Classification of drugs used as antidepressants:

8 Classes:

1. Tricyclic anti-depressants.
2. Mono-amine oxidase inhibitors
3. Serotonin Noradrenaline Reuptake inhibitors
4. Selective serotonin reuptake inhibitors.
5. Selective Noradrenaline reuptake inhibitors.
6. Serotonin Modulators
7. Tetracyclic and Unicyclic Anti-depressants
8. Circadian Rhythm regulators

Tricyclic anti-depressants

There are 2 categories:

Tertiary Amines (More 5-HT selective) and Secondary Amines (More NE selective).

Tertiary

• Amitriptyline, Butriptyline, imipramine, trimipramine, chlorimipramine Dothiepine.

Secondary

• Desimipramine, Nortriptyline, Amoxapine, Lofepramine.

Mono-amine oxidase inhibitors

Rasageline, Selegiline (Deprenil) = Selective MAO-B inhibitor.

Moclobemide – Selective MAO-A inhibitor (cheese reaction).

Tranylcypromine – Non selective MOA-A/B inhibitor (cheese reaction).

Serotonin Noradrenaline Reuptake inhibitors

More selective for 5-HT than NE.

Venlafaxine, Duloxetine.

Selective Serotonin Reuptake Inhibitors.

Fluoxetine, Paroxetine, Citalopram, Escitalopram, Sertraline, Fluvoxamine.

Selective Noradrenaline Reuptake inhibitor

Roboxetine

Serotonin modulators

Trazadone, Vortioxetine.   

Tetracyclic and Unicyclic AD’s

Mianserin, Mirtazepine, Bupropione (Unicyclic).

Circadian Rhythm Regulators  

Agomelatine.

What do they all have in common?

They all have an effect on the Serotonin and Noradrenaline reuptake inhibitors or agonist/antagonist of serotonin. – They all increase/stimulate Serotonin and Noradrenaline effects.

How long does it take for the anti-depressive effects of these drugs to appear? What is the reason for this?

It takes 6-8 weeks before Anti-depressant effect is optimal. Researchers says that it may be due to other changes that occur as a reaction to the changed serotonin levels.

How do the TADs and the selective serotonin reuptake inhibitors (SSRI’s) differ in respect of:

Efficacy

TAC – Less effective, used as an alternative for MDD- patients unresponsive to commonly used AD’s.

SSRI’s – More effective, better side effect profile, safe in acute overdose, help patients lose weight.

Side effects

TAC – Sedation, tremors, insomnia, Anticholinergic effects, cardiovascular, hypotension, psychosis, convulsions. Weight gain.

SSRI’s – Insomnia, tremors, GIT disturbances, headache, decreased libido and sexual dysfunction. Extra pyramidal symptoms. Weight loss- decreased appetite.

Safety

TAC – More dangerous – Cardio toxic

SSRI’s – More Safe.

What is the action of mirtazapine?

Blocks NA auto receptors which increases NA, and blocks 5-HT. It stimulates the release of Na and serotonin. There is indirect stimulation of 5-HT1a and blocks 5-HT3 and 5-HT2. It also blocks H1 and a1 receptors.

What is the action of venlafaxine?

Blocks both 5-Ht and NA reuptake, it is more potent for 5-HT than Na. It has a low affinity for M, H1 and A1 receptors.

What is the action of agomelatine?

MT1,MT2, 5HT-2c antagonist.

Discuss the possible mechanisms of action of lithium.
The possible mechanism of action of lithium is that it influences the secondary messengers (cAMP,IP3, and DAG) through the lowering of enzymes which is important for the conversion and re-circulation of membrane phospoinositides.IP3 and DAG is important in monoamine and cholinergic neurotransmission.

What is the therapeutic index of lithium and what is its clinical significance?
It has a small therapeutic index and therefor plasma concentration should be monitored carefully. Toxic levels could be reached easily. Lithium is not metabolised bu the liver and is safe in patients with liver problems. The half life for lithium is 20 hours daily doses are sufficient. 

When is lithium used as single drug and in which cases and with which type of drugs is lithium combined?
Clonazepam , Lorasepam and Lithium is used in combination for Bipolar disorder.
Lithium is used as monotherapy can be used for preventing mood instability or acute mania. 

Name 3 clinically significant interactions lithium may have with other drugs. Illustrate your answer with suitable examples of drugs.
Lithium has interactions with theophylline which increases the renal excretion of Lithium
Lithium in combination with Carbamazepine or Ca2+ blockers , losartan, methyldopa, metronidazole and pehnytoin can be neurotoxic.
Lithium in combination with Anti-psychotic drugs worsen extra pyramidal effects. 

Name the major side effects of lithium.
Tremors, aphasia and Sexual dysfunction.

What is the status of the use of lithium during pregnancy and lactation?
Lithium is effective for Bipolar disorder during pregnancy but it is not safe. The Baby's heart might not develop properly.

Name three other important indications for lithium.
Manic disorders (Such as manic depressive illness), anxiety, mood stabilizer or even suicidal.

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.

Camcolit is a controlled release lithium carbonate drug and Indocin is an NSAID (indomethacin). NSAIDS has an interaction with lithium. It increases Lithium levels and toxicity could be reached.One of the Lithium toxicity symptoms is weight gain. Water pills = Diuretic. Diuretic drugs are mainly for high blood pressure, there are no significant evidence for weight loss. That being said the diuretic lowerd her blood pressure and it lead to fatique due to low cerebral blood flow hence why she cant focus in class. NSAIDS and Lithium is the same as Diuretics and Lithium- both lead to toxic levels of lithium. Toxic levels of lithium causes tremors (shake of student), the body notice the toxic levels in the body and want to get rid of it (stimulating CTZ- Vomiting centre) which makes her feel nauseous. 

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.

The 3 sub-families/derivatives include 
- Alphatic side-chain - Low potency (little extra pyrimaidal effects, severe sedation, strong anti-cholinergic effects (dry mouth constipation urine retension etc), cardiotoxic (arrythmiasis) postural hypotension) 
- Piperidine side chain (goes together with alphatic side chain effects).
- Piperazine side chain (unlinke the previous 2 side chains it has opposite effects, high potency and more extra pyramidal effects, weakerer anti cholinergic, alpha lytic , sedation and cadriovascular effects.

Which receptors in particular are blocked by the typical antipsychotic drugs?
The Typical Antipsychotic drugs are likely to block the Dopamine Receptors in the mesolymbic pathyway (D2-R) and then the D2 receptors in the Mesolymbic system

How does the mechanism of action of the atypical drugs differ from that of the typical drugs?
The Typical drugs Mainly block the Dopamine reseptors and has an affinity to dopamine receptors only. The Atypical drugs has a high affinity for 5-HT2a and 5-HT2c receptors (antagonist).

Which of the receptors blocked by the older drugs reduce the risk of extrapyramidal side effects?
The Aliphatic and Piperidine side chain drugs such as Chlorpromazine and periciazine.

Which of the older drugs have a high incidence of extrapyramidal side effects? What is the reason for this?
Butyrophenone derivatives- Haloperidal has a high prevalence of Extrapyramidal side effects. 

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

• 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? 

Anti-epileptic drugs that affect metabolism of the Pill

Phenobarbitone, Carbamazepine, Phenytoin, Oxcarbazepine, topiramate. The implication of this is that in case a person is on epileptic drugs it could increase pregnancy risk because it decreases the pill’s effectiveness. The Concentration of the pill needs to be increased to maintain effective levels.

Pills that do not interfere with the metabolism of the pill.

Valproate, Lamotrigine, Gabapentin, Levetiracetam. Normal dose of pill can be used.

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

No. I could be wrong, but didn’t find anything on Google.

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

Babies and children metabolise Epileptic drugs faster than adults. Neonates metabolise slower. It is important to have be careful with some epileptic drugs because they have a narrow therapeutic window and there is more chance for toxicity then if metabolism rates is not taken into consideration. Especially for phenytoin.

• In which cases is plasma blood level monitoring indicated?

Definitely for Phenytoin, because Phenytoin starts off with 1^st order kinetics and then zero order kinetics once the plasma concentration of phenytoin is > 10 ug/ml. The drug can then accumulate and then reach a toxicity level which is very dangerous. Its also important when enzyme inducers are used. Lamotrigine can be used with Carbamazepine. Carbamazepine induce liver enzymes and the enzymes can break lamotrigine down.

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

- The more you drink alcohol the more Mixed function oxidation metabolism activity increases. You gain a tolerance since there is more metabolism of alcohol and you need to drink more to gain an CNS effect.

- Alcohol potentiates the GABA Complex receptor. The more CNS stimulation you have the more the body will compensate for the hyper-activity. Downregulation of the GABA complex receptor will take place and you will need more alcohol for a CNS effect. This being said other symptoms of alcohol will need more alcohol concentration to trigger the symptoms = tolerance.

I think also hypnotic – sedative drugs can play a roll in alcohol tolerance. Benzodiazepines (BDs) also work on the GABA complex receptor. Some people use BDs chronically and can also cause downregulation of receptors. Since Alcohol and BDs work on the same receptor more of both substances is needed for a CNS effect = tolerance.

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

Chronic alcohol consumption lowers the liver function and can lead to hepatitis and liver cirrhosis. The liver has various functions in the body which is also being reduced with chronic alcohol consumption.  Gluconeogenesis processes are being delayed and leads to hypoglycaemia (<3.9 mmol/L).

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

Wernicke-Korsakoff syndrome is a type of brain disorder caused by lack of Vit-B or Thiamine (Healthline, 2018). The main cause of this syndrome is due to alcohol misuse. It is being treated by giving a patient oral thiamine or vitamin B.

• Fully explain the foetal alcohol syndrome.

Foetal alcohol syndrome is when a pregnant mother misuse alcohol. Alcohol has a teratogenic affect. It causes mental retardation where the brain does not grow as it should There is a growth deficiency and causes atrophy. Its usually during alcohol abuse during the first trimester.

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

Chronic alcohol consumption increases metabolic transformation of other drugs.  Where acute alcohol consumption lowers metabolism of drugs.

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

Phenothiazines, Anti-Depressent drugs, sedative hypnotic drugs and aspirin. It also can have an effect on paracetamol where more NAPQI is being produced that could cause liver toxicity.

Reference :

Bertram G. Katzung 2018, B Basic & Clinical Pharmacolog, Lange, McGraw hill, University of California, San Francisco

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

Alcohol is lipophilic and therefor has a fast distribution and absorption rate. It can cross the blood brain barrier and be a CNS suppressant. When a person takes alcohol on an empty stomach peak levels can be reached within 30 minutes. The Peak concentrations in women can be reached more easily since men has more fluids in their body to dilute the alcohol. Alcohol is metabolised by the Liver and can activate 2E1 (Induce NAPQI formation when drinking Paracetamol with alcohol).

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

Ethanol metabolism occurs via 2 enzyme systems.

1)   Alcohol dehydrogenase system – Usually when there is a low amount of alcohol present in the body. Co-Enzyme NAD breaks down alcohol in acetaldehyde and aldehyde dehydrogenase enzyme converts that into acetate. This system can be saturated.

2) Microsomal ethanol oxidation (Mixed function oxidation) – usually when there is a higher amount of alcohol present in the body. (>100 mg/dL). Alcohol are being broken down into acetaldehyde and aldehyde dehydrogenase will convert it into acetate.

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

Disulfiram, Metronidazole, Cephalosporins and Hypoglycaemic drugs.

These drugs inhibit enzyme aldehyde dehydrogenase which converts acetaldehyde into acetate. The accumulation of acetaldehyde cause symptoms such as nausea, headache, dizzy etc. The feeling in general is not pleasant and in general these drugs are used in people who has a high tolerance for alcohol.

Psychic and Psychomotor drugs that contain “Xantic”  bases such as caffeine or theophylline acts as stimulants of the central nervous system. At therapeutic doses, they stimulate mental function, increasing the ability to concentrate and pay attention, while at high doses they cause restlessness and insomnia, and can stimulate the respiratory, vasomotor and vagal bulbar centres, especially when they are depressed. Drugs rich in xanthine bases are : Coffee, Tea, Cola, Guarana, Camphor, Rosemary, Lobella, Strychine. These herbal medicine acts are classified as Hypnotic agents, sedatives, tranquilizers, anti-cholinergic, and analgestic agents.

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

The polarity of the drug affects the absorption of the drug. BD’s are lipophilic and therefor can enter fat cells where it is stored and graduately released into the bloodstream to maintain drug concentration. BD’s are fat soluble and move through the bloodstream quickly and passes through the blood brain barrier for a fast onset of action.

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

Redistribution means that the drug moves from the body to the brain and from the brain to the body, the significance there of that for example Thiopental with this characteristic can be used for retrograde amnesia due to its lipophilicity, also the drug then is stored in fat cells where it acts as a depot to maintain the drug concentration

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

BDs are metabolized via 3 steps :

- Dealkylation – Active metabolites are being formed.

-Oxidation – Cytochrome P450: forms the active metabolites.

- Conjugation – Inactive metabolite are being formed.

The first 2 steps are Phase 1 and the Last step is Phase 2.

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

Diasepam, Chloorasepate, Prasepam, Chlordiapoxide, Cetazolam. These drugs are known as pro drugs and only has a pharmacological effect when they are in their active form. There drugs will therefor (after being metabolised via phase 1) have an hypnotic-sedative or anxiolytic effect in the central nervous system.

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

Oksasepam, Lorasepam, temazepam and lormetazepam. The advantages of this is that the drug is immediately in its active form and will have an effect on the body. These drugs will be ideal in patients who has a low P450 cytochrome count.

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

Enzyme induction can be defined as the increase in the biosynthesis of catalytically active enzyme following exposure of the organism to chemical agents or physiological conditions (Comprehensive Toxicology (Third Edition), 2018). .There drugs will therefor (after being metabolised via phase 1) have an hypnotic-sedative or anxiolytic effect in the central nervous system.

Reference :

Bertram G. Katzung 2018, B Basic & Clinical Pharmacolog, Lange, McGraw hill, University of California, San Francisco.

1)         What does anterograde amnesia mean and which drugs can cause this effect?

Anterograde amnesia means that a person cannot remember events or activities during a drugs duration of action. Certain Benzodiazepines cause this. Zolpidem (Stillnox S5) can cause this. It usually occurs in older people (range 40-60). Alprazolam,Bromazepam,Prazepam,Clonazepam (Benzodiazepines) – Zolpidem, Zopiclone (Benzodiazepines- like hypnotics) - fluoxetine, paroxetine and venlafaxine (Antidepressants) can cause this. (Br J Clin Pharmacol. 2011)

2)         Name the effects of the sedative-hypnotic drugs on the normal sleep pattern and explain their significance to the patient.

Benzodiazepines reduces the time to fall asleep and it increases the total sleep duration by 2 hours (Only in patients who sleep less than 6 hours). The significance is that the patients who struggle to sleep can now fall asleep easier and sleep longer. These drugs are most likely to form a dependency, the patient must use the recommended dose.

3)         Which of the sedative-hypnotic drugs are used as a supplementary therapy in anaesthesia?  Can you explain why?

Lorasepam, Midasolam, Diasepam are the drugs used in anaesthesia. Also Flumazenil.

4)         Which of the sedative-hypnotic drugs are used as anticonvulsants?

Diazepam, Lorasepam (status epilepticus), Nitrasepam. Klonasepam and Klobasam is used profalactic against epilepsy.

5)         What is the mechanism of the muscle-relaxing effects of some of the carbamates and the BDs?

Carbamate act as an acetylecholine(AC)- esterase inhibitor. There would be more AC in the body and would cause muscles to relax since it is responsible for parasympathetic actions. BDs bind to the GABA receptor complex increasing the affinity of the GABA receptor for GABA. This cause a calming sedative hypnotic and anxiolytic effect. The calming effect of this drugs indirectly leads to muscle relaxation.

6)         Discuss the effects of the sedative-hypnotic drugs on the respiratory and cardiovascular systems.

Sedative hypnotic drugs causes a calming effect. This calming effect indirectly causes low heart rate and bronchoconstriction. When sedative-hypnotic drugs are being abused it can cause total respiratory depression which can lead to death.

Reference :

Bertram G. Katzung 2018, B Basic & Clinical Pharmacolog, Lange, McGraw hill, University of California, San Francisco.