BBH 451 Exam 1, BBH 451 Exam 2, Exam 3 BBH 451

ADME

Absorption, Distribution, Metabolism, Excretion/Elimination

Axon

Action potential is transmitted down a long, tube-shaped extension (the axon) Axon carries the Action Potential from one end of the neuron to another

Enzymatic degradation - of a neurotransmitter

An enzyme that is present at the synapses breaks down excess neurotransmitter and is sent back into the presynaptic neuron to be used to create more neurotransmitter

How many half-lives until a drug is considered removed from the system?

6 half-lives (98.4% has been eliminated)

Criteria for neurotransmitters

1. be present in the presynaptic neuron, 2. be released into the synaptic cleft in response to an action potential 3. have receptors to interact with on the membrane of a postsynaptic cell.

A drug acts on GABA receptors by binding to those receptors and blocking all activity there. This drug is an:

Antagonist; An antagonist is a drug that binds to a receptor and blocks it, so this drug is the definition of an antagonist

how long until steady state is achieved

As administration continues on a regular schedule, a steady-state of drug concentration is reached usually takes about 5-6 half-lives less likely to experience side effects and withdrawal effects

COMT metabolizes what neurotransmitters

Catechol O- Methyltransferase (COMT) Dopamine, Norepinephrine

Neurotransmitter removal

Diffusion, enzymatic degradation, & reuptake

Explain the 3 ways that neurotransmitters are removed from the synaptic cleft. Then, discuss what would happen to neurotransmitter levels if a drug were to inhibit the effectiveness of one of these mechanisms.

Diffusion, enzyme degradation, reuptake are the three ways that neurotransmitters are removed from the synaptic cleft. The reason levels would increase would be that nothing is able to remove the neurotransmitter from the synaptic cleft. If nothing were causing a release, then the levels wouldn't go up at all.

therapeutic index efficacy

Drugs that are safe thus have very high Tis. Diazepam (aka Valium), for example, has a TI of 100:1. Alcohol only has a TI of 10:1. And heroin's TI is only 6:1.

Acetylcholine

Enzyme Degradation Terminated/metabolized by: Acetylcholinesterase

You are working in the ER when a patient comes in who has overdosed on heroin. She is in a semi-conscious state. There is a drug that can be given to reverse the symptoms of his overdose, but it must be able to take effect quickly and it is important that a very specific amount of the drug be administered. Which route of administration would you choose and why?

For this particular scenario, I would choose to administer the drug intravenously because this is a rapid and precise means of administration for a drug overdose in a clinical setting

randomized clinical trial (RCT)

Gold standard in pharmaceutical drug research A clinical study that uses a randomization process to assign subjects to either an experimental group(s) or a control (or comparison) group. Subjects in the experimental group receive the intervention or preventive measure of interest and then are compared to the subjects in the control (or comparison) group who did not receive the experimental manipulation

Describe a situation that might cause high levels of sympathetic nervous system activity and a situation that might cause high levels of parasympathetic nervous system activity.

High levels of sympathetic nervous system activity could result from being chased by a dog, which would create a fight-or-flight response because you are running for your life. On the other hand, high levels of parasympathetic nervous system activity could result from eating a heavy meal, which creates a rest-and digest response

Neurons (nerve cells)

Highly specialized to transmit messages from one part of the body to another

why is blinding used?

If participants know what group they are in, it can create bias as those who are in the treatment group might have expectations about the benefits of treatment that could influence the way they feel (this effect is known as the placebo effect and we'll discuss more in-depth shortly). If investigators know who is in what group, they might treat participants differently based on their group membership, again creating bias and disparities between the groups. If those who are analyzing the data are aware of who is in what group they could be tempted to manipulate data in order to obtain a specific result for the experiment

You are prescribing a seizure medication to a patient and it is important for the drug to be effective that it reach a steady-state level. The half-life of the drug is 6 hours. If the drug is administered every 6 hours, approximately how long will it take before the drug has reached a steady-state? Explain your reasoning.

If this drug is administered on a consistent schedule, a steady-state should be able to be achieved in five to six half-lives, which is approximately thirty to thirty-six hours because the blood concentration of the drug begins to remain consistent

For a drug to be safe, its TI should be as high as possible. Can you come up with an idea as to why this is the case?

If we have a drug with a low TI, then it means there is less of a difference between a potentially lethal dose and a potentially effective dose. The TI of 3 obtained above is a good example of a low TI. Imagine if you had a drug in your medicine cabinet that if you only took 3 times the effective dose, you had a 50% chance of dying. That's essentially what a TI of 3 means

Reuptake - of a neurotransmitter

Mechanism for removing excess neurotransmitter involving a specialized protein called a transporter or TRANSPORTER PROTEIN, present at the synapse. Excess neurotransmitter is transported back to the presynaptic neuron Inhibiting reuptake will cause neurotransmitter levels to RISE in the synaptic cleft

MAO metabolizes what neurotransmitters

Monoamine oxidase (MOA) Dopamine, Norepinephrine, Serotonin

An investigator discovered substance A, which is found in the axon terminals of neurons in a region of the prefrontal cortex. When an action potential excites these neurons, they release substance A. There are no receptors for substance A on postsynaptic neurons, but after substance A is released, it diffuses into the bloodstream and affects organs the peripheral nervous system. Is it a neurotransmitter?

NO; To answer this question, you need to consider the criteria we discussed for something to be considered a neurotransmitter. It must: 1) be present in the presynaptic neuron, 2) be released into the synaptic cleft in response to an action potential, 3) have receptors to interact with on the membrane of the postsynaptic cell. Substance A does not meet criterion 3, so it is not a neurotransmitter.

treatment/experimental group

One group receives an intervention, which involves exposing them to the independent variable (aka exposure), which is hypothesized to have some effect on the dependent variable (aka outcome)

Pharmacodynamics

Pharmacodynamics refers to how a drug interacts with the body and its receptors to produce effects

Define pharmacokinetics and pharmacodynamics. Give one example of each.

Pharmacokinetics explains the drugs bioavailability and how the drug is absorbed, distributed, metabolized, and eliminated from the body. An example of pharmacokinetics would be drug metabolism. Pharmacodynamics explains how the drug specifically affects the body and how the drug produces these effects (drug-receptor interactions). An example of this would be transporter proteins.

Pharmacokinetics

Pharmacokinetics refers to the course of a drug through the body. It involves things like absorption, distribution, metabolism, and elimination

Diffusion - of a neurotransmitter

Small amount of neurotransmitter will simply diffuse out of the synaptic cleft Not enough to remove all excess neurotransmitter from the synaptic cleft

How signaling occurs within and between neurons

Synapse - Presynaptic membrane (axon terminal of the neuron) Synaptic cleft Postsynaptic membrane (dendrite)

Imagine you have developed a new drug. Provide an example of an LD50 and ED50 that you think would be ideal for the drug to have (you can make up the doses, what is important is the relationship between the two). Explain what the therapeutic index would be and why this is ideal for your drug.

Tetraline has an ED50 of 10 mg and an LD50 of 1000 mg with a therapeutic index (TI) of 100 or 100:1. This is ideal because someone could take 100x or 1000 mg of Tetraline with only a 50% chance of dying; therefore consuming a lethal dose is less likely

ED50

The ED50 refers to the dose that is needed to elicit a response in 50% of the population; thus, it is the median effective dose (ED) They administer gradually increasing doses until they find the dose that works in 50% of the population (which puts the rats to sleep). This would be the ED50. In the figure above, this dose would be 10 mg. Then, researchers would continue increasing the dose of the drug until 50% of the rats died. The dose at which this occurred would be the LD50. In the figure above, this dose would be 30 mg.

LD50

The LD50 refers to the dose that results in the death of 50% of the population; it is the median lethal dose (LD). They administer gradually increasing doses until they find the dose that works in 50% of the population (which puts the rats to sleep). This would be the ED50. In the figure above, this dose would be 10 mg. Then, researchers would continue increasing the dose of the drug until 50% of the rats died. The dose at which this occurred would be the LD50. In the figure above, this dose would be 30 mg.

Briefly describe the structures that are considered part of the reward system, and explain generally how they interact when we experience something rewarding.

The structures that are considered part of the reward system are the ventral tegmental area and the nucleus accumbens. These two structures work together when we experience something rewarding by communicating with one another. This is accomplished because the ventral tegmental area releases axons to the nucleus accumbens, therefore, activating the release of dopamine.

Which of the following is true about a drug with a 4 hour half-life?

The time needed for the blood concentration to fall from 4 milligrams per milliliter to 2 milligrams per milliliter is 4 hours; If the half-life is 4 hours, then it would take 4 hours for the concentration of the drug to fall by 50%.

A chronic drinker has increased activity at GABA receptors due to their frequent alcohol consumption. Describe how their GABA receptor levels are likely to change in response to alcohol administration and explain why this is the case.

Their GABA receptor levels are likely to decrease due to receptor down-regulation recognizing the activity of the brain as being excessive. It is important to note that if these levels become too low, the individual could potentially experience a seizure

A presynaptic neuron is releasing serotonin. If a drug blocks the actions of the serotonin transporter, what would be the immediate effect on serotonin levels in the synapse?

They would increase; Remember that the function of the serotonin transporter is to remove serotonin from the synaptic cleft (and return it to the neuron that released it). Thus, if we block the actions of the transporter, levels of serotonin in the synaptic cleft would rise.

You are a physician with an elderly patient who is suffering from an anxiety disorder. You would like to prescribe an anti-anxiety medication known as a benzodiazepine, but you know that elderly patients often do not metabolize these drugs very effectively. You want to ensure the patient receives an adequate dose of the drug but also want to minimize the likelihood of disruptive side effects. Would you be inclined to prescribe a higher or lower dose than normal? What is your reasoning?

This elderly patient should receive a lower dose than normal because the benzodiazepine's effects will be stronger in an elderly patient that metabolizes the drug slower. It is found that enzymes levels may actually decrease and become less efficient with age and can also be affected by other medications that are being currently consumed, for instance, common medications like blood pressure medicine and cholesterol.

Axon Terminal/Synaptic Boutons

When action potential reaches the end of a neuron it causes the release of neurotransmitter to communicate the signal to other neurons

You are designing a drug that must be capable of crossing the blood-brain barrier. What characteristics does it need to have and why?

When designing a drug that is capable of crossing the blood-brain barrier it is important that it is soluble in lipids because the walls of the glial cells form a fatty layer that can only be penetrated by lipid soluble drugs like psychoactive drugs. These linings in the vessel walls of the brain are very important because they prevent pathogens and substances from crossing the blood-brain barrier through our blood supply and the substances be small enough to fit between tightly-fused endothelial cells.

partial agonist

a drug that binds to a receptor and causes a response that is less than that caused by a full agonist a partial agonist binds to that receptor and causes only a partial effect. If the agonist activates the receptor at 100%, a partial agonist may only activate it at 50%. This mechanism can have utility in creating drugs to replace those people are addicted to (more on this when we cover opioids and nicotine

A physician wants to treat a patient with a benzodiazepine. The patient has undergone genetic testing and is determined to have low levels of CYP3A4, the enzyme that metabolizes benzodiazepines. Compared to someone with normal levels of CYP3A4, the physician would probably want to prescribe:

a lower dose; If the individual has low levels of the enzyme that metabolizes benzodiazepines, then the drugs are likely to remain in their system longer, with the potential to have greater effects and side effects. Thus, a physician might want to consider prescribing a lower dose.

agonist

a molecule that, by binding to a receptor site, stimulates a response an agonist is a substance that binds to a receptor and activates it in a manner similar to how the neurotransmitter that typically binds there activates it

inverse agonist

a substance that binds to a receptor and causes it to do the opposite of what the naturally occurring transmitter does An inverse agonist binds to a receptor and causes the opposite effect of the typical ligand

half-life

amount of time it takes for 1/2 of an administered dose of a drug to no longer be bioavailable (due primarily to drug metabolism)

competitive agonist

an agonist that "competes" for the same binding site as another substance, and produces the same effect may cause other substances to be removed from their binding sites on the receptor

ligand

any substance that binds to a receptor

antagonist

blocks receptor keeps ligand from being able to bind antagonist makes a receptor less capable of being activated

Central Nervous System (CNS)

brain and spinal cord

cell body (soma)

cause initiation of new electrical impulse called action potential

experimental designs

clinical trials utilize experimental designs to determine if a drug works

Therapeutic Index (TI)

commonly-used measure of drug safety using the ratio between ED50 and LD50 So, if we use the example from the previous page showing the LD50 and the ED50 for a sleep drug, we can see again that the LD50 is 30 mg and the ED50 is 10 mg. A ratio between these two would be 3:1, or 3, so this would be the TI. Drugs that are safe thus have very high Tis. Diazepam (aka Valium), for example, has a TI of 100:1. Alcohol only has a TI of 10:1. And heroin's TI is only 6:1.

Pharmacokinetics

course of the drug though the body the study of drug movement throughout the body (time administered until the time excreted)

Pharmacokinetics

course/movement of the drug through the body absorption distribution metabolism elimination

Liver's role in drug metabolism

cytochrome p450 enzymes are responsible for most drug metabolism (75%) some people have higher or lower levels of p450 enzymes enzyme levels may decrease with age presence of other drugs in the body may affect the ability of their enzymes to metabolize drugs

control group

does not receive the intervention

dose-response curve

dose-response curves show the relationship between a unit increase in the dose of a drug, and the effects that are produced x-axis - increase in dosage y-axis - intensity of drug response

Allosterism (Neuromodulation)

drug binds to a receptor in a different location from where the neurotransmitter typically binds Allosterism can cause the effects of a neurotransmitter to be increased or decreased.

what is learned from a dose-response curve

efficacy - how effective a drug is how capable a drug is of producing a certain effect

sympathetic nervous system

fight or flight response

ionotropic receptors

forms an ion channel (passageway by which ions can enter and leave a neuron) ions are an essential part of neuronal signaling when a ligand interacts with the appropriate binding site on an ionotropic receptor, it opens and allows ions to pass

efficacy

how effective a drug is

potency

how potent a drug is how much of the drug is required to produce an effect represented by how far left or right on the xaxis the curve is found

parenteral administration

inhalation (quickest delivery to brain) intravenous (very efficient-none is lost but also dangerous) mucous membrane/sublingual - (mouth and nose) quick but not efficient due to loss transdermal - gradual absorption but inefficient

Myelin

insulating material that covers to prevent decaying of electrical impulses

Pharmacodynamics

interaction/effects of the drug with the body mechanism of action drug receptor interactions (signaling molecules like neurotransmitters can bind to)

blinding

involves concealing the group assignment of participants in an experiment from either the participants themselves, the investigators, or the individuals analyzing the data of an experiement

enteral

involving the gastrointestinal (GI) tract

two major types of receptors

ionotropic receptors g protein coupled receptors effects on neurons

endothelial cells

line the walls of blood vessels fused tightly to protect the blood-brain barrier so only very small substance are able to cross

G protein-coupled receptors (GPCRs)

metabotropic receptors neurotransmitter binds/activates g protein initiates a number of cellular mechanisms slower acting than ionotropic receptors widespread effect on a cell

Random assignment (randomization)

method in which participants in an experimental study are assigned to the treatment or control group it is used to create commonality between the two groups to prevent the factors or cause being attributed to their differences

drug metabolism

modification process of a drug that takes place in the liver

glial cells

non-neuronal cells which are an additional blood-brain barrier around blood vessels fatty layer - substances must be soluble in lipids

parenteral

not involving the gastrointestinal (GI) tract

Receptor down-regulation

occurs if neurotransmitter activity is higher than your brain is used to by REMOVING neurotransmitter receptors to reduce the chance that activity will occur, reducing the activity that your brain sees as excessive

receptor up-regulation

occurs if neurotransmitter activity is lower than your brain is used to by ADDING more neurotransmitter receptors for neurotransmitters to act at which increases the odds of actions at that neurotransmitter to occur happens when a drug inhibits action at that receptor (antagonist)

distribution

once a drug enters bloodstream its distributed throughout the body side effects (usually undesired) to a drug affecting other parts of the body

Enteral administration

oral (most common, safe but unreliable and inefficient) rectal (even less predictable and inefficient)

placenta

physiological barrier lipid soluble substances

endothelial cells and glial cells

prevent substances from crossing the blood-brain barrier

elimination

process by which a drug is removed from the body primarily via urine lipid soluble drugs must be modified before entering the kidneys or they will be reabsorbed across the membranes of the kidney

absorption

process by which drugs pass into the bloodstream

dendrites

receive messages from other cells

treatment vs control group

receives treatment being studied vs. receives no treatment or a different treatment

clinical trials

refers to studies that are conducted to determine if a treatment is safe and effective for use in humans to obtain approval from the FDA; drug manufacturers are required to conduct a series of clinical trials

parasympathetic nervous system

rest and digest

GABA gamma aminobutyric acid (amino acid)

reuptake

Glutamate (amino acid)

reuptake

Serotonin (monoamine)

reuptake Metabolized by: Monoamine oxidase (MOA)

Dopamine (monoamine)

reuptake metabolized by: Monoamine oxidase (MOA) Catechol O- Methyltransferase (COMT)

Norepinephrine (monoamine)

reuptake metabolized by: Monoamine oxidase (MOA) Catechol O- Methyltransferase (COMT)

blood-brain barrier

serves important protective function endothelial cells and glial cells prevent substances from crossing the blood-brain barrier

Slope of dose-response curve

slope shows us how much of an increase in effect we can expect to see with a unit increase in dose steep slopes - suggest less of a difference between the dose that produces very little effect and the dose that produces a large effect steep slopes can be dangerous because it means that accidentally taking to much may have serious consequences

what substances can pass the blood-brain barrier

small, lipid-soluble substances psychoactive drugs possess this quality

Peripheral Nervous System (PNS)

somatic and autonomic

If a person has lower levels of an enzyme that metabolizes drug A, will drug A likely have a stronger or weaker effect on them?

stronger effects If a person has a harder time getting a drug out of their system, it has the potential to exert stronger and longer-lasting effects

autonomic nervous system

sympathetic and parasympathetic

Bioavailability

the extent to which the body can absorb and use a nutrient measured by concentration of the drug in the plasma of the blood

Synapse

the junction between the axon tip of the sending neuron and the dendrite or cell body of the receiving neuron Presynaptic membrane (axon terminal of the neuron) Synaptic cleft Postsynaptic membrane (dendrite)

Peripheral Nervous System (PNS)

the sensory and motor neurons that connect the central nervous system (CNS) to the rest of the body.

dose-response relationship

used to quantify the interaction between drugs and receptors (the effects that result)