Lecture 8 Flashcards
Psychosis
1% of people
Schizophrenea
Was treated by asylums
Cost a lot so conditions dropped rapidly
Became horrible
Moved to outpatient care when antipsychotics came along
Now usually short term treatment as inpatients and care in community
Antipsychotics
Directly block the D2 dopamine receptor which is an inhibitory metabotropic receptor 1st gen (typical) were specific to D2 but had too many sides 2nd gen (atypical) are less specific to d2 and have less sides
Dirty drugs
Bind to many receptors
Direct serotonin receptor agonists
Recreational use as hallucinogens
Directly activate serotonin 2A receptors - inhibitory metabotropic receptors
BUT not all serotonin 2A receptor activation cases hallucinations
Hallucinogens
Mescaline, psilocybin and LSD bind to the serotonin 2a receptor and cause a signaling cascade that starts with G q/11
Serotonin usually does this too
BUT these three also activate the receptor in a way that stimulates Gi/o and causes hallucinations/ This action by the 5HT2A induced activation is what causes them
Lisuride is a treatment tfo migrated that also does not activate Gi/o
Biased Agonism
When a metabotropic receptor ligands causes the receptor to preferentially activate one type of intracellular g protein whereas another ligand preferentially activates another by binding to the same receptor.
Sasha Shulgin
Made many psychoactive drugs
Useful because you cannot test these on animals as they cannot tell you the results and it is unethical to use humans
He wrote a lot of books about this stuff and illegal drugs he created flooded the market after he made them
Drugs can affect postsynaptic receptor activity directly or indirectly
Direct agonist/antagonist - bind to the receptor and exert an effect
Indirect agonist/antagonist - the proteins they bind to are not postsynaptic receptors but they still have an effect here
Postsynaptic agonist = increase activity of postsynaptic receptor. Antagonists decrease it
We classify drugs based on
their effects on the postsynaptic receptor activity
Competitive agonists
Chemical level context
Act similarly to the endogenous neurotransmitter
Binds where this usually binds
Can be full or partial agonists
Full = like normal
CONTEXT
If your brain is full of serotonin, a full serotonin receptor agonist would not do much - same as normal
BUT
in this situation, if you had a partial agonist there would be less activation. In this individual it would be a partial antagonist
If the person had little serotonin at baseline, it would increase activity and hence be a partial agonist
What determines the competition for a receptor site between a neurotransmitter and an exogenous drug?
Affinity and relative concentration
Non-competitive binding
Drug binds to a site that does not interfere with the site used by the principle ligand
3 types of non-competitive drug
Non-competitive agonist, fully or partially activates the receptor
Non-competitive antagonist foully blocks receptor activation. It does not compete, it wins without competing
Allosteric modulators: Non-competitive drugs that only influence activity when the neurotransmitter is bound to the receptor
Negative allosteric modulators reduce the effect of primary ligands
Positive allosteric modulators increase them
Do yo need to bind to a receptor to influence their effects?
No. Many drugs influence the activity of post-synaptic receptors without binding to them
Parkinsons
Due to atrophy of dopaminergic neurons
Give L dopa as it passes BBB and is only taken up by dopaminergic neurons because they think its dopamine (via dopamine reuptake protein)
Does not have effects in the body as not dopamine. Endocrine cells do not take it up as they take back very little of the dopamine they release (it should all be carried away via the blood) so no large drop in BP
Is then changed into dopamine in the cytoplasm and results in an increased secretion of dopamine therefore is a dopamine post synaptic receptor agonist
Titrate dose up as neurons die off. Eventually stops working but minimizes symptoms well for years
Drug serves as a precursor
Agonist AGO
L dopa
Drug inhibits the release of NT
Inhibits synaptic vesicle release like Botox
Increasing neurotransmitter production and release
Conventional neurotransmitters are made in the axon terminals. Precursor molecules can be administered as drugs leading to increased synthesis and release. Agonist
Stopping enzymatic synthesis of NT
Blocking the enzyme which makes the neurotransmitter. Often used in research.
Blocking uptake into vesicles
Some drugs block uptake of NT into vesicles. When this happens, vesicles can remain empty so nothing is released when they fuse with the cell membrane
Drugs enhance the release of NT
Some agonists (black widow venom) bind and activate the vesicular release mechanism so directly causes the release of NT
agonist
Act on NT in synaptic cleft (3 mechanisms)
1) Block the enzymatic degradation (neostigmine) Agonist
2) Block reuptake proteins
Agonist
3) Reverse reuptake proteins such that the NT can leave directly through this pore Agonist
Block reuptake proteins of catecholamines
Methylphenidate (Ritalin)
Cocaine
Reverse reuptake proteins such that the NT can leave directly through this pore (catecholamines)
Adderall
Crystal meth
Autoreceptor drugs
Stimulates autoreceptors ANT
Blocks autoreceptors AGO
11 ways to lose your mind learning drug actions
1) Drug serves as chemical precursor AGO
2) Drug inactivates synthetic enzyme ANT
3) Drug prevents storage of NT in vesicles ANT
4) Drug stimulates the release of NT AGO
5) Drug inhibits the release of NT AGO
6) Drug stimulates postsynaptic receptors AGO
7) Drug blocks postsynaptic receptors ANT
8) Drug stimulates autoreceptors ANT
9) Drug blocks autoreceptors AGO
10) Drug blocks reuptake AGO
11) Drug inactivates acetylcholinesterase AGO
Dose Response Curve
is a graph of the magnitude of an effect of a drug as a function of the amount that is administered. It is obtained by giving subjects various doses.
2 curves. Difference between the two is the margin of safety, the therapeutic index is the ration between the dose that produces the desired effect in 50% of people and toxic effects in 50%
Pharmacokinetics
Process by which drugs are absorbed, distributed within the body, broken down and excreted
Different drugs will have different ones
Routes of drug administration
3 things
1) Does the drug naturally cross the BBB
2) Is it better to have a high concentration of drug for a short time or a low concentration of drug for a long time
3) Where are the body are there enzymes that break down the drug
Stomach? Blood? Liver?
Tolerance
IS when the effects of the drug diminishes because of the repeated administration. It is the body’s attempt to compensate for the effects of a drug
Having developed tolerance, they will experience withdrawal effects which are the opposite effects of the drug
Sensitization
Occurs when a drug becomes more and more effective through repeated use
A placebo
an inert substance that has not direct physiological effect. It is given to subjects to control the effects of mere administration of a drug
