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Flashcards in Intro to centrally acting drugs week Deck (14)
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What 4 NT systems bypass thalamic circuitry? What does this mean? What are the implications?

Four NT projection systems bypass the thalamus-DA, Ach, NE, 5HT. The thalamus is the central way-station (heart of the brain; in cross section it is heart shaped). Most information that enters the cortical mantle makes synapses in the thalamus. However, four major NT systems by and large bypass this structure. They thus modulate function of the cortex while innervating other sub-cortical structures that affect cortical function. This is important to appreciate because their modulatory effects do not “change or create” behavior, but rather subtly influence the behavior. View these 4 NT systems as the volume control of the function rather than choosing the radio station. Thus, DA and NE will enhance concentration, but not create it. Giving a drug that increases DA improves concentration in an individual (modulates it) but is not responsible for the actual alerting/arousing response.


Where is DA synthesized? 

Where do DA neurons project to? What is the function?

Where is ACh synthesized? 

Where do ACh neurons project to? What is the function?

DA from the midbrain (Substantia nigra and Ventral tegmental area (VTA)), project to the striatum (caudate + putamen), n. accumbens and frontal cortex to regulate the rate at which motor and limbic information passes through these systems.

ACh from the reticular formation (pedunculo pontine n. FA: Basal nucleus of Meynert) projects to reticular nuclei of the thalamus (regulates throughput of the thalamic nuclei themselves) to regulate the rate at which sensory information enters the cortex. From the basal forebrain, it projects to the hippocampus and cortex to regulate memory consolidation and recall, respectively.


Where is 5HT synthesized? 

Where do 5HT neurons project to? What is the function?

Where is NE synthesized? Where do NE neurons project to?

5HT from the raphe nuclear groups of the midbrain, pons, and medulla project to cortex, hypothalamus, and striatum to “gate” the limbic brain’s ability to interact with the cortex.

NE from the locus ceruleus projects to cortex, hypothalamus and basal forebrain to regulate the rate at which sensory information interacts with the cortex.


What are the issues with sustained release formulations?

What are depot formulations?  How are they administered? What are the issues with them?

Problems with Sustained release formulations include dose-dumping and delayed release.

Depot formulations are “oily based” formulations that are generally delivered i.m. where they slowly leach into the circulation. Major problem is they cannot be recalled after delivery (e.g., depot fluphenazine for schizophrenia).


Most CNS drugs are absorbed by what process?

How are more water soluble drugs absorbed?

Eating what type of meal may effect Levodopa absorption? How is levodopa absorbed?

1. Most CNS drugs are absorbed by bulk diffusion

2. Levodopa (anti-Parkinsonism drug) as well as other more water-soluble drugs are absorbed by facilitated diffusion and since it is carrier-mediated, competition can occur between the drug and other large neutral amino acids such as tryptophan. Taking in a meal high in large neutral amino acids can reduce the absorption of levodopa and reduce its antiparkinsonian efficacy.


Drugs with what property influence the brain first (before any other organ)? Why?

What is the most important factor for determination of effctive duration of action on the the CNS for a particular drug? Why?

Distribution: The movement of drug to its site of action into brain is dependent upon the drug’s partition co-efficient (K). Drugs entering brain must be lipid soluble to penetrate BBB. Fat soluble drugs influence the brain first because of the disproportionate percentage of blood perfused to brain (2% body weight/20% cardiac output). Drugs such as diazepam (Valium), therefore, influence brain first even though they prefer fat because of their high lipid solubility. Even though diazepam has a 96 hour half-life, it does not induce sedation for that long because the drug redistributes to other parts of the body (brain to muscle to organs and then fat).

Redistribution often determines the effective duration of action of a CNS drug more so than its half-life. Thus, the drug enters the brain to produce its effect and then leaves the brain to terminate its effect. The more lipid soluble a drug, the more quickly it enters brain; but the shorter its duration of effect there because of redistribution out of the brain.


What may effect the integrity of the BBB?

Principles of absorption seen in the gut (i.e., bulk diffusion, carrier mediated transport) apply to passage across the BBB as well.

Several factors influence the integrity of the BBB including inflammation, alcohol, trauma, stroke, epilepsy, and neurodegeneration.


What receptors are the most prominent in the chemoreceptor trigger zone (area postrema)?

What is the effect of NTs/drugs acting on the CTZ?

Where is the area postrema located?

The CTZ/area postrema is located in the floor of the 4th ventricle. It does not contain a BBB. 

The CTZ is rich in DA and 5HT receptors which trigger centrally mediated vomiting.

5HT and DA agonists induce vomiting. 5HT and DA antagonists are anti-emetics.




Clinical use


MOA:  5-HT3 antagonist;  decreased vagal stimulation. Powerful central-acting antiemetic. 

At a party but feeling queasy? Keep on dancing with ondansetron!

Clinical use: Control vomiting postoperatively and in patients undergoing cancer chemotherapy.

Toxicities: Headache, constipation, QT interval prolongation




Clinical use


MOA: D2 receptor antagonist.  resting tone, contractility, LES tone, motility. Does not influence colon transport time.

Clinical use: Diabetic and postsurgery gastroparesis, antiemetic.

Toxicities: increased parkinsonian effects, tardive dyskinesia. Restlessness, drowsiness, fatigue, depression, diarrhea. Drug interaction with digoxin and diabetic agents. Contraindicated in patients with small bowel obstruction or Parkinson disease (due to D1-receptor blockade).


MOA of the following drugs:



syrup of Ipepac

Prochlorperazine (Compazine) a structural relative of chlorpromazine (DA antagonist) and an antipsychotic was widely used at one time.

Apomorphine and syrup of Ipecac (both DA agonists) induce vomiting.


Why is diffusion of drugs limited even once a drug gains access to the CNS?


Once a drug gains access to the CNS compartment, however, its diffusion is severely limited. The brain has the lowest extracellular space of all organs in the body.

(1) There are physical barriers to bulk flow including glia

(2) Enzymatic processes and reuptake of drugs by neurons and glia reduce diffusion.


What two enzymes are responsible for most of the biotransformation of CNS drugs?

Which exhibits significant genetic polymorphism?

CYP2D6 and CYP3A4

CYP2D6 exhibits significant genetic polymorphism


CYP2D6 is not typically induced. Explain the significance of this.

Explain the significance of genetic polymorphisms in CYPD2D6.

CYP2D6, a major cytochrome P450 biotransforming enzyme that is also present in the BBB, is not typically induced. Thus, drugs such as haloperidol (an antipsychotic), most of the antidepressants, and codeine, that are normally metabolized by CYP2D6, do not change bioavailability as a result of chronic exposure because of enzyme induction. Thus, they do not exhibit pharmacokinetic tolerance.

However, CYP2D6 exhibits significant genetic polymorphism. Thus, the ability to biotransform a CYP2D6 substrate varies dramatically across the population. There are extensive metabolizers (EMs) and poor metabolizers (PMs). European descendants are 3-10% PMs whereas this phenotype is virtually non-existent in descendants of the Pacific rim countries. Thus, in 3-10% of European descendants, the prodrug codeine, which needs to be converted to morphine by CYP2D6 for its analgesic effects, is not very effective in European descendents while codeine is always converted to morphine in descendants of Pacific rim countries.