Discuss the possible mechanisms of action of Lithium

• Lithium can substitute sodium in generating action potentials
• Lithium also has effects on the second messengers. It influences specifically IP₃ and DAG 2^nd messenger systems by decreasing various enzymes that are important for the conversion and recirculation of membrane phosphoinositides. IP₃ and DAG is important in monoamine and cholinergic neurotransmission

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

• Lithium has a very narrow therapeutic index of 0.5-1.5 mM. Anything higher than 2mM can have toxic effects. Lithium toxicity can have severe side effects like Tremors, Muscle weakness, Polydipsia, Nephrogenic diabetes insipidus, Thyroid enlargement, Leucocytosis etc.

When is lithium used as a single drug, and in which cases and with which type of drug is Lithium combined?

• Lithium can be used as monotherapy with acute major depression
• It is often used in combination with an antipsychotic drug in the treatment of Schizophrenia
• Benzodiazepines and Lithium are used together in the treatment of Bipolar Disorder

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

• Drugs like Thiazides (Diuretics), ACE inhibitors (Enalapril) and Fluoxetine increase the levels of Lithium in the body, which could lead to lithium toxicity.
• Theophylline and caffeine increases the renal excretion of Lithium
• Carbamazepine, Ca²⁺ blockers, Losartan, Methyldopa, Metronidazole and Phenytoin in combination with Lithium can have serious neurotoxic side effects

Name the major side effects of lithium

• Tremors, sedation, ataxia, aphasia
• Muscle weakness, fatigue
• Polydipsia, polyuria, nocturia
• Nephrogenic diabetes insipidus
• Thyroid enlargement
• Leucocytosis
• Oedema
• Weight gain
• Acne, Alopecia
• Sexual dysfunction   

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

• Patients can continue taking Lithium whilst pregnant. It could help to reduce the risk for post-partem psychosis. If patients do decide to stop taking Lithium, they need to resume the treatment as soon as possible after giving birth.
• Lithium moves into the breastmilk and passes into the baby’s body, causing high concentrations of Lithium in the baby’s bloodstream. Lithium should be used with caution in women who are breastfeeding.

Name 3 other important indications for lithium

• Prophylaxis of manic and hypomanic episodes
• Treatment of resistant or recurrent (unipolar) depression to increase the effects of the antidepressants
• Aggressive or self-mutilating behaviour

Evaluate the case and motivate your recommendations.

The lithium falls in the therapeutic index, and her dose is correct for her weight according to the SAMF (20mg/kg/day). The lithium should not cause any adverse effects on its own, but by drinking her mother’s water pill (Diuretic), the levels of Lithium in her body has increased. Due to this increase, she is experiencing symptoms that can be seen with lithium toxicity, such as fatigue and the shakiness she is experiencing. She needs to stop using her mother’s water pills (diuretics) in an attempt to lose weight and drink more water to compensate for the effects caused by the water pill. By keeping herself hydrated and the cessation of the water pill, her lithium levels should return to normal, and the toxic effects will fade. If she is concerned about her weight, other options should be considered, like talking to her pharmacists about changes she can make to her lifestyle to lose weight in a healthy and controlled manner.

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

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

• It blocks the D₂ receptors mostly but it can also bind to muscarinic, alpha, histamine and serotonin receptors

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

• The typical drugs work by blocking the D₂ receptors found in the mesolimbic system
• The atypical drugs block the 5-HT_2A receptors more than the D₂ receptors

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

• The post-synaptic D₂ receptors that are blocked by Benzamides

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

• Butyrophenone derivatives (Haloperidol) due to the potent D₂ blocking effects
• Diphenylbutylpiperidines (Pimozide) due to potent D₂ blocking effects

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

• Due to the blockage of the a receptors

What are the two main groups of drugs used in the treatment of Parkinson's Disease (PD)

• Drugs that increase the dopamine activity
• Drugs that decrease cholinergic activity  

How does Amantadine act as a PD drug?

• Amantadine works by increasing the dopamine concentrations in the following ways
  • Increasing the release of dopamine
  • Increasing the synthesis of dopamine
  • Blocking the reuptake of dopamine

Discuss the mechanisms of antiparkinson's drugs that indirectly increase the concentration of dopamine.

• Carbidopa: This drug is an enzyme inhibitor. It inhibits the enzyme DOPA decarboxylase, which converts L-dopa into dopamine. By inhibiting the enzyme, the conversion of L-dopa peripherally is blocked. The L-dopa can then be transported into the brain and converted to dopamine, increasing dopamine concentrations. Benserazide is also a DOPA decarboxylase inhibitor 
• Entacapone: COMT inhibitor. By inhibiting this enzyme, less L-dopa will be converted to 3-O-methyldopa. This drug, therefore, decreases the peripheral metabolism of L-dopa. More L-dopa can be transported into the brain to be converted to dopamine, which will, in turn, increase the dopamine concentration in the brain

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

• Ergot derivatives
  • Bromocriptine

• Not-ergot derivatives
  • Pramipexole
  • Ropinirole

Dopamine receptors stimulated by each DA-agonist

• Bromocriptine: D2 receptors (partial agonist)
• Pramipexole: D3 receptors
• Ropinirole: D2 agonist

Which of the drugs above is neuroprotective? What does it mean?

• Neuroprotection refers to the ability of a drug to prevent neuronal cell death
• Bromocriptine, Pramipexole (is possibly neuroprotective)

What is the importance of MOA-B selective drugs in the treatment of PD?

• The selective MOA-B drugs are easier to use in patients with PD. Irreversible selective medicines are used for the treatment of akinesia and motor fluctuations.

How does a COMT inhibitor work in the treatment of PD?

• COMT is an enzyme responsible for the conversion of L-dopa into 3-O-methyldopa peripherally. L-Dopa and 3-O-methyldopa are transported through active transport processes and will compete to bind to active transporters. By inhibiting this COMT enzyme, L-dopa won't have to compete to attach to the transporters. More L-dopa will thus be transported across the BBB to be converted to dopamine. This will increase dopamine concentration.

How does Istradefylline act?

• It is a selective adenosine a2 antagonist used with carbidopa and levodopa for a patient's "off" episodes. This drug increases the dopamine activity

Discuss the mechanism of action of Safinamide.

• This drug works by reversibly inhibiting MAO-B and inhibiting the Dopamine reuptake. Therefore it increases dopamine activity.
• This drug also decreases the glutamate release, which reduces the formation of GABA and could decrease the excessive excitation caused when Ach binds to GABA

How does the sensitivity for the blockade of local anaesthetics compare regarding:

1. Myelinated and unmyelinated fibres

• Myelinated fibres are easier blocked than unmyelinated fibres. The myelinated fibres are thus more sensitive to the LA than the unmyelinated fibres

2. Pressure/touch nerves compared to dorsal nerves that transmit pain impulses

• The dorsal nerves that transmit pain impulses are much more sensitive for the LA’s than the pressure/touch nerves in the body

What are the effects of LA’s on other tissues?

• Heart: These drugs act like class 1 anti-arrhythmic drugs
• Skeletal muscle: The drugs have weak action on the muscles

What is the basis for selecting local anaesthetics?

• It is used for smaller surgical procedures, typically spinal anaesthesia
• It is used for autonomic blockade in ischaemic states and pain
• It is also used for postoperative analgesia

Why are local anaesthetic solutions saturated with CO2?

• CO2 helps with the diffusion of the drug across the membranes and maintain the pH

Which drugs are typically used as surface anaesthetics:

• Oxybuprocaine
• Cocaine
• Benzocaine

Inhalation drugs

What are the major toxic effects of inhalation drugs?

• Hepatotoxicity
• Cardiac arrhythmias
• Postoperative nausea and vomiting
• Respiratory depression and irritation

Which of the AED affect the metabolism of the pill (contraceptives)? What are the implications? Which drugs are safe to use in combination with the pill?

Drugs that affect the pill’s metabolism are:

• Phenobarbitone
• Phenytoin
• Carbamazepine
• Oxcarbazepine
• Topiramate

All of the drugs mentioned above decrease the pill’s effectiveness and could lead to the patient becoming pregnant whilst using contraceptives

Drugs that are safe to use in combination with the pill:

• Valproate
• Lamotrigine
• Gabapentin
• Levetiracetam
• Vigabatrin

Can the pill interfere with the effectiveness of the AED?

Yes. Oral contraceptives can decrease the serum levels of drugs such as Lamotrigine or Valproate, which could increase the patient’s risk for seizures

How does age affect the kinetics of these drugs?

Due to your geriatric patients having a decrease in renal function, it means they have decreased clearance of these drugs. They are therefore an increased risk for developing CNS toxicity

Neonates who also have a low renal function will need to receive small doses to prevent toxicity

When is plasma level monitoring necessary?

• When Lamotrigine and Valproate are given in combination. This combination can be fatal
• Patients who have decreased liver function

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

Tolerance can be due to many mechanisms such as:

• MEOS and CNS adjustments
• Increased metabolism rate
• Cross tolerance from other sedative-hypnotic drugs like BD’s
• Peripheral neuropathy – Neurological changes that are pathological of nature

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

• It leads to a progressive decrease in liver function, leading to symptoms of liver cirrhosis or hardening of the liver
• It also increases the microsomal enzymes
• It leads to the formation of salt retention oedema
• It can also cause hypoglycaemia
• It increases the chances of developing liver and other cancers

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

• It is a condition that leads to the paralysis of your inner eye muscles, Ataxia and confusion in the patient. It is treated by giving Thiamine to prevent permanent damage and reduce the effects of this condition

What is foetal alcohol syndrome?

• Alcohol has teratogenic effects, which could cause the baby to be born with side effects like mental retardation, growth deficiencies, microcephaly (where the brain is smaller than average) and underdeveloped middle facial features.

What are the pharmacokinetic interactions of acute alcohol consumption differ from chronic consumption?

• Chronic consumption will lead to an increase in the patient’s liver enzymes which affects the metabolism of other drugs that are metabolised by liver enzymes

Name four interactions with alcohol where the pharmacologic effects of other drugs are potentiated.

• With the use of CNS suppressants like BD’s
• With the use of vasodilatory drugs
• Hypoglycemic drugs
• Anti-platelet drugs

What type of kinetics applies to alcohol in the body? Explain the clinical significance.

There are two processes involved in alcohol metabolism: Alcohol Dehydrogenase (AD) and MEOS (Mixed Function Oxidases).

Alcohol dehydrogenase is typically the metabolism seen when smaller amounts of alcohol are consumed. It is a zero-order kinetic process, which means the enzymes can become saturated. This process catalyzes the conversion of alcohol to acetaldehyde

MEOS is the system that steps in when larger amounts of alcohol are consumed. It induces the enzyme system to produce more enzymes to metabolize the large amounts of alcohol that is consumed, which means more alcohol per time unit can be broken down.

Summary of the metabolic pathway of ethanol metabolism

The end product of alcohol metabolism is acetaldehyde, which is converted to CO2 and H2O to be excreted from the body. The alcohol is metabolised in the liver by the enzymes Aldehyde dehydrogenase and also dependent on the coenzyme NAD.

Which drugs affect metabolism, and what are the effects?

Drugs like Disulfiram, Metronidazole, Cephalosporins, and Hypoglycemics interfere with the metabolism by inhibiting the Aldehyde dehydrogenase enzyme. This inhibition leads to the build-up of acetaldehyde in the body resulting in side effects such as nausea, vomiting, headaches.

Botanicals refer to using plants and herbs as alternative treatment to medicine. Botanicals are often used for products which can be sold to patients who need help with a certain condition, but would like to try the natural product before opting for pharmaceuticals. In some cases, the botanicals will be effective and help the patient but only if they do not have a severe condition. If used correctly, these products can be beneficial but if patients do not use these products as intended, it could cause toxicity and side effects in the patient. Some examples of botanicals used as hypnotics for the treatment of insomnia and anxiety include: 

For the treatment of Insomnia: 

• Valerian root 
• Chamomile 
• Dried passionflower 
• Lemon balm 
• Lavender 
• Lactuca sativa (Garden lettuce) - The oil from the seed is especially used in Egypt 
• saffron 
• California poppy 
• Skullcap 

For the treatment of anxiety:

• St. John's wort 
• Ginkgo biloba 
• Ashwagandha (Withania somnifera)
• Kava kava 
• Valerian
• Theanine (found in green tea) 
• GABA (which occurs naturally in plants and herbs) 
• Hops 
• Lemon balm 
• Skullcap
• Passionflower 
• Rosenroot 
• Chamomile 

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

• The lipophilicity of the drug. The more lipophilic a drug is, the faster the drug is absorbed and the faster the drug can produce effects

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

• Redistribution is the process where a drug is absorbed systemically and distributed to other parts of the body like the fatty tissues 

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

• The metabolism of Benzodiazepines is made possible by the microsomal liver enzymes. Metabolism consists of three steps: 
  • Dealkylation where active metabolites are produced
  • Oxidation where the drug is also converted into active metabolites 
  • Conjugation where the metabolites are made more aqueous soluble so that they can be excreted by the kidneys 

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

• Only the drugs containing Desmethyldiazepam (Diazepam, Clorozepate, Prazepam, Chloridiazepoxide, Ketazolam) undergo the process and are turned into active metabolites. This is important for us because the active metabolites can extend the duration of action of the drug 

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

• Oxazepam, Lorazepam, Temazepam and Lormetazepam. These drugs have the advantage of being used when a patient has decreased liver function especially elderly patients, neonates, patients with liver cirrhosis or patients who are using cytochrome P450 inhibitors 

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

• When a drug induces an enzyme, it is known as enzyme induction. drugs like Phenobarbital and Meprobomate are known for this. By increasing/inducing the enzyme, the metabolism of the drug will be quicker, which will have a decrease in the elimination half-life and then duration of action of the drug