1. 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.

The three phenothiazine sub-families are: Aliphatic derivatives, Piperidine derivatives and Piperazine derivatives. The aliphatic and piperidine derivatives have low potency and cause severe sedation, anti-cholinergic effects, postural hypotension and they are cardiotoxic. The Piperazine derivatives have a high potency, but it causes weaker anticholinergic effects and less sedation, less cardiovascular effects and does not cause postural hypotension.

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

Antipsychotics block D2- receptors as well as H1-receptors, cholinergic receptors and alpha1-receptors (to a lesser extent).

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

Atypical drugs block serotonin 2A-receptors whereas typical drugs block mesolimbic D2-receptors.

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

Typical drugs block D3-receptors and this causes the risk of extrapyramidal effects to reduce.

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

The phenothiazines, particularly the piperazine derivatives, have a high incidence of causing extrapyramidal side effects.

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

The blockage of cholinergic neurons by the aliphatic derivatives cause the autonomic side effects.

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

Dopamine agonists and anti-cholinergic drugs. 

 In what way does amantadine act as an anti-parkinsonism drug?

Amantadine enhances dopaminergic neurotransmission by unknown mechanisms that involve increasing synthesis or release of dopamine or inhibition of dopamine reuptake. The drug also has muscarinic blocking actions. Amantadine improves bradykinesia, rigidity, and tremor. It also has antiviral effects. 

 Discuss the mechanisms of action of the anti-parkinsonism drugs that indirectly increase dopamine concentration.

Monoamine Oxidase Inhibitors ( Selegiline and Rasagiline): These are selective inhibitors of monoamine oxidase type B, the form of the enzyme that metabolizes dopamine. This indirectly increases dopamine concentrations by preventing its metabolism. Hepatic metabolism of Selegiline results in the formation of desmethylselegiline (neuroprotective) and amphetamine. 

Catechol-O-methyltransferase Inhibitors (Entacapone and Tolcapone): COMT is the enzyme that converts Levodopa to 3-O-methyldopa. These drugs inhibit COMT, thereby increasing the concentration of Levodopa. 

Amantadine: this drug inhibits the reuptake of dopamine, thereby indirectly increasing the concentration of dopamine. 

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

Ergot derivatives: Bromocriptine

Non-ergot derivatives: Pramipexole and Ropinirole

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

D2 receptor agonists:

-Ropinirole

-Bromocriptine

D3 receptor agonists:

-Pramipexole

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

Selective Monoamine Oxidase B (MAO-B) inhibitors (eg Rasagiline). This means that the MAO-B inhibitor prevents MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) from being converted to MPP + (N-methyl-4-phenylpyridium), which can therefore protect against the prevalence of Parkinsonism.

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

These drugs work with drugs such as Levodopa. MAO-B inhibitors prolong the duration of the effects of Levodopa.

How do the COMT-inhibitors act in Parkinsonism?

COMT inhibitors metabolize L-dopa to 3-O-methyl dopa (30MD), the increased levels of 3OMD leads to a weak therapeutic response with L-dopa. 30MD competes with L-dopa for active transport processes. These drugs increase the duration of L-dopa thus, decreasing peripheral metabolism and improving bioavailability of the drug.

How does Istradephyline act?

This drug inhibits Dopamine 2 functioning by antagonising adenosine activity preventing the inhibition of dopamine functions. It is an additional therapy to L-dopa or carbidopa therapy that experiences on-off episodes.

Discuss the MOA of safinamide

Safinamide, increases DA activity, this results in the potent reversible inhibition of MAO-B and results in the inhibition of DA reuptake. This drug also results in the decrease of glutamate release

How does the sensitivity for blockade by a LA compare regarding the following types of fibres:

(a) myelinated fibres with unmyelinated fibres; and

(b) pressure/touch nerves with the dorsal nerves that transmit pain impulses?

1. Unmyelinated fibres and smaller myelinated fibres are easier to block than larger myelinated fibres, thus they are more sensitive to the effects of local anaesthetics.
2. When type A fibres are blocked it influences the proprioception, touch, pressure, muscles, pain, and temperature functions. This fibre has high frequency pain transmission; thus blockade will be done with lower concentration of local anaesthetic. And does not appear to have high sensitivity for local anaesthetics.

Make a list of the effects of LA on other tissues.

CVS: cardiac depression

CNS: sedation, light-headedness, visual and auditory disturbances, restlessness, and CNS depression.

Skeletal muscle: it has a weak blocking action thus no clinical applications.

What is the basis for the selection of a LA?

• It depends on how long the LA will be used.

• What the LA will be used for, its clinical use.

• How long the LA lasts.

Why are LA solutions sometimes saturated with CO2?

It potentiates the LA, which therefore means the LA are accelerated.

Which of the LA are typically used for surface anaesthesia?

• Cocaine

• Benzocaine

• Oxybuprocaine

2.  

Hepatotoxicity

Hypoxia

Malignant hypothermia

Nephrotoxicity 

• 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? 

Anti-epileptic drugs that decrease the effectiveness of oral contraceptives include: phenobarbitone, phenytoin, carbamazepine, oxcarbazepine and topiramate. The implications of this are that the female patient can have an unwanted pregnancy, or the patient’s hormone levels will not be regulated as it should because of the contraceptive not reaching therapeutic effective levels to prevent ovulation. Anti-epileptic drugs that are safe to use with oral contraceptives are valproate, lamotrigine, gabapentin, levetiracetam, vigabatrin.

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

Oral contraceptives can decrease serum levels of anti-epileptic drugs; examples of these drugs are lamotrigine and valproate. Therefore Yes.

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

Neonates have a slower metabolism and should therefore receive lower dosages. Babies and children have a faster metabolism than adults and should receive higher dosages. For geriatric patient’s lower dosages are required due to slower metabolism and decreased renal function.

• In which cases is plasma blood level monitoring indicated?

Where protein binding takes place and in certain diseases that may affect protein binding, these cases are with chronic kidney failure, liver diseases, hypoalbuminemia, burns, pregnancy, malnutrition, age and where displacement drugs are involved. In these instances, plasma blood level monitoring is required.

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

Chronic alcohol intake may result in tolerance and physical or psychological dependence. This may occur due to several mechanisms. This takes place through changes in the central nervous system adjustment due to constant exposure on receptors or secondary messengers as well as an increase in the rate of alcohol metabolism induced by the MEOS when chronic alcohol consumption occurs allowing for increased metabolism of ethanol and clearance of other drugs in the body that are eliminated by CYP450 enzymes.

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

Liver diseases such as Hepatitis, Cirrhosis and Liver failure may all result from the progressive decrease in liver function caused by chronic alcohol use. This tissue damage results from the direct effects of ethanol and acetaldehyde and having to process an increased load of active metabolites. The decrease in gluconeogenesis causes hypoglycaemia and fat accumulation, also nutrient deficiencies may contribute to the damage.

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

A unique syndrome that occurs because of neuropathy. It is characterized by paralysis of external eye muscles, ataxia and confusion which may lead to coma and death. This syndrome is associated with a thiamine(B1) deficiency therefore patients with chronic alcohol effects are administered thiamine therapy parenterally to prevent any permanent brain damage.

• Fully explain the foetal alcohol syndrome.

Foetal alcohol syndrome is caused by the alcohol abuse of a mother while pregnant due to the ethanol consumed by the mother crossing the placenta and thus resulting in the foetus having the same alcohol blood concentration as the mother. Mental retardations and underdevelopment of the facial area are commonly seen in infants that has this syndrome and this syndrome usually has teratogenic effects.

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

Acute – the alcohol dehydrogenase enzyme plays a role with low to moderate levels of alcohol consumption which catalyses the conversion of alcohol to acetaldehyde.

Chronic- on the other hand the MEOS plays a role with the consumption of high concentrations alcohol as their activity gets induced by the chronic consumption of alcohol.

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

it has an interaction on vasodilators, sedatives and hypnotics, hypoglycaemic drugs and Aspirin where it will increase the platelet adhesion

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

Due to alcohol being so lipophilic it is rapidly absorbed and distributed across the blood brain barrier throughout the body . If alcohol is administered when someone is observing a fast the alcohol would reach its peak concentration within half an hour. The presence of food delays the absorption of alcohol by decreasing the rate it takes the stomach to become empty. Body fluids such as the volume of water in the body has an influence on the absorption of alcohol as it reaches its peak concentration faster in women than in men as women have less body fluids compared to that of men. Metabolism of alcohol primarily takes place in the liver.

Alcohol causes CNS suppression and if taken in access can be proven to be fatal and have severe side effects.

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

Metabolism of ethanol includes two pathways which includes:

1. Alcohol dehydrogenase system: low to moderate amounts of alcohol metabolised

Limited amount of NAD therefore the saturation of system l. Alcohol dehydrogenase catalyses the conversion of alcohol to acetaldehyde. Where aldehyddehidrogenase is responsible for the conversion of acetaldehyde to acetate.

2. Microsomal-Ethanol Oxidations System. Mixed function oxidases and higher concentrations of alcohol metabolised

 NADPH comes across as the cofactor and therefore this system is not easily saturated. Alcohol is broken down to acetaldehyde where aldehyde dehydrogenase will convert acetaldehyde to acetate.

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

Disulfiram, Metronidazole, Cephalosporin and Hypoglycaemic drugs

These drugs inhibit aldehyddehidrogenase which is the enzyme responsible for converting acetaldehyde to acetate. Acetaldehydes builds up and causes vomiting and nausea as well as headaches

The following can be used in order to help an individual cope with anxiety:

• Ashwagandha
• Chamomile
• Valerian
• Lavender
• Galphimia glauca
• Passionflower
• Kava Kava
• Cannabidiol
• Magnesium supplements

The following can be used for insomnia:

• Valerian Root
• Chamomile
• Melatonin
• Lemon Balm
• Lavender
• Hops
• Passion Flower

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

The main factor that affects the absorption and distribution of sedative-hypnotics is the lipophilicity of the drug. The lipophilicity affects the rate of drug absorption as well as distribution. The rapid onset of action and the effect on the CNS is also influenced. Drugs that have a high lipophilicity shows a rapid onset of action and a greater effect on the CNS compared to the drugs with a lower lipophilicity.

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

Redistribution happens when a drug gets absorbed into the systemic circulation and is distributed from the brain to the other tissues. Highly lipid soluble drugs are distributed to the brain, heart kidney etc followed directly by fat and muscle. The redistribution process prolongs the duration of action of the drug.

How are BD metabolised? Name the various steps in the process.

Benzodiazepines gets metabolised by the hepatic microsomal enzymes in the liver and this process includes:

1. Dealkylation to active metabolites.
2. Oxidation by the cytochrome P450 enzymes to an active metabolite.
3. Conjugation (Phase II) of the oxidised metabolite with glucuronic acid to form an inactive metabolite.

Which BD’s are converted to active metabolites? What is the significance thereof?

Benzodiazepines converted to Desmethyldiazepam includes: Diazepam, Cholarazepam, Prazepam, Chlorodiazepoxide, ketazolam. Active metabolites contribute towards the extended duration of action.

Which BD’s are not dependent on cytochrome P450 oxidative enzymes for metabolism? What are advantages thereof?

These drugs include Oxazepam, Lorazepam, Temazepam, Lormetazepam. These drugs bring great advantage to patients that suffer from liver cirrhosis, elderly , neonates and patients that make use of CYP-P450 inhibitors, due to the drugs not having an effect on the levels of CYP-P450 because it does not require the enzyme to produce an effect.

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 when a drug increases the production of an enzyme and leads to the  increase in the rate of metabolism. Barbiturates (phenobarbital,secobarbital,etc) and meprobamate are known to be potent enzyme inducers. This increases the metabolism of a drug, which causes a decrease of the drug in the systemic circulation, thus a decrease in the therapeutic effect.

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

Anterograde amnesia inability to remember events occurring during the drug's duration of action)

The drugs responsible includes the following:

Benzodiazepines (BD’s): triazolam, temazepam, lorazepam, diazepam.

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

• Decrease in the time it takes to fall asleep.
• Small doses lead in the decrease in the effect of REM sleep.
• High doses decrease the duration of REM sleep
• Increases the duration of phase 2 NREM.
• Decreases the duration of phase 4 NREM.
• It will ultimately increase the sleep duration.

Some tolerance to their effects on sleep patterns if hypnotics are used for more than 1 – 2 weeks. The sedative-hypnotic drugs are used in patients who suffer from insomnia, to fall asleep and increase the quality of sleep

Which of the sedative-hypnotic drugs are used as supplementary therapy for anaesthesia?

The drugs used are Barbiturates and some BDs: Thiopental, midazolam, diazepam, lorazepam.

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

Diazepam, lorazepam, clonazepam, clobazam, phenobarbitone.

What is the mechanism of the muscle-relaxing effects of some of the carbamates and BD’s?

Carbamates and benzodiazepines inhibit polysynaptic reflexes. It increases the level of calming chemicals in your brain allowing you to feel relaxed and drowsy.

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

Respiratory system:

Sedative-hypnotics can cause severe respiratory depression in patients with pulmonary disease. Effects on respiration are dose-related and a overdose can cause too much depression on the medullary respiratory centre which can lead to death a times.

Cardiovascular system:

Sedative-hypnotics may cause cardiovascular depression in patients that suffer with diseases which cause cardiovascular impairment. The depression caused, can be due to action at the medullary vasomotor centre. The high doses cause myocardial contractility and vascular tone may both be depressed by central and peripheral effects, which  lead to circulatory collapse.