• LSD and PCP (angel dust) is the two most known hallucinogenic drugs known.

Effects of hallucinogenic drugs:

• Dizziness.
• Sleeplessness
• Euphoria.
• Dry mouth
• Paraesthesia.
• Blurred vision.
• Sense of well-being and relaxation.
• Numbness
• Impulsiveness
• Increase in body temperature and heart rate

Clinical profile of patient who had taken them:

• Change in behaviour.
• Impaired judgement
• Alertness
• Agitated
• Blood shot eyes

• To calm the patient down a benzodiazepine is given to reduce the agitation and is also administered to protect patient against convulsions.  Supportive care and rehabilitation
• Physostigmine is known as a ACE inhibitor and is used to reverse the toxicity

Effects of alcohol:

• People tend to consume alcohol due to the pleasant feeling that is associated with it and they feel that a party has not fully started or is not fully enjoyable until it involves the presence of alcohol. Alcohol is seen to affect people in varies ways such as increase their confidence, allowing a person to let loose of all their stress , makes them forget and is seen as a source of escape and is overall there to ensure a “good time”. However, it does have unpleasant effects associated with it like, enhancing reckless behaviour, blackouts, not being in the right state of mind so perpetrators see it as a chance to take advantage of their victims, it can cause nausea and vomiting and alcohol can assumed to such an extent that it can become toxic to the body and can thus lead to death.  And not to talk about the aftermath after a good night of partying
• It is the safest option to not drink more than 1 drink a day and not consume two drinks after one another. And not to drink more than 3 times a week.
• To determine that you have developed a problem will be justified to how much alcohol you assume in a week, how much you feel like you need it and how it affects your overall performance, such as your concentration, your willingness to participate, memory etc. If you have come to the realisation that you have grown dependence (not being able to go without alcohol for a period of time) than it is most likely that you have developed a problem and it thus of utmost importance that you seek medical help of any person that you are entrusted to like a teacher, a parent, or any adult that may be able to assist you in this manner so they can help you to determine the way forward.

Pain is described as an unpleasant feeling of a sensation in the body and it can be as a result of the stimulation of the nociceptors (pain receptors) located in varies places of the body. These nociceptors are very sensitive to temperature, mechanical damage and dissolved chemicals released from injured cells and is thus these factors are seen as the “stimuli” that would cause the stimulation of the nociceptors which does lead to the pain sensation felt. This sensation can last from up to a few hours to months (that can last or return on several occasions).

People also tend to describe the painful sensation as burning, stinging, pinching or sharp stab depending on the localisation of the painful sensation, it can either be localized or more generalized where it affects more areas of the body.

Pain tolerance is seen as the maximum pain level an individual can endure and it does differ from person to person as some people may have a high pain tolerance and will not be so sensitive to the painful sensations, whereas other people may have a low pain tolerance and will there be more sensitive to the painful sensation.

To manage your pain sufficiently, treatment is available to reduce pain that can provide minimal side effects and is there to improve a patients overall functioning. Depending on the severity of the pain or how injured a patient may will determine whether around the clock medical treatment would be needed, thus if pain is superficial like headache there is no need to to refer patient but if the patient has pain due to injuries they must be referred to a medical practitioner

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

SSRI’s	SNRI’s	TCA’s	5-HT antagonist	Tetracyclic and Unicyclic	MOAI	NARI
Fluoxetine Sertraline Citalopram Paroxetine Escitalopram	Venlafaxine Duloxetine Desvenlafaxine	Tertiary amine: Impramine Amitriptyline Trimipramine Chlorimipramine Secondary amine Nortriptyline Desimipramine	Trazodone Nefazodone Vortioxetine	Bupropion Mirtazapine Amoxapine Maprotiline	Phenelzine Isocarboxazid Tranylcypromine Selegiline Moclobemide	Reboxetine

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

All of these drugs promote monoamine activity by increasing NA and serotonin levels at the central synapse, by either re-uptake inhibition, degradation inhibition or the blockage of the presynaptic alpha 2 receptor.

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

The onset is very slow and can take up to 6-8 weeks for effects to be seen due to the action that of the anti-depressants that still needs to be altered in the brain.

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

Efficacy  

TAD: needs to be titrated to the minimum effective dose whereas SSRI’s can be started on the full dose. All these drugs does however take 6-8 weeks for effects to be seen.

Side effects

 TAD: sedation, tremors, insomnia, disturbed vision, dry mouth, urinary retention, confusion, orthostatic hypotension, dysrhythmias convulsions, weight gain and sexual dysfunction. 

SSRI: Insomnia, tremors, GIT disturbances, headache, ↓ libido, sexual dysfunction, anxiety (acute), EPS, withdrawal syndrome. ↓ appetite, non-sedating,  acute increases 5-HT synaptic activity = acute anxiety, later 5-HT reduces again.

Safety

TAD: Not safe in overdose but it is commonly the drug used for suicide. It causes lethal ventricular arrythmias and fibrillation and seizures.

SSRI: it is very safe with regards to overdose and this drug is better tolerable.  

• What is the action of mirtazapine?

It blocks the action of alpha 2, 5-HT2A, 5-HT2c and 5-HT3 receptors. It also blocks histamine 1 and alpha 1 and causes the indirect stimulation of 5-HT1A

• What is the action of venlafaxine?

Blocks both 5-HT - and NA re-uptake, more potent for 5- HT than for NA. Moderately selective blockade of SERT and NET..

• What is the action of agomelatine?

Antagonist: 5-HT2C

Agonist: Melatonergic R’s – MT1 & MT2.  and NA release.

• Discuss the possible mechanisms of action of lithium.

The MOA is mediated by Li⁺. Lithium inhibits 2 signal transduction pathways where it suppresses IP₃ and glycogen synthase kinase-3. It influences IP₃ and DAG 2^nd messenger system by decreasing various enzymes which are important for conversion and re-circulation of membrane phosphoinositide. IP₃ and DAG are important in monoamine and cholinergic neurotransmission.

 

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

It has a narrow therapeutic index of 0.5-1.5mM; >2mM = toxic

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

Lithium is used in monotheraphy for prophylaxis of manic and hypomanic episodes and for treatment of acute mania.

And in combination therapy it is used treatment of resistant depression and aggressive behaviour.

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

When used in combination with a diuretic, NSAID, ACE I and fluoxetine it increases lithium levels and leads to toxicity.

In combination with caffeine, it increases renal excretion of lithium

And in combination with a typical APs it worsens EPS.

• Name the major side effects of lithium.

Tremors, sedation, ataxia, aphasia, muscle weakness, fatigue, polydipsia, polyuria, nocturia, nephrogenic diabetes insipidus, thyroid enlargement, leucocytosis, edema weight gain, acne, alopecia, sexual dysfunction.

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

Category D drug. The use of lithium during lactation is not encouraged.

• Name three other important indications for lithium.

Bipolar disorder, Schizoaffective disorder, Major depression

• 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

The NSAID she is currently taking has an interaction with the lithium treatment that she is taking. NSAIDS are known to cause increase levels of lithium making it toxic thus it explains the side effects she has been experiencing like. I would suggest that she replaces the medication she is taking for her muscle injury with something like Cyclobenzaprine which is an antispasmodic or paracetamol to help relieve the pain. I would also suggest to her to try physical activities to try and reduce the weight she has been gaining.

• 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.

There are 3 sub-families which is primarily based on the side chain:

1. 1. Aliphatic side chain: Chlorpromazine
   2. Piperidine side chain: Periciazine and Thioridazine
   3. Piperazine side chain:  Fluphenazine, Perphenazine, Trifluoperazine, Prochlorperazine.

Aliphatic and piperidine compounds:

• Low potency thus little EPS
• Severe sedation
• Strong anti-cholinergic effects
• Strong α-lytic effects
• Cardiotoxic

Piperazine compounds:

• Higher potency thus more EPS
• Less sedation
• Less anti-cholinergic effects
• Less α-lytic effects
• Less cardiovascular side effects

• Which receptors are blocked by the typical antipsychotic drugs?

The D2 receptors in the mesolimbic pathway.

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

Atypical drugs have a higher affinity for 5-HT_2A receptor thus they block more serotonergic receptors than D2 receptors and it also blocks M1, H1 receptors, whereas typical drugs only block D2 receptors in the mesolimbic pathway.

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

Benzamides block both D2 and D3 receptors but the risk of EPS are reduced due to the localisation of D3 receptors in the limbic area.

Aliphatic compound also tends to have a lower potency thus have less EPS.

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

Extrapyramidal side effects are known to be caused by the blockade of D2 receptors in the nigrostriatal pathway, therefore drugs that block D2 receptors cause EPS.

Drugs known to cause EPS is the piperazine derivatives due to their high potency thus extensively blocking D2 receptors.

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

Autonomic side effects are caused by the blockage of alpha and cholinergic (muscarinic) receptors in the sympathetic and parasympathetic nervous systems

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

Drugs that increase dopamine activity thus Dopamine agonist like Pramipexole and drugs that would decrease the cholinergic levels to restore the imbalance implicated by this disease, thus anticholinergic drugs.

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

Amantadine is a metaffiniod potentiator of dopamine which means that it will increase dopamine activity by increasing dopamine release, increasing the synthesis of dopamine, and blocking the reuptake of dopamine.

It is however classified as a NMDA antagonist; thus, it has anti-dyskinetic properties.

It also has the ability to act as an adenosine A2a antagonist, contributing to antiviral effects.

This broad mechanism of action gives amantadine the ability to improve bradykinesia, tremors, and rigidity, associated with parkinsonism.

Unfortunately, this drug only works for a few weeks.

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

MOA B inhibitors (Rasagiline and Selegiline): Inhibits MOA which is the enzyme responsible for the metabolism of dopamine. Therefore, increasing dopamine levels.

COMT inhibitor (Entacapone): Extends the duration of action of l-dopa by decreasing peripheral metabolism and increasing its bioavailability.

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

Ergot derivatives: Bromocriptine

Non-ergot derivatives: Ropinirole and Pramipexole

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

Pramipexole – direct agonist on D3 receptors

Ropinirole- D2 agonist

Bromocriptine – Partial agonist on D2

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

Selegiline and Rasagiline has been said to have neuroprotective properties by preventing the metabolism of dopamine it ensures that the dopamine neurons are stimulated.

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

It prevents the metabolism of dopamine thus increasing the dopamine levels and ensuring that the dopamine neurons are stimulated continuously.

• How do the COMT-inhibitors act in Parkinsonism?

COMT metabolises L-dopa to 3OMD. Where increased levels of 3OMD has a weak therapeutic response with L-dopa due to them competing for active transport, thus it increases the duration of action of L-dopa by decreasing peripheral metabolism and increasing it bioavailability.

• How does istradephyline act?

It acts as Adenosine a_2A  antagonist. Adenosine is known to block dopamine 2 receptors thus blockade of adenosine improves dopamine 2 function.

• Discuss the MOA of safinamide

MOA: Noval dual MOA where it increases dopamine activity by causing reversible inhibition of MAO-B. Inhibition of DA uptake decreases glutamate release.

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

(a) myelinated fibres with unmyelinated fibres; and

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

1. Unmyelinated fibres and smaller myelinated fibres are easier to block than larger myelinated fibres, thus they are more sensitive to the effects of local anaethetics.
2. When type A fibres are blocked it influences the proprioception, touch, pressure, muscles, pain, and temperature functions. This fibre has high frequency pain transmission; thus blockade will be done with lower concentration of local anesthetic. And does not appear to have high sensitivity for local anesthetics.

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

CVS: cardiac depression

CNS: sedation, lightheadedness, visual and auditory disturbances, restlessness, and CNS depression.

Skeletal muscle: it has a weak blocking action thus no clinical applications.

 What is the basis for the selection of a LA?

it is chosen by the type of procedure that is done, the target tissue it is must be used for and the duration of the numbering effect.

Why are LA solutions sometimes saturated with CO₂?

It buffers the local anesthetics. Reduces the pain of injection and thus a faster onset is achieved. It also raises the effective concentration of nonionized form of the local anesthetic, onset of regional block is shortened.

Which of the LA are typically used for surface anaesthesia?

Oxybuprocaine, benzocaine and cocaine

Drug	Effects on System
Halothane	Central Nervous System Increased cerebral blood flow. Increase in intracranial pressure. Fast smooth muscle induction. Autonomic Nervous System Bradycardia Cardiovascular System Depress normal cardiac contractility. Decrease BP. Decreases atrial mean pressure. Sensitized myocardium for arrhythmic effects of catecholamines. Respiratory System Drug of choice if patients has airway problems because it causes no: Saliva, bronchial secretions, or cough. Musculo-skeletal   Skeletal muscle effects in stage 3. Increases action on non-depolarizing muscle relaxants (competitive antagonist) Decreases action on depolarizing muscle relaxant. Post-operative shaking that leads to hypoxia due to decrease oxygen flow to the tissue. Uterus Decreases muscle contraction. External twisting of baby Liver Hepatotoxicity
Enflurane	Central Nervous System:  Fast smooth muscle induction. Not for use in epileptic patients because it may result in convulsions. Cardiovascular System No sensitization of myocardium Less blood pressure. Respiratory System Causes more respiratory suppression than Halothane. Pungency effect makes drug less suitable for induction of anaesthesia in patients with active bronchospasm.
Isoflurane	Central Nervous System Faster induction and recovery phase than Halothane Cardiovascular System Less suppression in blood pressure than Halothane and Enflurane. No sensitization of myocardium. Respiratory System Potent supressing effect. Strengthens due to potent skeletal muscle relaxing effect.
Desflurane	Central Nervous System Faster induction and recovery phase than Isoflurane. Increases cerebral blood flow and intracranial pressure. Cardiovascular System Less supressing than Halothane and Enflurane. Respiratory System Strong smell irritates airway if used as an induction drug. Causes: Cough, shortness of breath, and laryngospasms.
Sevoflurane	Same effects than Desflurane. Respiratory System Less irritating to airway than desflurane.
Nitric Oxide	Central Nervous System Weak anesthetic effect, potent analgesic, amnesia Fast recovery phase Cardiovascular System No effect Respiratory System Can lead to hypoxia thus needs to be used in combo with oxygen.

 

2) Nephrotoxicity, Hematotoxicity, Malignant hyperthermia, 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 decrease the effectiveness of the pill are as follows: Phenobarbitone, phenytoin, carbamazepine, oxcarbazepine and topiramate. Due to its decreasing the effectiveness of the pill it may lead to an unwanted pregnancy.

Drugs that are safe to use in combo with the Pill: Valporate, Lamotrigine, Gabapentin, Leviteracetam and Vigabartin.

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

Yes, oral contraceptives decrease the serum levels of anti-epileptic drugs for example, Valporate.

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

Metabolism of anti-epileptic drugs are slower in neonates than in adults, but metabolism of these drugs is faster in babies and in children than adults. And due to lowered metabolic activity in  geriatrics metabolism does appear to be slower in geriatrics than in adults.

In which cases is plasma blood level monitoring indicated?

it is indicated to see how well a patient’s body tolerates a drug and help a practitioner to identify if any unwanted effects are experienced with the drug. For example, in the case of Valporate and lamotrigine, as valproate deceases the metabolism of lamotrigine which leads to the increased levels of lamotrigine in the blood and in its turn can cause toxicity.