Prepare a short “lecture” of not longer than 5 minutes (200 words), explaining to a patient what pain is, its possible causes, why different people experience pain differently and what the generally important principles of pain management and referral involve. The videos above will also be of value to complete this assignment. 

Pain is an uncomfortable sensation, It is entirely based on subjective sensory and emotional experience, meaning that for one person it will hurt a lot more than for another person. Pain is usually associated with potential or actual tissue damagE

Each individual experiences pain in a different way and the pain can be severe on one person and less severe on the next one .

Pain is subjective therefor the pain experienced by one person in note equal that which another person may feel. 

Pain varies from acute pain to Chronic pain.

Acute pain happens in the skin bone, joint ,muscle, connective tissues or it may also take place in the visceral : internal organs; e.g large intestine and pancreas. 

whilst during Chronic pain it may take place via the functional which is the fibromyalgia,Ibs, tension type headache or pain can be seen in the Neuropathic where the nerve is damaged also during post neuralgia and diabetic neuropathy.

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.  

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

SSRIs: Fluoxetine, Citalopram, Escitalopram, Paraxetine, Sertraline

SNRIs: Duloxetine, Venlafaxine, Levomilancipran

TCAs: Imipramine and many others

5HT Receptor Modulator: Nefazodone, Trazadone, Vortioxetine

Tetracyclics, Unicyclics: Bupropion, Amoxapine, Maprotiline, Mirtazapine

Monoamine Oxidase Inhibitors: Phenelzine, Tranylcypromine, Selegiline

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

The existing drugs all have an effect on the Serotonin neurotransmitter by blocking 5HT receptors or SERT.

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

Effectivity of antidepressants takes 6-8 weeks to be seen. This is because to have an effect on Serotonin receptors takes time. As the 5HT receptors will be desensitized or they will be reduced.

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

TAD:

Efficacy:  Drug titrated to minimum effective dose

Side effects: anticholinergic, alpha blocking effects, sedation, weight gain, arrhythmias and seizures in overdose

Safety: Seizures can occur as a result of overdose, lethal ventricular arrhythmias and fibrillation. Commonly used in suicide attempts. 

SSRIs:

Efficacy: Initial dose can be administered fully.

Side effects:  Sexual dysfunction, insomnia, headaches, nausea, diarrhoea, insomnia, hypersomnia, weight gain

Safety: Uncommon fatalities occur with overdose of SSRI alone.

• What is action of mirtazapine? 

Blocks alpha 2, increases NA and 5HT release; 5HT2A results in depressant effect, 5HT3 results in anxiolytic and decreases nausea; H1 and Alpha 1 has an indirect stimulation of 5HT1A which is anxiolytic.

• What is action of venlafaxine?

Moderate selective blockage of NET and SERT, more potent for 5HT than for NA. 

• What is the action of agomelatine?

MT1 and MT2 receptor agonist , also 5HT2C antagonist with antidepressant properties. 

Katzung B.G. et al. 2019. Pharmacology examination & board review. United States of America. Cenveo Publisher Services.

• 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.

1. Aliphatic sidechain: Chlorpromazine
2. Piperidine sidechain: Periciazine
3. Piperazine sidechain: Fluphenazine, Perphenazine, Trifluoperazine, Prochlorperazine.

Aliphatic and piperidine compounds:

• Low potency*, little EPS
• Severe sedation
• Strong anti-cholinergic effects,
• Strong α-lytic effects (postural hypotension), 
• Cardiotoxic

Piperazine derivatives:

• High potency, more EPS,
• Weaker anti-cholinergic side effects  
• Weaker α-lytic effects,
• Less sedation
• Less cardiovascular (CVS) side effects
• Which receptors in particular are blocked by the typical antipsychotic drugs?

Mesolimbic D2 Receptors

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

Atypical drugs : block 5-HT_2A receptors more than D₂. 

Typical drugs: block mesolimbic DA 2 receptors.

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

Benzamides block D₂ (selectively) and D₃ receptors. The risk of extra pyramidal side effects is reduced due to the limbic localisation of the D₃ receptors. Furthermore, Aliphatic side-chain typical drugs such as Chlorpromazine compounds have a low potency and few extra pyramidal side effects

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

Extrapyramidal side effects are caused by the blockade of D2 receptors in the nigrostriatal pathway which occurs potently by drugs of the piperazines derivatives.

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

Autonomic side effects occurs as a result of Muscarinic and α1 blockade effects.

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 

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

(a) myelinated fibres with unmyelinated fibres; 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 anaesthetic is chosen due to the following factors:

• • The type of procedure that is being done
  • The type of tissue that the local anaesthetic 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 Anaesthetic. This will potentiate the effects of the local anaesthetic.

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

1. Effects of inhalation anesthetics:

2. The 4 major acute toxicities of inhalation anesthetics include:

• Nephrotoxicity
• Hematotoxicity
• Malignant hyperthermia  and hepatotoxicity
• Effects of inhalation anesthetics:
• The 4 major acute toxicities of inhalation anesthetics include:
• Nephrotoxicity
• Hematotoxicity
• Malignant hyperthermia  and hepatotoxicitY 

• 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 (Which decreases the  levonorgestrel that icontains 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 and effective to use in combination are 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?

It is a classified 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 damage and  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 and  the benzodiazepine’s metabolism should be 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.

REFERENCES:

Brand, L. 2021. Alcohols. SU. 3 [PowerPoint Presentation]. Unpublished Lecture Notes on eFundi, FKLG 312. Potchefstroom, NWU.

Katzung, B.G. 2018. Basic and Clinical Pharmacology. 14^th ed. United States of America: McGraw-Hill Education.