1. Possible mechanism of action of Lithium:

Lithium inhibits several enzymes involved in the recycling of neuronal membrane phosphoinositides. This action may result in depletion of the second messenger source, phosphatidylinositol biphosphate (PIP2), which, in turn would decrease generation of IP3 and DAG. These second messengers are important in amine neurotransmission, including that mediated by central adrenoreceptors and muscarinic receptors. 

2. Therapeutic index of lithium and its clinical significance:

The therapeutic index of Lithium is very small, it ranges between 0.5-1.5 mM. >2mM is toxic. It is for this reason that plasma levels should be monitored. 

3. When is Lithium used as a single drug and in which cases and with which drugs is it combined?

Lithium is used as a single drug /monotherapy for the treatment of manic, hypomanic, and acute-manic episodes. Lithium is used in combination with anti-depressants in the treatment of resistant or unipolar depression. 

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

• Diuretics (thiazides), NSAIM's, ACE inhibitors and fluoxetine: increase Li levels = toxicity
• Theophylline and caffeine increase the renal excretion of lithium.
• Neurotoxic combination with carbamazepine, CA2+ blockers, losartan, methyldopa, metronidazole and phenytoin. 
• Traditional anti-depressants worse EPS when used in combination with lithium 

5. Name the major side effects of Lithium:

Tremors, sedation, ataxia, aphasia, muscle weak\ness, fatigue, polydipsia, polyuria, nocturia, nephrogenic diabetes insipidus, thyroid enlargement, leukocytosis, edema, weight gain, acne, alopecia, sexual dysfunction. 

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

During pregnancy, Lithium is safe in the lowest possible dose. However, breastfeeding is not allowed at all. 

7. Name 3 other important indications of lithium

Lithium is used to treat acute mania, manic episodes, hypomanic episodes and is used to prevent relapse in depression. 

8. Case study recommendations: 

The patient's weight gain, fatigue, nausea, shaking and thirst are all adverse effects of lithium due to drug interactions. The "water pills" and the non-steroidal anti-inflammatory Indocid both have adverse interactions with lithium and increase the concentration of lithium. This is what is causing the lithium toxicity and side effects. IO would recommend that the patient stops using her moms water pills and instead of using a NSAIM, she should rather use a different painkiller such as acetaminophen. 

1. Name an example of each of the 3 phenothiazine sub-families and state how they differ from one another in terms of potency and side effects.

• Aliphatic side-chain: Chlorpromazine
• Piperidine side-chain: Periciazine 
• Piperazine side-chain: Fluphenazine

Aliphatic and piperidine compounds have a low potency, little EPS, severe sedation, strong anti-cholinergic effects, strong alpha-lytic effects (postural hypotension) and are cardiotoxic. 

Piperazine compounds have a high potency, more EPS, weaker anti-cholinergic effects, weaker alpha-lytic effects, less sedation and less cardiovascular side effects. 

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

Typical antipsychotics block the mesolimbic D2 receptors, and to a lesser extent, they also block H1 receptors, cholinergic receptors and alpha-1 adrenergic receptors. 

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

Atypical drugs have a higher affinity for serotonin receptors. Atypical drugs block the 5HT2a receptors more than the D2 receptors. Typical antipsychotics on the other-hand have a higher affinity to block D2 receptors.

4. Which of the receptors blocked by older drugs reduce the risk of EPS?

Typical drugs (Benzamides) have a lower risk of EPS due to localisation of the D3 receptors.

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

Haloperidol is a typical antipsychotic and has a very high binding affinity for the blockade of D2 receptors. It has a very high potency and therefore results in severe extra-pyramidal symptoms. 

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

The blockage of cholinergic (muscarinic) receptors. 

1. Which two main groups of drugs are important in the treatment of parkinsonism? 

Dopamine agonists and anti-cholinergic drugs. 

2. In what way does amantadine act as an anti-parkinsonism drug?

Amantadine enhances dopaminergic neurotransmission by unknown mechanisms that involve increasing synthesis or release of dopamine or inhibition of dopamine reuptake. The drug also has muscarinic blocking actions. Amantadine improves bradykinesia, rigidity, and tremor. It also has antiviral effects. 

3. Discuss the mechanisms of action of the anti-parkinsonism drugs that indirectly increase dopamine concentration.

Monoamine Oxidase Inhibitors ( Selegiline and Rasagiline): These are selective inhibitors of monoamine oxidase type B, the form of the enzyme that metabolizes dopamine. This indirectly increases dopamine concentrations by preventing its metabolism. Hepatic metabolism of Selegiline results in the formation of desmethylselegiline (neuroprotective) and amphetamine. 

Catechol-O-methyltransferase Inhibitors (Entacapone and Tolcapone): COMT is the enzyme that converts Levodopa to 3-O-methyldopa. These drugs inhibit COMT, thereby increasing the concentration of Levodopa. 

Amantadine: this drug inhibits the reuptake of dopamine, thereby indirectly increasing the concentration of dopamine. 

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

Ergot alkaloids: Bromocriptine

Non Ergot alkaloids: Pramipexole and Ropinirole. 

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

Pramipexole: D3 receptors

Bromocriptine and Ropinirole: D2 receptors. 

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

The monoamine oxidase inhibiting drug Selegiline is metabolised to form desmethylselegiline and this is classified as neuroprotective. A neuroprotective drug in terms of Parkinsonism is a drug which delays or prevents the death of dopamine producing cells in the brain, thereby slowing or halting the progression of the disease. 

7. What is the importance of MAO-B selective drugs in the treatment of parkinsonism?

MAO-B selective drugs are important in the treatment of parkinsonism because they inhibit the enzyme MOA-B which metabolizes dopamine. This results in an increase in dopamine levels in the body, thereby providing symptomatic relief in patients with Parkinson's. 

8. How do the COMT-inhibitors act in parkinsonism?

COMT inhibitors (Entacapone and Tolcapone) are useful in the treatment of Parkinsonism because they inhibit the conversion of Levodopa to 3OMD. 3OMD increased concentrations in the plasma is associated with poor response to Levodopa because it competes with Levodopa for active transport into the CNS. Therefore COMT inhibitors decrease plasma levels of 3OMD and increase the levels of Levodopa. 

9. How does istradefylline act?

Istradefylline is an adenosine alpha 2A receptor used to treat Parkinsonism by reducing the overactivity of the striatal pathway restoring the balance of the basal ganglia. 

10. Discuss the MOA of safinamide 

Safinamide is is a monoamine oxidase B inhibitor. It is used to reduce response fluctuations in patients taking Carbidopa-Levodopa, diminishing off-periods in patients with wearing-off effect or on-off phenomena. It's mechanism of action, like Rasagiline and Selegiline, it inhibits the dopamine metabolising enzyme MAO-B, thus increasing dopamine concentrations.  

1. How does the sensitivity blockade by LA compare regarding the following types of fibers: 

• Myelinated fibers with unmyelinated fibers:

Unmyelinated fibers are more sensitive to the effects of local anesthetics, because there are easier to block than myelinated fibers. 

• Pressure/ touch nerves with the dorsal nerves that transmit pain impulses?

Sensory fibers have a high firing rate and relatively long action potential duration. As type A delta and C fibers participate in high frequency pain transmission, this characteristic may favor blockade of these fibers earlier and with lower concentrations of local anesthetics. 

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

CNS: local anesthetics are capable of producing a spectrum of central effects, including: light-headedness, sedation, restlessness, nystagmus, and tonic-clonic convulsions. Severe convulsions may be followed by coma with respiratory and cardiovascular depression. 

Cardiovascular: with the exception of cocaine, all LA's are vasodilators. Patients with pre-existing cardiovascular disease may develop heart block and other disturbances of cardiac electrical function at high plasma levels of local anesthetics. Cardiovascular toxicity can occur. 

3. What is the basis of the selection of a LA?

The duration of the procedure, the type of procedure, the target site of the procedure. 

4. Why are LA solutions sometimes saturated with CO2?

CO2 acts as a buffer for the local anesthetic and reduces the pain of the injection and it increases the onset rate of action of the anesthetic. 

5. Which of the LA are typically used for surface anesthesia? 

Cocaine, Benzocaine and Oxybuprocaine. 

1. 

2. Hepatotoxicity, nephrotoxicity, malignant hyperthermia, 

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?

Phenobarbitone, Phenytoin, Carbamazepine, Oxcarbazepine and Topiramate are the anti-epileptic drugs which decrease the effectiveness of the Pill. They increase the metabolism of the pill thereby making it less effective, this can lead to unwanted pregnancy. 

Valproate, Lamotrigine, Gabapentin, Leviteracetam and Vigabatrin do not affect pill metabolism and are therefore safe to us in combination with the pill. 

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

Yes they can. Oral contraceptives decrease the Lamotrigine and Valproate serum levels. Oral contraceptives can decrease the levels of anti-epileptic drugs and thus cause loss of control over seizures as well as toxicity. 

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

In neonates, the anti-epileptic of choice is Phenobarbitone, however it can cause hyperactivity.

In geriatrics, they have a decrease in renal function. This can decrease the rate of drug clearance and in turn increase the possibility of CNS toxicity. It can also cause a higher incidence of hyponatremia. 

In which cases is plasma blood level monitoring indicated?

Blood plasma monitoring is important when the patient is pregnant, or on oral contraceptives.  Furthermore, it should be monitored when undergoing therapy with the following drugs that could cause serious toxicities: phenytoin, lamotrigine, phenobarbitone, valproate, carbamazepine. 

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

Consumption of alcohol over long periods of time can cause both physical and psychological dependence. The more you consume alcohol, the higher your tolerance to it becomes, so you would have to keep consuming more and more of it to reach the same stimulating CNS effects. 

Tolerance results from ethanol-induced up-regulation of a pathway in response to the continuous presence of ethanol. Dependence can result from over-activity of that same pathway after the ethanol effect disappears and before the system has time to return to a normal ethanol-free state. 

GABA neurotransmission plays an important role in tolerance as well as in alcohol withdrawal, because: sedative hypnotic drugs that enhance GABAergic neurotransmission are able to substitute for alcohol during alcohol withdrawal, and there is evidence of down regulation of GABA-mediated responses with chronic alcohol exposure. 

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

Liver disease is one of the most common toxic side effects of excessive alcohol consumption, 15-30% of chronic drinkers eventually develop liver disease. Alcoholic fatty liver (a reversible condition) may progress to alcoholic hepatitis and the finally to liver cirrhosis and liver failure. 

Women are more susceptible to hepatotoxicity than men. Concurrent infection with hepatitis B or C virus increases the risk of severe liver disease. Cirrhosis contributes to elevated portal blood pressure and esophageal and gastric venous varices. These varices may rupture and result in massive bleeding. 

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

Wernicke-Korsakoff-syndrome is characterized by paralysis of the external eye muscles, ataxia, and a confused state that can progress to coma and death. 

It is associated with thiamine deficiency but is rarely seen in the absence of alcoholism. Patients who suspect they have this syndrome must receive thymine therapy. 

Often, the ocular signs, ataxia, and confusion improve after administration of thymine. But, most patients are left with a chronic disabling memory disorder known as Korsakoff's psychosis. 

Fully explain the fetal alcohol syndrome

Chronic maternal alcohol abuse during pregnancy is associated with teratogenic effects, and alcohol is the main cause of mental retardation and congenital malformation. 

The abnormalities that have been characterized as fetal alcohol syndrome include:

1. Intrauterine growth retardation
2. microcephaly
3. Poor coordination
4. Under development of midfacial region (appears as a flattened face)
5. Minor joint abnormalities

In more severe cases, congenital heart defects and mental retardation. 

Ethanol rapidly crosses the placenta and reaches concentrations in the fetus that are similar to that in the maternal blood. The fetal liver has no alcohol dehydrogenase activity, so the fetus relies solely on maternal and placental enzymes for the elimination of alcohol. Alcohol triggers apoptotic neurodegeneration. 

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

Chronic alcohol consumption differs from that of acute alcohol consumption in the following way: chronic alcohol consumption increases the metabolic transformation of other drugs whereas acute alcohol consumption decreases the metabolic transformation of other drugs. 

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

Phenothiazines (eg: promazine), tricyclic anti-depressants (eg: amitriptyline), sedative-hypnotics (eg: zaleplon) and vasodilators (eg: enalapril). 

Bertram G. Katzung. (2018). The Alcohols. In: Bertram G. Katzung Basic & Clinical Pharmacology. New York: Mc Graw-Hill Education. 396-408.

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

Alcohol is lipophilic, meaning it is rapidly absorbed and distributed across the blood brain barrier.

Food in the stomach decreases the gastric emptying rate and thereby decreases alcohol absorption. It is for this reason that when in a fasting state, alcohol administered can reach its peak concentration within 30 minutes. Total body water content also plays a role in the absorption of alcohol: women have less body water than men do and it is for this reason that the absorption of alcohol reaches its peak concentration faster in women than in men. 

Over 90% of alcohol consumed is oxidized in the liver, and the remainder is excreted through the lungs and urine. The rate of alcohol oxidation follows zero order kinetics. It is independent of time and concentration of the drug. The typical adult can metabolize 7-10g of alcohol per hour.  

Give a brief summary of the metabolic pathways of ethanol metabolism

Metabolism of ethanol to acetaldehyde occurs via two major pathways:

1. Alcohol dehydrogenase system: This is the primary pathway for alcohol metabolism . Cytosolic enzymes catalyze the conversion of alcohol to acetaldehyde. These enzymes are mainly located in the liver, but are also found in smaller amounts in the brain and stomach. Women have lower amounts of gastric enzyme than men do, therefore accounting for the lower rate of alcohol metabolism in the stomach than men. During the conversion of ethanol by ADH to acetaldehyde, hydrogen ion is transferred from ethanol to the cofactor nicotinamide adenine dinucleotide (NAD) to form NADH. As a net result, alcohol oxidation generates an excess of reducing equivalents in the liver, chiefly as NADH. 
2. Microsomal ethanol oxidizing system (MEOS): This enzyme system uses NADPH as a cofactor in the metabolism of alcohol and consists primarily of CYP450, 2E1, 1A2 and 3A4. Alcohol is metabolized to acetaldehyde and acetaldehyde will be converted by aldehyde dehydrogenase to acetate. 

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

Disulfiram, Metronidazole, Cefotetan and Trimethoprim can inhibit the oxidation of acetaldehyde to acetate, by inhibiting Aldehyde dehydrogenase. This can result in acetaldehyde to accumulate and thus cause side effects such as: facial flushing, nausea, vomiting, dizziness, and headaches. 

Source

Katzung, B.G. 2018. Basic & Clinical Pharmacology. 14th ed. New York: Mc Graw Hill Education 

Natural preparations for the treatment of insomnia and anxiety: 

Insomnia:

Melatonin is a serotonin derivative produced mainly in the pineal gland. It regulates sleep-wake cycles. Melatonin improves sleep onset, duration and quality of sleep. Melatonin levels naturally rise at night and they decrease in the mornings. It is used extensively for treatment of insomnia. Ramelteon and Tasimelteon are agonists for melatonin receptors. 

Valerian root, is a herb found in Asia and Europe. It is used to aid insomnia. 

Magnesium, is also used to induce sleep and treat insomnia. Magnesium increases the levels of GABA in the brain thus producing a calming effect. It also regulates the production of melatonin, thus serving as a sleep aid to patients struggling with insomnia. 

Glycine is an amino acid in the CNS that also improves sleep. Glycine is believed to lower body temperature at night signaling to the body it is time to sleep. Glycine helps you to fall asleep faster and it improves the quality of your sleep. 

Anxiety:

Chamomile is a herb used to reduce anxiety. Its anxiolytic properties can be attributed to the flavonoid apigenin, which increases GABA in the brain. 

Ginkgo is prepared from the leaves of Ginkgo biloba, and contains glycosides and terpenoids.  Ginkgo is used as a herbal anxiolytic. It possesses antioxidant effects and increases nitric oxide formation. 

St. John's Wort is made from dried flowers of Hypericum perforatum, which contains the active constituents hypericin and hyperforin. This produces a decreased activity of serotonergic reuptake systems. It is used to treat anxiety as well as mild to moderate depression. 

Sources

Petre, A. (7 August 2020). 9 Natural Sleep Aids. Available: https://www.healthline.com/nutrition/sleep-aids#_noHeaderPrefixedContent. Last accessed 3 March 2021.

Bertram G. Katzung. (2015). Dietry Supplements and Herbal Medication. In: Anthony J. Trevor Katzung & Trevor's Pharmacology Examination & Board Review . 11th ed. United States of America: Mc Graw-Hill Education. 492-495.

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

Rates of absorption of sedative hypnotics differ. It depends on factors such as lipophilicity. Lipid solubility plays a major role in determining the rate at which a particular sedative hypnotic enters the CNS. This property is responsible for the rapid onset of the effects of triazolam, thiopental and the newer hypnotics. Lipophilic drugs are absorbed into the blood much faster. The higher a drugs lipophilicity, the more rapid its onset following administration and therefore the greater the effect exerted in the central nervous system. All sedative hypnotics can cross the placental barrier during pregnancy. Examples of drugs with a rapid onset of action in the CNS: eszopiclone, zaleplon and zolpidem. 

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

Redistribution is when a lipid soluble drug that was initially distributed and absorbed by vascular organs and the brain, gets withdrawn from these sites by less vascular and highly perfused tissues, such as skeletal muscles. 

How are the BD'S metabolized? Name the various steps in the process

Benzodiazepines are metabolized step-by-step by hepatic microsomal enzymes. The steps include:

1. Dealkylation to active metabolites
2. Oxidation to active metabolites through CYP450
3. Conjugation (Phase II) of oxidized metabolite with glucuronic acid to form inactive metabolite.  

Which BD's are converted to active metabolites? What is the significance thereof? 

Diazepam, Chlorazepate, Prazepam, Chlordiazepoxide, Ketazolam are converted to Desmethyldiazepam. Desmethyldiazepam is then oxidized to Oxazepam. Active metabolites contribute to the extended duration of action. Cumulative effects with multiple doses. 

Which BD's are not dependent on CYP450 oxidative enzymes for metabolism? What are the advantages thereof?

Oxazepam, Lorazepam, Temazepam and Lormetazepam are not dependent on cytochrome P450 to exert an effect and they do not undergo dealkylation or oxidation. This is useful in patients with liver cirrhosis, elderly, neonates and patients undergoing therapy with CYP450 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 a drug administered increases the production of a specific enzyme, this enzyme increases the rate of drug metabolism and thus decreases the effect the drug has in the body. Examples of enzyme inducers: phenobarbital and meprobamate. These drugs increase the rate of drug clearance. 

Source:

Katzung, B.G. 2018. Basic & Clinical Pharmacology. 14th ed. New York: Mc Graw Hill Education