Prepare a short “lecture” of not longer than 5 minutes (200 words), explaining to a patient what pain is, its possible causes, why different people experience pain differently and what the generally important principles of pain management and referral involve.

Pain is defined as an uncomfortable subjective sensory and emotional experience associated with actual or potential tissue damage.

 Pain is then further divided into acute and chronic pain. Acute pain is short lasting pain, like when you suffer an injury by falling off your bike and scraping your knee. When the tissue damage has healed the pain has also subsided. Chronic pain however is long lasting pain and is most often due to nerve damage so even when the injury has long healed you still suffer from pain that does not want to go away. Subjectively the best way to then treat pain would be to ask the intensity of pain by rating it on a scale from 0 to 10 where 0 is no pain and 10 is the most excruciating pain you have experienced furthermore, pain can also have a character which is then described as a sharp, dull, burning of even throbbing pain.

Why do people experience pain differently?

The simplest answer would be to say that the way peoples brain are structured varies and the pathways that regulate and interpret out pain response can be more sensitive or less sensitive in various individuals. This sensitivity can be influenced by factors such as: past experience with pain, emotional state at the time pain is experienced, and expectations about pain

Pain killers are used in both instances to manage pain. As a guideline the WHO has set up a ‘ladder’ that is a guideline to treating pain. For mild pain it is suggested to use a non-opioid analgesic such ass paracetamol or ibuprofen  ±adjuvant, for moderate pain a weak opioid analgesic such as codeine ± adjuvant and only in severe cases if the previous medications do not work we consider stronger opioid analgesics such as morphine and methadone.

Adjuvants include glucocorticoids, hypnotics, anticonvulsants

Wake Forest University Baptist Medical Center. (2003, June 24). Brain Imaging Confirms That People Feel Pain Differently. ScienceDaily. Retrieved May 28, 2021 from www.sciencedaily.com/releases/2003/06/030624090043.htm

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

• SSRI's ( Selective Serotonin Re-uptake Inhibitors): Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Sertraline, Paroxetine
• SNRI's (Selective Serotonin Norepinephrine Re-uptake Inhibitors): Venlafaxine, Duloxetine, Levomilnacipran
• TCA's (Tricyclic anti-depressants):    Tertiary amines- Amitriptyline, Imipramine, Trimipramine, Butriptyline, Chlorimipramine, Dothiepine   Secondary amines- Nortriptyiline, Desimipramine, Lofepramine
• 5-HT R Modulators : Nefazodone, Trazodone, Vortioxetine
• Tetracyclic/ unicyclic: Tetracyclic- Mianserin, Mianzepine, Maprotiline, Amoxapine      Unicyclic- Bupropione
• MAOI ( Monoamine Oxidase Inhibitor)- Tranylcypromine (non selective), Moclobemide ( A selective), Isocarboxazid( non selective irreversible)      Selegiline/Rasagiline/deprenil- (B selective), phenelzine ( non-selective irreversible)
• Circadian rhythm regulator: Agomelatine
• Selective NA re-uptake inhibitor- Reboxetine

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

Most antidepressants cause potentiation of neurotransmitter action of norepinephrine or serotonin or both at central synapses.

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

2-4 weeks or even longer for a clinical effect to start but about 6-8 weeks for optimal effects it is suspected that it takes about 2 weeks for neurotrophic factors to be synthesised to increase neurogenesis and synaptic connectivity so that monoamines are better regulated to induce desired responses. Even with an acute surge in the monoamines with the first dose of an antidepressant in order to reach homeostasis and provide a long term response in balancing the neurotransmitters in the brain it takes for the receptors and processes to acclimate to the antidepressant medication and fix the dysregulation. Possibly also because most ADs are highly protein bound and lipophilic so they distribute to various tissues

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

• Efficacy: efficacy is the same, individuals just respond differently to the individual drugs
• Side effects: TADs have more anticholinergic and cardio related toxicities that include severe sedation, tachycardia, confusion, agitation, sweating, orthostatic hypotension, ECG abnormalities, weight gain and tremors. SSRIs have fewer side effects because it has a much higher affinity for blocking only serotonin reuptake transporters and may cause nausea, headaches, sexual dysfunction, anxiety, agitation, insomnia and jitteriness and CNS stimulation
• Safety: SSRI’s are safer than TCAs because they cause less interactions than the TCAs and also less cardiotoxic. TCAs lethal in overdose whereas as SSRIs are safer in overdose. SSRIs the most common side effects of SSRIs (nausea, vomiting, nervousness, insomnia, headache and sexual dysfunction) are usually mild and typically disappear as treatment continues.. Thus the severity and frequency of adverse effects experienced on an acute and chronic basis makes SSRIs a safer drug than TCAs .

     What is the action of mirtazapine?

   Increases amine release from nerve endings by antagonism of presynaptic alpha 2 adrenoceptors involved in feedback inhibition increasing both serotonin and norepinephrine release. Indirect stimulation   of HT-1A :  a   anxiolytic effect, antagonism of 5-HT 3: anxiolytic and decrease nausea as well as blockade of 5-HT2 with anti-depressive effects

   What is the action of venlafaxine?

   Blocks both the 5-HT and NA re-uptake, however more potently the 5-HT opposed to NA. Thereby increasing both serotonin and noradrenaline levels.

   What is the action of agomelatine?

I  A circadian rhythm regulator that normalised reduced amplitudes and phase modifications in sleep-wake cycle by antagonising 5-HT2C receptors thus having antidepressant and improved sleep action and  also having a    an agonism action on melatonergic MT 1 AND MT 2 receptors that benefits sleep by increasing melatonin production especially in the suprachiasmatic nucleus (anterior hypothalamus) region.

• Discuss the possible mechanisms of action of lithium.

The mechanism of action of Lithium are mediated via Lithium ions that influence multiple neurotransmission process. It influences both the adenylyl cyclase & phospholipase C protein couples messenger systems. Influences IP₃ & DAG and Camp 2^ND messengers by decreasing the various enzymes which are important for the conversion and the re-circulation of membrane phosphoinositides. IP₃ and DAG are important in monoamine and cholinergic transmission.

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

Very small therapeutic index (0.5-1.5 Mm) to produce therapeutic benefits in this range. This implies that plasma monitoring is very important as if the values are below 0.5 then there will be sub therapeutic effects and pharmacological treatment is not effective. If ranges of above 2 Mm are reached then toxicity occurs and leads to various adverse effects and which are dangerous and potentially harmful

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

Monotherapy for bipolar disorder and acute manic episodes lithium is indicated.

In rapid cycling lithium can be considered as monotherapy

Combination therapy: lithium and antidepressants for severe depressant episodes and initial treatment with SSRI can cause manic episode this reduces the occurrence.

Lithium and valproate when there is no or partial response to monotherapy

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

1. Lithium toxicity is reached in combination with drugs that interfere with the electrolyte-water balance of the body such as diuretics (thiazides), NSAID’s and fluoxetine
2. Increased renal excretion of lithium which means a decreased efficacy of he drug when it is administered with antacids (Na-bicarbonate), theophylline and caffeine
3. Neurotoxic in combination with carbamazepine, Ca blockers, losartan (ACE inhibitor), methyldopa, metronidazole and phenytoin

• Name the major side effects of lithium.

Acute toxicity: GI disturbances including nausea, vomiting and diarrhoea

Neurological toxicity: tremor, sedation, ataxia, muscle weakness, fatigue, polydipsia, polyuria, nocturia, nephrotic diabetes insipidus, thyroid enlargement, leucocytosis, edema, weight gain, acne, alopecia, sexual dysfunction

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

Cautionary use in pregnancy, should not be used especially during the first semester. It crosses the placental barrier which can cause the foetus to show lethargy and flaccid muscle tone. Contraindicated during breastfeeding as it is secreted in breast milk

• Name three other important indications for lithium.

Depression, schizophrenia and mania

• 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 NSAID. 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

The indocid (NSAID) % diuretic she has been using are increasing her lithium plasma levels which are contributing to the side effects experienced such as the weight gain, fatigue, nausea, shakiness and polydipsia and muscle injury. Especially because within the first 2 weeks she already reached 0.8mmol/l the half-life can lead to accumulation when administered with NSAIDs & diuretics.

The recommendation I would make would be to stop using the NSAID as well as the ‘water pills” immediately and then to check and monitor her plasma levels weekly until a stable plasma level is obtained. Her symptoms have to be monitored when she is not on any concurrent treatment that can affect her lithium levels to establish if a lower dosage will reduce some of her symptoms.

As B Polar is still very young and of child bearing potential I would recommend to switch her to an alternative treatment now like Lamotrogine since this is also safe in pregnancy if she chooses to want children in the near future especially since lithium is not recommend during pregnancy and breastfeeding. Regarding her weight gain that clearly is bothering her I would recommend healthy eating plan and more frequent exercise to start with and then later additional therapy if required.

Brand, L.Prof.  2021.  Study Unit 9:Anti-psychotic Drugs and Lithium.  Unpublished lecture notes on efundi, FKLG 312.  Potchefstroom: NWU.  [PowerPoint presentation]

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.

1. Phenothiazine derivatives with aliphatic side chain: chlorpromazine
2. Phenothiazine with piperidine side chain: periciazine
3. Phenothiazine derivative with piperazine side chain: fluphenazine

Aliphatic and piperidine side chains have a lower potency meaning that it has less EPS side effects and a higher dosage of the drug is needed to induce the side effects as the affinity for the Dopamine receptors are not as high and thus it will bind to other receptors more likely for example to H1 receptor causing severe sedation, M receptors in the heart responsible for the cardiovascular effects, M receptors in the body accounts for the strong anti-cholinergic effects and A1 blockade responsible for postural hypotension.

Piperazine however is a high potency drug indicating a strong affinity for binding to the D receptors which is then responsible for the larger EPS side effects but less sedation, less anti-cholinergic, cardiotoxic and postural hypotension side effects

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

Mesolimbic D2 receptors are blocked in particular. Other receptors like M, alpha, H & serotonin are also blocked but to a lesser extent.

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

Atypical drugs have a stronger binding affinity for 5-HT_2A receptors more than D₂ receptors

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

The reduced risk is associated with the affinity of blockage of the D2 receptors. Lower potency drugs have a decreased chance for causing severe EPS symptoms where as high potency drugs have an increased risk. The lower potency of drugs is typically linked to having a lower affinity for binding to the D2 receptors and will possibly bind to additional receptor having anti-cholinergic effects or even some serotonergic reducing effects.

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

Haloperidol, it has a very high potency for blocking D₂ receptors primary located in the basal ganglia.

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

The autonomic systems are a system that is large manage unconsciously which regulates body functions such as heart rate, digestion, respiratory rate, urination, sexual arousal and pupillary response. Thus blocking alpha 1 receptor it influences both blood pressure (can precipitate orthostatic hypotension) and muscarinic receptor blockage influences urinary retention, blurred vision, constipation and even sexual dysfunction.

Brand, L. Prof.  2021.  Study Unit 9: Anti-psychotic Drugs and Lithium.  Unpublished lecture notes on efundi, FKLG 312.  Potchefstroom: NWU.  [PowerPoint presentation].

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

1. Drugs that increase dopamine activity
2. Drugs which decrease cholinergic activity

In what way does amantadine act as a antiparkinsonism drug?

Amantadine is a metaffinoid potentiator of dopamine. The mechanism ivolves increasing the reease of DA, increasing the synthesis of DA and blocking the re-uptake of DA. An additional mechanism for antiparkinsonism activity is the antagonistic action on NMDA receptros which decreases excitatory glutamate.

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

Selective MAO-B inhibitors indirectly increases DA levels. By inhibiting monoamine-oxidase which is responsible for the metabolism of dopamine it indirectly increases the DA still available.

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

Ergot derivatives- bromocriptine

Non ergot derivative- pramipexole & ropinirole

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

Bromocriptine is a partial agonist on D₂ receptos

Pramipexole- agonist with affinity for D₃ receptors

Ropinirole- D₂ agonist

Amantadine- metaffinoid potentiater of dopamine

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

MAO-B inhibitors like Rasagiline is classified as neuron-protecting. Neuroprotection is an effect that may result in salvage, recovery or regeneration of the nervous system, its cells, structure and function. A type of prophylactic drug that can be used to prevent neurodegeneration to a certain extent.

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

MAO-B is an isomer of the MAO enzymes. MAO-B specifically has an affinity for dopamine and tyramine so this specificity creates a direct increase of dopamine by decreasing its metabolism via this pathway.

How do the COMT-inhibitors act in Parkinsonism?

COMT enzymes metabolize l-dopa (precursor of dopamine) to 3-O-methyl dopa (3OMD). By inhibiting these enzymes less 3OMD is formed and less competition for active transport into the brain between l-dopa and 30MD is achieved and thus decreased metabolism via COMT of l-dopa and less competition for transport then improves the bioavailability of l-dopa that can cross the blood brain barrier.

How does istradephyline act?

Via Adenosine A_2A antagonism thus having anticholinergic activity. D₂ function is inhibited by adenosine

Discuss the MOA of safinamide

Has a dual mechanism of action. It increases DA activity by inhibiting the re-uptake as well as being a potent reversible blocker of MAO-B. Additionally it also decreases glutamate release.

https://pubmed.ncbi.nlm.nih.gov/11749009/

Brand, L. 2021. Parkinsonism. Unpublished Lecture notes on eFundi. [PowerPoint Presentation]. Study Unit 8, FKLG 312. Potchefstroom, NWU.

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

(a) myelinated fibres with unmyelinated fibres; and

smaller and myelinated fibers are blocked easier than larger and unmyelinated fibers

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

Dorsal nerves (type C fiber) that transmit pain impulses have a higher sensitivity to be blocked by local anaesthetics than pressure/touch nerves (type A fiber)

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

Heart: class 1 antiarrhythmic drugs like lidocaine, blocks sodium channels in the heart, shortens the duration of action potential and increases the refractory period.

Weak blocking effects on skeletal neuromuscular junction and thus as no clinical application

Mood elevation induced by cocaine reflects actions on dopamine or other amine-mediated transmission in CNS rather than a local anaesthetic action on membranes.

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

1. The type of procedure that is being done
2. The type of tissue that the local anesthetic should be used on
3. The duration of the numbing effect that is needed

• Why are LA solutions sometimes saturated with CO₂?

CO₂ acidifies the solution; a lower pH increases the concentration of the active cationic protonated forms of the local anesthetic. Adding COD thus potentiates the effects of the LA by increasing the concentration of the ionised form of the drug that is more effective in blocking of the Na ion channel and enhances/ increases the onset of the pharmacological action

Which of the LA are typically used for surface anaesthesia?

• Benzocaine
• Cocaine
• oxybuprocaine

Brand, L. 2021. Local Anesthetics. Study Unit 6 [PowerPoint Presentation]. Unpublished Lecture Notes on eFundi. FKLG 312. Potchefstroom:NWU

https://pubmed.ncbi.nlm.nih.gov/9026253/

• 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

extensions of effects on brain, heart/vasculature and lungs. Drug interactions are additive with other CNS depressants with agents such as opioids and sedative hypnotics.

nephrotoxicity- metabolism of enflurane and sevoflurane

hematotoxicity- prolonged exposure to nitrous oxide decreases methionine synthase activity that could lead to megaloblastic anemia. Al inhaled anesthetics can produce carbon monoxide that in turn reduces oxygen delivery.

malignant hyperthermia- heritable genetic disorder of skeletal muscle that occurs in susceptible individuals exposed to volatile anesthetics. Succinylcholine ( depolarizing muscle relaxant) may also trigger this.

hepatotoxicity (halothane hepatitis)-hepatic dysfunction most likely cause by hypovolemic shock, infection conferred by blood transfusion or other surgical stresses rather than volatile anesthetic toxicity. Small subset exposed to halothane can develop hepatic failure (rarely) happens. Free radical formation or initiated immune response is believed to cause hepatocellular damage.

Katzung, B.G., 2018. Basic & Clinical Pharmacology. 14th ed. United States of America: McGraw-Hill Education.

Brand, L. 2021. General Anesthetics. Study Unit 5[PowerPoint Presentation]. Unpublished lecture notes on eFundi, FKLG 312. Potchefstroom, NWU.

• 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
• Topiramate
• Perampenel decreases levonorgestrel-containing contraceptives

As listed above these medications decrease the pill effectiveness by increasing liver metabolism via isozyme CYP450 especially of these drugs.Another mechanism this can happen by is via increased sex0hormone binding globulins leaving less free active ingredients. Decreased effectiveness of oral contraceptives will lead to increased amounts of unwanted pregnancy and the possibility of teratogenicity effects in these pregnancies.

Drugs safe to use in combination with the Pill includes: valproate, lamotrigine, gabapentin, leviteracetam and vigabatrin however oral contraception can decrease plasma serum levels in combination with lamotrigine and valproate that in turn can cause breakthrough seizures due to decreased serum levels.

Preverred contraceptive methods for women on anti-epileptic drugs of child bearing age include Depo-provera injections, levonorgestrel IUD (Mirena), Copper IUD as well as progestin only pills instead of combined contraceptives.

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

Yes oral contraceptives can decreased the serum levels of drugs such as lamotrigine and valproate, causing breakthrough seizures and sub therapeutic levels due to increased glucuronation of free and total valproate and lamotrigine concentrations.

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

Neonates- slower metabolism thus lower dosages

Babies and children- faster metabolism than adults thus higher dosages required

Geriatrics- decreased liver metabolism and renal function thus lower dosages

• In which cases is plasma blood level monitoring indicated

Plasma blood monitoring is required where protein binding is involved. Almost all anti-epileptic agents effect protein binding except gabapentin, ethosuximide and topiramate.

In cases where diseases affect protein binding, plasma blood monitoring is thus needed and includes chronic kidney failure, liver diseases, hypoalbuminemia, severe burns, pregnancy, malnutrition, age and where displacement drugs are used. Also when combination therapy is used between enzyme inducers (carbamazepine, phenobarbitone, phenytoin) with lamotrigine or other drugs metabolised by CYP P450 enzymes as well as during perimenopause stages and the use of valproate (enzyme inhibitor) with lamotrigine to ensure the levels are within the therapeutic index range and not near toxic levels.

Brand, L. 2021. Antiepileptic drugs. Study unit 4 [PowerPoint Presentation]. Unpublished lecture notes on eFundi, FKLG312. Potchefstroom: NWU

https://www.uspharmacist.com/article/antiepileptic-drugs-and-contraception#:~:text=ABSTRACT%3A%20Certain%20antiepileptic%20drugs%20(AEDs,of%20seizure%20control%20or%20toxicity. 

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

The consumption of high doses of alcohol over long periods result in tolerance and in physical and psychological dependence. Via poorly understood changes in the nervous system and pharmacokinetic changes such as: up regulation of Microsomal ethanol oxidising system, responsible for metabolising higher concentrations of blood alcohol levels is induced with chronic alcohol consumption leading to an increased amount of ethanol metabolism and also the clearance of other drugs eliminated by cytochrome P450s. Down regulation of GABA_A responses with chronic alcohol exposure indicates subsensitivity after continues exposure. 

Low tolerance to alcohol can be explained via ADH1B*2 allele in some populations which are protective against alcohol dependence because of rapid conversion of ethanol to acetaldehyde and thus individuals will feel the effects of alcohol at lower blood concentration levels and can help decrease the urge to drink more.

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

Tissue damage caused by chronic alcohol consumption results from the combination of direct effects of ethanol and acetaldehyde and the metabolic consequences of processing a heavy load of active metabolites. Increased oxidative stress coupled with depletion of glutathione, damage to mitochondria, growth factor dysregulation and potentiation of cytokine induced injury all contribute to liver disease. Alcoholic hepatitis, cirrhosis and liver failure means a vital organ is compromised and n need for a liver transplant since the removal of toxic products in the body is compromised. Cirrhosis contributes to elevated portal blood pressure and esophageal and gastric venous varices

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

This syndrome is characterized by paralysis of external eye muscles, ataxia and a confused state that can progress to coma and death. It is associated with thiamine deficiency and therefore treatment includes administration of parenteral thiamine. Tis syndrome is very rarely seen in the absence of alcoholism nut is characterized by generalized symmetric peripheral nerve injury.

• Fully explain the foetal alcohol syndrome.

Chronic alcoholic abuse during pregnancy is associated with these teratogenic affects where alcohol is the leading cause of mental retardation and congenital malformation of foetuses. This syndrome is characterized by intrauterine growth retardation, microcephaly, poor coordination, underdevelopment of midfacial region and minor joint anomalies. In severe cases congenital heart defects and mental retardation. The mechanisms underlying ethanol’s teratogenic effects are unknown. Since ethanol is very water soluble and rapidly dissolves it crosses the placenta and reaches concentrations in the fetus similar to that of the mother’s blood. A foetal liver however has little to no alcohol dehydrogenase and thus the effects are extremely damaging and harmful and the fetus must rely on maternal and placental enzymes for elimination of alcohol. Alcohol syndrome indicates that ethanol triggers apoptotic neurodegeneration and aberrant neuronal and glial migration in a developing nervous system.

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

Acute alcohol use can inhibit/ decrease metabolism because of decreased enzyme activity or decreased liver blood flow. Rate and extent of absorption with more limited effects on clearance of drugs such as phenothiazine’s, tricyclic antidepressants and sedative hypnotic drugs.  Chronic alcohol consumption without damage to the liver can enhance the metabolic transformation of drugs especially those eliminated by cytochrome P450 like acetaminophen since increased metabolism of acetaminophen to reactive hepatotoxic metabolites  (NAPQI) that increases the risk of hepatotoxicity and should be avoided in alcoholics

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

Phenothiazines, tricyclic antidepressant and sedative hypnotics like diazepam, oxazepam and midazolam are all potentiated by alcohol consumption since they all cause CNS depression in an additive manner and is thus very dangerous to combine with the use of alcohol. It can lead to respiratory and cardiac depression working on GABA_A potentiation. Vasodilatos combined with alcohol can cause extreme vasodilation and a drop in blood pressure this can cause heart rate to increase and respiratory rate as well to maintain sufficient blood flow rates to vital organs, ethanol potentiates the anti-platelet effects of aspirin by decreasing the number of platelets via suppression bone marrow production as well as causing the platelets to be less sticky and hypoglycemic/diabetic medications are potentiated by alcohol causing the pancreas to not be able to release glucose into the blood but he excess sugar in alcoholic drinks causes an increased release of insulin and thus in combination with hypoglycemic drugs this can lead to insulin shock and very low blood glucose levels.

Katzung, B.G., 2018. Basic & Clinical Pharmacology. 14th ed. United States of America: McGraw-Hill Education.

Brand, L. 2021. Sedative Hypnotic drugs. Study Unit 3 [PowerPoint Presentation]. Unpublished lecture notes on eFundi, FKLG 312. Potchefstroom, NWU.

Renaud, S. C., & Ruf, J. C. (1996). Effects of alcohol on platelet functions. Clinica chimica acta; international journal of clinical chemistry, 246(1-2), 77–89. https://doi.org/10.1016/0009-8981(96)06228-6

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

Ethanol is a small water soluble molecule which produces fast absorption, due to the lipophilic properties fast distribution also occurs especially across the blood brain barrier and into the central nervous system. When alcohol is consumed on an empty stomach blood plasma peeking results within 30 minutes as opposed to the stomach being lined with food that will decrease the stomach emptying time and allow gastric enzymes to help metabolize ethanol molecules before reaching the liver. Total body fluids also play a major role in distribution time where the more body fluids ( 0.5-0.7L/KG) you poses the longer it will take for your blood alcohol concentration to reach toxic levels because dissolution and increased amounts of volume dilutes this concentration. Metabolism of ethanol is mainly through the liver (90%) and the rest will be excreted through the lungs and urine.

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

2 enzymes systems in the liver are responsible for ethanol metabolism.

Through zero order kinetics which means that the pathway can become saturated and is not dependent on the concentration of ethanol nor time exposure. Alcohol dehydrogenase metabolizes low to moderate amounts of alcohol (7-10g/h) and is dependent on the co-enzyme NAD. Microsomal Ethanol-Oxidizing System -MEOS- metabolizes ethanol In higher concentrations (>100mg/Dl). Both these metabolic pathways metabolises ethanol to acetaldehyde where aldehyddehidrogenase will convert it further into acetate that is ultimately broken down into carbon dioxide and water for excretion.

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

Disulfiram, Metronidazole, cephalosporin & hypoglycemics

These drugs interfere/inhibit the actions of aldehyddehidrogenase and thus cause an increase in the accumulation of acetaldehyde in the body. These abnormal concentrations will precipitate the negative side effects of a night out drinking including nausea, vomiting, ataxia etc. and are typically used in individuals with high alcohol tolerance or disulfiram to treat alcoholism. Patient taking these medications should always be warned of the possible side effects and advise to not consume any alcohol during their treatment period.

Katzung, B.G., 2018. Basic & Clinical Pharmacology. 14th ed. United States of America: McGraw-Hill Education.

Brand, L. 2021. Sedative Hypnotic drugs. Study Unit 2[PowerPoint Presentation]. Unpublished lecture notes on eFundi, FKLG 312. Potchefstroom, NWU.