• 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. 

Brand, L. 2021. Parkinsonism and other movement disorders. Study unit 8 [PowerPoint Presentation]. Unpublished lecture notes on eFundi, FKLG312. Potchefstroom: NWU

 

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

(a)   myelinated fibres with unmyelinated fibres; and 

Myelinated fibres are small and easily blocked where as unmyelinated are large. 

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

The dorsal nerves are more sensitive to blockade compared to the pressure nerves. 

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

Heart: class 1 anti-arrhythmic drugs. Shortens the action potential. 

Skeletal muscle: weak Blocking effect takes place, Thus there is no clinical application.

Cocaine: it increases mood, affects the central Catecholamines mediated neurotransmission and therefore block the re-uptake of NA. 

• What is the basis for the selection of a LA? 
    Duration of the effect.
    The process followed.  
   The local anaesthetic that is being used. 
• Why are LA solutions sometimes saturated with CO₂?

It is because the CO2 plays as a buffer and thus potentiates and speeds the LA. 

• Which of the LA are typically used for surface anaesthesia?

• Cocaine 
• Benzocaine 
• Oxybuprocaine 

Brand, L. 2021. Local Anesthetics. Study unit 6  [PowerPoint Presentation]. Unpublished lecture notes on eFundi, FKLG312. Potchefstroom: NWU

• Compile a table, listing the major effects on every system (cardiovascular, CNS, renal, hepatic and uterus) for all the inhalation anaesthetics. This table is important when it comes to the selection of drugs in certain individuals.

Systems	Halothane	Enflurane	Isoflurane	Desflurane	Sevoflurane	N20
Cardiovascular	Decreased blood pressure, sensitized myocardium for arythmogemic effects of catecholamines.	No sensitisation of the myocardium	Lower than Halothane and Enflurane, no sensitisation of myocardium	Lower than Halothane and Enflurane	Similar to Desflurane	No effect
CNS	Fast smooth induction, stadium ll absent	Smooth induction in rare case convulsions may occur (epilepsy)	Faster induction and faster recovery than Halothane	Faster induction and recovery than Isoflurane, increases the cerebral blood flow and intracarnial pressure	Similar to Desflurane	Weak anaesthetic, potent analgesic, amnesia
Renal	Decrease urine flow.	Decrease urine flow and glomerular filtration takes place	Decrease urine flow	Decreases urine flow in the kidney	Decrease urine flow	Decrease urine flow and glomerular filtration takes place
Hepatic	Hepatotoxic in the liver (in rare case)
Uterus	Decrease muscle contractions thus external twisting of baby occurs.

• Name the major acute toxic effects of the inhalation drugs.
  • Nephrotoxicity 
  • Hypoxia
  • Malignant hypothermia 
  • Hepatotoxicity 

Brand, L. 2021. General anaesthetics. Study unit 5 [PowerPoint Presentation]. Unpublished lecture notes on eFundi, FKLG312. Potchefstroom: NWU

 

• 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 the metabolism of the pill(oral contraceptive): Carbamazepine, phenytoin, Oxcarbazepine, Topiramate and Phenobarbital. The implication is that it prevents pregnancies and decrease the effectiveness of the pills.

Drugs that are safe to use in combination with the pill: Valproate, Lamotrigine, Gabapentin, Levetiracetam and Vigabatrin. 

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

Yes, Oral contraceptives decreases the levels of the drugs namely: Lamotrigine and Valproate. 

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

Neonates has slower metabolism and thus small doses should be given. Babies and children have a faster metabolism than adults therefore they jeed to be given higher doses. For elder patients, small dosages are given due to slow metabolism. 

• In which cases is plasma blood level monitoring indicated?

When the drugs contains enzyme inhibiting factors such as Valproate, Phenytoin, Phenobarbital and Lamotrigine. In the drug phenytoin, it is used because of the saturation of metabolism in the liver. Thus, plasma blood level monitoring should be indicated when taking pills. 

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

Chronic alcohol intake may lead to tolerance and dependence. The adjustment of central never (due to exposure on the messengers) system leads to increases metabolic rates. Cross-tolerance may take place due to sedative hypnotics. Psychological and physical dependence can occur. Withdrawal symptoms may take place. Peripheral neuropathy may therefore be evident.

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

The toxic effects in the lover are as follows: there is a consistent decline in the liver function and thus leads ro hepatitis and liver cirrhosis. The effect on the liver is worse in women compared to men. Additionally, decrease in gluconeogenesis, hypoglycaemia and fat accumulation further has a toxic effect on the liver. Increased activity of liver microsomal enzymes can also have a toxic effect. 

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

Is a brain disorder because of lack of vitamin B1 and thiamine. The symptoms are as follows: confusion, ataxia alcohol withdrawal and changes in vision. It  is treated with intravenous administration of thiamine in order to prevent permanent damage to the brain. 

• Fully explain the foetal alcohol syndrome.

It is a condition that takes place in a person whose mother consumed alcohol during pregnancy period. It further caused brain damage and growth problems. The alcohol taken by the mother will be in the bloodstream and thus passed on to the fetus via the umbilical cord. The symptoms are indicated as follows: small head, lack of focus, learning difficulties, problems seeing and hearing, heart defects, mood swings and etc. The symptoms vary from infant to infant and the defects cause by this syndrome is irreversible. 

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

Chronic alcohol consumption: metabolic transformation of other drugs is increased such a paracetamol (hepatotoxicity with high therapeutic doses. 

Acute alcohol use: leads to decrease metabolism of drugs examples of drugs are Phenothiazines and other sedative hypnotics. 

• Name 4 drug interactions with alcohol where the pharmacological effects of the other drugs are potentiated by alcohol.
  1. Paracetamol 
  2. Phenothiazines
  3. TAD’s and 
  4. Other sedative hypnotics

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

It has fast absorption and distribution rate and it is highly lipophilic. The peak levels in a persons body can be evident in 30 minutes of fasting state. The volume of distribution of ethanol is equal to total body fluid which is 0.5-0.6 L/kg. The oral equivalent dose are higher in women compared to men. The metabolism process is that, alcohol is metabolised by liver (90%) and the rest is lung and urine. Adults metabolize 7-10g/h. 

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

There are 2 systems:

1. Alcohol dehydrogenase: takes place in low to moderate amounts. Limited amount of NAD (co-enzyme) therefore zero-order kinetics (7-10g/h). 
2. MEOS ( Microsomal ethanol oxidation): take place at high concentrations (greater than 100mg/dL) . The activity of MEOS increases with chronic use, can be induced and is responsible for tolerance partially. Therefore, the end product is acetaldehyde.

• Which drugs can effect this metabolism and what are the effects thereof.

Drugs that can affect this metabolism: 

Disulfiram

Metronidazole

Hypoglycaemic drugs

Cephalosporins 

The effects are namely: inhibiting of Aldehyde Dehydrogenase which further leads to the accumulation of Acetaldehyde in the entire body which can cause nausea, dizziness, vomiting and headache. 

Alternative medications used for anxiety and insomnia include herbal medication. The number of people making use of herbal medication for the therapy of depression, anxiety and depression are increasing in number.

Anxiety is a completely natural human feeling. If this feeling is endured for longer period of time, it affects physically and mentally. Alternative medicines for the treatment of anxiety include the following: Kava-kava, St. John’s wort, Ginko biloba, Kamishoyosan etc. Some herbal medicines can cause side effects thus it is vital to contact the doctor. These herbal medicines mentioned above are classified as SSRI’s (Selective serotonin reuptake inhibitors) which are in other words the antidepressants. SSRi’s increases the serotonin level in the brain to treat depression. Serotonin is a neurotransmitter that carries signals between the brain and neurons.

Insomnia is a health prevalence health concern in the general population which can lead to physical disorders. Alternative medicines for the treatment of insomnia include the following: Valerian root, Chamomile, Melatonin, Passionflower, Hops, Lavender e.t.c. Valerian root and Chamomile is set to have an onset of sleep and sleep maintenance. Melatonin is a hormone and plays a vital role in the regulation of sleep. Passionflower and Hops also tend to work effectively and induces relaxing effect.

Some of the above mentioned herbal medications are botanicals in other words they are nature's goodness, extract made from plant roots flowers and leaves. Furthermore, these plant parts are dissolved using special solvent. However, solution is extracted from the plants which is thus insoluble  

Reference:

Alternative Treatments for Insomnia. WebMD. https://www.webmd.com/sleep-disorders/alternative-treatments-for-insomnia.  Date of access: 06 March 2021.

Bertram G. Katzung 2018, B Basic & Clinical Pharmacology, Lange, McGraw hill, University of California, San Francisco. 14^th ed. p1113.

The most commonly prescribed type of antidepressant. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/depression/in-depth/ssris/art-20044825. Date of access: 06 March 2021.

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

Lipophilicity is one of the factors that may affect absorption and distribution of these drugs. Lipid solubility plays a vital role in determining the rate at which a particular sedative-hypnotic enters the central nervous system. This process is thus responsible for the rapid onset of action of triazolam. Drugs that exert high lipophilicity have a rapid onset of action whereas drugs with lower lipophilicity does not have a rapid onset of action.

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

Redistribution occurs when a drug gets absorbed in the systematic circulation and thus gets distributed to certain organs of the body. In case of highly soluble drugs it gets distributed to the brain heart and kidney. The significance thereof is to ensure that the drug gets distributed to the organs

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

Benzodiazepines are metabolized by hepatic microsomal enzymes. The process consists of:

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

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

Benzodiazepines are converted to desmethyldiazepam which includes:

Diazepam, Chlorazepate, Prazepam, Chlordiazepoxide and Ketazolam. These active metabolites thus leads to extension of duration of action.

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

Oxazepam, Lorazepam, Temazepam,Lormetazepam are the drugs that do not depend on oxidative enzymes for metabolism. These drugs plays an advantage to the patients that suffer from liver cirrhosis, elderly, neonates and patients that make use of CYP-P450 inhibitors thus they do not require oxidative enzyme to induce an effect.

6. 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 metabolic processes of the enzyme. Phenobarbital and Meprobamate are known as enzyme inducers. The clinical significance is when an enzyme induce causes an increase in metabolism of the drug which causes drug decrease in the systematic circulation therefore decrease in the therapeutic effect.

1. What does anterograde amnesia mean and which drugs can cause this effect?         Anterograde amnesia refers to decreased ability to remember new information. Drugs that can cause these are: Triazolam, Lorazepam and Midazolam

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

• Decrease the time it takes to fall asleep thus increased sleep duration
• Decrease the duration of REM sleep
• Increase the duration of phase NREM
• Decrease the duration of phase 4 NREM
• These effects thus are significant in helping patients who experience insomnia

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

Thiopental , midazolam, diazepam, and lorazepam. These drugs can be grouped as anxiolytics meaning treating people with anxiety. The drug has the ability to induce sleep thus patients cannot feel or remember the anaesthesia.

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

Phenobarbitone, clonazepam, diazepam, clobazem and lorazepam.

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

Inhibits polysynaptic reflexes. During high doses reduce transmission at skeletal neuromuscular junction leading to muscle relaxation.

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

Respiratory system: significant respiratory depression evident in patients with pulmonary disease. Effects on the respiration are dose related and an overdose may be dangerous. Depression can occur on the medullary respiratory center.

Cardiovascular system: significant cardiovascular depression will take place in patients that suffer from diseases by cardiovascular impairment. Furthermore, the depression is caused because of medullary vasomotor center. Central and peripheral effects may depress the high doses in myocardial contractility and vascular tone this whole process may lead to circulatory collapse which is dangerous.

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

1. Voltage-gated ion channels
2. Ligand-gated ion channels

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

1. Changes in the membrane potential of the cell
2. Transfers signal from cell body to nerve terminal
3. Sodium(Na⁺), Potassium(K⁺) and Calcium(Ca²⁺) channels  

•    Ligand-gated ion channels

1.  Binding of ligand (Neurotransmitter) to the ion channel
2. Ionotropic channel recptor controls the gating of the channel 
3. Responds to Acetylcholine, gamma aminobutyric acid (GABA), glutamate and serotonin binding to receptors 

• Compare ionotropic and metabotropic receptors.

Ionotropic receptprs	Metabotropic receptors
Contains multiple subunits per receptor	7 transmembrane G-protein receptors
Binding of the receptor directly opens the ion channel  thus no formation of  second messanger	Formation of second  messanger and therefore transduction relys on the formation of this messager
Channels are insensitive or weakly sensitive to membrane potentials	Activation of these results in indirect voltage-gated ion channel regulation.
Does not have a last long effect	Longer effect
Responsible for opening of ion channels	Responsible for metabolic change

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

The Ionotripic receptors in the CNS consists of GABA_A , nicotinic receptors, Excitatory Amino Acid (EAA) and 5-HT₃ receptors. 

Metabotropic receptors makes use of two transduction system in order to function which is 

1. Adenylyl Cyclase                                                                                                                                             This system contains both postitive and negative bound receptors. The postive bound receptors leads to the formation of second messanger which is ATP to c-AMP. The negatively bound receptors does not form second messangers in other words c-AMP does not form (inhibition effect).
2. Phospholipase C                                                                                                                                              This system contains postively bounded receptors which are α₁,5-HT₂,M₁ and H₁. It forms Inositol Triphosphate and Diacyglycerol from Phosphoinositol diphosphate. 

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

EPSP(Excitatory Postsynaptic Potential) refers to the activation of additional action potential as a result of depolarization. This is an example of Nicotinic receptors when Acetylcholine binds, the Sodium channels then open resulting in depolarization due to Sodium flowing in. 

IPSP( Inhibitory Postsynaptic Potential) forms a graded potential which makes a Postsynaptic neuron less likely to cause an action potential as a result of hyperpolarization. This is an example of GABA_A  receptor when gamma-butyric amino acid binds therefore Chloride channels open resulting in hyperpolarization as Chloride flows in. 

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

Depolarization takes place when an action potential arrives at the axon terminal of prestnaptic neuron, thus influx of Calcium forms in the presynaptic membrane. There is a spike of Calcium which leads to the fusion of synaptic vesicle with presynaptic membrane. Neurotransmitters are then formed from the synaptic vesicle in the synaptic cleft.The neurotransmitters are then released in the synaptic cleft which then binds to the postsynaptic receptors to elicit an effect. Therefore Calcium plays a vital role in the formation of Neurotransmitters.