Lecture 2 - Introduction to Neuropharmacology

neuropharmacology

effects of chemicals on the cells of the nervous system

psychopharmacology

effects of chemicals on behavior

neuropsychopharmacology

combination of neuropharmacology and psychopharmacology, involves studying how chemicals affect the cells of the nervous system

what is a drug?

a chemical substance that produces biological effects when ingested, it can be naturally occurring or manufactured, drugs are distinguished from food and minerals

routes of administration

determine the magnitude of the drug’s effects, could be by injection, orally, inhalation, etc,  determines onset and duration of drug effect

cannabis

very highly ranked, even true in places where it is illegal/highly regulated

potential therapeutic uses of drugs

more positive and less tightly regulated than those with significant drawbacks/risks

drugs with potential risks/drawback 

includes those that have a risk for potential overdose, concerning side effects, etc

harmfulness

not the ole predictor of a drug’s legal status, the score would never be zero, could be a physical sense or in a psychological, legal sense, could refer to dependence

desired effect

therapeutic

unwanted effects

side effects

classifying drugs

what is a good effect is relative to the context, desired and unwanted effects are both related to the drug’s dose so as it increases the effects increase too, psychedelics are objectively less harmful but way more regulated than alcohol

cheese effect

hypertension, take a drug that interferes with ability to process a certain food that causes hypertension

dose response curves

different drugs could have the same effect at different doses, increase the dose and observe the response, it doesn’t happen at the same rate for every drug so the effect could be very large for a small dose and vice versa, the relationship varies depending on the drug context and potency 

potency

the association between the drug and the effect, amount of drug required to elicit an effect, highly potent drugs require low doses because they are very strong

ED50

stands for effective dose 50, dose at which 50% of population shows the desired effect, looking for change in the pain, normalized to out of 100%, only go up to 100, have different responses

pain relief drugs

hydromorphone, morphine, codeine and aspirin (very high doses required for an effect such as codeine and aspirin but opposite is true for hydromorphone and morphine), so aspirin is weaker than say hydromorphone, ED50 for these drugs are different, the curves are the same so it is the same molecular mechanism that is being differentially activated by the drug (hydromorphone, morphine and codeine have the same shape but aspirin doesn’t)

TD50

toxic dose 50, dose at which toxic effects occur in 50% of people, for a drug to be widely used it has to be likely to cause positive effects and unlikely to cause unwanted ones, (we want a low ED50 and a high TD50)

therapeutic index

measures the difference between dose response curves for desired and unwanted effects, the size varies from wide to narrow, in this window, a dose where desired effects are maximal, unwanted effects are minimal

what issues do we see with TI?

oversimplification, understates the value of some drugs, ignores chronic effects and species differences

oversimplification

like polypharmacy where you use a combo of drugs to target the same thing, administration of multiple drugs at once

understating the value of drugs

narrow therapeutic windows but still used if no other option if available, leads to small TI

pharmacokinetics

study of how a drug gets to its target and what the body does to the drug (absorption, metabolism, distribution, excretion), determines how hard a drug hits you (if its quickly metabolized the effect is very short)

intravenous drug administration

hits hard and fast (in emergency situations, overdosing is more likely cause it circulates more quickly, some people are very scared of needles, need trained personal to administer it)

oral drug administration

slow distribution (perioral routes, takes longer to hits you, accessibility and effects last longer, less likely to overdose), convenience in safety

epidural drug administration

when the drug is injected in the spine, used for pain relief during labor

enteral drug administration

include GI tract and first pass liver metabolism (oral and rectal), sometimes metabolism generates active compounds

parental drug administration

bypasses the GI tract (everything else)

blood brain barrier

astrocytes control entry of substances into the brain, regulated by passage, some things can cross easily, some can cross sometimes and some not at all

catecholamines

can’t cross the blood brain barrier, example would be dopamine

compartments

brain is separate from the rest of the body and blood supply so peripheral measurements of neurotransmitter levels are different from central ones

drug metabolism

metabolic processes in the stomach and liver can turn drugs into active forms

prodrugs

drugs activated by metabolic processes only once inside the body

half life

can be short or long, after 6 a drug is considered eliminated, this varies between and within the drug classes

why does half life matter?

because if it hits early and clears quick it is associated with abuse potential,, multiple drug doses are required at specific intervals to maintain a steady state level

pharmacodynamics

the study of the drug interactions with its target and how it brings about the drug’s effects

drug mechanisms

they can affect many parts of a neurotransmitter

orthostatic binding site

primary agonist binding site (other compounds can interact with other parts of the receptor

benzodiazepine site

on another part of the receptor (interaction of a drug with a different site)

allosteric

a location on a protein like an enzyme or receptor that is separate from its primary active site

antagonist interaction

bind to a binding site and not activate anything at all

full agonistic interaction

binds and activates as much as the primary ligand

partial agonist 

binds and activates but not as much 

inverse agonist

binds and other things can happen like lowering baseline activity

agonist and antagonist

usually a competitive interaction so when both are present, they compete because only one can bind, the one with the stronger concentration outcompetes the other, for instance in overdose you need enough antagonist to outcompete the drug and prevent overdosing (naloxone)

transporter blockers

SSRIs and psychostimulant drugs, they block other transmitters without directly affecting the receptors

selective releasing agents

increase the release of a given transmitter (ex; SSRAs increase serotonin release, different tool for modulating serotonin than blocking the transporter)

potentiation

can occur because drugs target the same site or interact with the same enzymes (ex: benzos and alcohol)

individual differences factors

perceptions, current state/mood, history, expectations and genetics

expectations about drugs

pre-existing beliefs about drug efficacy and can influence the reaction to drugs, people who believe a drug won't work might not respond at all, ppl who believe a drug will work might respond more strongly (same applies for a fake drug)

placebo

pharmacologically inert substance with no chemical effects

placebo effect

response to treatment that cannot be attributed to its active ingredient, they are real affects but the mechanism by which the effect arises is different, the strength is lower but it is a real response, a better definition of it is a substance that influences behavior by an alternative mechanism

classical conditioning in dogs

compare variety of cues with drugs repeatedly, signal delivery and some kind of response

placebo effect in classical conditioning

acquired through conditioning, stimulates an effect similar to the drug response, mimics the drug, more common for desirable effects, mitigated by distinct pathways 

unconditioned stimulus

drug’s effect

unconditioned response

body’s response to that state

conditioned stimulus

anything paired with the drug

classical conditioning response effects

defensive responses opposite to the drugs’ effect

verbal suggestions

boosted expectations (stronger), lowered expectations (weaker)

nocebo effect

expectation that can also influence report of unpleasant side effects

is the placebo effect a bad thing?

not necessarily because it can help treat problems but poses risk for exploitation, pursuit of these effects could be weaker over available treatments but you could potentially alternate between the real drug and placebo during a therapeutic program and if it works, it could reduce risk and costs

single blinding

when you only blind the participant, don’t know whether or not you are getting the real treatment, it helps identify placebo effect but its harder for extreme treatments

double blinding

this is when the subject and the administrator don’t know the treatment, it is good for identifying placebo effects and limits researcher bias

enzyme CYP2D6

contributes to drug metabolism, controversy over the use of medicine in drug testing, some gene variants for alcohol metabolism are associated with poor alcohol tolerance and reduced risk of alcoholism

parkinson’s disease

a movement disorder where there is less dopamine signaling in the mesostriatal pathway, treatment is meant to increase dopamine levels to supplement the deficiency

what are the side effects of dopamine drugs

changes in cognition, reward guided behavior, compulsive behavior, and causes hallucinations

what pathways are affected in parkinson’s disease?

the mesostriatal pathway primarily but also the mesolimbic, mesocortical and tuberoinfundibular pathway 

parkinson’s disease treatment

the precursor is given to supplement DA deficiency instead of dopamine itself because it can’t cross the blood brain barrier, so they inject L- DOPA

tolerance

decline in drug response as body adapts to the drug (related to frequency of use and drug-taking environment), it doesn’t last forever, intake increase and as blood alcohol level increases it falls off at a certain point with tolerance this happens quicker due to drinking alcohol more frequently, it is observed in many drugs and leads to taking higher doses creating safety concerns

what are the different types of tolerance?

metabolic, pharmacodynamic and behavioral

metabolic tolerance

change in metabolic pathways (ex; alcohol)

pharmacodynamic tolerance

change in how cells respond to the drug, change in drug target, most common type

behavioral tolerance

people compensating for the effects of a drug (learned), effort to mask speech problems with too much alc

cross tolerance

this is when you take one drug and become tolerant to another, the drugs have to have a common target, for instance, alcohol tolerance may involve changes to GABA receptors

withdrawal

level depends on the class of drug, it is seen for recreational and therapeutic drugs, effects can be severe and contributing reason for relapse is the pain experienced during this stage

sensitization

this is an increase in drug response, in can be observed in amphetamines and cocaine you can tell by presentation of rearing or locomotor activity in animals

what factors should you consider when looking at drug treatments?

efficacy, onset, safety and access/cost

efficacy

how well the treatment works, individual differences in response

onset

how quickly the treatment works

safety 

the therapeutic window and side effects

what is drug classification based on?

based on chemical structure, biological effects, behavioral effects, abuse potential, legal status, etc

psychoactive drugs

these are drugs that alter mood, thought and behavior, they manage neuropsychological illness and can be abused 

AA agents and sedative-hypnotics

these are the first category of drugs, they include benzodiazepines, alcohol, gamma-hydroxybutyrate (GHB) and anesthetics like ketamine, they act in GABAa receptors and affect consciousness

antipsychotics

they are the second category of drugs, they are used to treat psychosis, they block dopamine receptor 2

1st gen psychotics

includes chlorpromazine and haloperidol

2nd gen psychotics

they are atypical antipsychotics like clozapine, they still target dopamine receptors but they also affect other targets

psychosis

this is a condition where the mind loses touch with reality, it used to be treated with lobotomy or psychiatric institutions

antidepressants and mood stabilizers

this is the third category of drugs, they include lithium for bipolar disorder and treatment for mood disorders like depression, other examples include TCAs, SSRIs and most of them affect the monoamine system

opioid analgesics

they are the fourth class of drugs, they include morphine and heroin, they target opiate receptors which are involved in mood, pain, etc, they have strong pain relieving effects but also a very high potential for tolerance, addiction and withdrawal, misuse is a major factor for the opioid crisis

psychotropics

affect a person’s mental state, they are a broad category that includes cocaine, amphetamine, nicotine and caffeine, there are many hallucinogenic drugs in this category, they have pleasurable psychological effects that make them attractive for recreational use (ex; LSD)

near death like experiences

these include drugs like DMT, they are profound and life changing drugs

micro-dosing

taking in low sub-hallucinogenic doses for many different reasons like enhancing creativity and dealing with anxiety