Blog #13 (SU 9.5)

• Discuss the possible mechanisms of action of lithium.

Lithium influences the second messenger systems decreasing their sources and thus decreases the generation of IP₃ and DAG. These second messengers are important for amine neurotransmission and influences multiple neurotransmission processes.

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

The therapeutic index of lithium is between 0.5 – 1.5millimolar. Lithium has a narrow therapeutic index. The clinical significance of this is that the drug is only effective between the limit of the therapeutic index, if the plasma level of lithium is below the therapeutic index no clinical effect is seen and if the plasma level of lithium is above the therapeutic index a toxic effect will be seen at as little as 2millimolar. 

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

Lithium is used as a single drug in the treatment of bipolar disorder.

Lithium is used in combination with valproate or carbamazepine in the treatment of psychiatric symptoms.

Lithium is also used in combination with olanzapine or quetiapine for treatment of acute mania.

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

• Lithium in combination with diuretics (e.g. thiazides), NSAIDs, ACE inhibitors and fluoxetine can cause dehydration and electrolyte imbalances causing toxic levels of lithium.
• Lithium in combination with caffeine, theophylline or anti-acids cause increased excretion of lithium in the urine, decreasing plasma lithium and lowering the clinical effects of lithium.
• Lithium in combination with typical antipsychotics (e.g. chlorpromazine) increase extrapyramidal side effects.
•  

• Name the major side effects of lithium.

• Sedation
• Tremor
• Ataxia
• Aphasia
• Muscle weakness
• Fatigue
• Polidypsia
• 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?

Lithium is not safe to use during pregnancy and lactation. Taking lithium during early stages of pregnancy increases the risk that your baby’s heart does not develop properly. Breastfeeding while on lithium can cause heard defects in your baby.

• Name three other important indications for lithium.

Schizophrenia

Depression

Psychosis

• 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 600mg tablets contain lithium carbonate, which is used to treat and prevent mania, bipolar disorder and depression in adults. For acute symptoms the target plasma therapeutic concentration is 8-12mmol/L and maintenance is 0.4-0.7mmol/L. The plasma levels of Ms Polar is 0.8mmol/L, this plasma concentration exceeds the prescribed therapeutic index of lithium. This can be a result of the NSAI-drug, Indocid® (Indocid® is used for pain, swelling and joint stiffness caused by arthritis or gout. It is an anti-inflammatory drug), she is taking, the NSAID together with the lithium causes electrolyte changes and dehydration and thus also an increase in lithium plasma levels.

This increase in the lithium ion plasma levels and cause adverse side effects, such as weight gain, fatigue, sedation, polydipsia (thirsty) and tremors.

The “water pill” (a diuretic) of her mother’s she is taking in hopes that it will help her lose weight only worsens her symptoms because diuretics increase the lithium ion levels and cause adverse side effects.

Therefore, Ms Polar’s physician needs to re-evaluate her antipsychotic as to not cause adverse effects with her NSAID or she needs to use an alternative pain killer (not a NSAID) and she needs to stop using the diuretic if she remains on the lithium.

Reference list.

Brand, L. 2021. SU 9 Antipsychotic Drugs and Lithium. https://efundi.nwu.ac.za/access/lessonbuilder/item/6005036/group/dd46f2da-d3be-402e-9ba7-2c5955cedd9d/English%20power%20point/English%20PP%202021/SU%209.pdf Date of access: 26 Apr. 2021. [PowerPoint presentation]

Katzung, B.G.  2018.  Basic & Clinical Pharmacology.  14^th ed.  California, San Francisco: McGraw-Hill Companies, Inc.

Blog #11 (SU 9.2)

• 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.

Phenothiazine derivatives:

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

Typical antipsychotics block mesolimbic D₂ receptors.

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

Atypical (newer) drug’s mechanism of action is to block serotonin (5-HT_2A) receptors much more potently than D₂ receptors where typical drug’s mechanism of action is mainly to block dopamine (D₂) receptors. Atypical drugs also block muscarinic (M₁), histamine (H₁) and alpha (α₁) receptors more potently than typical drugs.

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

Dopamine (D₂) receptors are blocked by the older (atypical) drugs decreasing the extrapyramidal side effects.

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

Haloperidol. Haloperidol has a high incidence of extrapyramidal side effects because of its high potency and affinity for D₂ receptors.

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

The blockade of muscarinic receptors.

Reference list.

Brand, L. 2021. SU 9 Antipsychotic Drugs and Lithium. https://efundi.nwu.ac.za/access/lessonbuilder/item/6005036/group/dd46f2da-d3be-402e-9ba7-2c5955cedd9d/English%20power%20point/English%20PP%202021/SU%209.pdf Date of access: 26 Apr. 2021. [PowerPoint presentation]

Katzung, B.G.  2018.  Basic & Clinical Pharmacology.  14^th ed.  California, San Francisco: McGraw-Hill Companies, Inc.

Blog #10 (SU 8.2)

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

Dopamine agonists and anticholinergic drugs.

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

Amantadine is a metaffinoid potentiator of dopamine. It works indirectly to increase dopamine activity, increase the release of dopamine, increase the synthesis of dopamine and blocks dopamine re-uptake thus making it effective as an anti-Parkinson’s drug. It is a NMDA antagonist thus having anti-dyskinetic effects. It is an adenosine-α_2A antagonist inhibiting D₂ receptors, by blocking the adenosine receptor you improve D₂ function. Amantadine improves rigidity, tremors and bradykinesia.

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

Drugs that indirectly increase dopamine concentration do not need to be converted to an active metabolite by enzymes, do not act directly on the post synaptic dopamine receptors and have no potentially toxic metabolites.

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

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

• Bromocriptine: D₂ receptors
• Pramipexole: D₃ receptors
• Ropinirole: D₂ receptors

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

Rasagiline (MOA-B inhibitor) is classified as a neuron protecting drug because it increases the dopamine stores in the neurons of the brain.

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

MOA-B selective drugs are used in combination with levodopa to decrease the metabolism of dopamine thus prolonging the effect of levodopa.

• How do the COMT-inhibitors act in Parkinsonism?

COMT-inhibitors convert levodopa to 3OMD, this creates a weak response with levodopa because they compete for transport into the CNS. This increases the effect of levodopa.

• How does istradephyline act?

Istradephyline inhibits D₂ function. It does this by antagonising adenosine thus preventing inhibition of dopamine function. It is used as additional therapy to levodopa and carbidopa to decrease the on-off phenomenon.

• Discuss the MOA of safinamide

Safinamide has a novel dual mechanism of action. It 1. increases dopamine activity by potentiating reversible inhibition of MAO-B and inhibits dopamine re-uptake and 2. decreases glutamate release.

Reference list.

Brand, L. 2021. SU 8 Drugs Used In The Treatment Of Parkinsonism And Other Movement Disorders. https://efundi.nwu.ac.za/access/lessonbuilder/item/5911728/group/dd46f2da-d3be-402e-9ba7-2c5955cedd9d/English%20power%20point/English%20PP%202021/SU%208.pdf Date of access: 1 Apr. 2021. [PowerPoint presentation]

Katzung, B.G.  2018.  Basic & Clinical Pharmacology.  14^th ed.  California, San Francisco: McGraw-Hill Companies, Inc.

 Blog #9 (SU 6.3)

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

1. myelinated fibres with unmyelinated fibres; and

Myelinated fibres are blocked easier than unmyelinated fibres and thus myelinated fibres are more sensitive for blockade by local anaesthetics.

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

Activated pain fibres fire faster so pain sensation can be selectively blocked by local anaesthetics. Fibres that are outside the thick nerve bundles are blocked before fibres that are in the middle of thick nerve bundles which are blocked slower. This is because fibres on the outside of nerve bundles are exposed too higher concentrations of the anaesthetic earlier than the fibres at the middle of the fibre bundle.

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

Effects of local anaesthetics on the heart:

• • Local anaesthetics have a class I antiarrhythmic drug effect.
  • Sodium channels in the heart muscle tissue is blocked.
  • This can cause toxicity and lead to cardiac depression.

Effects of local anaesthetics on the skeletal muscle:

• • Has weak blocking effects.
  • Has no clinical application.

• What is the basis for the selection of a LA?
  • Type of procedure being done.
  • The duration of the procedure and duration the drug needs to have an effect.
  • The type of tissue the drug needs to be administered in to.

• Why are LA solutions sometimes saturated with CO₂?

CO₂ potentiates the effect of the local anaesthetic thus acting as a buffer.

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

Reference list.

Brand, L. 2021. SU 6 Local Anaesthetics. https://efundi.nwu.ac.za/access/lessonbuilder/item/5726323/group/dd46f2da-d3be-402e-9ba7-2c5955cedd9d/English%20power%20point/English%20PP%202021/SU%206.pdf Date of access: 30 Mar. 2021. [PowerPoint presentation]

Katzung, B.G.  2018.  Basic & Clinical Pharmacology.  14^th ed.  California, San Francisco: McGraw-Hill Companies, Inc.

Blog #8 (SU 5.3)

1. 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.

Table of effects of inhaled anaesthetics on body systems.

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

• Total Central nervous system suppression
• Total Respiratory suppression
• Nephrotoxicity
• Haematotoxicity
• Malignant hyperthermia 
• Hepatotoxicity

Reference list

Brand, L. 2021. SU 5 General Anaesthesia. [PowerPoint]. https://efundi.nwu.ac.za/access/lessonbuilder/item/5698352/group/dd46f2da-d3be-402e-9ba7-2c5955cedd9d/English%20power%20point/English%20PP%202021/SU%205.pdf Date of access: 19 Mar. 2021.

Katzung, B.G.  2018.  Basic & Clinical Pharmacology.  14^th ed.  California, San Francisco: McGraw-Hill Companies, Inc.

Blog #7 (SU 4.3)

• 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?

1. Phenobarbitone
2. Phenytoin
3. Carbamazepine
4. Oxcarbazepine
5. Topiramate

These above listed drugs decrease the effectiveness of oral contraceptives. This increases the risk of a female patient using these drugs as therapy to fall pregnant even when she is taking oral contraceptives.

1. Valproate
2. Lamotrogine
3. Gabapentin
4. Leviteracetam
5. Vigabatrin

These above listed drugs do not affect oral contraceptives and can be used in combination.

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

Yes. Oral contraceptives decrease the serum levels of Lamotrogine and Valproate. Higher doses of this drug is thus needed to reach therapeutic serum levels to effectively treat the condition. If these drugs are taken in combination with oral contraceptives there is an increase in the risk of the patient experiencing seizures.

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

Neonates metabolise the drug slower, so a lower dose needs to be given as to not induce toxic serum levels. Babies and children metabolise the drug faster than adults and the dose should be higher to achieve therapeutic levels and get desired clinical outcomes. Geriatric patients a lower dose needs to be administered because often their liver and kidney function start to decline or are impaired thus affecting the metabolism (slower metabolism) of the drug.

• In which cases is plasma blood level monitoring indicated?

Plasma blood levels are indicated in patients that have impaired liver and kidney function if the drug they are using is metabolised in the impaired organ system.

Reference list

Brand, L. 2021. SU 4 Anti-Epileptic Drugs. https://efundi.nwu.ac.za/access/lessonbuilder/item/5613419/group/dd46f2da-d3be-402e-9ba7-2c5955cedd9d/English%20power%20point/English%20PP%202021/SU%204.pdf Date of access: 17 Mar. 2021.

Blog #6 (SU 3.3)

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

Tolerance originated because of the toxic effects of chronic alcohol use. The central nervous system adjusts to the effects of the alcohol and metabolism is induced, so there is a higher rate of metabolism taking place so the effects of the alcohol decrease and are short lived thus tolerance is created.

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

Toxic effects of chronic alcohol use on the liver are progressive decrease in liver function, symptoms of hepatitis and liver cirrhosis present and liver cells harden. Toxic effects of chronic alcohol use on hepatic metabolism are suppression of gluconeogenesis leading to hypoglycaemia, fat accumulation and nutrient deficiencies and an increase in activity of liver microsomal enzymes leading to induction of metabolism and an increase in metabolism rate.

These effects are worse in women than in men.

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

Wernicke-Korsakoff-syndrome is a brain disorder caused by lack of vitamin B1 or thiamine. Wernicke-Korsakoff-syndrome is treated by administering thiamine (Vit B1) to the patient.

• Fully explain the foetal alcohol syndrome.

Foetal alcohol syndrome (FAS) occurs when there is alcohol use ither acute or chronic during pregnancy. The use of alcohol during pregnancy causes teratogenic effects. When there is alcohol use especially in the first trimester signs like growth deficiencies, mental retardation, microcephaly and underdevelopment of the middle facial area are often seen.

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

Pharmacokinetic interactions of acute alcohol consumption are decreased metabolism of certain drugs like phenothiazines, tricyclic antidepressants and sedative hypnotics.

Pharmacokinetic interactions of chronic alcohol consumption are increased transformation of other drugs, especially paracetamol. Paracetamol and chronic alcohol use cause hepatic toxicity of paracetamol’s metabolite.

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

1. Alcohol has additive central nervous system suppressant effects. Alcohol has a drug interaction with other central nervous system suppressant drugs.
2. Alcohol has a drug interaction with vasodilators. Alcohol potentiates the effects of vasodilators causing over vasodilation. Drug interaction with blood pressure controlling drugs.
3. Alcohol has a drug interaction with hypoglycaemic drugs. Alcohol decreases the effects of the hypoglycaemic drugs so correction will not take place.
4. Alcohol has a drug interaction with aspirin. Alcohol increases antiplatelet aggregation of aspirin so increased bleeding problems will occur if used in combination.

Reference list

Brand, L. 2021. SU 3 Alcohols. https://efundi.nwu.ac.za/access/lessonbuilder/item/5557061/group/dd46f2da-d3be-402e-9ba7-2c5955cedd9d/English%20power%20point/English%20PP%202021/SU%203.pdf Date of access: 3 Mar. 2021. [PowerPoint presentation]

Blog #5 (SU 3.1)

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

- The alcohol dehydrogenase system that metabolises alcohol by means of zero-order kinetics at a rate of 7-10g/hour. The clinical significance of this system is that only low to moderate amounts of alcohol can be metabolised by this system because there is a limited amount of the co-enzyme NAD that saturates the system.

- The mixed function oxidase system (MEOS) metabolises higher concentrations of alcohol (> than 100mg/dL). The clinical significance of this system is that with chronic alcohol users this system’s activity increases and is induced so more alcohol is metabolised per time unit and tolerance is created.

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

Ethanol is metabolised and acetaldehyde is formed as an end product. Acetaldehyde is converted by enzyme aldehyddehidrogenase (dependent on co-enzyme NAD) to acetate which is in turn converted to carbon dioxide and water and is excreted.

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

1.  Disulfiram
2.  Metronidazole
3. Cephalosporins
4. Hypoglycaemic drugs

These drugs block the effects of the alcohol by inhibiting the metabolism of alcohol. Aldehyddehidrogenase’s activity is blocked and acetaldehyde builds up in the body because it is not converted to acetate.

Reference list

Brand, L. 2021. SU 3 Alcohols. https://efundi.nwu.ac.za/access/lessonbuilder/item/5557061/group/dd46f2da-d3be-402e-9ba7-2c5955cedd9d/English%20power%20point/English%20PP%202021/SU%203.pdf Date of access: 3 Mar. 2021. [PowerPoint presentation]

Blog #4

Use of alternative herbal/natural medicines in the treatment of anxiety and insomnia.

Herbal and natural medicines in the treatment of anxiety.

Kava-kava

Lavender

Lemon balm

Chamomile

Passionflower

These natural herbs and herbal supplements my help provide some relief from anxiety symptoms. These supplements are available in capsule or pill form or van be taken as herbal teas.

Lavender

Ylang ylang

Grapefruit

Clary sage

Bergamont

These essential oils through aroma therapy can help you feel calm and relaxed and reduce your anxiety.

Herbal and natural medicines in the treatment of insomnia.

Valerian root

Chamomile

Passionflower

Hops

Lemon balm

These herbs and supplements are believed to be alternative treatments for insomnia.

Also.

CBD oil

There are several studies that provide information that CBD oil helps with anxiety and insomnia relief.

Bibliography

https://www.webmd.com/anxiety-panic/natural-remedies-for-anxiety

Natural Remedies to Alleviate Anxiety.

Reviewed by Dan Brennan, MD on November 14, 2020.

https://www.webmd.com/sleep-disorders/alternative-treatments-for-insomnia

Alternative Treatments for Insomnia

Reviewed by Neha Pathak, MD on October 13, 2020

Blog #3

• What factors may affect the absorption and distribution of sedative-hypnotic drugs? What is the clinical significance thereof?

Different kinetics like: lipophilicity, biotransformation and elimination half-life affect the absorption and distribution of these drugs. Lipophilicity determines the rate at which the drug is absorbed and distributed, more lipophilic drugs are absorbed faster and are distributed through the body at a faster rate and thus have a rapid onset of action. Metabolism also has an effect on absorption and distribution, less lipophilic drugs are not affected or metabolised by the hepatic microsomal enzymes and can be excreted by the kidneys where more lipophilic drugs form active metabolites and must undergo oxidation and conjugation to be excreted in the urine. The elimination half-life also has an clinical significance because the shorter the elimination half-life the faster the drug is excreted and the faster it must be absorbed.

• What is meant by redistribution and what is the significance thereof?

The drug is redistributed from the brain to other tissue in the body. Highly lipid soluble drugs are absorbed and are distributed to the brain quite fast where they are then redistributed to the heart, kidneys and other body tissues then muscle and fats where these drugs can create a deppo-preparation so they are released in the body systematically over long periods of time

• How are the BDs metabolized? Name the various steps in the process.

1. Dealkylation
2. Oxidation
3. Conjugation

• Which BDs are converted to active metabolites? What is the significance thereof?

1. Diazepam
2. Chlorazepate
3. Prazepam
4. Chlordiazepoxide
5. Ketazolam

These drugs are metabolized by the hepatic microsomal enzymes, especially the Cytochrome P450 enzyme, these drugs undergo oxidation and conjugation to form an active metabolite that contributes to the drug effect. In patients with impaired liver enzyme function, like: the elderly, neonates, patients with liver cirrhosis and patients receiving therapy with Cytochrome P450 enzyme inhibitors, these drugs can be dangerous because the cannot be metabolised properly.

• Which BDs are not dependent on the cytochrome P450 oxidative enzymes for metabolism? What are the advantages thereof?

1. Oxazepam
2. Lorazepam
3. Temazepam
4. Lormetazepam

These drugs are not affected or metabolised by the hepatic microsomal enzymes and can be excreted by the kidneys. These drugs can be given to patients with impaired liver enzyme function, like: the elderly, neonates, patients with liver cirrhosis and patients receiving therapy with Cytochrome P450 enzyme inhibitors.

• What is enzyme induction? Which of the sedative hypnotic drugs are known for this? What is the clinical significance of enzyme induction?

Enzyme induction is when the drug causes an increase in production of specific enzymes that increase the metabolism of the drug. Enzyme induction causes a decrease in the amount of drug in the body’s circulation and thus causes a decrease in the effect of the drug on the body. Enzyme induction typically takes place with barbiturates like phenobarbitone and meprobamate the effect being lighter suppression of the central nervous system and lighter sedation.