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

Drugs that decrease the effectiveness of the pill are as follows: Phenobarbitone, phenytoin, carbamazepine, oxcarbazepine and topiramate. Due to its decreasing the effectiveness of the pill it may lead to an unwanted pregnancy.

Drugs that are safe to use in combo with the Pill: Valporate, Lamotrigine, Gabapentin, Leviteracetam and Vigabartin.

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

Yes, oral contraceptives decrease the serum levels of anti-epileptic drugs for example, Valporate.

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

Metabolism of anti-epileptic drugs are slower in neonates than in adults, but metabolism of these drugs is faster in babies and in children than adults. And due to lowered metabolic activity in  geriatrics metabolism does appear to be slower in geriatrics than in adults.

In which cases is plasma blood level monitoring indicated?

it is indicated to see how well a patient’s body tolerates a drug and help a practitioner to identify if any unwanted effects are experienced with the drug. For example, in the case of Valporate and lamotrigine, as valproate deceases the metabolism of lamotrigine which leads to the increased levels of lamotrigine in the blood and in its turn can cause toxicity.

1. Alcohol tolerance may result from ethanol-induced up-regulation of a pathway in response to the continuous presence of alcohol. Alcohol dependence may result from overactivity of that same pathway after ethanol effect dissipates and before the system has time to return to a normal ethanol-free state. Furthermore, GABA neurotransmission is believed to play a role in tolerance because there is evidence of down-regulation of GABA-A mediated responses with chronic alcohol exposure.
2. Chronic alcohol consumption can cause metabolic repercussions of ethanol oxidation in the liver, liver injury caused by the toxicity of the metabolic byproducts of alcohol (acetaldehyde) as well as inflammation caused by these metabolic by products. Chronic alcohol consumption can also cause dysregulation of fatty acid-oxidation and synthesis as well as activation of the innate immune system.
3. Wernicke-Korsakoff syndrome is a syndrome caused by a thiamine deficiency and is characterized by paralysis of external eye muscles, ataxia and a confused state that can lead to a coma and eventually death. This syndrome uncommon, but is rarely seen in the absence of alcoholism. The syndrome is treated with parenteral thiamine that is given to the patient.
4. Fetal alcohol syndrome is a syndrome caused by chronic maternal alcohol abuse during pregnancy and is associated with teratogenic effects. Mental retardation and congenital malformations are seen commonly in infants with this syndrome. Other abnormalities often include: intrauterine growth retardation, microcephaly, underdevelopment of the midfacial region, congenital heart defects and well as minor joint abnormalities. This syndrome is caused because ethanol rapidly crosses the placenta and causes the fetal blood to reach the same concentration as that of the maternal blood. The fetal liver, however, does not have alcohol dehydrogenase activity and relies on the enzymes of the maternal blood to metabolize the alcohol. The ethanol in the fetal bloodstream then triggers apoptotic neurodegeneration and causes neuronal and glial migration in the developing nervous system.
5. In acute alcohol consumption the most important enzymes at play are mostly alcohol dehydrogenase and MEOS can come into play when alcohol concentrations become too high. In chronic alcohol consumption the MEOS are the most active enzymes and their activity is induced by the chronic alcohol consumption and this increases the alcohol metabolism.  
6. Alcohol potentiates the effects of vasodilators, hypoglycemic drugs, sedatives and depressants (alcohol can increase their depressant response) as well as aspirin’s anti-platelet effects.

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

Alcohol is a small water-soluble molecule that is rapidly absorbed from the GIT. Due to the high lipophilicity of alcohol allows for a rapid distribution occurs across the blood brain barrier into the central nervous system. Peak alcohol levels in the blood can be seen within 30 minutes after consumption in fasting state. The total fluid in the body has an important role in the distribution of alcohol, the more body fluids, the longer the alcohol will take for the concentration to reach toxic levels. Alcohol is mainly metabolized by the liver (90%) by means of 2 enzyme systems, namely Alcohol Dehydrogenase and the MEOS (mixed function oxidases).

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

The 2 enzyme systems responsible for the metabolism of alcohols (ethanol) in the liver namely the Alcohol Dehydrogenase System and MEOS .

• •  The Alcohol Dehydrogenase system which catalyses the conversion of alcohol to Acetaldehyde using zero-order kinetics, resulting in the pathway becoming  saturated and independent on the concentration of ethanol. This pathway  metabolizes low to moderate amounts of alcohol [7-10g/h] and is dependent on NAD as a co-enzyme.
  • The Microsomal Ethanol-oxidising system (MEOS) is responsible for metabolizing ethanol at higher concentrations [>100mg/dL] to Acetaldehyde. Its activity can be induced with chronic consumption of alcohol.
  • Once alcohol is converted to Acetaldehyde, Aldehyde-dehydrogenase converts it to Acetate which is thereafter broken down be to Carbon Dioxide and water to be excreted through the urine or used to from Acetyl Co-A.
• Which drugs can affect this metabolism and what are the effects thereof?

Drugs that influence the metabolism of alcohol include: Disulfiram, Metronidazole, Cephalosporin and Hypoglycaemic drugs. These drug result in the inhibition of Aldehyde Dehydrogenase leading to the accumulation of Acetaldehyde in the body. The increased concentrations of Acetaldehyde in the body will cause the same negative effects experienced with excessive drinking such as nausea, vomiting, ataxia, headaches.

The following can be used in order to help an individual cope with anxiety:

• Ashwagandha
• Chamomile
• Valerian
• Lavender
• Galphimia glauca
• Passionflower
• Kava Kava
• Cannabidiol
• Magnesium supplements

The following can be used for insomnia:

• Valerian Root
• Chamomile
• Melatonin
• Lemon Balm
• Lavender
• Hops
• Passion Flower

1. Factors affecting the absorption and distribution of sedative hypnotics

The lipophilicity of the drug affects the rate of absorption which in turn affects its distribution. The more lipid soluble a drug is, the more likely it is to cross the bbb and more likely to have a rapid set of action and thus suppress the CNS

2. What is meant by redistribution?

This happens when drugs get absorbed into the systematic circulation and is distributed from the brain to other tissue. Most lipid soluble are distributed to the brain, heart, kidney etc and then it gets distributed to the fat and muscle. This process prolongs the duration of action of the drug.

3. BD metabolised

• Dealkylation to active metabolites
• Oxidation by cyp P450 to active metabolite
• Conjugation of the oxidised metabolite with glucuronic acid to form an inactive metabolite.

4. BD converted to desmethyldiazepam include diazepam, cholarazepam, prazepam, chlorodiazepoxide, ketazolam. Acitve metabolites gives us a longer duration of action.

5. Oxazepam, lorazepam, temazepam, lormetazepam. This helps with patients who have liver cirhosssis , patients who on cimetidine or sort and therefore help as it does not depend on the enzyme to produce an effect.

6. This is when a drug increases the amount of enzymes in the body and thus increase the rate of metabolism and thus results in a lesser therapeutic effect.

1. Anterograde amnesia

This refers to when a person experiences loss of memory of any new experience done during the drug’s use of action, drugs such as triazolam, lorazepam and midazolam may cause this.

2. Effects of sedative hypnotics on sleep patterns

• Decrease the time it takes to fall asleep
• Decrease the duration of REM sleep
• Increase the duration of NREM phase 2 sleep
• Increase the amount of sleep in patients with <6 of sleep/night

3. Sedative hypnotics used as supplementary for anaesthesia

• Thiopental
• Midazolam
• Diazepam
• Lorazepam

4. Sedative hypnotics used for anticonvulsants

• Diazepam
• Lorazepam
• Clonazepam
• Clobazam
• Nitrozepam
• Phenobarbitone

5. Carbamates and BDs, muscle-relaxing effect

These drugs result in hyperpolarization and thus cause an inhibitory effect on the post synaptic neurons and the internueronal transmission resulting in skeletal neuromuscular junction depression and they cause muscle relaxation.

6. Sedative hypnotics on the respiratory and CS

RS: these drugs can cause the medulla respiratory center to be depressed, this depression is usually seen in patients with pulmonary disease

CVS: These drugs can cause depression of the medullary vasomotor, and is this depression is seen in patients with CVS problems and impairments which may lead to fatal problems

1. Ligand gated ion channels and  voltage gated ion channels
2. Voltage gated: -  Activation by means of changes in the action potential of the cell , transmit signals from the cell body to nerve terminal , involves Na, Ca, K channels for action potential propagation(binds to specific  ions)

Ligand gated : Activation by means of a ligand coming and binding to the receptor the neuronal membrane leading to the direct open of channels , non-specific and binds to neurotransmitters  such as serotonin, dopamine etc. 

3.  

4. Ionotropic 

- GABA A

-Nicotinic receptor

-EAA

- 5-HT3

Metabotropic

1. Adenyl cyclase

• B1+2 and D1 : These stimulate the production of 2^nd msg CAMP
• D2, A2, M2, GABA B , 5HT1A ,5HT1B: these suppress the production of 2^nd msg CAMP

2. Phospholipase C

• A1, 5HT2, M1, H1 : stimulate the formation of 2^nd msg DAG and IP3

5. 

1. EPSP : This refers to when there’s an influx of sodium and calcium into cell through the opening of channels due to depolarization of the membrane resulting in an excitory post synpatic potential . Eg. Nicotine receptor when Ach comes and stimulates this receptor theres an influx of Na
2. IPSP: this refers to the suppression of action potential as a result of hyper-polarization

Eg.: GABA a being suppressed by the gama butliyic amino acid resulting due to an influx of chloride ions as a result of hyper polarization of membrane resulting in IPSP.

6. It is important for the release of  NT into the synaptic cleft. This happens when the action potential arrives at the axon terminal of the presynaptic neuron resulting in the depolarization of the membrane rendering an influx of calcium into the cell,This then causes the vesicle to rupture by means of fusion thereby releasing the neurotransmiiter to allow for effect.