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

The consumption of alcohol in high doses over a long period results in tolerance and in physical and psychological dependence. it cross tolerance other sedative- hypnotics. it changes some of the process in the CNS and increases metabolic tempo

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

Progressive ↓ liver function, hepatitis & cirrhosis 

• Worse in women than in men

 • Gluconeogenesis ↓, hypoglycemia and fat accumulation, nutrient deficiencies contributes to this 

• ↑ activity of liver microsomal enzymes

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

Wernicke- korsakoff syndrome is thiamine deficiency  characterised by ataxia, confusion, paralysis of facial muscles.

administer parenteral thiamine to prevent brain damage.

• Fully explain the foetal alcohol syndrome.

Teratogenic effects 

Children exposed to alcohol abuse during the 1st trimester in utero may exhibit a wide range of developmental disabilities and cognitive and behavioral deficits that reflect damage to the developing neurons. These effects may include: mental retardation, attention deficit disorders, perceptual problems, memory and learning disabilities, and psychomotor dysfunction. FAS, which is characterized by CNS impairments, growth retardation and characteristic facial dysmorphology is the most severe manifestation of alcohol neurogenesis.

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

Chronic ethanol ↑ metabolic transformation of other drugs and Acute alcohol: ↓ metabolism of drugs

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

paracetamol

phenobarbitone 

TCAs

sedative- hypnotics e.g. diazepam

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

Absorption

Distribution

Metabolism

 rapid absorption in GI tract after ingestion, increase distribution, which reaches peak after 30 mins, the distribution depends on the body weight. 90% of alcohol is metabolism in the liver this implies that it interacts with most of the enzymes in the liver, therefore cautioned in patients with liver diseases and the rest is metabolised by lungs and urine.

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

ethanol is metabolism by 2 enzyme systems, namely:

1. Alcohol dehydrogenase: low to moderate amounts • Limited amount of NAD (co- enzyme): zero-order kinetics, (7 – 10 g/h) • 

2. MEOS (mixed function oxidases) higher concentrations (>100mg/dL) • MEOS activity ↑ with chronic use, can be induced, partially responsible for tolerance

end product : Acetaldehyde

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

disulfiram

metronidazole 

cephalosporins 

hypoglycemics

inhibits aldehydrogenase  and aldehyde will accumulate and cause unpleasant reaction of facial flushing, nauseous, vomiting dizziness and headaches

For quite a number of preparations of herbal/natural origin in pharmacies or shops, claims are made that they have anxiolytic and/or sedative-hypnotic properties. Your textbook (Katz) discusses a number of these preparations in Chapter 64. Use that information together with a search on the internet and compile a brief report on the use of these alternative medicines in the treatment of anxiety and insomnia. You may use any search engine (e.g. Google) and keywords such as “botanicals” and “anxiety” and “insomnia”. 

botanicals for anxiety 

1. ginkgo biloba 

increases blood flow, reduces blood viscosity and promotes vasodilation thus enhancing tissue perfusion. enhancement of nitric oxide effects such as relaxing, this is used for anxiety 

side effects : 

do not give patients with allergic and asthmatic bronchoconstriction 

drug interactions 

ginkgo has an antiplatelet effect but do not use with other antiplatelets and anticoagulation medications 

virologic failure with combination to efavirenz

sedation with triazolam 

priapism with risperidone 

seizures with valproic acid phenytoin 

dosage 

ginkgo biloba is standardized to contain 24%flavone glycoside and 6%terpene lactones

daily dose of 120 to 240 mg of the dried extract in two or three divided doses.

2. ST. John’s wort ( hypercium perforatum )

indicated for anxiety 

side effects : 

photosensitization is related to hypericin and pseudohypericin. advice patients to use sunscreen and eye protection while of the this product 

drug interactions: 

inhibit reuptake of various amines transmitters .

use with caution antidepressants or avoid  due to serotonin syndrome 

inducer of hepatic CYP enzymes

HIV medication

anticonvulsants and cyclosporine

drug dosage:

product standardized to have 2-5% hyperforin 

for moderate depression  dose of 900 mg of the dried extract per day 

onset of effect may take 2 to 4 weeks 

botanicals for insomnia 

1. melatonin 

It improves sleep onset, duration and quality when administered to healthy volunteers. it also increases rapid eye movement 

side effects 

next day dizziness, fatigue, headaches and irritability 

affect blood pressure 

drug interactions:

antidepressants

NSAIDs 

B-Adrenoceptor agonists and antagonists 

sodium valproate 

metabolized by CYP450 1A2

dosage :

0.3 to 10 mg of the immediate release formulation given orally once nightly 

Valeriana officinalis

Valerian is one of the most popularly used herbal medicines for insomnia and is also used to treat anxiety. Hydroalcoholic and aqueous extracts of valerian roots have shown affinity for the GABA-A receptor in the brains of rats

 reference 

Zehnder, J., Katzung, S.M. and Trevor, A., 2019. Basic and clinical pharmacology. 12th Ed. New York: McGraw-Hill Medical

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

1.lipophilicity, more lipophilic a drug the faster it is absorbed and reaches the target tissue. more distributed 

2.  biotransformation hepatic microsomal enzymes 

3. elimination half life may differ, this causes some BDs to be eliminated faster than others

• What is meant by redistribution and what is the significance thereof?

Redistribution means the drug is redistributed from one tissue to other tissues 

A drug like thiopentone which is used as an induction anesthetic, high lipophilic,quickly moves from the brain to other tissues such as the muscle tissue. it can a depot effect in other tissues as it is not easily removed because of its lipophilicity

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

they are metabolized by biotransformation by hepatic microsomal enzymes 

1.  dealkylation: active metabolites 

2. oxidation: cytochrome p450, active metabolite

3. conjugation ( phase 2) of oxidised metabolite with glucuronide acid to form an inactive metabolite 

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

diazepam 

clorazepate

prazepam

chlorodiazepam

ketazolam 

if you get active metabolites contribute to extended duration of action increase elimination half life to greater than 40hours

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

oxazepam 

lorazepam 

temazepam

lormetazepam

drugs of choice where cytochrome p450 activity is reduced, especially in elderly, neonates and in patients with liver cirrhosis 

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

Enzyme induction refers to when a drug increases the production of an enzyme that will lead to an increase in the rate of metabolism of the drug.

barbiturates and meprobamate . they decrease the therapeutic effect by increasing the metabolism and decrease the overall drug in the systemic circulation 

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

anterograde amnesia means the inability to remember events occurring during the drug’s duration of action

drugs that cause this : triazolam and temazepam

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

• they decrease the time to fall asleep 

• increases total sleep duration 

• benzodiazepines increases the duration of phase 2 NREM 

• Decreases the duration of phase 4 NREM

• Zolpidem decreases REM sleep, has minimum effect on SWS 

it helps the patient sleep where patients normally have less than 6 hours of sleep.

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

phenobarbitone 

phenytoin 

diazepam 

lorazepam 

midazolam 

they are highly lipophilicity, rapid onset of action and have CNS effects 

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

phenobarbitone, clonazepam, clobazam

diazepam lorazepam 

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

inhibits postsynaptic reflexes

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

medullar depression: therapeutic doses significant respiratory depression in pulmonary disease and cardiovascular depression in cardiovascular disease 

• increased dose, death  due to depression of medullary respiratory center

respiratory and CVS  effects are more marked with IV administration 

Blog #1

• Which types of ion channels are found on the nerve cell membranes?

Voltage and ligand-gated channels. 

• Name 3 differences between voltage-gated and ligand-gated ion channels. 

Voltage gated 

. Changes in membrane potential of the cell

. Transmits signal from cell body to nerve terminal

. Na+, k+ and Ca2+ channels 

Ligand-gated channels 

. Binding of ligand or neurotransmitter to ion channel 

. Ionotropic receptors

. GABA – a, nicotinic, choline, glutamate, serotonin receptors 

• Compare ionotropic and metabotropic receptors.

Ionotropic receptor is opening of ion channels  and metabotropic is the metabolic change that causes the channels to open allow binding 

• Classify the CNS receptors into ionotropic and metabotropic and know the transduction mechanism of each receptor.

Ionotropic receptors 

GABA – A : inhibits postsynaptic potential

Nicotinic : activates postsynaptic potential 

Glutamate : activates post synaptic potential 

Serotonin : activates postsynaptic potential 

Metabotropic 

G protein coupled receptors which works by 2 transduction systems which is the adenylyl cyclase system and phospholipase c.

In adenylyl cyclase system B1, 2 and dopamine 1 receptors which are positively bound results in change of ATP to cyclic Amp  and D2, alpha 2 and serotonin A and B as well as muscarinic are negatively bound will inhibit the effect. No second messenger is formed

Phospholipase c system works via stimulation of Alpha 1, serotonin 2, muscurinic and histamine 1 receptors thus stimulate PIP2 to form IP3 AND DAG 

• Explain the difference between an EPSP and an IPSP and give examples of each

EPSP means the excitatory of post synaptic potential by depolarization of ion channels e. g sodium and calcium channels 

IPSP means inhibitory of post synaptic potential by hyperpolarizing the ion channels e. g. Chloride 

• What is the role of calcium in the development of a synaptic potential

Calcium ions trigger the release of neurotransmitter from synaptic vesicles into the synaptic cleft