Block 6 drugs Flashcards
How are cholinergic neurons and Alzheimer’s related ?
It is thought that a portion of the cognitive and behavioral decline associated with Alzheimer’s are the result of decreased cholinergic transmission in the central nervous system.
One way we break down acetylcholine is using acetylcholinesterase.
Donepezil selectively and reversibly inhibits the acetylcholinesterase enzyme, which normally breaks down acetylcholine.
Donepezil
Drug class: acetylcholinesterase inhibitor
Indication: is used for the treatment of dementia of the Alzheimer’s type. Orally or trans dermally.
Mechanism: Donepezil selectively and reversibly inhibits the acetylcholinesterase enzyme, which normally breaks down acetylcholine.
Contraindications:
-it can only be taken by adults not children
- careful if you have liver problems
- if you have had stomach or gut ulcers
- epilepsy
Side effects:
- sleep disorders, vomiting, GI problems
How is the continuous activation of the NMDA receptor and alzheimers related?
- NMDA receptor is a type of glutamate receptor which uses the neurotransmitter glutamate.
- Too much glutamate is thought to causes neurotoxicity which causes the symptoms of Alzheimer’s.
- Memantine blocks the NMDA receptors stopping the excitatory effects of glutamate which would cause neurotoxicity leading to the symptoms of Alzheimers.
Memantine
Drug class: NMDA receptor antagonist
Indications: used to treat moderate to severe dementia in Alzheimer’s.
Mechanism:
The pharmacological effect of memantine likely occurs via the drug’s behavior as an uncompetitive (open-channel) NMDA receptor antagonist, preventing glutamate action on this receptor.
Contraindications:
- severe hepatic impairment
-history of epilepsy
Side effects:
- hypertension, dyspnea (laboured breathing)
What are SSRIs ?
- selective serotonin reuptake inhibitors
- They stop the reuptake of serotonin by inhibiting SERT ( serotonin transporter)
- Serotonin helps regulate mood, emotions and feeding behaviour.
- SSRIs are the first line therapy for depression
Fluoxetine
Drug class: SSRI ( selective serotonin reuptake inhibitor)
Indicator: used to treat major depressive disorder, bulimia, OCD, prremenstrual dysphoric disorder, panic disorder, and bipolar I.
What is a TCA?
- Tricyclic Antidepressants (TCAs)
- Major depressive disorder: is feelings of persistent sadness and a loss of interest in everyday activities
- Exact cause of MDD is unknown however it is thought to be caused by low levels of the neurotransmitter SEROTONIN, NOREPINEPHRINE and DOPAMINE.
- TCAs increase the level of serotonin and norepinephrine to alleviate the symptoms of depression.
- The common suffixes for TCAs are -ipramine and -tryptyline
TCA’s are not first line treatment for depression because of their severe side effects
The severe side effects:
-3cs ( convulsion, coma, and cardiotoxicity)
- serotonin syndrome
Amitriptyline
Drug class:
non- selective tricyclic antidepressant (TCA)
Indication:
- major depressive disorder in adults
- management of neuropathic pain in adults
- prevention of chronic tension type headache (CTTH) in adults
- prevention of migraines
Mechanism: stops the reuptake of serotonin and NE from the synaptic cleft
Contraindications:
- arrhythmias
- heart block
- immediate recovery period after myocardial infarction.
Side effects:
- prolonged QT interval
- Arryhthmias
- drowsiness
- Anticholinergic syndrome
- Serotonin syndrome
- inhibits P450 enzymes which are used to metabolize other drugs so can lead to the build up of other drugs.
Serotonergic neurons ?
Noradrenergic neurons ?
Serotonergic neurons (produce and store serotonin):
- serotonin is also known as 5-HT
- 5-HT binds to 5-HT2 receptors on the postsynaptic membrane which increases the amount of serotonin which regulates mood, feeding and reproductive behaviour.
Noradrenergic neurons ( produce and store norepinephrine :
- norepinephrine binds to norepinephrine receptors
- which increases the amount of norepinephrine which boosts alertness
What are SERT and NET ?
- On the presynaptic membrane of serotonergic neurons we have serotonin transporters (SERT)
- On the presynaptic membrane of noradrenergic neurons we have norepinephrine transporters (NET).
- These transporters transport neurotransmitters (serotonin and noradrenaline) which are inside the synaptic cleft back into the presynaptic neuron. This leads to decreased neurotransmitter concentration within the synaptic cleft, causing the postsynaptic neurons to stop firing.
- So, in conditions such as major depressive disorder, tricyclic antidepressants can be used to increase the levels of serotonin and norepinephrine.
- As long as there is neurotransmitter in the synaptic cleft teh post synaptic neuron will continue to fire
What are primary and secondary TCAs ?
Primary TCAs ( non selective TCAs) : inhibit the reuptake of both norepinephrine and serotonin
Secondary TCAs ( selective): only inhibit the reuptake of NE.
Buspirone
- unlike benzodiazapenes and barbiturates buspirone is not associated with a risk of developing physical dependence.
- In clinical trials buspirone showed limited clinical effectiveness in treating panic disorders, severe anxiety, phobias and OCD.
- There are two receptors involved in the brains anxiety and fear circuit, these are 5-HT1A receptor subtypes.
- 5-HT1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of seretonergic neurons. When activated 5-HT1A autoreceptors causes neuron hyperpolarisation and reduces the firing rate of the serotonergic neuron.
- Buspirone acts as a full agonist at presynaptic 5-HT1a receptors
Buspirone
Drug class: azaspirodecanedione
anxiolytic agent
Indication:
- used for the management of anxiety disorders
- short term relief of the symptoms of anxiety
- second line treatment for depression
- takes 2-4 weeks for anxiety symptoms to get better.
Mechanism :
- serotonin 5-HT1A receptor agonist
Contraindications:
- do not take if you have EPILEPSY
Side effects:
abdominal pain, anger, concentration is impaired
Avoid if you are pregnant
What causes psychiatric disorder like anxiety and neurological disorders like seizures and epilepsy ?
Excitatory neurotransmitter:
When one neuron is stimulated, it’ll release excitatory neurotransmitters like glutamate which bind to receptors on the next neuron.
This causes the next neuron to depolarize and release its own excitatory neurotransmitters, propagating the signal throughout the brain.
Inhibitory neurotransmitter:
- Inhibitory neurons stop an action potential from being started in the post synaptic neuron.
- The inhibitory neurons release GABA ( neurotransmitter). GABA binds to GABA receptors.
- GABA receptors are ligand gated ion channels that open up and allow Cl- to enter the ion cell. The influx of negatively charged ions causes hyperpolarization (membrane potential becomes more negative), which means its more difficult for it to depolarize and fire off an action potential
- Alright, now there are cases where neurons in the brain start sending out more excitatory signals than normal.
This can occur due to either too much excitation by the excitatory neurotransmitters, or too little inhibition by the inhibitory neurotransmitters like GABA.
Excessive excitatory signals can cause psychiatric disorders like anxiety, and neurological disorders like seizures and epilepsy.
- Okay, so one way we can decrease the excitatory signals is by enhancing the effect of inhibitory neurons through medication like benzodiazepines.
How do benzodiazepines work ?
These medications target the BZ site of GABAA receptors, which is located between ⍺1 and 𝛾2 subunits of the receptor.
When both benzodiazepine and GABA bind to their separate sites on the receptor, benzodiazepines increase the frequency of Cl- channels opening, thereby increasing the influx of Cl- ions.
As a result, high intracellular concentrations of Cl- ions cause membrane hyperpolarization, which means it’s much more difficult for neuron to depolarize and fire off an action potential.
Lithium metabolism ?
- Lithium is only metabolized in the KIDNEYS
- Reabsorbed via Na+ channels (primary PCT)
- Narrow therapeutic index - must measure serum levels frequently. Small alterations in lithium dose, concentration, or metabolism may quickly precipitate acute toxicity. As a result, patients on lithium benefit from strict adherence and frequent serum level monitoring.
- Clearance decreased when taken with NSAIDs, thiazides, ACE inhibitors, vancomycin and contrast agents
- Lithium accumulation - can cause decreased urine concentration which leads to polyuria. Lithium-induced nephrogenic diabetes insipidus would be expected to induce increased output of dilute urine (polyuria).
Typical Antipsychotics (1st generation )
-Typical antipsychotics block D2 (dopaminergic) receptors.
-Their side effects often stem from their inhibition of HAM: histamine receptors, α1 adrenergic receptors, and muscarinic receptors.
- Typical antipsychotics are not very specific in their inhibition of dopamine receptors. Therefore, several dopaminergic pathways can be inhibited by typical antipsychotics. The intended action of typical antipsychotics is to inhibit D2 receptors in the mesolimbic pathway, thereby reducing the positive symptoms of schizophrenia (hallucinations, delusions, etc.). Unintended blockage of the nigrostriatal pathway may lead to (extrapyramidal symptoms) EPS, while unintended blockage of the tuberoinfundibular pathway may lead to hyperprolactinemia.
Atypical antipsychotics (second generation ) ?
- D2 receptor blockade
- D2 receptor blockade is weaker than 1st gen antipsychotics
- Atypical antipsychotics 5HT2 antagonism
- Atypical antipsychotics are our fist choice of antipsychotic as they have fewer side effects
Dopaminergic pathways
