Pain:

The uncomfortable, subjective sensory and emotional experience associated with actual or potential tissue damage.

Causes of pain:

Pain can be acute or chronic.

Acute pain is described as nociceptive. It originates in somatic tissue, like skin, bone, etc or visceral tissue, e.g. organs

Chronic pain is functional and neuropathic pain. Functional pain can be described as fibromyalgia, IBS, tension-headaches etc. Neuropathic pain is due to nerve damage or injury.

Why do different people experience pain differently?

The sensitivity and tolerance people show towards pain varies predictably according to several factors, including gender, ethnicity, personality and culture, all interacting, overlapping and playing out in the tissues and synapses of the body.

Pain management

The primary aim of acute pain management is to provide treatment that reduces the patient's pain, with minimal adverse effects, while allowing them to maintain function. A secondary aim is to prevent acute pain from progressing to chronic pain

Classification of drugs

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

The antidepressants inhibit reuptake of neurotransmitters through selective receptors, thereby increasing the concentration of specific neurotransmitter around the nerves in the brain.

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

• It takes approximately four to six weeks for antidepressant medications to reach their full therapeutic effect.
• n people with depression, G proteins tended to congregate in lipid rafts, areas of the membrane rich in cholesterol. Stranded on the rafts, the G proteins lacked access to a molecule called cyclic AMP, which they need in order to function. 
• AD's accumulates in the lipid rafts over time and as they do so, G proteins in the rafts decreases.
• It's likely that this effect on the movement of G proteins out of the lipid rafts towards regions of the cell membrane where they are better able to function is the reason these antidepressants take so long to work.

Difference

What is the action of mirtazapine?

• NaSSA (NA & Specific Serotonin Antidepressant)
• Blocks alpha 2, 5-HT2A, 5-HT3
• Blockade of inhibitory alpha 2 receptors advance both NA (autoreceptor) & 5-HT (heteroreceptor) release.
• Indirect stimulation of 5-HT1A
• Blocks 5-HT3 as well as 5-HT2

What is the action of venlafaxine?

• Moderately selective blockade of NET and SERT
• More potent for 5-HT

What is the action of agomelatine?

• Melatonin 1 and -2 agonist and 5-HT2C antagonist
• 5-HT2C antagonism: disinhibition of DA and NA release in FC (increase DA and NA release)

Discuss the possible mechanisms of action of lithium.

• Mediated by Li+
• Influences IP3 and DAG 2nd messenger systems by decreasing various enzymes which are very important for conversion and re-circulation of membrane phosphoinositides.
• IP3 and DAG is important in monoamine and cholinergic neurotransmission.

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

• 0.5 - 1.5 mM
• >2mM is toxic
• Plasma levels is very important and therapeutic drug monitoring should be executed.

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

• Clonazepam and lorazepam is used in combination with lithium.
• Tradition APD's worsen EPS in combination with lithium, therefore it will then be used in mono therapy.

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

• Neurotoxic combination with carbamazepine, calcium channel blockers, losartan, etc.
• Traditional APD (chlorpromazine, periciazeine, etc.) worsen EPS in combination with lithium
• Diuretics, such as thiazides increases Li+ which can result in toxicity.
• Theophylline and caffeine increases renal excretion of lithium

Name the major side effects of lithium.

• Tremors, sedation, ataxia, aphasia
• Muscle weakness, fatigue
• Polidypsia, Poliuria, Nocturia
• Nephrogenic diabetes insipidus
• Thyroid enlargement

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

Given the very high risk of relapse in the postpartum period, a high target therapeutic lithium level is recommended. Most clinical guidelines discourage breastfeeding in women treated with lithium.

Name three other important indications for lithium.

• Anxiety
• OCD
• Prophylactic use can prevent mood swings between mania and depression
• Hypomania and mania

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.

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

• Dopamine agonists
• Anticholinergic drugs

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

• Amantadine is a metaffinoid potentiator of dopamine. This means that amantadine:

• Increases release of dopamine
• Increases synthesis of dopamine
• Block reuptake of dopamine

• Amantadine also acts as NMDA antagonist which results in the anti-dyskinetic effect.
• Amantadine is an adenosine A₂ antagonist – adenosine inhibits D₂ function
• Amantadine improves rigidity, tremors and bradykinesia.

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

Selective MAO-B inhibitors

• MAO-B preference for DA as substrate 
• This increases DA concentration in CNS

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

• Ergot derivatives

• Bromocriptine

• Non ergot derivatives:

• Pramipexole
• Ropinirole

List the specific dopamine receptors that are stimulated by each agonist

• Bromocriptine: partial agonist on D₂ receptors
• Pramipexole: D₃ receptors
• Ropinirole: D₂ receptors

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

• Pramipexole
• Decreases disease progression and affective symptoms

What is the importance of MAO-B selective drugs in the treatment of Parkinsonism?

• MAO-B has preference for DA as substrate
• This causes an increase in Dopamine in the central nervous system

How do the COMT inhibitors act in Parkinsonism?

• COMT metabolizes l-dopa to 3-O-methyl dopa (3OMD)
• 3OMD competes with l-dopa for active transport processes which causes increased plasma levels of 3OMD and weak therapeutic response with l-dopa
• COMT-inhibitors extend the duration of action of l-dopa and decreases peripheral metabolism which results in an improved bio-availability

How does Istradefyllin act?

• Istradefyllin is an adenosine A_2A antagonist
• Adenosine inhibits Dopamine 2 receptor function
• By inhibiting adenosine, it will prevent the inhibition of dopamine functions

Discuss the MOA of Safinamide

• Novel dual Mechanism of action
• Increases dopamine activity

• Potent reversible inhibition of MAO-B
• Inhibition of dopamine uptake

• Decreases glutamate release.

Source

Brand, L. 2021. Parkinson’s Disease. Study unit 8 [PowerPoint Presentation]. Unpublished lecture notes on eFundi, FKLG312. 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 

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

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

b) Activated pain fibers fire faster, pain sensation selectively blocked by LA. Fibers in a thick bundle blocked slower than those at the outside of the bundle.

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

• Heart: Class I anti-arryhthmic drug
• Skeletal muscle: Weak blocking action, no clinical application.

What is the basis for the selection of a LA?

Type of procedure necessary;

• Smaller surgical procedures
• Spinal anaesthesia
• Autonomic blockade in ischemic conditions
• Postoperative analgesia

Why are LA solutions sometimes saturated with CO₂?

It is used as a buffer. The pH of the tissue should not influence the reaction.

Which of the LA are typically used for surface anaesthesia?

• Benzocaine
• Cocaine
• Oxybuprocaine

Name the major acute toxic effects of the inhalation drugs.

• Hepatotoxicity - Halothane
• Hypoxia
• Nephrotoxicity
• Malignant hypothermia

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? 

Affects the metabolism:

• Phenobarbitone
• Phenytoin
• Carbamazepine
• Oxcarbazepine
• Topiramate

Oral contraceptives’ serum concentration may be decreased by anti-epileptic drugs. This can cause unplanned pregnancies. Higher doses of contraceptives is then needed and additional contraceptive methods should be used if breakthrough bleeding occurs.

Safe to use:

• Valproate
• Lamotrigine
• Gabapentin
• Levetiracetam
• Vigabatrin

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

Yes. Oral contraceptives decreases lamotrigine and valproate serum levels.

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

Neonates: Slow metabolism of drugs

Children: Metabolism is faster than adults.

Adults: Metabolism is slower than children

Geriatrics: Slow metabolism of drugs.

In which cases is plasma blood level monitoring indicated?

• A change in dosage is made
• Finding a suitable maintenance dose
• To monitor any side-effects
• Neonates
• Geriatrics
• During pregnancy
• When seizures occur
• Drug interactions.

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

Tolerance to chronic alcohol intake causes the central nervous system to adjust to this chronic exposure. Adjustments include changes to the receptors and second messengers involved in the metabolism of alcohol. it also increases metabolism tempo.

The enzyme system MEOS (mixed function oxidases) is also partially responsible for tolerance. This enzyme system is involved when consuming higher concentrations of alcohol, 100mg/dL and above. 

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

Chronic alcohol consumption causes the following:

• Progressive decrease in liver function
• Hepatitis
• Liver cirrhosis
• Increased activity of liver microsomal enzymes
• Decreased gluconeogenesis
• Hypoglycaemia
• Fat accumulation (nutrient deficiencies contribute to this)

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

Wernicke-Korsakoff syndrome is peripheral neuropathy as a result of Thiamine (Vitamin B1) deficiency. This syndrome presents as: ataxia, confusion, paralysis of facial muscles, etc.

This can be treated by administering parenteral thiamine to prevent permanent damage.

Fully explain the Foetal Alcohol Syndrome.

The foetal alcohol syndrome is caused by consumption of alcohol during pregnancy. The alcohol causes teratogenic effects. If exposed to alcohol in uterus, it may exhibit development disabilities and cognitive and behavioural defects. This is because of damage to the developing neurons. It presents as: mental retardation, growth deficiency, microcephaly (smaller brain), characteristics under development of middle facial area.

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

Acute alcohol consumption decreases the metabolism of drugs. This causes the drug to build up in the body and accumulative central nervous system suppression is a result. Drugs include: Phenothiazines, tricyclic anti-depressants and other sedative-hypnotics.

Chronic consumption of alcohol increases the metabolic transformation of other drugs. This causes a shortened effect of the drug.

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

• Vasodilators
• Hypoglycaemic drugs
• Aspirin
• Paracetamol

Sources 

Brand, L. 2021. Alcohols. Study unit 3 [PowerPoint Presentation]. Unpublished lecture notes on eFundi, FKLG312. Potchefstroom: NWU.

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

Zero-order kinetics applies for alcohol.

There is a limited amount of NAD co-enzyme in the body. This cause a saturated enzyme system. This will lead to toxic side effects.

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

Metabolism of alcohol (ethanol) follows two enzyme systems:

1. Alcohol dehydrogenase

2. MEOS (mixed function oxidases)

1. Alcohol dehydrogenase is the system that takes place during low to moderate consumption of alcohol. This is a zero-order kinetic system which means that a constant amount of alcohol is eliminated per unit time.

2. MEOS is the enzyme system that occurs during higher concentrations of alcohol consumption. This is usually concentrations above 100mg/dL. MEOS activity increases with chronic use and can be induced. This is partially responsible for tolerance.

The end product of these systems is acetaldehyde. 

Acetaldehyde is then further metabolized to acetate by the enzyme, aldehyddehidrogenase. Acetate is then converted to water and carbondioxide which is then eliminated.

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

Drugs that affect this metabolism include:

• Disulfiram
• Metronidazole
• Cephalosporins
• Hypoglycemics

These drugs inhibit or block aldehyddehidrogenase enzyme which then result that acetaldehyde cannot be converted to acetate. Buildup of acetaldehyde then occurs. This causes nausea, vomiting, etc. 

Sources

Brand, L. 2021. Alcohols. Study unit 3 [PowerPoint Presentation]. Unpublished lecture notes on eFundi, FKLG312. Potchefstroom: NWU.