• Which different groups of hallucinogenic drugs are known?

PCP and LSD

• Name a few typical effects of the hallucinogenic drugs and discuss the clinical profile of a patient who had taken them.

Effects of hallucinogenic drugs:

• Dizziness.
• Vomiting.
• Euphoria.
• Nausea.
• Weakness.
• Paraesthesia.
• Blurred vision.
• Sense of well-being and relaxation.

 

Clinical profile of patient who had taken them:

• Change in behaviour.
• Poor skin tone.
• Lack of energy.
• Bloodshot eyes.
• Poor performance.
• Tired and run down.

• How is an over-dose of LSD dealt with? 

Intravenous administration of anticoagulants, vasodilators or sympatholytic. Supportive care and rehabilitation.

• How is an over-dose of anticholinergic drugs dealt with?

By administering a reversible acetylcholine inhibitor such as physostigmine salicylate.

1.  Influences camp, IP3 and DAG second messengers

2.  it is a mood stabilizer, helps with manic phase.

3.  dangerous with diuretics, NSAIMS, ACE inh, fluoxetine, caffeine, teofilien, carbamazepine

4.  diuretics cause toxicity

caffeine increase LI levels

carbamazepine causes neurotoxicity

5.  tremors, sedation, ataxia, weak muscles, edeem, acne, sexual dysfunction, ens

6.  it is safe

7.  scitzophrenia, bipolar disorder, mood disorders

Pain is used to describe uncomfortable sensations in the body that stems from activation of the nervous system. Pain has a broad range: it can range from annoying to debilitating, it may be consistent, it may start and stop frequently, it may only occur under certain conditions, it can develop suddenly and only last for a short period of time or it may be ongoing sensations that last or return over several months or even years.  Pain can also be described in many different ways: it may feel like a sharp stab or dull ache, it may be described as throbbing, pinching, stinging or even burning.  Pain may also be localized, only affecting a specific part of the body or it my by generalized like with overall body ached.

People also respond differently to pain: some have a high tolerance for pain and don not feel pain that easily/frequently and others have a low tolerance for pain and feel pain very intensely. Thus, pain is highly subjective.

The causes of pain can be due to a specific injury or medical condition or in some cases the cause of pain can even be less obvious or unknown. Illnesses and disorders that cause pain include: flu, arthritis, endometriosis and fibromyalgia. Pain can also be caused by bruises, burns, broken bones, etc.

Important principles of pain management include providing treatment that reduces the pain with minimal side effects, while still being able to maintain daily functions as well as preventing acute pain from progressing to chronic pain.

Medical attention is needed when the pain is a result of an injury or accident that may have caused damage to the body like bleeding, broken bones or a head injury. It is also needed when an acute, sharp internal pain is felt for it may be a sign of a serious problem like a ruptured appendix. Medical attention for pain is also needed when the pain is located in the chest, back, shoulders, neck or jaw together with other signs of a heart attack like shortness of breath, nausea, dizziness and weakness OR when the pain is interfering with your daily life, including the ability to sleep, work or taking part in any other activities that is enjoyed.

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

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

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

They al promote monoamine activity by increasing NA and 5-HT levels at the central synapse( re-uptake inhibition, degradation inhibition or the blockage of the presynaptic α2 receptor)

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

The onset of the drug is very slow and can take up to 6-8 weeks for effects to be seen even thou the increase in monoamine concentrations can bw seen within hours after administration 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’s: needs to be titrated to the minimum effective dose

SSRI’s: can be started on the full dose

• side effects

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

SSRI’s: Insomnia, tremors, GIT disturbances, headache, ↓ libido, sexual dysfunction, anxiety (acute), EPS, withdrawal syndrome. ↓ appetite, non-sedating,  acute increase in 5-HT synaptic activity initially causes acute anxiety, later 5-HT decreases again.

• safety?

TAD’s: Not safe in overdose but it is commonly the drug used for suicide.

SSRI’s: safer with regards to overdose.

• What is the action of mirtazapine?

Blockade of α2, 5-HT2A, 5-HT2c and 5-HT3 receptors. It also blocks H1 and α1 and causes the indirect stimulation of 5-HT1A

• What is the action of venlafaxine?

Blockade of 5-HTand 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 &NA release.

• 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: Pramipexole and Pergolide
• Non ergot derivative: Ropinirole, Rotigotine and Bromocriptine

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

• D1
• D2 
• D3

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 adjunctive to Levodopa therefore smooths Levodopas's response. 

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?

• Add on therapy to Levodopa/ carbidopa experiencing on-off episodes.

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

 

Halothane:
Central Nervous system:	Causes fast and smooth induction Increases cerebral blood flow Increases intracranial pressure
Autonomic system:	Causes Bradycardia
Cardiovascular system:	Decreases blood pressure Causes a sensitized myocardium for arythmogenic effects of the catecholamines
Respiratory system:	No saliva, bronchial secretions, or coughing
Musculo-skeletal:	Skeletal muscle relaxing effects Increases action non-depolarization Decreased action depolarization Post-operative shaking due to hypoxia
Uterus:	Decreased muscle contractions External twisting of a baby
Liver:	Hepatotoxic effects (unpredictable and can be very rare)
Enflurane:
Central Nervous system:	Fast, smooth induction convulsions sometimes (not epileptic convulsions)
Cardiovascular system:	No sensitization of the myocardium. Less suppression than Halothane
Respiratory system:	More suppression than Halothane
Isoflurane:
Central Nervous system:	Faster induction Faster recovery than Halothane
Cardiovascular system:	Less suppression than Halothane No sensitization of the myocardium
Respiratory system:	Potent suppression effects
Desflurane:
Central Nervous system:	Even faster induction than Isoflurane Even faster recovery compared to Isoflurane Increased cerebral blood flow and intracranial pressure
Cardiovascular system:	Less suppressing effects compared to Halothane and Enflurane
Respiratory system:	Strong smell that irritates airways When used as an induction drug it may cause coughing, shortness of breath and a laryngospasm
Sevoflurane:
Musculo-skeletal:	Potentiates the effects of the non-depolarising muscle relaxants like the other halogenated ethers.
Has effects similar too Desflurane with less airway irritation
Nitrous Oxide:
Central Nervous system:	Weak anaesthetic effects Potent analgesic effects Amnesia
Cardiovascular system:	No effects
Respiratory system:	Pure Nitrous oxide results in hypoxia Always mix with oxygen or air Recovery phase: fast diffusion from the blood to the alveoli
Musculo-skeletal:	No skeletal muscle relaxation

• Name the major acute toxic effects of the inhalation drugs.

• Hepatotoxicity
• Hypoxia
• Malignant hypothermia
• Nephrotoxicity

• 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 (decreases levonorgestrel-containing 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 to use in combination is 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?

A unique 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 intrauterine 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, TCA’s and sedative hypnotics like the benzodiazepine’s metabolism is 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.