• Discuss the possible mechanisms of action of lithium.

The suppression of IP₃ and DAG 2^nd messengers lead the decrease in the various enzymes that are needed for the conversion and recirculation of membrane phosphoinositide. This, in turn, has an effect of monoamine and cholinergic transmission.

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

The therapeutic index of lithium is between 0.5 – 1.5 mM. this is clinically significant because if the therapeutic index exceeds 2, then it becomes toxic for the patient. The therapeutic index also gives an indication of the plasma levels. In the case of lithium, the plasma half-life is 20 hours which means that it can be prescribed twice daily.

• 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 bipolar disorder (manic phase) and recurrent depression.

Lithium is used in combination for schizoaffective disorder, with antipsychotics as a combination.

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

Diuretics (such as thiazides), NSAIDS (Diclofenac), ACE inhibitors (Enalapril) and Fluoxetine: increase lithium toxicity

Carbamazepine, calcium blockers, losartan, methyldopa, metronidazole, and phenytoin: neurotoxic effects

Caffeine: increases renal excretion of lithium

• Name the major side effects of lithium.

Tremors

Decreased thyroid function

Oedema

Polydipsia and polyuria (reversible)

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

Lithium should not be used during pregnancy as the renal clearance increases but then goes back to normal after delivery of the baby. This means that if the renal clearance during pregnancy is good, then after pregnancy it may become toxic as it decreases after giving birth.

Lithium should not be used in breastfeeding as it can be transferred to the nursing baby through breast milk. This can cause lithium toxicity in the baby.

• Name three other important indications for lithium.

Recurrent depression

Resistant schizophrenia

Aggressive behaviour

• 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.

Ms B. Polar’s are within the therapeutic index of lithium, which is very good. However, since she had a muscle injury, she was using Indocid® which is an NSAID. NSAIDs increase lithium toxicity by decreasing renal clearance. The wight gain in a side-effect of using lithium. The “water pills” are thiazide diuretics, which increase lithium toxicity by decreasing renal clearance. Fatigue, sedation, increased thirst, shakiness, and nausea are all side-effects of lithium use.

• 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 with the specific sidechain	Example	Potency	Side-effects
With an aliphatic sidechain	Chlorpromazine	Low	Less extrapyramidal side-effects Severe sedation Strong anti-cholinergic effects (dry mouth, visual disturbances, urine retention etc.) Strong α-lytic effects (postural hypotension)
With a piperidine side chain	Periciazine	Low	Same as the aliphatic sidechain
With a piperazine side chain	Fluphenazine	High	More extrapyramidal side-effects Less sedation Weaker anti-cholinergic effects Weaker α-lytic effects

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

D₂ receptors are blocked by typical antipsychotic drugs

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

Atypical drugs block the 5-HT_2A receptors whereas typical drugs block the D₂ receptors

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

The receptors that are blocked by older drugs, that reduce the risk of extrapyramidal side effects, is the D₂ receptors. An example would include Sulpiride.

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

Fluphenazine has a high incidence of extrapyramidal side effects as it is a potent drug. Potency refers to how likely a drug is to bind to a specific receptor, in this case, fluphenazine is very likely to bind to D₂ receptors. The thioxanthenes have a similar pharmacological profile thus they have a high likelihood (but less than fluphenazine) to bind to D₂ receptors. Haloperidol is a potent D₂ blocker thus producing the most extrapyramidal side-effects.

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

DA, M, α, histamine and 5-HT receptors.

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

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

2. In what way does amantadine act as an antiparkinsonism drug?

• Metaffinoid potentiator of dopamine – increases the synthesis and release of dopamine but decreases the reuptake of dopamine
• It is an NMDA antagonist therefore having anti dyskinesia effects
• It is an adenosine A₂ antagonist – adenosine inhibits D₂ function

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

• Enzymatic conversion to an active metabolite is not needed

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

• Ergot derivatives: Bromocriptine and pergolide
• Non-ergot derivatives: Pramipexole, ropinirole and rotigotine

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

• Bromocriptine: D₂
• Pergolide: D₁ and D₂
• Pramipexole: D₃
• Ropinirole: D₂
• Rotigotine: no specificity

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

• Rasagaline
• Neuroprotective means that the drug slowed down the disease progression

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

• These drugs selectively metabolise dopamine

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

• Prolong levodopa’s action by diminishing its peripheral metabolism, thus decreasing the clearance but increasing the relative bioavailability

9. How does istradephyline act?

• It is an adenosine A₂ antagonist

10. Discuss the MOA of safinamide

• Safinamide – increases DA function
• It has a potent reversible inhibition of MAO-B and inhibits DA uptake
• But also decreases glutamate release

References: Katzung and Powerpoint notes

For quite a number of preparations of herbal/natural origin in pharmacies or shops, claims are made that they have anxiolytic and/or sedative-hypnotic properties. Your textbook (Katz) discusses a number of these preparations in Chapter 64. Use that information together with a search on the internet and compile a brief report on the use of these alternative medicines in the treatment of anxiety and insomnia. You may use any search engine (e.g. Google) and keywords such as “botanicals” and “anxiety” and “insomnia”. 

Jin Bu Huan and Kava-kava are considered to be used as a sedative and for anxiety, respectively, however, due to their side-effects (hepatotoxicity), these products should be avoided.

Ginkgo may be used to treat anxiety, but only in Alzheimer’s disease patients. This product was tested and results showed that the receptor density increased for the 5-HT_1A receptors.

Melatonin is used in treating insomnia as it is a serotonin derivative thus it helps regulate sleep-wake cycles. This increases REM sleep and has a hypnotic effect (it was reported to improve sleep onset, quality, and duration). Melatonin can also be used as an anxiolytic before and after surgery. Lavender also helps with insomnia, as it antagonises serotonin transporters and NMDA receptors.

Valerian, hops, passion-flower and lemon balm products may be used in the treatment of anxiety and insomnia.

• Valerian works similar to the mechanism of action of benzodiazepines, however, it binds to the β-subunit (instead of the γ-subunit) on the GABA_A receptor. To relieve insomnia, it interacts with the serotonin neurotransmitter.
• Hops increase GABA’s effects because it modulates the GABA_A receptor. It also binds to serotonin and melatonin receptors.
• Passion-flower has thought to have the same mechanism of action as benzodiazepines. This also has shown positive effects on Circadian rhythms.  
• Lemon balm increases GABA by inhibiting GABA transaminase.

 

References:

• https://www.intechopen.com/books/different-views-of-anxiety-disorders/herbal-remedies-to-treat-anxiety-disorders
• https://www.ebmconsult.com/articles/valerian-valeriana-officinalis-treating-insomnia-sleep#:~:text=Valerian%20(Valeriana%20officinalis)%20is%20most,the%20GABA%2DA%20receptor%20instead .
• https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0037290#:~:text=The%20main%20mechanism%20of%20action,A)%20receptors%20%5B1%5D.&text=There%20are%20also%20effects%20of,mechanism%20of%20sleep%20%5B17%5D.
• https://civilizedcaveman.com/health/benefits-lemon-balm-sleep-wellness/
• http://accurateclinic.com/accurate-education-passion-flower/#:~:text=Passion%20Flower%20is%20believed%20to%20exert%20its%20anti%2Danxiety%20effects,shown%20to%20produce%20anxiolytic%20effects.
• https://blog.bioticsresearch.com/botanicals-for-a-better-sleep
• Katzung

1. How does the sensitivity for blockade by a LA compare regarding the following types of fibres:
   1. myelinated fibres with unmyelinated fibres - Easily blocked
   2. pressure/touch nerves with the dorsal nerves that transmit pain impulses - Activated pain fibres are fired faster but Las block the pain sensation

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

• Tongue numbnees and a metallic taste
• Cardiotoxicity
• Neurotoxicity

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

• Dosage
• Site of administration
• Surgery to be performed
• Postoperative pain
• Potential toxic effects

4. Why are LA solutions sometimes saturated with CO₂? 

• LA solutions are saturated with CO₂ so that its effects are potentiated because CO₂ can act as a buffer

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

• Procaine
• Benzocaine
• Cocaine

Inhalation anaesthetic	Effects
	Cardiovascular	CNS	Respiratory	Hepatic	Uterus
Halothane	Depress cardiac contractility Sensitises myocardium to adrenaline Ventricular arrhythmias	Increase cerebral blood flow and intracranial pressure	Bronchodilation Causes rapid, shallow breathing Depresses muco-ciliary function No salivary secretions, bronchial secretions, or functions	Hepatotoxicity
Desflurane	Depress cardiac contractility Greater vasodilation with minimum effect on cardiac output Increase blood pressure and heart rate	Increase cerebral blood flow and intracranial pressure	Bronchodilation Causes rapid, shallow breathing Depresses muco-ciliary function		Muscle relaxant
Enflurane	Depress cardiac contractility	Sometimes convulsions can occur	Bronchodilation Causes rapid, shallow breathing Depresses muco-ciliary function	Potential nephrotoxicity
Isoflurane	Depress cardiac contractility Greater vasodilation with minimum effect on cardiac output Increases heart rate		Bronchodilation Causes rapid, shallow breathing Depresses muco-ciliary function
Sevoflurane	Depress cardiac contractility Greater vasodilation with minimum effect on cardiac output	Increase cerebral blood flow and intracranial pressure	Bronchodilation Causes rapid, shallow breathing Depresses muco-ciliary function		Muscle relaxant
Nitrous oxide	Megaloblastic anaemia	Potent analgesic Amnesia Increases cerebral blood flow therefore increasing intracranial pressure	Depresses muco-ciliary function

 

Name the major acute toxic effects of the inhalation drugs.

• hypoxia
• increase in intracranial pressure

1. 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 Pill metabolism	Drugs that are safe to use in combination with the Pill
Phenobarbital	Valproate
Phenytoin	Lamotrigine
Carbamazepine	Gabapentin
Topiramate	Levetiracetam
Perampenel	Vigabatrin
Oxcarbazepine

The drugs that affect the metabolism of the Pill, induce the cytochrome P450 enzyme, which decreases the efficacy of the Pill.

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

• Yes, the serum levels of the anti-epileptic drugs will decrease

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

• Neonates have a slower metabolism than children
• Babies and children metabolise the drug faster than adults
• In adults, the metabolism varies due to the severity of the epilepsy
• Geriatrics also have a lower hepatic metabolism therefore lower dosages are needed

4. In which cases is plasma blood level monitoring indicated?

• When phenytoin is used because there is saturated metabolism in the liver
• When carbamazepine is used as it is an auto-inducer
• Drugs that have long and short t_1/2
• Drugs that may cause transient toxicity

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

• GABA effects are potentiated as the ethanol binds to the sedative site on the GABA_A receptor which can induce a feeling of sedation which can be mistaken for a ‘subjective high’
• Inhibition of glutamate on the NMDA receptors – glutamate is an excitatory neurotransmitter. Due to the inhibition of the excitatory neurotransmitter, less action potentials will be fired thus leading to a relaxing effect, which can lead to a loss of inhibitions

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

• Progressive decrease in liver functioning, thus leading to hepatitis of symptoms of cirrhosis
• Decrease in gluconeogenesis due to hypoglycaemia, fat accumulation and nutrient deficiencies
• Oedema in a cirrhotic liver

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

• Wernicke-Korsakoff syndrome is a brain disorder due to the lack of vitamin B₁
• Lack of vitamin B₁ stems from chronic alcohol use – it is needed for the synthesis of coenzyme thiamine phosphate
• A patient must be treated with thiamine

4) Fully explain the foetal alcohol syndrome.

• When a pregnant woman abuses alcohol during her pregnancy, this will lead to the baby having cognitive and behavioural deficits due to the damaged developing neurons
• Alcohol can cross the placental barrier and since the foetus has little to no ALDH activity, alcohol cannot be eliminated so the foetus must rely on only the mother’s and placental enzymes for alcohol elimination

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

• Acute alcohol consumption decreases the metabolism of other drugs
• Chronic alcohol consumption increases the metabolism of other drugs

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

• Tricyclic antidepressants
• Phenothiazines
• Some sedative-hypnotics
• Anti-inflammatory agents

https://medlineplus.gov/ency/article/000771.htm

https://pubs.niaaa.nih.gov/publications/arh23-1/40-54.pdf

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

• Alcohol follows zero-order kinetics as 1g/hours is metabolised for every 10kg of body weight.
• This is clinically significant because it shows that there is a linear relationship between alcohol and the metabolism rate and is used as a measure of how much alcohol content is in a person’s blood and how much will be excreted during one hour

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

• There are 2 systems: the alcohol dehydrogenase pathway and the microsomal ethanol-oxidising system (MEOS)
• Alcohol dehydrogenase pathway: alcohol dehydrogenase (ADH) catalyses the conversion of alcohol to acetaldehyde. During this conversion, a hydrogen ion is transferred from ethanol to nicotinamide adenine dinucleotide to form NADH, thus there is a low to moderate amount of NADH
• MEOS: NADPH (made up of cytochrome P450, 2E1, 1A2 and 3A4) is the cofactor in ethanol metabolism. With chronic alcohol consumption, MEOS activity is induced therefore there is an increase in ethanol metabolism 

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

• Drugs that inhibit aldehyde dehydrogenase (ALDH) (eg disulfiram, metronidazole, cephalosporins and hypoglycaemics) which can cause a build-up of the ALDH which can cause nausea, vomiting and headaches

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

• The lipophilicity of the BDs determines the rate at which it is absorbed. If the drug has high lipophilicity, then it is strongly absorbed and if the drug has low lipophilicity, then it has a low absorption rate.
• Lipophilicity also affects the distribution. The more lipid-soluble a drug is, the faster it is distributed throughout the body. Therefore, the less lipid-soluble a drug is, the slower the distribution throughout the body.
• This is clinically significant because this shows that the more lipid-soluble a drug is, the faster an effect will be seen (onset), but the shorter the duration of action

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

• Redistribution means that the drug goes to the brain and then to the rest of the tissues
• This is significant because it determines the duration of action of the drug

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

1. Dealkylation: active metabolites are formed
2. Oxidation: the active metabolites are oxidised by the cytochrome P450 enzyme
3. Conjugation: the oxidised active metabolites bind to glucuronic acid and form the inactive metabolite (which are aqueous-soluble and can easily be excreted)

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

• Triazolam, zolpidem and zaleplon
• These are significant because these drugs have increased lipophilicity, resulting in a rapid onset of action

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

• Oxazepam, lorazepam, temazepam and bromazepam
• There are many advantages to these drugs: they can be used in the elderly, neonates, in patients with liver cirrhosis and when cytochrome P450 enzyme inhibitors are used

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

• Enzyme induction refers to when a drug induces (initiates) its own metabolism
• Phenobarbital and meprobamate are drugs that are enzyme inducers
• Enzyme induction is clinically important because this phenomenon is responsible for many drug interactions and increasing the metabolic rate of itself or other drugs