• Discuss the possible mechanisms of action of lithium.

It is a small monovalent cation that does not produce any acute effect but on prolonged use, acts as a mood stabilizer. It has no psychotropic effect in normal persons. The drug influences the secondary messengers (cAMP,IP3, and DAG) through the lowering of enzymes which is important for the conversion and re-circulation of IP3 and DAG is important in monoamine and cholinergic neurotransmission..

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

Very narrow therapeutic index,monitor carefuly. Plasma concentration of lithium should be 0.5-0.8 mEq/L for maintenance therapy of bipolar disorder and 0.8-1.2 mEq/L for acute mania. Toxic symptoms are seen if plasma concentration exceeds 1.5mEq/L. Lithium is not metabolised by the liver and is as a result safe in patients with liver problems. The half life for lithium is 20 hours.

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

Single

It is the drug of choice for the prophylaxis of bipolar disorder.

Combined

It can be used in acute mania but benzodiazepines like lorazepam must be added (due to the slow action of Li). In patients not controlled by BZDs, antipsychotics like olanzapine may be added.

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

Thiazides - Increased plasma levels of lithium due to decreased total body water. 

ACE inhibitors, angiotensin II receptor antagonists (sartans), diuretics, and non-steroidal anti-inflammatory drugs (NSAIDs).

Medications for depression (Antidepressant drugs) interacts with LITHIUM

Lithium increases a brain chemical called serotonin. Some medications for depression also increase the brain chemical serotonin. Taking lithium along with these medications for depression might increase serotonin too much and cause serious side effects including heart problems, shivering, and anxiety. Do not take lithium if you are taking medications for depression.
Some of these medications for depression include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), amitriptyline (Elavil), clomipramine (Anafranil), imipramine (Tofranil), and others.

Medications for depression (MAOIs) interacts with LITHIUM

Lithium increases a chemical in the brain. This chemical is called serotonin. Some medications used for depression also increase serotonin. Taking lithium with these medications used for depression might cause there to be too much serotonin. This could cause serious side effects including heart problems, shivering, and anxiety.
Some of these medications used for depression include phenelzine (Nardil), tranylcypromine (Parnate), and others.

• Name the major side effects of lithium.
  • Increased tremors (Most common side effect)
  • Hypothyroidism
  • Increased urine - Nephrogenic diabetes insipidus, can be used for the treatment of SIADH.  Amiloride is DOC for lithium-induced DI.

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

Should be avoided in expectant Mothers as it causes Ebstein’s anomaly. 

• Name three other important indications for lithium.

Leucocytes are Useful in the treatment of cancer chemotherapy-induced leucopenia.

• 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:

My recommendation is to immediately  stop the NSAIM and diuretic treatment to prevent further side-effects. Decrease the current dose to only once per day, or if it is possible for the patient, change treatment to Valproate or Carbamasepine seeing as both are mood stabilisers 

• MAO inhibitors: phenelzine, selegiline, tranylcypromine
• Tricyclic antidepressants: amitriptyline, clomipramine, imipramine
• Heterocyclic antidepressants: amoxapine, bupropion, mirtazapine
• 5-HT-NE reuptake inhibitors: duloxetine, venlafaxine
• 5-HT antagonists: nefazodone, trazodone
• Selective serotonin reuptake inhibitors: escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline

• What do the existing drugs all have in common regarding their mechanisms of action?

Through several mechanisms, most antidepressants cause potentiation of the neurotransmitter actions of NE, 5-HT, or both.

• How long does it take for the antidepressive effects of these drugs to appear? What is the reason for this?
  1. 1. Postmortem studies of patients do not reveal decreases in the brain levels of NE or 5-HT;
     2. Although antidepressant drugs may cause changes in brain amine activity within hours, clinical response requires weeks;
     3. Most antidepressants ultimately cause downregulation of amine receptors;
     4. Bupropion has minimal effects on brain NE or 5-HT;
     5. Brain-derived neurotrophic factor (BDNF) is depressed in the brains of depressed patients.

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

Most of the TCAs inhibit the reuptake of norepinephrine, though not dopamine, and as a result, they show some efficacy in remedying the disorder.

• • Side Effects

The adverse effects of TCAs, which result largely from their anticholinergic and antihistaminic properties, include the following: Sedation, confusion, dry mouth, orthostasis,  constipation, urinary retention, sexual dysfunction and weight gain.

• • safety?

Some tricyclic antidepressants are more likely to cause side effects that affect safety, such as Disorientation or confusion, particularly in older people when the dosage is too high. Increased or irregular heart rate.  More frequent seizures in people who have seizures.

• • What is the action of mirtazapine?

Mirtazapine is part of the tetracyclic antidepressants (TeCA) group that works by exerting antagonist effects on the central presynaptic alpha-2-adrenergic receptors, which causes an increased release of serotonin and norepinephrine.

• • What is the action of venlafaxine?

Venlafaxine works by increasing serotonin levels, norepinephrine, and dopamine in the brain by blocking transport proteins and stopping their reuptake at the presynaptic terminal.

• • What is the action of agomelatine?

Agomelatine has been shown to block 5-HT2C receptors within corticolimbic structures in the hippocampus. Hyperactivity of the 5-HT2C receptors may contribute to the symptoms of MDD and agomelatine induced 5-HT2C antagonism has been shown to increase the release of dopamine and norepinephrine in the frontal cortex.

• 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.

-Alphatic side-chain: Has Low potency (a few pyrimidial effects, severe sedation, strong anti-cholinergic effects (dry mouth constipation urine retension etc), cardiotoxic (causes arrythmias) and postural hypotension)
- Piperidine side chain: ( together with alphatic side chain effects).
- Piperazine side chain: (opposite effect of the previous 2 chains, high potency and more extra pyramidal effects, weaker anti-cholinergic, alpha lytic , sedation and cardio vascular effects.)

• Which receptors, in particular, are blocked by the typical antipsychotic drugs?
  • They block the Dopamine Receptors in the mesolymbic-pathway (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?

Typical antipsychotic drugs act on the dopaminergic system, blocking the dopamine type 2 (D2) receptors. 

VS.

Atypical antipsychotics have lower affinity and occupancy for the dopaminergic receptors and a high degree of occupancy of the serotoninergic receptors 5-HT2A.

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

Extrapyramidal symptoms (due to D2 blockade in the limbic system) are closely related to the antipsychotic potency of typical antipsychotic drugs. 

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

High potency drugs are more likely to cause extrapyramidal symptoms (maximum with haloperidol) whereas it is least common with thioridazine.

• Because of which receptor(s) blockade do the aliphatic groups of drugs have a high incidence of autonomic side effects?
  • These drugs act by blocking D2 receptors and differ significantly in potency.
  • High potency drugs have low anticholinergic and autonomic side effects as compared to low potency drugs.
    • Anticholinergic (maximum with thioridazine).

• Which two main groups of drugs are important in the treatment of Parkinsonism?
• Drugs that increase dopamine energy activity
• Drugs that work by that lowering cholinergic activity
• In what way does amantadine act as an antiparkinsonian drug?
• Amantadine increases the release of dopamine as well as increasing its synthesis.
• It also works by blocking the reuptake of dopamine
• Amantadine is an NMDA antagonists. 
• It is also adenosine  antagonist = adenosine inhibits dopamine and thus antagonize to increase dopamine activity. 
• It improves rigidity, tremors and bradykinesia.

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

?

• Which of the dopamine agonists are ergot derivatives and which are not?
  • The ergot derivatives are:
    • Pramipexole
    • Pergolide
    • Bromocriptine
  • Non-ergot derivatives:
    • Ropinirole
    • Rotigotine

• List the specific dopamine receptors that are stimulated by each agonist.
  • DA3 = Pramipexole
  • DA2 = Ropinirole, Bromocriptine
  • DA1,DA2 and DA3 = Rotigotine
  • DA1 and DA2 = Pergolide

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

MAO-B inhibitors (Rasagiline and Selegiline) are classified as neuro-protective drugs. This means that the DA concentration levels in the central nervous system are increased.

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

The importance of MAO-B inhibitors is that they prolong the duration of the effects of Levodopa. 

• How do the COMT-inhibitors act in Parkinsonism?

Catechol-O-methyltransferase (COMT) Inhibitors

1. Mechanism of action:

Entacapone and tolcapone are inhibitors of COMT, the enzyme in both the CNS and peripheral

tissues that convert levodopa to 3OMD.

Increased plasma levels of 3OMD are associated with poor response to levodopa partly because the compound competes with levodopa for active transport into the CNS.

Entacapone acts only in the periphery.

• How does istradephyline act?

This drug inhibits DA2 functioning by antagonising adenosine activity, preventing the inhibition of dopamine functions. It is an additional therapy to L-dopa or carbidopa therapy that experiences on-off episodes.

• Discuss the MOA of safinamide

Safinamide increases DA activity, this results in the potent reversible inhibition of MAO-B and results in the inhibition of DA.

• How does the sensitivity for blockade by a LA compare regarding the following types of fibres:
  1. Myelinated fibres with Unmyelinated fibres; and

Smaller fibres are blocked more easily than larger fibres

Myelinated fibres are blocked more easily than unmyelinated fibres.

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

Pressure/ Touch- Has heavy Myelination

Pain- Dorsal root with  No Myelination

• • Activated pain fibres fire rapidly; thus, pain sensation appears to be selectively blocked by local anaesthetics. Fibres located in the periphery of a thick nerve bundle are blocked sooner than those in the core because they are exposed earlier to higher concentrations of the anaesthetic.
  • Pain sensation selectively is blocked by local anaesthetics.

• Make a list of the effects of LA on other tissues.
  • Skeletal muscles: weak blocking action
  • Heart: class 1 anti-arrhythmic drug

• Peripheral Nervous System And Central Nervous System

As local anaesthetics are absorbed from the injection site, their concentration in the bloodstream rises and the peripheral nervous system and central nervous system (CNS) are depressed in a dose-dependent manner.

• Cardiovascular System

Low serum concentrations are used clinically for suppressing cardiac arrhythmias and status seizures, but ironically, higher concentrations induce seizure activity. Convulsive seizures are the initial life-threatening consequence of local anaesthetic overdose. Presumably, this is due to selective depression of central inhibitory tracts, which allow excitatory tracts to run amuck.

• Respiratory System

As serum concentrations continue to rise further, all pathways are inhibited, resulting in coma, respiratory arrest, and eventually cardiovascular collapse.

• What is the basis for the selection of a LA?

The basis of selection of the local anaesthetic is for:

• • small surgical procedures,
  • spinal anaesthesia or
  • post-operative analgesia.

• Why are LA solutions sometimes saturated with CO₂?

To potentiate the effects of local anaesthetics. 

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

• Postoperative hepatitis has occurred (rarely) after halothane anaesthesia in patients experiencing hypovolemic shock or other severe stress.
• The mechanism of hepatotoxicity is unclear but may involve the formation of reactive metabolites that cause direct toxicity or initiate immune-mediated responses.
• Fluoride released by the metabolism of methoxyflurane (and possibly enflurane and sevoflurane) may cause renal insufficiency after prolonged anaesthesia.
• Prolonged exposure to nitrous oxide decreases methionine synthase activity and may lead to megaloblastic anaemia.  Susceptible patients may develop malignant hyperthermia when anaesthetics are used together with neuromuscular blockers (especially succinylcholine).
• This rare condition is thought in some cases to be due to mutations in the gene loci corresponding to the ryanodine receptor (RyR1).
• Other chromosomal loci for malignant hyperthermia include mutant alleles of the gene-encoding
• skeletal muscle L-type calcium channels.
• The uncontrolled release of calcium by the sarcoplasmic reticulum of skeletal muscle
• leads to muscle spasm, hyperthermia, and autonomic lability.
• Dantrolene is indicated for the treatment of this life-threatening condition, with supportive management.

Give classification of the LA based on the chemical characteristics. Also indicate the relative duration of action of every drug.

1. Esters:

• Long-acting:
  • Tetracaine
• Medium acting:
  • Cocaine
• Short-acting:
  • Procaine
• Surface active:
  • Benzocaine,
  • Cocaine,
  • Oxybuprocaine

2. Amides:

• Long-acting:
  • Bupivacaine,
  • Levobupivacaine,
  • Ropivacaine
• Medium acting:
  • Lidocaine,
  • Prilocaine,
  • Mepivacaine

• Postoperative hepatitis has occurred (rarely) after halothane anaesthesia in patients experiencing hypovolemic shock or other severe stress.
• The mechanism of hepatotoxicity is unclear but may involve the formation of reactive metabolites that cause direct toxicity or initiate immune-mediated responses.
• Fluoride released by the metabolism of methoxyflurane (and possibly enflurane and sevoflurane) may cause renal insufficiency after prolonged anaesthesia.
• Prolonged exposure to nitrous oxide decreases methionine synthase activity and may lead to megaloblastic anaemia.  Susceptible patients may develop malignant hyperthermia when anaesthetics are used together with neuromuscular blockers (especially succinylcholine).
• This rare condition is thought in some cases to be due to mutations in the gene loci corresponding to the ryanodine receptor (RyR1).
• Other chromosomal loci for malignant hyperthermia include mutant alleles of the gene-encoding
• skeletal muscle L-type calcium channels.
• The uncontrolled release of calcium by the sarcoplasmic reticulum of skeletal muscle
• leads to muscle spasm, hyperthermia, and autonomic lability.
• Dantrolene is indicated for the treatment of this life-threatening condition, with supportive management.

Give classification of the LA based on the chemical characteristics. Also indicate the relative duration of action of every drug.

1. Esters:

• Long-acting:
  • Tetracaine
• Medium acting:
  • Cocaine
• Short-acting:
  • Procaine
• Surface active:
  • Benzocaine,
  • Cocaine,
  • Oxybuprocaine

2. Amides:

• Long-acting:
  • Bupivacaine,
  • Levobupivacaine,
  • Ropivacaine
• Medium acting:
  • Lidocaine,
  • Prilocaine,
  • Mepivacaine

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. These drugs decrease the effectiveness of the pill, and could as a result lead to an unwanted pregnancy

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

Valproate, Lamotrigine, Gabapentin, Levetiracetam. Oral contraception does however decrease the plasma levels of Valproate and Lamotrigine 

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

No

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. 

Elderly will need a lower dose because liver and kidney doesn't function optimally.

In which cases is plasma blood level monitoring indicated?

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 MEOS activity increases. You gain a tolerance since there is more metabolism of alcohol and you need to drink more to gain an CNS effect. Another way how tolerance is achieved is by receptor subsensitivity, which causes the receptors to be less sensitive for alcohol molecules.

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

Chronic alcohol consumption lowers the liver function and can cause: hepatitis and liver cirrhosis. Alcohol consumption can also cause the liver to be unable to perform its many important functions as effectively.  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. This is due to alcohol misuse. It is commonly 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.

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.

What type of kinetics applies for alcohol in the body? 

Because alcohol is a lipophylic molecule, it has a very fast distribution and absorbtion time. Peak levels in the body are achieved after just 30 minutes. The peak concentrations are usually higher in women, seeing as how men have more fluids to dilute the alcohol in the body. 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. The coenzyme NAD is limited, and thus 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.

Aldehyde dehydrogenase is inhibited by these drugs.  The accumulation of acetaldehyde cause symptoms such as nausea, headache and dizziness.