocks serotonin and noradrenalin re-uptake.

What is the action of agomelatine?

• Agonist on the melatonin 1&2 receptors and antagonist on serotonin 2A receptors.

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 e.g. Chlorpromazine and Piperidine side chain e.g. periciazine, both have a  low potency with little EPS, severe sedation, strong anticholinergic effects, strong α-lytic effects and cardiotoxicity.

While piperazine side chain e.g.  Fluphenazine, has a high potency, more EPS, weaker anticholinergic effects, weaker α-lytic effects, less cardiovascular effects and less sedation.

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

DA, M, α, and histamine and serotonin

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

Typical drugs block mesolimbic D₂  receptors, while atypical  block 5-HT_2A  receptors more than D₂ receptors.

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

D₂  receptors

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

Piperazine side chains such as fluphenazine, perphenazine, trifluoperazine and prochlorperazine due to their high potency. 

Also Haloperidol due to it's potent D₂ blockage.

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

Alpha receptors

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

DA agonists and the anticholinergic drugs.

In what way does amantadine act as a antiparkinsonism drug?

Amantadine is an adonesine A2 antagonist, adenosine inhibits D2 receptor function

Also a metaffinoid pontetiator of DA, amantadine increases the release of DA, the synthesis of DA and blocks DA reuptake.

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

Monoamine oxidase B inhibition, MAO-B  breaks down dopamine therefore MAO-B antagonism increases DA concentration in the CNS.

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

Bromocriptine is an ergot derivative, while promipaxole and ropirinole are non-ergot derivatives.

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

 Bromocriptine - D2 receptor (partial agonist)

Pramipaxole- D3 receptor

Ropirinole- D2 receptor

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

Pramipaxole and MAO-B inhibitors (Selegiline and rasagiline) are neuroprotective, they can alter the course of metabolic events after the onset of ischaemia and therefore have the potential to reduce stroke damage.

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

MAO-B  breaks down dopamine therefore MAO-B antagonism increases DA concentration in the CNS.

How do the COMT-inhibitors act in Parkinsonism?

COMT inhibitors extend the duration of action of L-dopa, decreases its metabolism and improves it's bioavalability. L-dopa is converted to DA by DOPA-decarboxylase, Increasing DA concentrations in the CNS.

How does istradephyline act?

Istradephyline is an adonesine A2 antagonist, adenosine inhibits D2 receptor function.

Discuss the MOA of safinamide

Safinamide is a novel dual MOA-B, a potent reversible inhibitor of MAO-B. It inhibits DA uptake  therefore increasing DA activity. Safinamide also decreases glutamate release.

• Compile a table, listing the major effects on every system (cardiovascular, CNS, renal, hepatic and uterus) for all the inhalation anesthetics. 

Name the major acute toxic effects of the inhalation drugs

• Nephrotoxicity
• Hematotoxicity
• Malignant hyperthermia
• Hepatotocixity

Which of the anti-epileptic drugs affect the metabolism of the Pill (oral contraceptive) and what are the implications of this? Which drugs are safe to use in combination with the Pill? 

- Phenobarbitone, carbamazepine, phenytoin, oxcarbazepine and topiramate all decrease pill effectiveness and therefore should not be given to women on oral contraceptives. Rather use valproate, lamotrigine, gabapentin, leviteracetam or vigabatrin as they do not effect pill metabolism.

Can oral contraceptives also affect the effectivity of the anti-epileptic drugs?

- Estrogen has a seizure activating effect, while progesterone has a seizure protective effect.

How does age affect the kinetics of these drugs (from neonates to old age)?

Neonates and  geriatrics tend to have a slow metabolism, while babies and children have a faster metabolism than adults.

In which cases is plasma blood level monitoring indicated?

- In the case of phenytoin, as the dose increases, there is saturation of metabolism and a shift from first-order to zero-order kinetics, in which a constant quantity per unit time is metabolized. A small
increase in dose can result in a large increase in concentration. In such cases, the half-life of the drug increases markedly, steady state is not achieved in routine fashion (since the plasma level continues to rise), and patients quickly develop symptoms of toxicity.

What are the possible mechanisms involved in the occurrence of tolerance to chronic alcohol intake?

• Tolerance may result from ethanol-induced up-regulation of a pathway in response to the continuous presence of ethanol. GABA neurotransmission is believed to play a significant role in tolerance and withdrawal because sedative-hypnotic drugs that enhance GABAergic neurotransmission are able to substitute for alcohol during alcohol withdrawal, and  there is
  evidence of down-regulation of GABAA-mediated responses with chronic alcohol exposure.

What are the toxic effects of chronic alcohol consumption on the liver and hepatic metabolism?

• Chronic alcohol consumption leads to a progressive decline in liver function, which may progress to alcoholic hepatitis, liver cirrhosis and liver failure. Gluconeogenesis is decreased, resulting in hypoglycemia and fat accumulation. there is also and increase in the activity of liver microsomal enzyme.

What is Wernicke-Korsakoff-syndrome and how is it treated?

• Paralysis of the external eye muscles, ataxia, and a confused state that can progress to coma
  and death. It is associated with thiamine deficiency but is rarely seen in the absence of alcoholism.
• Treated with parenteral thiamine.

Fully explain the fetal alcohol syndrome.

• Teratogenic effects associated with chronic maternal alcohol abuse during pregnancy .The abnormalities that have been characterized as fetal alcohol syndrome include intrauterine growth retardation, microcephaly, poor coordination, underdevelopment of midfacial region (appearing
  as a flattened face), and minor joint anomalies. More severe cases may include congenital heart defects and mental retardation.

How do the pharmacokinetic interactions of acute alcohol consumption differ from that of chronic alcohol consumption?

• Chronic alcohol consumption enhance the metabolic biotransformation of other drugs  e.g paracetamol. acetaminophen. Chronic consumption of three or more drinks per day increases the risk of hepatotoxicity due to toxic or even high therapeutic levels of acetaminophen as a
  result of increased P450-mediated conversion of acetaminophen to reactive hepatotoxic metabolites.
• Acute alcohol use can inhibit metabolism of other drugs because of decreased enzyme activity or decreased liver blood flow e.g  Phenothiazines, tricyclic antidepressants, and sedative
  hypnotics. 

Name 4 drug interactions with alcohol where the pharmacological effects of the other drugs are potentiated by alcohol.

• Visodilators
• Oral hypoglycemic agents
• Sedative hypnotics
• Anti-depressants

What type of kinetics applies for alcohol in the body? Also, explain the clinical significance of this.

• Alcohol follows zero-order kinetics, meaning that the same amount of alcohol is metabolized at a time even if the concentration of alcohol in the body increases (7-10g/h). This leads to intoxication as the body ends up with more alcohol than it can metabolize.

Give a brief summary of the metabolic pathways of ethanol metabolism.

• Ethanol metabolism follows two enzyme systems, the alcohol dehydrogenase system and the microsomal ethanol-Oxidizing system (MEOS).
• Alcohol dehydrogenase are cytosolic NAD dependent enzymes, that metabolize low to moderate amounts of alcohol. This is due to the fact that there is a limited supply of the NAD coenzyme, the reaction follows zero order kinetics.
• The MEOS kicks in at blood ethanol levels higher than 100mg/dL, an  increase in MEOS activity with chronic use can be induced. This is partially responsible for tolerance.
• The end product of both systems is acetaldehyde.

Which drugs can affect this metabolism and what are the effects thereof?

• Aldehyde dehydrogenase inhibitors such as disulfiram. metronidazole, hyperglycemic drugs and cephalosporines effect this metabolism, they prevent acetaldehyde from being metabolized to acetate by aldehyde dehydrogenase. This causes a nausea and flushing reaction in individuals even with small amounts of alcohol absorption, due to the accumulation of acetaldehyde.

 

 

What factors may affect the absorption and distribution of sedative-hypnotic drugs? What is the clinical significance thereof?

• Lipophilicity, which determines the rate at which a particular sedative-hypnotic enters the CNS. 

What is meant by redistribution and what is the significance thereof?

• Redistribution occurs with highly lipid soluble drugs that distribute to the brain, heart and kidney then  immediately followed by muscles and fats. This makes them suitable for continuous infusion.

How are the BDs metabolized? Name the various steps in the process.

• Dealkylation
• Oxidation
• Conjugation

Which BDs are converted to active metabolites? What is the significance thereof?

• Diazepam, chlorazepate, prazepam, chlordiazepoxide and ketazolam (more lipophilic) are converted to active metabolites which contributes to their extended duration of action. 

Which BDs are not dependent on the cytochrome P450 oxidative enzymes for metabolism? What are the advantages thereof?

• Oxazepam, lorazepam, temazepam and lormetazepam (less lipophilic), these drugs are drugs of choice where  cytochrome P450 activity is reduced e.g elderly, neonates and liver cirrhosis.

What is enzyme induction? Which of the sedative hypnotic drugs are known for this?. What is the clinical significance of enzyme induction?

Enzyme induction is  increase in the biosynthesis of catalytically active enzyme, Enzyme induction increases metabolism of drugs and may lead to therapeutic levels not being reached.

What does anterograde amnesia mean and which drugs can cause this effect?

• Anterograde amnesia is the inability to remember events occuring during a drug's duration of action. Benzodiazepines cause this effect e.g Midazolam

Name the effects of the sedative-hypnotic drugs on the normal sleep pattern and explain their significance to the patient.

• Benzodiazepines increase the duration of phase 2 NREM, they have a small decreased effect on REM sleep and in in high dosages decrease REM sleep. Benzodiazepines decrease the time to fall asleep and increase the total sleep duration in patients who normally less than 6 hours at night.

Which of the sedative-hypnotic drugs are used as a supplementary therapy in anesthesia?  Can you explain why?

• Benzodiazepines because they cause anterograde amnesia.

Which of the sedative-hypnotic drugs are used as anticonvulsants?

• Barbiturates in high doses e.g phenobarbitone  and certain benzodiazepines e.g Diazepam and clonazapam.

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

• They inhibit postsynaptic reflexes.

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

• Therapeutic doses cause significant respiratory depression in pulmonary disease and cardiovascular depression in cardiovascular disease.

Which types of ion channels are found on the nerve cell membranes?

• Ligand-gated ion channels
• Voltage-gated ion channels

Name 3 differences between voltage-gated and ligand-gated ion channels.