Whats is pain

Pain is an unpleasant sensory and emotional experience associated with an actual or potential tissue damage

The possible causes of pain

Pain is divided into two main categories namelu Acute pain and Chronic pain. Acute pain is regulated by nociception, which forms part of the nervous systems protective response to harmful or potentially harmful stimuli. Acute pain is caused by stimulus on a somatic or visceral level. Chronic pain is usually due to a pain can be functional (Fibromyalgia) or Neuropathic (Due to nerve damage).

Why different people experience pain differently

Pain is a subjective sensory or emotional response. Due to the variability in pain circuits within the brain as well as personal and environmental factors every person experiences and copes with pain differently.

Factors that influence pain include:

• Biological factors that amplify nociceptive signals to the brain 
• Psychological factors play big role in pain
• Environmental features
• Social factors

Important principles of pain management and referral involved

In order to effectively treat pain, it is important to determine how an individual persons brain reacts to pain. The most effective approach to pain management is to make use of multiple health care professions such as Pain specialists, physical therapists, clinical psychologists and nurses.  

https://www.ted.com/talks/karen_d_davis_how_does_your_brain_respond_to_pain

https://www.ted.com/talks/joshua_w_pate_the_mysterious_science_of_pain?language=en 

1. Discuss the possible mechanisms of action of lithium.

Lithium is a monovalent cation that is able to mimic the role of Na+ in excitatory tissues, and it therefore is able to move across voltage-gate Na+ channels which are responsible for action potential generation. In this way Lithium is able to adjust the balance between excitatory and inhibitory neurotransmitters and decreases glutamate (Excitatory Neurotransmitter) activity.

Lithium also inhibits IMPase= decrease in free inositol

Decrease in inositol= decrease in second messenger PIP2= Decrease in release of IP3 and DAG

Decrease in PIP2 dependent pathways= mood stabilising effect ( PIP2 activity increased during manic episodes)

https://slideplayer.com/slide/7027021/

https://www.slideshare.net/drashutoshtiwari/mood-stabilisers-antimanic-drugs

2. What is the therapeutic index of lithium and what is its clinical significance?

Lithium has a very small therapeutic index  (0.5-1.5 mM; >2 mM toxic), it is therefore very important to carefully monitor the concentration in blood plasma to prevent toxicity. Serum levels need to be monitored at regular intervals: 1 week after each dose increment, then at one month, 3 months and 6 monthly during maintenance

3. When is lithium used as single drug and in which cases and with which type of drugs is lithium combined?

Monotherapy: Used for prophylaxis of manic and hypomanic episodes and for treatment of acute mania.

Combination therapy with antipsychotics: treatment of resistant depression and aggressive behaviour.

Combination with antipsychotics and benzodiazepine: treatment severely manic patient

4. Name 3 clinically significant interactions lithium may have with other drugs. Illustrate your answer with suitable examples of drugs.

• Lithium + Neuroleptic (Phenothiazine)= Increased EPS
• Lithium + Xanthines (Theophylline, Caffeine) = Increased renal excretion of Lithium
• Lithium + SSRI (Fluoxetine) = Increased Lithium plasma levels

5. Name the major side effects of lithium.

• Tremors
• Sedation
• Ataxia
• Aphasia
• Muscle weakness
• Fatigue
• Polidypsia
• Poliuria
• Nocturia
• Nephrogenic diabetes insipidus (Li+ interferes with kidney’s ability to concentrate urine)
• Thyroid enlargement
• Leucocytosis
• Edema
• Weight gain
• Acne,
• Alopecia
• Sexual dysfunction

6. What is the status of the use of lithium during pregnancy and lactation?

Category D drug. Teratogenic effects and excreted in high concentrations in breast milk

7. Name three other important indications for lithium.

• Recurrent depression
• Augmentation in Acute major depression
• Bipolar disorder

8. Evaluate the following case and fully motivate your recommendations:

Ms B. Polar (21 years, 60 kg) is a student and used the following medication for the past two months:

Camcolith 600mg bd. The plasma levels after two weeks were 0.8mmol/l. She sustained a muscle injury and has been using Indocid® 75mg nocte for the past 10 days. On questioning she reveals that “she had picked up a lot of weight” and is now using some of her mother’s “water pills” in the hope of losing a few of the extra kilos. However, she complains of fatigue, that she has difficulty in keeping her eyes open in class, remains thirsty and constantly feels shaky and nauseous.

• Camcolith= Lithium Carbonate

• 20mg/kg/day = 1200mg
• Dosage is correct.

• Plasma levels = within therapeutic range (0.5-1.5), but plasma levels have not been recently tested= need to be tested at regular intervals
• Indocid = NSAID= decrease renal excretion of lithium = increase toxic effects
• Water pills= diuretics= Diuretics may increase serum concentration and predispose to lithium toxicity

Adverse effects

• Fatigue and tiredness= Adverse effects of Lithium
• Thirst= due to renal adverse effects of lithium use
• Shaky =Tremor= normal side effects of Lithium that occurs at therapeutic dosages.
• Nauseous= GIT effects of Lithium
• Weight gain= adverse effect of Lithium use

Fatigue, Tiredness, thirst (Dehydration) and nausea are all early symptoms of Lithium toxicity.

The combination of Lithium with a NSAID and a diuretic causes an increase in Lithium Serum levels. Lithium has a very small Therapeutic index, therefore small increases in blood serum levels can lead to toxic effects. The effects she is experiencing may very likely be due to toxic levels of Lithium within the blood.

I recommend that stops taking the NSAID and Water pills immediately, and that her serum levels are tested. The toxic effects she is experiencing such as the tiredness, fatigue, thirst and nausea should decrease once her serum levels have been restored to therapeutic levels. Her Shakiness (Tremors) can be treated with the use of Propranolol or atenolol. I also recommend that she drinks lots of water and oral rehydrate solutions to treat potential dehydration. For the muscle injury she can use Paracetamol and Cyclobenzaprine to treat the pain.

Brand, L. 2021. Anti-psigoriese middels. Leergedeelte 9. [PowerPoint Presentation]. Study Unit 9, FKLG 312. Potchefstroom, NWU

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

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

Multipotent actions on numerous monoamine receptors which leads to the non-specific increase of 5-HT or NA

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

The clinical response can take up to 3-5 weeks. This long period can be explained by the effects of the antidepressant drug on the neurotrphic factors. It can take two weeks or longer for the synthesis of neurotrophic factors to take place.

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

*Look up in textbook and add

5. What is the action of mirtazapine?

Tetracyclic Antidepressant. Mirtrazepine primarily blocks a2 receptors which causes an increase in NA(autoreceptors) and 5-HT(heterorecpetors) release.

It also blcoks  5-HT2A (Anti-depressive effects)  and blocks 5-HT3 (anxiolytic and decrease nausea).

Additionally it also blocks H1 receptors which leads to sedation and weight gain, and it blocks a1 receptors which can lead to postural hypotension.

6. What is the action of venlafaxine?

Serotonin and noradrenaline reuptake inhibitor. Blocks both 5-HT and NA re-uptake, but has a higher affinity for 5-HT than NA

7. What is the action of agomelatine?

Circadian rhythm regulator. MT 1 and MT 2 agonist and 5-HT2c antagonist. MT 1 and MT 2 agonism helps in regulation of circadian rhythyms and improves sleep. 5-HT2C antagonism improves sleep through regulation of circadian rhythms and also provides antidepressant action. 5-HT2C antagonism leads to disinhibition of DA and NA release in the frontal cortex, which leads to an increase in Dopamine and NA release.

Brand, L. 2021. Anti-depressants. Study Unit 10. [PowerPoint Presentation]. Study Unit 10, FKLG 312. Potchefstroom, NWU.

1. 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.

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

The Mesolimbic D2 Receptors are particularly blocked by typical APD’s  

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

Atypical drugs: Multipotent antagonists/inverse agonists. They have a higher affinity for 5-HT2 receptors. They Block 5-HT2A Receptors more than D2 Receptors

Typical Drugs: Block mesolimbic D2 Receptors

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

Dopamine-2 receptors reduces the risk of Extra pyramidal side effects

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

Piperazine Phenothiazine derivatives ( Fluphenazine, perphenazine, trifluoperazine, prochlorperazine): Potent D2 blockade

Butyrophenone derivatives (Haloperidol): Potent D2 blocker

Extra-pyramidal side effects are caused by D2 blockade in the Nigrostriatal pathway, therefore drugs that are potent D2 blockers will lead to EPS even at very low dosages.

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

α1-Receptor blockade. Blockade of α1 Receptors leads to vasodilation, decreased peripheral resistance and decreased blood pressure. Autonomic side effects experienced are Postural hypotension and ejaculatory impotence.

Brand, L. 2021. Anti-psychotic Drugs and Lithium. Study Unit 9. [PowerPoint Presentation]. Study Unit 9, FKLG 312. Potchefstroom, NWU.