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

• Drugs that increase DA activity
• Drugs that decrease cholinergic activity

In what way does amantadine act as a antiparkinsonism drug?

• Amantadine in a metaffinoid potentiator of DA therefore it increases the DA activity. 

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

• These drugs do not require enzymatic conversion to an active metabolite.
• They do not act directly on the post synaptic dopamine receptors 
• They have no potentially toxic metabolites. 

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

• Ergot derivatives: Bromocriptine
• Non ergot derivative: Ropinirole and Pramipexole

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

• D1
• D2 

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

• MAO- B inhibitor: Rasagiline 
• This means it increases the DA stores in neurons.

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

• They work in combination to Levodopa to treat secondary parkinsonism 

How do the COMT-inhibitors act in Parkinsonism?

• COMT metabolises L-dopa to 3OMD. Increased plasma levels of 3OMD leads to a weak therapeutic response with L-dopa (3OMD competes with L-dopa for active transport)

How does istradephyline act?

• it acts as an adenosine 2 antagonist

Discuss the MOA of safinamide

• Increases DA activity 
• Decreases glutamate release 

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

(a) myelinated fibres with unmyelinated fibres:- Smaller myelinated fibres are blocked easier than larger unmyelinated fibres. 

(b) pressure/touch nerves with the dorsal nerves that transmit pain impulses:- Fibres in the middle of a thick nerve bundle is blocked slower than those at the outside of the bundle. 

2.  A list of the effects of LA on other tissues.

Heart: Class 1 anti arrhythmic drugs block the sodium channels in the heart with the goal of blocking the propagation of an action potential and prolonging the refractory period. 

Skeletal muscles: LA have very weak blocking action therefore are not used in clinical application. 

3. What is the basis for the selection of a LA?

Systemic or localized distribution and absorption. 

4. Why are LA solutions sometimes saturated with CO₂?

To lower the pH of the blood during the use of LA. 

5. Which of the LA are typically used for surface anaesthesia?

Benzocaine 

Cocaine 

Oxybupuvacaine 

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? 

Affects the metabolism:

• Phenobarbitone
• Phenytoin
• Carbamazepine
• Oxcarbazepine
• Topiramate

Oral contraceptives’ serum concentration may be decreased by anti-epileptic drugs. This can cause unplanned pregnancies. Higher doses of contraceptives is then needed and additional contraceptive methods should be used if breakthrough bleeding occurs.

Safe to use:

• Valproate
• Lamotrigine
• Gabapentin
• Levetiracetam
• Vigabatrin

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

Yes. Oral contraceptives decreases lamotrigine and valproate serum levels.

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

Neonates: Slow metabolism of drugs

Children: Metabolism is faster than adults.

Adults: Metabolism is slower than children

Geriatrics: Slow metabolism of drugs.

In which cases is plasma blood level monitoring indicated?

• A change in dosage is made
• Finding a suitable maintenance dose
• To monitor any side-effects
• Neonates- children
• Geriatrics- old people
• During pregnancy
• When seizures occur

What are the possible mechanisms involved in the development of tolerance to chronic alcohol consumption?

Microsomal ethanol oxidation (MEOS) activity increases with the chronic use of alcohol and can be induced and is partly responsible for alcohol tolerance.

What toxic effects does chronic alcohol use have on the liver and liver metabolism?

There is a decrease in gluconeogenesis that indicates hypoglycemia and fat accumulation, nutrient deficiencies also contribute to liver metabolism. There is increased activity of liver microsomal enzymes. There ʼn progressive reduction in liver function, hepatitis & cirrhosis can occur. Damage to liver function is worse in women than men.

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

Wernicke-Korsakoff is accompanied by neurological damage to the lower part of the brain, thalamus and hypothalamus. This syndrome can be caused by the deficiency of thiamine- Vitamin B1. The syndrome causes chronic memory disorders. Symptoms of Wernicke-Korsakoff syndrome are: Confusion, paralysis of facial muscles and ataxia. Parenteral thiamine can be administered to prevent permanent brain damage.

What is fetal alcohol syndrome? Explain in full.

This is the syndrome that occurs to a baby whilst in the uterus due to the mother's chronic consumption of alcohol during her pregnancy, the fetus in the uterus is constantly exposed to alcohol. Teratogenic effects occur in this syndrome. The syndrome certainly includes features such as: mental retardation, microcephaly, growth defects, characteristic underdevelopment of the middle facial area.

How do the pharmacokinetic interactions of acute and chronic alcohol use differ?

In chronic alcohol use, metabolic transformation of other drugs increases with acute alcohol use, there is a reduced metabolism of drugs, e.g. Phenotia, TADs and others sedative-hypnotic drugs.

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

1. Hypoglycemic agents

2. Blood pressure lowering drugs

3. Paracetamol

4. Vasodilators.

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

Ethanol has a zero-order kinetic uptake, which ensures that it is absorbed from the bloodstream at a steady rate. This means that the amount you ingest will last longer in the body if you drink it rapidly. Since the alcohol does not have enough time to leave the body, the blood alcohol levels can increase quickly, causing an impact.

Give a brief summary of the metabolic pathways of ethanol metabolism

Alcohol dehydrogenase and coenzyme NAD, as well as MEOS and coenzyme NADPH, convert ethanol to acetaldehyde. Aldehyde dehydrogenesis will then convert acetaldehyde to acetate. 

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

The drug fomepizole inhibits alcohol dehydrogenase, preventing the development of acetaldehyde. Aldehyde dehydrogenase can be blocked by medicines like disulfiram, metronidazole, cephalosporins, and hypoglycemic drugs, preventing the formation of acetate. Acetaldehyde build up may cause symptoms including nausea, vomiting, headaches, and fire.

Jin Bu Huan and Kava-kava are considered to be used as a sedative and for anxiety, respectively, however, due to their side-effects (hepatotoxicity), these products should be avoided.

Ginkgo may be used to treat anxiety, but only in Alzheimer’s disease patients. This product was tested and results showed that the receptor density increased for the 5-HT_1A receptors.

Melatonin is used in treating insomnia as it is a serotonin derivative thus it helps regulate sleep-wake cycles. This increases REM sleep and has a hypnotic effect (it was reported to improve sleep onset, quality, and duration). Melatonin can also be used as an anxiolytic before and after surgery. Lavender also helps with insomnia, as it antagonizes serotonin transporters and NMDA receptors.

Valerian, hops, passion-flower and lemon balm products may be used in the treatment of anxiety and insomnia.

References:

• https://www.intechopen.com/books/different-views-of-anxiety-disorders/herbal-remedies-to-treat-anxiety-disorders
• https://civilizedcaveman.com/health/benefits-lemon-balm-sleep-wellness/
• https://blog.bioticsresearch.com/botanicals-for-a-better-sleep

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

Lipophilicity. This affects the onset of action of the drug as well as the extent of the effect on the central nervous system. Drugs that have a high lipophilicity have a rapid onset of action hence a great effect on the CNS, whereas drugs with a lower lipophilicity have a slow onset of action and does not yield a great effect on the CNS because it cannot cross the blood brain barrier.

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

Drug redistribution happens when drug that is absorbed into the systemic circulation gets distributed to other tissues into the body, e.g. the lipophilic tissue. This can in turn prolong the duration of action of the drug.

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

Benzodiazepines are metabolized by the hepatic microsomal enzymes in a three step process:

• Dealkylation to active metabolites.
• Oxidation via the CYP-P450 enzymes to active metabolites.
• Conjugation with glucuronic acid to form inactive, water-soluble metabolites.  

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

Benzodiazepines converted to the active metabolite desmethyldiazepam include: diazepam, chlorazepate, prazepam, chlordiazepoxide and ketazolam. The formation of active metabolites can increase the duration of action of the drugs (advantage) and can also cause cumulative effects with multiple doses (disadvantage).

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

Benzodiazepines that are not dependent of the CYP-P450 enzyme for metabolism include: oxazepam, lorazepam, temazepam, lormetazepam. These drugs provide an advantages for patients with liver cirrhosis, elderly patients, neonates as well as patients that use CYP-P450 enzyme inhibitors for these drugs do not affect the levels of CYP-P450 in the body because it does not require the enzyme to elicit its 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 a certain enzyme that then increases the rate of metabolism of the drug. Enzyme induction is seen more often with the older barbiturates (especially phenobarbital) and meprobamate. Enzyme induction, as previously stated, increases the rate at which drugs are metabolized and that then causes a decrease in the level of the drug in the systemic circulation which decreases the therapeutic effect of the drug.

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

Anterograde amnesia is the decreased ability of a patient to remember new information or occurring events during the drugs duration of action. The drugs that cause this effect are triazolam, lorazepam, midazolam.

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

• Decrease in the time takes to fall asleep.
• Decrease in the duration of REM sleep.
• Increases the duration of phase NREM.
• Decreases the duration of phase 4 NREM.
• increase the sleep duration in individuals who have less than 6 hours of sleep per night

These effects are significant in helping patients who suffer from insomnia or have problems sleeping as well as assist in improving the quality of sleep.

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

• Lorazepam
• Midazolam
• Thiopental
• Diazepam

These drugs have an increased lipophilicity and can thus cross brain tissue and distribute rapidly after intravenous administration. The benzodiazepines have long half-lives, form active metabolites and slow onset of action. This causes the prolonging of effects working ideal for anesthesia.

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

• Nitrozepam
• Clonazepam
• Clobazam
• Lorazepam
• Phenobarbitone
• Diazepam

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

These drugs have an inhibitory effect on polysynaptic reflexes and the internuncial transmission and therefore depressing the skeletal neuromuscular junction, at high doses. These selective action causes muscle relaxation.

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

On the respiratory system there is a relative depression seen in patients with pulmonary disease. Effects on respiration are dose-related and overdose may be fatal  as complete depression on the medullary respiratory center will occur .

On the cardiovascular system there is a relative depression that will occur in patients that suffer from diseases which cause cardiovascular impairment, the depression caused because of  medullary vasomotor center. Increased doses also result in the myocardial contractility and vascular tone may both be depressed by central and peripheral effects leading to circulatory collapse which is fatal.

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

The two types of ion channels are voltage gated ion channels and ligand-gated ion channels. The Ligand-gated ion channels are then further sub-divided into Ionotropic and Metabotropic.

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

Voltage gated ion channels open due to changes in the membrane potential of a cell, whereas Ligand gated channels open when a neurotransmitter binds to the channel.

Voltage gated channels typically only allow the entry of 1 type of ion into the membrane of the cell, whereas the Ligand gated channels are not as selective and normally allow the entrance of 2 or more types of ions.

There are 3 examples of voltage gated channels, namely: Sodium, Potassium and Calcium. Ligand gated channels consist of 4 examples, including: GABA-A, 5-HT3, Nicotinic and then finally EAA.

3. Compare ionotropic and metabotropic receptors.

Ionotropic

-Are responsible for the opening of ion channels

-Neurotransmitters bind to the receptor on the neuronal surfaces.

-The effects of these receptors do not last as long as metabotropic.

Metabotropic

-Are responsible for metabolic changes.

-Neurotransmitters bind to the G-proteins, which results in production of 2nd messengers.

-Due to the involvement of G-proteins the effects of these receptors last much longer.

4. Classify the CNS receptors into ionotropic and metabotropic and know the transduction mechanism of each receptor.

Ionotropic receptors include: GABA_A, Nicotinic receptors, Excitatory Amino Acid(EAA) and lastly the 5-HT₃ receptors.

Metabotropic receptors are sub-divided into 2 types of transduction systems, this includes the Adenylyl Cyclase system and also the Phospholipase C system. 

The Adenylyl Cyclase system is activated when receptors that are positively bound, such as β₁₊₂ and D₁, result in converting ATP to cAMP through Adenylyl cyclase when stimulated. But the formation of the 2nd messenger c-AMP can be inhibited when the receptors that are negatively bound, such as D₂, α₂, 5-HT_1A+B  and M₂ are stimulated to react. 

In the Phospholipase C system, positively bound receptors, such as α₁, 5-HT_2, M₁ and H₁, result in the formation of Inositol Triphosphate (IP₃) and also Diacylglycerol (DAG) from Phosphoinositol diphosphate (PIP₂).

5. Explain the difference between an EPSP and an IPSP and give and example of each.

An Excitatory Postsynaptic Potential (EPSP) facilitates the generation of an action potential on the postsynaptic membrane. For example, the Nicotinic receptor when Acetylcholine binds, opening the Sodium channels resulting in a depolarization.

An Inhibitory Postsynaptic Potential (IPSP) results in the inhibition of the action potential on the postsynaptic membrane. For example, GABA_A when Gamma - butyric acid binds and opens the Chloride channels, it results in a hyper polarization. 

6. What is the role of Calcium in the development of a synaptic potential?

When calcium is released from the neurotransmitter at the synaptic cleft, the neurotransmitter will then bind to the neuron which will induce a specific reaction depending on the neurotransmitter that has bound.