Pain, a uncomfortable, sensory and emotional experience caused by actual or potential tissue damage. It can be measure on a scale from 0, no pain to 10, unbearable pain. Pain can be described as a burning, stinging , dull, sharp and aching. Nociceptors, tissue damage cells, picks up the pain stimulus and sends it to the brain via spinal-cord, this is interpreted by neurons in the grey matter of the brain, this pain signal activates the salience network. Further the motor network is stimulated to remove the source of the pain from body part where the pain is experienced. Other chemical sis also releases to help the brain and the body to cope with the pain, for example enkephalins and endorphins. These different methods to manage pain in the body is different for every person thus people experience pain different, and the management there off also differ. Mild pain is treated with over-the-counter medication to treat the cells where the pain starts. Severe pain is treated with prescribed medication where the perception of the pain is influenced, by blocking the stimulus or by increasing the excretion of endogenous peptides such as endorphins to help with the coping of the pain.

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

Tricyclic antidepressants

Imipramine

Mono amine oxidase inhibitors

Phenelzine

Tranylcypromine

Selegiline

Serotonin noradrenaline reuptake inhibitors

Duloxetine

Venlafaxine

Levomilnacipran

Serotonin Modulators

Nefazodone

Trazodone

Vortioxetine

Noradrenalin receptor inhibitors

Reboxetine

Tetracyclic and unicyclic antidepressants

Bupropion

Amoxapine

Maprotiline

Mirtazapine

Mianserin

Cascadic rhythm regulators      

Agomelatine

Selective serotonin reuptake inhibitors

Fluoxetine

Citalopram

Escitalopram

Paroxetine

Sentraline

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

All drugs that treat depression has an effect on the neurotrophic and endocrine factors within the brain.

How long does it take for the anti-depressive effects of these drugs to appear? What is the reason for this?

14-21 days or even longer because it takes up to two weeks or more for neurotrophic factors to be synthesised

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

• Efficacy

TAD’s has an high affinity for the serotonin and noradrenaline re-uptake transport receptor because of their structure while SSRis only has an affinity for blocking the re uptake of serotonin.

• side effects

They have a large amount of side effects anticholinergic side effects such as sedation, weight gain , alpha receptor blockage, arrythmia and seizures if high doses is administered while SSRI causes sexual dysfunction and increases risk for serotonin syndrome if co administered with monoamine oxidase inhibitors

• safety?

It as a long half life and causes convulsions at high doses while SSRI’s as the risk for serotonin syndrome is used with other drugs. SSRI’s is first line treatment thus its is relatively safe at recommended dosage.

• What is the action of mirtazapine?

Block alpha 2 receptors and both Noradrenaline(autoreceptors) and serotonin release (heteroreceptors) which stimulates serotonin 1A indirectly and serotonin 2  an 3 blockage

• What is the action of venlafaxine?

Block both Serotonin and Noradrenaline re uptake

• What is the action of agomelatine?

Is a agonist of both melatonin 1 and 2 receptors and serotonin 2 C antagonist

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.

Chlorpromazine as an aliphatic side chain.

Periciazine has a piperidine side chain.

Fluphenazine has a piperazine side chain.

Both aliphatic and piperidine compounds has a low potency and is highly sedative and has a strong anti-cholinergic effect and has strong alpha lytic effects (is cardiotoxic) while piperazine has a high potency with weak anti cholinergic side effects and weak alpha lytic effects.

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

Block dopamine 2 receptors in the mesolimbic

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

A atypical drug differs from a typical drug because it blocks serotonin 2A receptor more than dopamine 2 receptors unlike typical drug that selectively blocks dopamine 2 receptors.

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

Older drugs (Typical drugs) such as Chlorpromazine and periciazine has little extra pyramidal side effects both of these blocks mesolimbic dopamine 2 receptors.

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

Older drugs (Typical drugs) such as Fluphenazine, perphenazine, trifluoperazine and prochlorperazine as high extra pyramidal side effects because these drug as an long halve life an is extremely potent.

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

Muscarinic and histamine receptor blockage caused the side effects on the autonomic system.

Blog 10

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

Drugs that increase Dopamine activity in the brain like, L-dopa or dopamine agonists or drugs that decrease the cholinergic activity in the brain like anticholinergic drugs.

In what way does amantadine act as a antiparkinsonism drug?

Amantadine indirectly treats Parkinson’s, because Amantadine is an metaffinoid potentiator on the dopamine receptor it potentiates the release and synthesis of dopamine and it also blocks the re-uptake of dopamine and thus its metabolism. This will increase dopamine’s effect on the body and restore balance between the Ach and dopamine in the brain and thus decrease the symptoms of Parkinson’s.

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

Drugs like Amantadine and MAO-B inhibitors indirectly increases dopamine concentrations because, as explained above Amantadine is a metaffiniod potentiator thus it binds to a dopamine receptor and potentiates its effect in this case it will increase dopamine release and synthesis, it also blockes the reuptake of dopamine.

MAO-b inhibitors indirectly increases dopamine concentration by blocking the metabolism of dopamine.

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

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

• Dopamine 2 receptors agonists: Bromocriptine and Ropinirole
• Dopamine 3 receptors agonist: Pramipexole

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

Pramipexole, it is a neuroprotective which means it is drug that can alter the course of a ischemic event in an neuron, in other words it alters the metabolic event of the neurons to decrease the damage that is done to the neuron. In the case of a Parkinson’ disease cycle in which the dopamine neurons die over time the neuroprotective drugs can stop or slow this degradation down.

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

These drugs is isomers of dopamine which means is can bind to MAO-B receptors and block them from dopamine this will increase the amount of dopamine centrally and this will help to get the balance between dopamine and Ach more normal because this balance is inadequate in Parkinson patients.

How do the COMT-inhibitors act in Parkinsonism?

COMT inhibiter drugs block COMT enzymes, this enzyme metabolizes L-Dopa to 3-O-methyl dopa, and by blocking this enzyme the amount and life time of the L-Dopa Centrally will increase and the L-Dopa can be converted to dopamine by carboxylase, which will help to improve the symptoms of Parkinson disease.

How does istradephyline act?

Istradephyline binds to Adenosine A_2A and blocks its effects. It is added to L-dopa and carbidopa combinations to improve a patient’s off episodes, patient struggles to move voluntarily.

Discuss the MOA of safinamide

Safinamide has a dual action it increases dopamine activity by blocking MAO-B enzymes that metabolises L-Dopa, this increases dopamine concentration and it inhibits dopamine reuptake, it also decrease glutamate release.

Both these actions is beneficial for the treatment of Parkinsons disease.

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

1. myelinated fibres with unmyelinated fibres;

Smaller myelinated fibres are easier blocked than larger unmyelinated fibre because of the diameter of the nerve plays a very large role in the distribution of LA

While unmyelinated fibres are blocked faster than myelinated fibres (both fibres have the same diameter) because of the Myelin sheath that surrounds the fibre (lipid barrier)

2.  pressure/touch nerves with the dorsal nerves that transmit pain impulses?

(Dorsal nerve is larger the ventral motor nerve)

Because the dorsal nerve that transmits pressure and touch impulses is an active pain fibre nerve, then blockage of this nerve will be relatively fast, thus its sensitivity will be high to LA blockage.

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

Most LA has a vasodilatory effect on the circulation system.

LA has a CNS depression effect.

What is the basis for the selection of a LA?

The pH should be taken in consideration before deciding on a LA because pH interferes with ionized and unionized forms of the agents. Unionized agents crosses lipid membranes but ionized agents blocks the sodium channel more effective.

The total duration of action should be considered before selecting a LA, Esters has a shorter duration of action than Amides.

Why are LA solutions sometimes saturated with CO₂?

Some can reached with CO₂ and be exhaled in that form, and may even be re-inhaled in to the body,

Which of the LA are typically used for surface anaesthesia?

Benzocaine, cocaine and Oxybuprocaine is used as surface anaesthesia.

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.

Name the major acute toxic effects of the inhalation drugs:

• Bradycardia.
• Increase intracranial pressure.
• May cause convulsions.
• Irretention of airways.

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? 

Phenobarbitone, phenytoin, carbamazepine, oxcarbazepine, Topiramate. These drug decrease the effectiveness of the contraceptives thus increase a women chance for a unplanned pregnancy.

It is safe for a women to use Valproate and lamotrigine, gabapentin, leviteracetam and vigabatrin with contraceptives.

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

Yes, oral contraceptives decrease lamotrigine and valproate serum levels in the blood, thus effecting the effectiveness of these drugs.

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

Neonates’ metabolism is slower than adults and children thus they metabolised these drugs slower. But children’s metabolism is faster than adults thus dosage should be higher.

Geriatrics metabolise drug slower because they usually have a decreased renal function.

In which cases is plasma blood level monitoring indicated?

All cases because anti-epileptic drug has a small therapeutic index.

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

If a patient consumes very high concentrations of alcohol chronically, higher then 100mg per decilitre. Then the MEOS (Mixed function oxidation) enzyme system, if stimulated regularly the system will desensitise and the patient will become more tolerant to alcohol.

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

Sedation, loss of inhibitions, nausea, decrease in judgement, the speech of the patient is effected patient may experience ataxia, impaired balance and coordination, the patient may even fall in to a coma and if untreated death.

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

Neurological damage which is paired with ataxia, movement disorder and confusion, paralysis of face muscles.

It is treatment when thiamine is given parenterally to prevent permanent brain damage.

Fully explain the foetal alcohol syndrome.

The mother drinks alcohol chronically, the baby will be born with mental retardation, growth deficiencies, microcephaly and under developed middle facial area if the mother drinks alhole during her first trimester of pregnancy.

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

Chronic alcohol consumers have to ingest al lot more alcohol to experience the same effect as acute alcohol consumers.

Chronic differs because the blood glucose levels decreases, immune system decreases which means the patient will get more infections and cancer may arise because a beverage may contain up to 15 carcinogenic compounds.

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

Paracetamol and alcohol= paracetamol induces hepatotoxicity metabolite in heights therapeutic doses of alcohol, because paracetamol forms toxic metabolite, glutathione ions in the liver is depleted, and alcohol induces Cyp 2E1 enzyme and this causes toxicity 

CNS suppression and alcohol= Alcohol is a CNS suppression thus if you co-administer it with a other drug that causes CNS suppression this will enhances the effect.

Aspirin and alcohol= alcohol enhances anti plated aggregation effect of aspirin.

Alcohol = decrease the blood glucose levels in blood thus if co-administered with hypoglycaemic drug the blood glucose levels will decrease to dangerous levels.

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

Both absorption and distribution of alcohol through the body is fast. The distribution of alcohol is directly proportional to the amount of fluid in the body.

Thus the clinical significance is that if a patient has higher amounts of fluid in their bodies for example women has more body fluids the men, for this reason is alcohol faster distributed through a women’s body then a man’s.

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

Ethanol is metabolised in two different ways, depending on the total amount and concentration.

If the total amount of alcohol that was consumed is low to moderate the Alcholdehydrogenase system is used, this is a zero order kinetic enzyme system because there is a limited amount od NAD, co enzymes (7-10 g alcohol is metabolized per hour). If very high concentrations of alcohol is in the bloodstream, higher then 100mg per decilitre. Then the MEOS (Mixed function oxidation) enzyme system is used to metabolise alcohol, but this system can become more tolerant to Alcohol, if it is ingested chronically.

Both enzyme systems metabolise alcohol to acetaldehyde that is converted to acetate through the enzyme aldehyddehydrogenase. Acetate is excreted out of the body.

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

Disulfiram, Metronidazole, Cephalosporins and Hypoglycemics all these drugs influence the metabolism of alcohol because they block the effect of the enzyme Aldehyddehydrogenase, this enzyme converts acetaldehyde to acetate if this action is prevented the patient will experience the side effects of alcohol toxicity more quickly and alcohol will not be excreted out of the body.

For quite a number of preparations of herbal/natural origin in pharmacies or shops, claims are made that they have anxiolytic and/or sedative-hypnotic properties. Your textbook (Katz) discusses a number of these preparations in Chapter 64. Use that information together with a search on the internet and compile a brief report on the use of these alternative medicines in the treatment of anxiety and insomnia. You may use any search engine (e.g. Google) and keywords such as “botanicals” and “anxiety” and “insomnia”. 

The clinical use of botanical agent for the treatment of anxiety and insomnia is risky, because their safety and efficiency are not always well studied. There is a lack of adequate testing for the drug interactions with botanical agents. This is a time consuming and costly task because there are hundreds of active and inactive agent that has to be tested.

There is also a misconception about botanic agents, that it is relatively safe to use. This may not always be the case adverse effects may not always be reported and thus not always be updated. Enough clinical trails may not have been done to establish all the side effects and drug interactions.

Here is a few example of botanical agents that is used for anxiety and insomnia.

Ginseng, a herb that is frequently used in traditional Chinese medicine to improve mood and keep healthy in the western world, thus it helps to overcome anxiety. Its mechanism of action is to increase the levels of NE and 5-HT in the brain and to inhibiting the reuptake of monoamine.

Another drug that helps for anxiety and insomnia is Peony, a portion of the root of the Paeonia lactiflora Pall (Ranunculaceae). Icariin in Epimedium herbs suppress the elevation of corticosterone concentration when a person is stressed this force the patient to be less stressed (Lei, 2015).

Other agents was on the marked but is now classified as a risk to use, because of the lack of clinical studying, for example Kava-kava that was used for anxiety as well as Jin Bu Huan that was used to treat insomnia is both prone to cause hepatotoxicity.

This you should advise a patient to take exactly the doses that is prescribed on the insertion and if they experience any side effects thy should report it to help improve the safety of the products.

Reference list

Lei L., Changhong L., Yicun W., Pu W., Yuxin L., Bingjin L.  2015.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790408/  Date of access 20 March.  2021.