Answer the following for a Blog Summary:

• Using your textbooks, draw up a classification of the drugs that are used as antidepressants.

MAOIs: Mono-amine inhibitors ex. Phenelzine, Selegiline, Tranylcypromine.

TCAs: Tricyclic antidepressants ex. Amitriptyline, Clomipramine, Imipramine.

TCAs are further subdivided into: 

• Tertiary amine: Amitriptyline, Imipramine, Trimipramine, Chlorimipramine, Dothiepine etc.
• Secondary amine: Nortriptyline ,Desimipramine etc.

SNRI: Serotonin, Norepinephrine re-uptake inhibitors ex. Duloxetine, Venlafaxine

SSRIs: Serotonin re-uptake inhibitors ex. Escitalopram, Citalopram, Fluoxetine, Paroxetine, Sertraline

Circadian rhythm regulators: Agomelatine

Serotonin receptor modulators: Trazodone, Vortioxetine

Tetracyclic & Unicyclic Ads: Manserin, Mirtazapine, Bupropion.

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

They all promote mono-amine activity by increasing noradrenaline and serotonin concentrations at the central synapse through either re-uptake inhibition, degradation inhibition or blockade of pre-synaptic alpha2 auto receptors.

• How long does it take for the antidepressive effects of these drugs to appear? What is the reason for this?

Onset of action is very slow (14-21 days or more). The actual anti depressive effects can only be seen after about 6 - 8 weeks since the mono amine regulation in the brain is altered either through re-uptake inhibition, degradation inhibition or the blockade of alpha 2 auto receptors.

• How do the TADs and the selective serotonin reuptake inhibitors (SSRI’s) differ in respect of: efficacy, side effects, safety?

Effectivity:

All AD need approximately 6 – 8 weeks with sufficient dosages before AD effects can be observed.

TAD requires titrations to the minimum effective dose whils SSRIs can usually be used immediately.

TCA’s

Side effects of TCAs:

• Sedation
• Sympathomimetic: tremors, insomnia
• Anticholinergic: disturbed vision, dry mouth constipation, urinary retention, confusion 
• CVS: orthostatic hypotension, dysrhythmias 
• Psychosis, precipitates mania 
• Convulsions
• Metabolic /endocrine: weight gain, sexual disturbances 

TAD safety: An overdose in TCAs is very dangerous. 10x daily dose can be fatal. Common symptoms of overdose include; Agitation, delirium, neuromuscular irritability, convulsions, coma, respiratory suppression, circulatory collapse, hyperpyrexia, dysrhythmia. In severe cases it can lead to Coma, Convulsions, Cardiotoxicity. TADs should also not be used with MAOIs as it can cause serotonin syndrome.

SSRI’s:

Side effects of SSRIs:

• Insomnia, tremors, GIT disturbances, headache, ↓ libido, sexual dysfunction, anxiety (acute), EPS (needles ‘n pins, restless legs), withdrawal syndrome. 
• ↓ appetite, overweight patients = lose weight. 
• Non-sedating
• Acute ↑ 5-HT synaptic activity = acute anxiety, later 5-HT reduces again. 

Safety: SSRIs unlike TCA’s do not bind aggressively to histamine, muscarinic or other receptor. It allosterically inhibits the transporter by binding to the SERT receptor at a site other than the serotonin binding site. These drugs must be discontinued for at least 4 weeks or longer before an MAOI can be administered to remove the risk of serotonin syndrome. Fluoxetine is the only AD approved for use in children. It also has the longest half-life of all the SSRIs. A combination of SSRIs with carbamazepine can also lead to toxicities.

SSRIs are the preferred Ads along with newer drugs because they have a better side-effect profile, safer in acute overdose and SSRI’s can suppress appetite, overweight patients may lose weight. 

• What is the action of mirtazapine?

Is a NaSSA: NA & specific serotonin anti-depressant
Blockade of α2, 5-HT2A & 5-HT3. Also block H1, α1 and indirect stimulation of 5-HT1A. 

Blockade of the inhibitory α2 R’s advance both NA (auto receptors) & 5-HT release (on the heteroreceptors). 

Indirect stimulation of 5-HT1A: anxiolytic 

Blockade 5-HT3: anxiolytic, ̄nausea 

Blockade 5-HT2: anti-depressive effects 

• What is the action of venlafaxine?

Blocks both 5-HT - and NA re-uptake, more potent for 5- HT than for NA. Moderately selective blockade of SERT and NET. Venlafaxine is a weak inhibitor of NET.

• What is the action of agomelatine?

Antagonist: 5-HT2c , Agonist: Melatonergic R’s – MT1 & MT2. The blockade of 5-HT2c receptors causes a disinhibition of DA & NE release in the frontal cortex =éDA and NA release. This promotes the anti-depressive effect. Melatonin is a by-product of 5-HT. It is responsible for the regulation of biological clock mechanism. Melatonin repairs the malfunctioning rhythms caused due to depression. Depression influences melatonin release.

Name of Blog: Blog #13

Answer the following for a Blog Summary:

Q. Discuss the possible mechanisms of action of lithium.

MOA is mediated by Li⁺. The drug inhibits several enzymes involved in recycling of neuronal membrane phospholipids. This action result in the depletion of the 2^nd messenger source, phosphatidylinositol bisphosphate (PIP₂), which in turn decreases the generation of inositol trisphosphate (IP₃) and diglycerol (DAG). These 2^nd messengers are IMP in amine neurotransmission including those mediated by central adrenoreceptors and muscarinic receptors. It also inhibits glycogen synthase kinase-3 (GSK-3).GSK-3 is a component of diverse intracellular signalling pathways. 

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

Small therapeutic index of 0.5 – 1.5mM; >2mM = toxic.

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

Monotherapy for acute major depression.

Bipolar disorder it is used, but Benzodiazepines or antipsychotic agents are often required at the initiation of treatment because lithium has a slow onset of action.

Schizoaffective disorders used in combination with other APDs.

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

1. When used in combination with diuretics it decreases Lithium clearance = lithium toxicity due to increased Lithium plasma levels Ex. Chlorothiazide.

2. When used in combination with other APDs it worsens EPS.

3. When used in combination with NSAIDs (Diclofenac) it decreases Lithium clearance which leads to lithium toxicity due to increased Lithium plasma levels.

4. When used in combination with Phenytoin or carbamazepine it causes neurotoxicity.

Q. Name the major side effects of lithium.

Leucocytosis, Nephrogenic Diabetes Insipidus, Thyroid enlargement, sexual dysfunction, weight gain, oedema, acne & alopecia, tremors, dysarthria, aphasia, ataxia, polyuria, polydipsia & nocturia, muscle weakness and fatigue.

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

Category D drug. There is evidence that show human foetal risk. The use of lithium during lactation is not encouraged however there have been many woman who have breastfed their babies while on lithium who have not experienced any negative side effects. 

Q. Name three other important indications for lithium.

- Bipolar disorder (manic phase), Schizoaffective disorder, acute Major depression

Q. 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 is showing clear side effects of Lithium with the weight gain, thirst, polyuria, fatigue, tremors, nausea and water retention (oedema). I would recommend her dosage be decreased to relive of the side effects or give a propranolol for the tremors and recommend regular physical activity for the weight gain it usually also helps with better motor functioning and overall wellbeing (thus fatigue might be improved). 

#Blog 11:

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.

Phenothiazines are multi-potent competitive antagonists.

There are 3 sub-families based primarily on the side chain:

1. Aliphatic side-chain: Chlorpromazine (Largactil )
2. Piperidine side-chain: Periciazine (Neulactil ) & Thiordazine
3. Piperazine side-chain: Fluphenazine (Modecate ), Perphenazine, Trifluoperazine, Prochlorperazine.

Aliphatic and piperidine compounds:

• Low potency*, little EPS
• Severe sedation
• Strong anti-cholinergic effects,
• Strong α-lytic effects (postural hypotension), 
• Cardiotoxic

*These drugs do not bind very strongly to D₂ receptors (has a low affinity for D₂) thus need to administer large amounts to elicit strong therapeutic effects. 

Piperazine derivatives:

• High potency, more EPS,
• Weaker anti-cholinergic side effects  
• Weaker α-lytic effects,
• Less sedation
• Less cardiovascular (CVS) side effects

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

Block mesolimbic Dopamine (more specifically D₂) receptors.

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

Atypical drugs:

• These drugs block 5-HT_2A receptors more than D₂ (has a higher affinity for 5-HT_2A receptors) . 
• MOA: D₂ blockade, strong M₁, H₁ and serotonin. Receptors.

Typical drugs:

These drugs block mesolimbic DA 2 receptors.

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

Benzamides block both D₂ and D₃ receptors. The risk of extra pyramidal side effects is reduced due to the limbic localisation of the D₃ receptors.

Then also Aliphatic (Chlorpromazine) compounds because they are known to have a low potency and few extra pyramidal side effects.

Block of Muscarinic R's.

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

Extra-pyramidal symptoms are also known as ‘drug-induced movement disorders’ and typical side effects include involuntary or uncontrolled movements, muscle tremors and contractions. The extrapyramidal system in the brain includes the basal ganglia – the nigrostriatal pathway. The nigrostriatal pathway consists of neurons that project from the substantia nigra to the striatum; it is involved in coordination of voluntary movement . Blockade of the D₂ receptors in t the nigrostriatal pathway is responsible for EPS. 

Piperazine derivatives has a high potency, therefore more extrapyramidal side effects. It very strongly blocks the D₂receptors causing extra-pyramidal side effects due to the dopamine content in the mesolimbic area being cut-off or significantly decreased.

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

Autonomic effects are those drug blocking alpha receptors, cholinergic receptors in the parasympathetic systems & sympathetic nervous system. Blockade of Muscarinic receptors.

Name of Blog: Blog #10

Answer the following for a Blog Summary:

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

Drugs that ↑ DA activity/ restore dopaminergic activity with levodopa and dopamine agonists alleviate many of the motor features of the disorder.  Drugs that ↓ Cholinergic activity (to restore the normal balance of cholinergic and dopaminergic influences on the basal ganglia) with antimuscarinic drugs. By decreasing ACh activity = match the low DA activity = new balance achieved.

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

Amantadine has 3 three way MOA. It is a Metaffinoid potentiator of DA (↑ in DA activity - ↑ DA release ,↑ DA synthesis , blocks reuptake of DA), a NMDA antagonist (antidyskinetic effects) Adenosine A2a Antagonist (Adenosine Inhibits D2 receptors.\By blocking the adenosine receptor, improve D2 function & antiviral) This MOA enable amantadine to improve rigidity, tremors and bradykinesia which is often associated with parkinsonism. It is however only effective for a few weeks before disappearing.

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

MAO inhibitors – By inhibting MAO (the enzyme responsible for metabolising DA), the DA concentrations will increase.

COMT inhibitors - COMT metabolises L-dopa to 3OMD. Increased plasma levels of 3OMD leads to a weak therapeutic response with L-dopa (3OMD competes with L-dopa for active transport). Thus, a COMT-inhibitor extend the duration of action of L-dopa by: ↓ its peripheral metabolism , ↑ its bioavailability.

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

Ergot derivatives: Bromocriptine, Pramipexole

Non ergot derivatives: Ropinirole, Apomorphine

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

Pramipexole: Direct agonist at D3 receptors. 

Ropinirole: D2 agonist

Bromocriptine: D2 agonist

Pergolide: Directly stimulates both D1 and D2 receptors 

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

The MAO inhibitors are said to have neuroprotective effects such as Rasagiline. By preventing DA metabolism it ensures the DA neurons can be continuously be stimulated thus preventing the degeneration of DA neurons due to continuous stimulation.

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

By inhibiting MAO (the enzyme responsible for metabolising DA), the DA concentrations will increase. It ensures the DA neurons can be continuously be stimulated thus preventing the degeneration of DA neurons due to continuous stimulation.

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

COMT inhibitors - COMT metabolises L-dopa to 3OMD. Increased plasma levels of 3OMD leads to a weak therapeutic response with L-dopa (3OMD competes with L-dopa for active transport). Thus, a COMT-inhibitor extend the duration of action of L-dopa by: ↓ its peripheral metabolism , ↑ its bioavailability.

9. How does istradephyline act?

AdenosineA2A antagonist. Adenosine Inhibits D2 receptors.By blocking the adenosine receptor, improve D2 function & it is also an antiviral

10. Discuss the MOA of safinamide

MOA: Novel dual MOA. ↑ DA activity. Potent reversible inhibition of MAO-B .Inhibition of DA uptake ↓ Glutamate release 

Name of Blog: Blog #9

Answer the following for a Blog Summary:

• How does the sensitivity for blockade by a LA compare regarding the following types of fibres:

(a) myelinated fibres with unmyelinated fibres; and 

(b) pressure/touch nerves with the dorsal nerves that transmit pain impulses?

a.) Smaller myelinated fibres are easier blocked than larger and unmyelinated fibres.

b.) Fibres in the middle of a thick nerve bundle is blocked slower than those at the outside of the bundle.

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

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

Depending on the desired effect and the type of procedure/ clinical application.

• Why are LA solutions sometimes saturated with CO2?

All inhaled anesthetics can produce some carbon monoxide (CO) from their interaction with strong bases in dry carbon dioxide absorbers. CO binds to hemoglobin with high affinity, reducing oxygen delivery to tissues. Desflurane produces the most CO, and intraoperative formation of CO has been reported. CO production can be avoided simply by using fresh carbon dioxide absorbent and by preventing its complete desiccation.

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

Cocaine is used in procedures requiring high surface activity & vasoconstriction, eg. ear,nose and eye surgery.

Answer the following for a Blog Summary:

• Compile a table, listing the major effects on every system (cardiovascular, CNS, renal, hepatic and uterus) for all the inhalation anaesthetics. This table is important when it comes to the selection of drugs in certain individuals.

• Name the major acute toxic effects of the inhalation drugs.

1. Nephrotoxicity

2. Hematoxicity

3. Malignant hypernatremia

4. Hepatotoxicity

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

Tolerance is a complex process involving both changes in the CNS & pharmacokinetic processes. Tolerance may result from ethanol-induced up-regulation of a pathway in response to continuous presence of ethanol. Up-regulation of the NMDA subtype of Glutamate receptors & voltage-sensitive Ca2+ channels (cause of the seizures that accompany alcohol withdrawal symptoms). Like other drugs of abuse, ethanol modulates neural activity in the brains’ mesolimbic dopaminergic pathway (dopamine reward circuit) leading to an increase in DA release in the nucleus accumbens. This produces that feeling of euphoria often associated with alcohol consumption. Chronic alcohol drinkers, when forced to reduce/ stop experience withdrawal symptoms which indicates physical dependence.

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

LIVER: Progressive ↓ liver function, hepatitis & cirrhosis. Liver disease is most common medical complication of alcohol abuse. Alcoholic fatty liver progress into alcoholic hepatitis & liver cirrhosis. & liver failure. Chronic alcohol abuse is the leading cause of liver cirrhosis & need for liver transplantation.

Pathogenesis of alcoholic liver disease is multifactorial process involving:

• • Metabolic repercussions of ethanol oxidation in the liver
  • Dysregulation of FA oxidation & synthesis (fat accumulation)
  • Gluconeogenesis ↓, hypoglycemia

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

Relatively uncommon syndrome characterized by paralysis external eye muscles, ataxia, paralysis of facial muscles, confused state develops to coma/ death. It is associated with chronic alcoholism and thiamine deficiency, therefore receive parenteral thiamine therapy. Ataxia & confusion improve with thiamine administration. Thiamine therapy also prevent permanent brain damage.

Q. Fully explain the foetal alcohol syndrome.

Chronic maternal alcohol abuse during the 1^st trimester of pregnancy is associated with teratogenic effects. Ethanol rapidly crosses the placenta and reaches concentrations in the fetus that are similar to those in maternal blood. The fetal liver has little or no alcohol dehydrogenase activity (foetus is still developing), so the fetus must rely on maternal and placental enzymes for elimination of alcohol. Alcohol is the leading cause of mental retardation & congenital malformation. This is a syndrome of craniofacial dysmorphia, heart defects, and mental retardation caused by teratogenic effects of ethanol or alcohol consumption during pregnancy.

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

• • (1) intrauterine growth retardation, 
  • (2) microcephaly, 
  • (3) poor coordination, 
  • (4) underdevelopment of midfacial region (appearing as a flattened face), and 
  • (5) minor joint anomalies. 

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

Chronic alcohol usage induce cytochrome P450 enzymes leading to increased ↑ metabolism of other drugs. The most common pharmacokinetic alcohol-drug interactions stem from alcohol-induced increases of drug-metabolizing enzymes. Thus, prolonged intake of alcohol without damage to the liver can ↑ enhance the metabolic biotransformation of other drugs.  

Acute alcohol usage: ↓ metabolism of drugs. Acute alcohol use can inhibit metabolism of other drugs because of decreased enzyme activity or decreased liver blood flow. Phenothiazines, tricyclic antidepressants, and sedative- hypnotic drugs are the most important drugs that interact with alcohol by this pharmacokinetic mechanism. 

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

CNS depression is potentiated. The additive CNS depression that occurs when alcohol is combined with other CNS depressants, particularly sedative-hypnotics. Alcohol also potentiates the pharmacologic effects of many non-sedative drugs, including vasodilators and oral hypoglycaemic agents. And last but not the least, ↑ anti- platelet aggregation effects of aspirin.

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

Ethanol or alcohol metabolism follow zero-order kinetics. This means, that a constant amount alcohol is metabolised per unit of time. By increasing the amount of alcohol, the metabolism rate will still remain constant. This means that an increase in alcohol consumption would not mean an increase in the rate of its metabolism. The body will continue to metabolize the alcohol at a constant rate. The accumulation of acetaldehyde in the body is what leads to individuals becoming intoxicated or drunk.

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

Alcohol is metabolised by 2 major systems in the liver: Alcohol dehydrogenase (ADH) system and the Microsomal Ethanol-Oxidizing system (MEOS).

Alcohol dehydrogenase system is responsible for metabolising low to moderate levels of alcohol. The primary pathway for alcohol metabolism involves alcohol dehydrogenase, about 80- 90%. These enzymes are located mainly in the liver (small amounts found in brain & stomach). These alcohol dehydrogenases are cytosolic enzymes in the liver that catalyze the conversion of ethanol (alcohol) to acetaldehyde, NADH and H⁺ ion. 

MEOS is induced during chronic alcohol consumption (high concentrations of alcohol). This enzyme system, also known as the mixed function oxidase system, uses NADPH as a cofactor in metabolism of ethanol. In this enzyme system alcohol is converted to acetaldehyde.

Acetaldehyde dehydrogenase converts the acetaldehyde into acetate, a non-toxic metabolite.

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

Drugs that affect the metabolism of alcohol include: disulfiram, metronidazole, cephalosporins and hypoglycaemics. These drugs inhibit the enzyme aldehyde dehydrogenase, thus acetaldehyde cannot be converted into the non-toxic metabolite acetate. 

This causes acetaldehyde to accumulate causing an unpleasant reaction of:

• • Facial flushing
  • Nausea
  • Vomiting
  • Dizziness
  • Headaches

​​​​​​​Ex. Disulfiram is used to deter drinking by patients with alcohol dependence.

The above table is only some of the natural remedies/ drugs.

The sources used include:

Katzung Basic & Clinical Pharmacology 14th Edition Betrag G. Katzung

Herbal Medicine for Anxiety, Depression and Insomnia. (2015, July 1). PubMed Central (PMC). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790408/

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

Lipophilicity is an important factor which affect the absorption and distribution of sedative-hypnotic drugs.

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 action/ effects of Triazolam (a benzodiazepine) , thiopental (a barbiturate) as these drugs are rapidly absorbed into surrounding tissues.

Usually highly lipid soluble drugs are redistributed from the brain to other tissues including the heart, kidneys, muscles and fatty tissues.

 All sedative-hypnotics cross the placental barrier during pregnancy due to their lipophilic nature. If given during the predelivery period, it could lead to depression of neonatal vital functions. It can also enter into the breast milk and so forth cause depressant effects in the nursing infant.

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

Due to high lipophilicity of the drugs, they initially distribute to highly vascularized tissues/ areas such as the brain, heart and kidneys. Thereafter the quickly distribute to surrounding tissues (muscle and fats). Redistribution from brain to other tissues. The drugs often move to fatty tissues where it causes the depot effect resulting in the slow and controlled release of the drug.  Thiopentone, a barbiturate is the most lipid soluble drug and used as induction anesthetic.

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

Benzodiazepine undergo 3 step biotransformation by hepatic microsomal enzymes.

The 3 steps are as follows:

1. Dealkylation 
   1. Active metabolite, Desmethyldiazepam is formed (elimination half-life = 40hours)
2. Microsomal oxidation
   1. Phase 1 reactions; 
   2. Catalysed by liver cytochrome P450 enzymes; especially CYP3A4.
   3. Active metabolite Desmethyldiazepam undergoes oxidation and a new active metabolite, Oxazepam is  formed
3. Conjugation 
   1. Phase II reactions; 
   2. Conjugation of oxidised metabolites with glucuronic acid to form inactive metabolite
   3. Oxazepam undergoes glucuronide conjugation to become an inactive metabolite known as glucuronides.
   4. The glucuronides are water-soluble and is excreted in urine.

The drugs Diazepam, Clorazepate, Prazepam, Chlordiazepoxide, Ketazolam all undergo all 3 of the metabolic steps: Dealkylation, Oxidation and Conjugation.

Exceptions on the above metabolic biotransformation of benzodiazepines include the drugs Oxazepam, Lorazepam, Temazepam & Lormetazepam. They do not undergo dealkylation or oxidation. It immediately undergoes a conjugation reaction where it forms inactive metabolites, Glucuronide, that are water-soluble  and thus excreted into urine for elimination. NO ACTIVE METABOLITES ARE FORMED

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

The drugs Diazepam, Clorazepate, Prazepam, Chlordiazepoxide, Ketazolam all undergo all 3 of the metabolic steps: Dealkylation, Oxidation and Conjugation.  After dealkylation of the above-mentioned drugs it forms the active metabolite Desmethyldiazepam. This drug has a very long elimination half-life of 40hours. This is then further oxidised to Oxazepam (active metabolite) which is then conjugated to become water-soluble for excretion in urine.

The formation of the active metabolites contribute to the extended duration of action/ prolonged CNS suppression of the drugs.

The formation of active metabolites are of great importance in the following instances:

1. Elderly people ,neonates and patients suffering from liver cirrhosis tend to have reduced enzymatic effectivity or activity. The drugs mentioned above all require biotransformation hepatic microsomal enzymes. If these enzymes are not functioning at full capacity, it could lead to the accumulation of the sedative-hypnotic drugs as it is not able to be metabolised at full potential. THis could be very dangerous as it could lead to an extended duration of action of these drugs and cause several side effects.
2. People using cytochrome P450 enzyme inhibitors such as Erythromycin, Ketoconazole or Cimetidine j will inhibit the enzymes from metabolising the above mentioned drugs. Thus, the drug concentrations will elevate in the body due to decreased metabolism of the drug. Once again, accumulation of the drugs occur which could be very dangerous.

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

The drugs Oxazepam, Lorazepam, Temazepam and Lormetazepam do not undergo dealkylation or oxidation. It immediately undergoes a conjugation reaction where it forms inactive metabolites, Glucuronide, that is water-soluble  and thus excreted into urine for elimination. No active metabolites are formed. Because these above mentioned drugs are not metabolised by the CYP450 enzymes, it is the drugs of choice for people who have reduced CYP450 activity.

People with reduced CYP450 activity: Elderly, neonates, liver cirrhosis patients and patients using CYP450 inhibitors.

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

Enzyme induction occurs when chemicals/ drugs cause an increase in synthesis and activity of enzymes, thereby increasing the metabolism of drugs that are catalysed by those enzymes. If drug metabolism is increased, it will decrease the overall drug concentrations in the body which could dampen the therapeutic effects of the specific drug being metabolised.