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

Increase Dopamine (DA) activity 

Decrease cholinergic activity 

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

Amantadine is known as Metaffinoid potentiator of DA and thus increase the release of DA and increase synthesis of DA and also blocks the reuptake of DA. It has antidyskinetic effects thus it acts as NMDA antagonist. It functions as Adenosine A2 antagonist so the adenosine blocks D2 receptor function ans thus it is antiviral. This way the Dopamine decreases. 

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

Amentadine: Metaffinoid potentiator of DA which increases the release of DA and also increases the synthesis of DA and further blocks the reuptake of DA. 

Selective MAO-B inhibitors: prefers dopamine as a substrate. Increases dopamine concentration in the central nervous system. The drugs can be as follows: Selegaline and Rasagiline. 

COMT inhibitors: Entacapone

COMT metabolizes l-dopa to 3-O-methyl dopa (3OMD). The increased plasma levels of 3OMD results in weak therapeutic response with l-dopa, because they compete for active processes. Furthermore, the COMT-inhibitor prolongs the duration of action of l-dopa  this way peripheral metabolism will decrease and bioavailability will thus be improved. 

• 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: Ropinirole and Bromocrptine 

D3: Pramipexole 

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

Selective monoamine inhibitors(MAO-B) inhibitors such as Rasagalinw and Selegaline. The MAO-B inhibitors does not allow the conversion MPTP to MPP which further acts as a protector and prevents neuronal/cell death. 

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

Prefers Dopamine as a subtrate therefore increases the concentration of DA in the central nervous system. 

• How do the COMT-inhibitors act in Parkinsonism? 

COMT metabolizes l-dopa to 3-O-methyl dopa (3OMD). The increased plasma levels of 3OMD results in weak therapeutic response with l-dopa, because they compete for active processes. Furthermore, the COMT-inhibitor prolongs the duration of action of l-dopa  this way peripheral metabolism will decrease and bioavailability will thus be improved. 

• How does istradephyline act?

This drug acts as Adenosine a2-A antagonist and furthere adds on therapy to l-dopa/carbidopa experiencing the Off episodes. 

• Discuss the MOA of safinamide

Safinamide consists of dual mechanism of action. This drug increases the activity of dopamine by the potent reversible inhibition of MAO-B and also the inhibition of dopamine uptake and decreases glutamate release. 

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

(a) myelinated fibers with unmyelinated fibers; and

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

a.  The smaller and myelinated fibers are blocked much easier in comparison to the larger, unmyelinated fibers which are much less sensitive to blockade by the local anesthetics.

b.  Activated pain fibers fire rapidly, thus pain sensation may be selectively blocked by local anesthetics. Fibers that are located in the periphery of nerve thick nerve bundles are blocked sooner than the fibers located in the core of thick nerve bundles. This is because they are exposed too higher concentrations of the anesthetic much earlier.

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

Heart: Local anaesthetics have Class I anti-arrhythmic drug effects resulting in cardiac depression

Skeletal muscle: Weak blocking effects, no clinical application.

• What is the basis for the selection of a LA?

A local anesthetic is chosen due to the following factors:

• • The type of procedure that is being done
  • The type of tissue that the local anesthetic should be used on
  • The duration of the numbing effect that is needed

• Why are LA solutions sometimes saturated with CO₂?

The Carbon Dioxide acts as a buffer to the Local Anesthetic. This will potentiate the effects of the local anesthetic.

• Which of the LA are typically used for surface anesthesia?
  • Benzocaine
  • Cocaine
  • Oxybuprocaine

• Name the major acute toxic effects of the inhalation drugs.

• 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? 

Drugs that affect metabolism of the Pill: Perampenel (decreases levonorgestrel-containing contraceptives) and Phenobarbitone, phenytoin , carbamazepine and oxcarbazepine all decrease the effectiveness of the oral contraceptive pill leading to increased pregnancies and the possibility of teratogenic effects in these pregnancies.

Drugs that are safe to use in combination is Valproate, Lamotrigine, Gabapentin, Levetiracetam and Vigabatrin.

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

Yes, oral contraceptives can decrease serum levels of drugs such as Lamotrigine and Valproate.

• 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.

The chronic use of alcohol during pregnancy causes teratogenic effects that result in mental retardation and malformation of the foetus. This syndromes abnormality may be classified  by mental intrauterine growth retardation, microcephaly, poor coordination and the underdevelopment of the midfacial area and minor joint abnormalities. In extreme cases the foetus may develop congenital heart defects and mental retardation. Due to the pharmacokinetics of alcohol, it can cross over into the placenta and reach levels in the foetus that are like that in the mother’s blood which is rather dangerous for a foetus that is still developing.

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

Chronic alcohol use induces increased metabolism of alcohol and other drugs metabolised by CYP450. While acute alcohol consumption causes the effects of an opposite nature and thus reduces the metabolism processes.

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

Phenothiazines, TCA’s and sedative hypnotics like the benzodiazepine’s metabolism is decreased or inhibited under the influence of acute alcohol consumption due to a decrease in enzyme activity and liver blood flow. Vasodilating drugs and hypoglycaemic drugs effects are potentiated by acute alcohol consumption  result in extreme vasodilation throughout the body causing a drop in blood pressure leading to increased heart rates to maintain vital organ function. Alcohol increases the anti-platelet aggregation effects of aspirin.

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

Alcohol is lipophilic and therefor has a fast distribution and absorption rate. It can cross the blood brain barrier and be a CNS suppressant. When a person takes alcohol on an empty stomach peak levels can be reached within 30 minutes. The Peak concentrations in women can be reached more easily since men has more fluids in their body to dilute the alcohol. Alcohol is metabolised by the Liver and can activate 2E1 (Induce NAPQI formation when drinking Paracetamol with alcohol).

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

Ethanol metabolism occurs via 2 enzyme systems.

1)   Alcohol dehydrogenase system – Usually when there is a low amount of alcohol present in the body. Co-Enzyme NAD breaks down alcohol in acetaldehyde and aldehyde dehydrogenase enzyme converts that into acetate. This system can be saturated.

2) Microsomal ethanol oxidation (Mixed function oxidation) – usually when there is a higher amount of alcohol present in the body. (>100 mg/dL). Alcohol are being broken down into acetaldehyde and aldehyde dehydrogenase will convert it into acetate.

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

Disulfiram, Metronidazole, Cephalosporins and Hypoglycaemic drugs.

These drugs inhibit enzyme aldehyde dehydrogenase which converts acetaldehyde into acetate. The accumulation of acetaldehyde cause symptoms such as nausea, headache, dizzy etc. The feeling in general is not pleasant and in general, these drugs are used in people who has a high tolerance for alcohol.

Herbal drugs that can be used to treat anxiety include:

• Ashwagandha
• Chamomile
• Valerian
• Lavender
• Galphimia Glauca
• Passionflower
• Kava kava
• Cannabidiol

Herbal drugs that can be used to treat insomnia include:

• Valerian root
• Chamomile
• Passionflower
• Hops
• Lemon balm

Melatonin

1. A factor that influences the absorption of a drug is the drugs lipophilicity. This can influence the onset of action of the drug and the extent of the effects that the drug will have on the Central Nervous System. Drugs with a high lipophilicity will have a rapid onset of action and will have a greater effect on the CNS whereas drugs with a lower lipophilicity will have a slower onset of action and has minimal effects on the CNS because these drugs cannot cross over the blood brain barrier as effectively as drugs with a high lipophilicity.

2. Redistribution of a drug is when the drug is absorbed into the systemic circulation and then transported to other tissues in the body. This process helps to prolong the duration of action of the drug.

3. 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.  

4. Benzodiazepines that are converted to an active metabolite known as Desmethyldiazepam, these include: Diazepam, Chlorazepate, Prazepam, Chordiazepoxide and Ketazolam.

Drugs that are converted into an active metabolite can increase the duration of action but can also result in cumulative effects with multiple doses.

5. 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.

6. Enzyme induction is when a drug results in the increased production of certain enzymes that will increase the rate of metabolism of the drug. This process is seen mostly with older Barbiturates such as Phenobarbital and Meprobamate.  Enzyme induction causes a decrease in the amount of drug in the systemic circulation which will cause a decrease in the therapeutic effects of the drug.

1. Anterograde amnesia refers to the inability to remember or retain new information. Drugs that cause this effect are the Benzodiazepines: Midazolam, lorazepam, nitrazepam, triazolam, temazepam and nimetazepam.

2. 

- Decrease the time it takes to fall asleep.

- Increase in total sleep duration.

- There is an increase in stage 2 of non-rapid eye movement

- Decrease in the duration of stage 4 non-rapid eye movement.

3. Barbiturates such as Midazolam, Diazepam and Lorazepam are used as a supplement therapy in anaesthesia. They can induce a calming effect in patients and even induce sleep.

4.  

- Phenobarbitone

-Clonazepam

-Clobazam

-Diazepam

-lorazepam.

- Nitrazepam

5. Inhibition of polysynaptic reflexes intern uncial transmission and depression of transmission at skeletal neuromuscular junctions (at high doses).

6. These drugs cause significant respiratory depression in pulmonary diseases and cardiovascular depression in cardiovascular diseases.  High doses of these drugs can result in death due to the depression of the medullary respiratory centre.

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

Voltage-gated channel

Ligand-gated channel

G-protein coupled receptor

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

Voltage-gated channels changes in membrane potential of the cell whereas Ligand-gated channels bind ligand(neurotransmitters) to ion channel.

Voltage-gated channels’ initial segments act on a much slower time scale to modulate the rate at which neurons are discharged whereas Ligand-gated channels activates typically in a brief (very quick) opening of the channels.

• Compare ionotropic and metabotropic receptors.

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

• Ionotropic: GABAᴀ (y-amino butyric acid), Nicotinic (Acetyl choline), EAA (Glutamate) and 5HT3 (Serotonin)
• Metabotropic:

There are 3 systems involved in metabotropic receptors.

1. 1. Adenylyl cyclase system- this system involves the ß1 + 2, D1 receptors for an effect to take place. The D2, α2,5-HTI A+B, M2 receptors cause an inhibitory effect
   2. Phospholipase C system- this system involves α1 5-HT2 M1, H1 are involved in the activation of this system.
   3. G-Protein-coupled receptors

• Explain the difference between an EPSP and an IPSP and give examples of each

EPSP-meaning 'excitatory postsynaptic potential'. This demonstrates that when such a pathway is invigorated, a depolarization impact happens. An illustration of this is when Acetyl choline animates the nicotinic receptors, the sodium channel is enacted, and a depolarizing impact is seen creating EPSP.

IPSP-meaning 'inhibitory postsynaptic potential'. At the point when such a pathway is invigorated, the postsynaptic layer is hyperpolarized inferable from the opening of the chloride channel and along these lines creating an IPSP. An illustration of this is with the GABAᴀ (y-amino butyric corrosive receptor which causes a specific opening of the chloride ion channel which brings about hyperpolarization and consequently IPSP.

• What is the role of calcium in the development of a synaptic potential?

Calcium is significant during the time spent synapse (NT) discharge. At the point when Calcium channels open Calcium races into the neuron terminal and afterward the vesicle containing the synapses are being delivered into the neurotransmitter where the NT ties to postsynaptic receptors (or Pre-synaptic = Negative input framework) for a further interaction.