Drugs And Their Actions Exam 1

Front 1

What is pharmacology?

Back 1

The scientific discipline that investigates the interactions between living organisms and drugs.

Front 2

What is pharmokinetics?

Back 2

the study of what living things (especially the human body) do to drugs.

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What is pharmodynamics?

Back 3

the study of what drugs do to living things (especially the human body).

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What are poisons?

Back 4

Chemical substances that cause injury, illness, or death in living organisms.

Front 5

What is toxicology?

Back 5

The sub-discipline of pharmacology that investigates the adverse effects of poisons, including drugs that can
act as poisons, on living things.

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Bernard’s Scientific Method

Back 6

i. goal is to discover new facts and formulate new theories to explain diseases and the
responses to drugs and poisons
ii. theories should try to explain cause and effect relationships
iii. theories should be testable and continuously tested by experimentation
iv. theories must be reformulated if contradicted by experimentally observed facts

Front 7

1938 Federal Food, Drug, and Cosmetic Act

Back 7

(1) Prior to the 1938 Federal Food, Drug, and Cosmetic Act, the formulation, marketing,
and sale of most drugs was not regulated.
(2) The 1938 Federal Food, Drug, and Cosmetic Act was a response to heath problems
and deaths caused by unregulated drugs.
(3) Science of pharmacology became the basis for drug approvals and regulations in
the United States.

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Clinical Pharmacology

Back 8

The science of using drugs in humans

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Phase I Clinical Trials

Back 9

use small numbers of subjects to evaluate the safety of a new drug.

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Phase II Clinical Trials

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use an intermediate number of people and continue safety evaluation while providing the first test of efficacy.

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Phase III Clinical Trials

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use large numbers of subjects to provide a definitive test of drug efficacy.

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Phase IV Clinical Trials

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are for new tests on already FDA approved drugs
(example, rofecoxib).

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ED50

Back 13

dose of drug that produces the desired effect in 50% of test subjects

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LD50

Back 14

dose of drug that is lethal for 50% of test subjects (animals)

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TD50

Back 15

dose of drug that causes unacceptable side effects in 50% of test subjects (humans)

Front 16

Therapeautic Index (TI)

Back 16

the ratio of the LD50 and the ED50. A drug with a large
TI is generally safer.

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Absorption

Back 17

the movement of drugs into the bloodstream.

Front 18

Vascular System

Back 18

important for understanding how drugs are handled by the
body because it moves drugs to sites of action, sites of metabolism, and sites of
secretion. The vascular system is also the location in the body where drug can most
easily be measured in the clinic because obtaining a blood sample is a simple and
straightforward medical procedure.

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Arteries

Back 19

Large vessels that blood travels in after it leaves the heart. Arteries lead to capillaries.

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Capillaries

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very small vessels in all tissues where nutrients, waste products, and drugs are exchanged between blood and the cells of the body

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Veins

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Larger vessels that follow capillaries and return blood to the heart.

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portal systems

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groups of vessels arranged such that blood flows through a second capillary bed before reaching the heart.

Front 23

Area Under the Curve

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(1) The AUC is the geometric area under a curve that plots the venous drug
concentration on the Y-axis and time on the X-axis.
(2) AUC is directly proportional to bioavailability and inversely proportional to clearance.

Front 24

Bioavailability

Back 24

the fraction of a drug dose that reaches systemic circulation. It
is always a number between 0 and 1.
(1) By definition, F = 1 for intravenous injection.
(2) For oral dosing, F = (fraction absorbed) X (fraction escaping 1st-pass clearance)
(3) For equal doses, F = AUCoral ÷ AUCintravenous

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Intravenous Injection

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results in immediate and complete absorption of drugs.
This corresponds to F = 1 (100% bioavailability).
(2) Good for drugs that must act very quickly.
(3) Good for drugs that can’t survive in the digestive tract.
(4) Good for drugs that can’t survive 1st-pass metabolism.
(5) Formulation is usually a liquid containing the drug as well as chemicals to control the pH and act as preservatives.

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Oral Administration

Back 26

administration of drugs is the taking of pills, capsules, or elixirs via the mouth.
(1) Very convenient method that usually gives reduced bioavailability of drugs.
(2) A large fraction of the drug must survive the digestive tract and 1st-pass metabolism.
(3) Formulation is typically a pill, capsule, or elixir.
(4) Formulation can control the rate and location of absorption in the digestive tract.

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Topical Drug Delivery

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placing of drugs onto an “exposed” surface of the body
other than transit through the GI tract after being swallowed. This includes skin patches
as well as inhaled medicines that are placed on the respiratory surface of the lungs.
(1) Good for small and hydrophobic drugs that can pass easily through the skin.
(2) Good for local drug delivery such as localized pain relief or delivery of asthma drugs
to the lung.
(3) Skin patches can achieve very slow and sustained drug release over many hours or
days.
(4) Gives reduced bioavailability compared to IV injection.

Front 28

Ionic Bonds

Back 28

relatively weak bonds occurring between atoms that can easily become charged.

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Epithelial Cells - Barrier to Absorption

Back 29

(1) Epithelial cells line all surfaces of the body exposed to the outside environment
including the skin, gastrointestinal tract, respiratory tract, and reproductive tract.
(2) Epithelial tissues contain no blood vessels. Capillaries lie in the tissue layer adjacent
to epithelial tissues.
(3) Epithelial cells create a barrier because they are held together by protein-based
junctions such that most drugs cannot pass around the cells and must pass through the
cells instead.

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Different Types of Epithelial Cells

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(1) The skin is a stratified squamous epithelium with many cell layers including dead,
keratinized cells that form a high barrier to drug entry. Some small hydrophobic drugs
can pass through the skin, but many drugs can only get past the skin by injection.
(2) The lung has a simple stratified epithelium that lies in close association with
capillaries. For drugs that can be delivered as a gas or aerosol, inhalation is a very fast
and efficient route for drug delivery that avoids 1st-pass metabolism.
(3) The gastrointestinal (GI) tract has several types of epithelium along its length. The
epithelium of the small intestine is specialized for nutrient absorption, and it also
absorbs many drugs efficiently.

Front 31

GI tract Absorption

Back 31

(1) The GI tract is a series of several organs that create a tube approximately 20 feet
long.
(2) The different GI organs have different epithelial structures that influence drug
absorption.
(3) The pH changes along the tract also influence drug absorption: neutral pH in the
mouth and esophagus, acidic pH in the stomach, and mildly basic pH in the small
intestine.
(4) The small intestine is lined by a single layer of absorptive epithelial cells that are in
close association with capillaries. The surface area for absorption in the small intestine
is very, very high due to macroscopic villi and microscopic microvilli.
(5) Many oral drugs are formulated to be absorbed in the small intestine.

Front 32

1st Pass Clearance

Back 32

The metabolism of a drug prior to reaching systemic circulation

Front 33

Clearance (CL)

Back 33

(1) Irreversible elimination of a drug can be due to excretion of the drug into the urine,
gut contents, expired air, sweat, etc.
(2) Irreversible elimination of a drug can also be by metabolic conversion of the drug
into another chemical. This can occur anywhere in the body, but most metabolic
conversion occurs in the liver.
(3) A CL value can be determined for the whole body or for a single organ.

Front 34

CL determines...

Back 34

the dosing needed to achieve a desired level of drug in the body.
(1) At steady state, the amount of drug administered per unit time must equal the
amount eliminated per unit time.
(2) The elimination rate is determined by the plasma drug concentration and the CL
value.
(3) For any given dose rate of drug delivery, a higher CL value will result in a lower
plasma drug concentration.

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Volume of Distribution

Back 35

describes the tendency of a drug to reside in the
bloodstream relative to the tendency to reside in tissues of the body. V is one of the two
primary pharmacokinetic parameters.
a. V = (total amount of drug in the body) ÷ (plasma drug concentration)
(1) A small value for V means that most of a drug resides in the bloodstream.
(2) A large V value means that most of a drug resides in the tissues of the body.
(3) V is determined by comparing the amount of drug in the body at the time of dosing
(Time=0) to the amount of drug that would be in the bloodstream at the time of dosing
(Time=0, extrapolated based on later measurements).

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Half Life

Back 36

is a pharmacokinetic parameter that can be derived from CL and V.
(1) Half life is the length of time for the drug plasma concentration to fall 50%.
(2) Half life applies for drugs with a plasma drug concentration that declines as an
exponential decay. This is true for most drugs.
(3) When drug metabolizing enzymes are saturated, half life does not apply. The most
common example of this is ethyl alcohol when drinking heavily.
(4) t1/2 = (0.693 X V) ÷ CL

Front 37

Receptors

Back 37

Receptors are proteins on the surface of (or within) a cell that provides the site(s) where
biologically active, naturally-occurring, endogenous compounds induce their normal
biological effects.

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Ligands

Back 38

Ligands are usually small, diffusible compounds that bind to a receptor and elicit a response. Within the nervous system, neurons use many different types of these small molecules to communicate with each other. These neuronally-released ligands are called neurotransmitters, each binding their corresponding receptor (more about neurotransmitters in future lectures).

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Molecular Switch

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upon binding, the ligand induces a conformational change in the receptor leading to a change in its function. For example, a ligand can turn on the activity of a receptor it binds.

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Reversible Binding

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receptor-ligand binding is usually governed by reversible
molecular interactions that allow cycling between a bound and unbound state. How quickly it cycles between these states, depends on the strength of the
receptor-ligand interaction (also referred to as binding affinity).

Front 41

modulated signal intensity

Back 41

the intensity of the signal transduced by a ligand is
dependent on the number of receptors occupied by the ligand (i.e., “dose”; more ligand, more receptors bound). The intensity of the signal transduced is also dependent on the amount of time the ligand stays bound on the receptor (i.e., strength of binding; the stronger the binding, the longer it’s bound, the longer the receptors stays activated).

Front 42

Specificity of binding

Back 42

the specificity of binding (which receptor a given ligand
will bind) is dependent on the “molecular fit” between ligand and the ligandbinding pocket of the receptor. Therefore, an exogenously applied compound (a drug) that looks like the endogenous ligand, will also interact with the receptor but with slightly different dynamics depending on its binding affinity or “molecular fit”.

Front 43

Agonist

Back 43

when the binding of a compound initiates a similar cellular response as the endogenous ligand. This agonistic action may be a result of a compound that mimics and thus binds the molecular site used by the naturallyoccurring, endogenous compound. Alternatively, the agonistic action could also be a result of binding to a nearby site that facilitates the binding of the endogenous compound.

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Antagonist

Back 44

when a compound blocks access of the endogenous ligand to its binding site, resulting in an inhibition of receptor function.

Front 45

Ion Channels

Back 45

these receptors have a pore in the central portion that spans the cell membrane and allows flow of a specific ion (like chloride). This pore is normally closed and opens upon binding of the appropriate ligand.

Front 46

G-Protein Coupled Receptors

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The activation of these receptors induces the
release of an attached intracellular protein (a G protein) that, in turn, controls activity of other proteins inside the cell.

Front 47

Carriers or Transporters

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this class of receptor transports small molecules (such
as neurotransmitters) across cell membranes against concentration gradients.

Front 48

Enzymes

Back 48

although not receptors, these drug targets function to breakdown neurotransmitters. Inhibition of these types of enzymes increases the availability of the endogenous neurotransmitters they eliminate.

Front 49

Dose-response Curves

Back 49

There are two types of dose-response curves: (1) A curve obtained by plotting the dose of drug against the intensity of response observed in any single person at a given dose.
(2) A curve obtained by plotting the dose of drug against the percentage of subjects showing a given response at any given dose.

Front 50

Potency

Back 50

provides a measure of how well drug molecules attach to their sites of action. Thus, the strength of binding (or affinity) of drug to receptor is reflected by the dose required to elicit a physiological response. The higher the potency, the lower the dose required.

Front 51

Efficacy

Back 51

provides a measure of how well a drug produces the desired effect. It is essentially, the maximum effect obtainable, with additional doses producing
no effect. A drug with higher efficacy has the ability to trigger a higher intensity of the desired physiological response (higher max).

Front 52

Variability and Slope

Back 52

refers to individual differences in drug response; some
patients respond at very low doses and some require much more drug.

Front 53

Drug Toxicity

Back 53

provides a measure of the unwanted responses (or side effects) of a drug. These unwanted responses could be related to the principal mode of action of the drug that, for example, causes serious side effects or death at
certain doses. These side effects could also be a consequence of expected modes of action, like severe allergic reactions to the drug in some patients.

Front 54

Therapeutic Index

Back 54

a drug represents a dose that has the most desired
response with the least toxicity. This is usually represented as a ratio of the lethal or toxic dose (LD) for a specific percentage of patients to the effective
dose (ED) for a specific percentage of patients (for example, LD50/ED50 or LD1/ED99).

Front 55

Variability of Responsiveness

Back 55

shows that the dose that produces a specific
response varies considerably among patients.

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Central Nervous System

Back 56

composed of the brain and the spinal cord

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Peripheral Nervous System

Back 57

composed of neurons that reside outside the CNS and the nerves connecting them to the CNS.

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Somatic Nervous System

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peripheral neurons and nerves associated
with skeletal muscles, skin and sense organs like eyes, ears and tongue

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Autonomic Nervous System

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peripheral neurons and nerves regulating
involuntary functions like heart rate, digestion, perspiration, etc).

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The Spinal Cord

Back 60

The spinal cord sits inside the vertebral column and is composed of neurons and nerve tracts responsible for carrying sensory information from the body to the brain. The spinal cord also houses the motor neurons that control the skeletal muscles in the body.

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Brain Stem

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relays impulse between the brain and the spinal cord and regulates vital bodily functions (breathing, blood pressure, heart rate, GI function, sleep & wakefulness, alertness, attention, arousal, etc).

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Cerebellum

Back 62

primarily coordinates movement and posture.

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Hypothalamus

Back 63

is responsible for integration of the autonomic nervous system that ultimately controls eating, breathing, drinking, sleeping, body temperature, blood pressure, sexual behavior, water balance, etc.

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Subthalamus

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is one of our motor systems and contains the substantia nigra (part of the brain that is defective in patients with Parkinson’s).

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Cerebral Cortex

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is the part of the brain that controls the “higher” functions. The cortex is traditionally divided into four lobes that broadly correspond to different functions: the frontal (conscious thoughts), parietal (body sensations), temporal (smell and sound) and occipital lobes (vision).

Front 66

Synthesis and Vesicle Loading of Neurotransmitters

Back 66

Neurotransmitters are first synthesized from precursor molecules that the neuron imports from the environment (NTs can also be recycled at the synapse; see below). The synthesis of NTs is mediated by biosynthetic enzymes. The NTs are then loaded into vesicles to create concentrated packets and prepared to be released when an action potential reaches the synapse.

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Vesicle fusion, neurotransmitter release and receptor binding

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Once the action potential reaches the synapse, the electrical current is converted into the fusion of vesicles to the presynaptic membrane. The neurotransmitters released into the synaptic cleft diffuse across to the postsynaptic membrane where they bind (and
activate) their corresponding receptors. Once a threshold level of activation of the postsynaptic membrane is achieved, it results in the re-initiation of an action potential that will travel down this neuron. Thus, chemical messengers at synapses allow the
transmission of an electrical signal from one neuron to another.

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Termination of synaptic transmission

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The signal initiated by receptor binding and activation at the postsynaptic membrane is terminated by the removal of neurotransmitters from the synaptic cleft. This is primarily accomplished in one of two ways: re-uptake by specific transporters and/or breakdown by dedicated enzymes.

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Criteria for Neurotransmitters

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- the neurotransmitter needs to be synthesized in neurons (i.e., the biosynthetic
enzymes for building it must be present in neurons)
- the neurotransmitter must be present in vesicles at the presynaptic terminal
and released into the synaptic cleft after an action potential
- the exogenous application of the neurotransmitter must mimic the effect (on
the postsynaptic neuron) of the endogenous chemical signal
- there must be specific mechanisms at the synaptic cleft for terminating the
signal initiated by neurotransmitter release

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Classes of Neurotransmitters

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a) Small molecules: There are several “classical” low-molecular weight
neurotransmitter substances: acetylcholine (ACh), dopamine (DA),
norepinephrine (NE), epinephrine, serotonin (5HT), glutamate and GABA. All
of these are amines and six derived from amino acids (ACh is the exception).
These neurotransmitters share many biochemical similarities including
biosynthetic and degradation pathways.
b) Peptides: although these are also “small” molecules, these are typically larger
than the previous class. There is an incredible diversity of peptide
neurotransmitters in the brain, but they can be grouped into the opioid-type
peptides (like endorphins and enkephalins), gut-brain peptides (like
substance P), hypothalamic-releasing hormones and the pituitary hormones.

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Acetylcholine

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ACh is an excitatory neurotransmitter used in the CNS and PNS. In the PNS, ACh is
used by motor neurons to trigger muscle contractions. In the CNS, it maintains the
electro-encephalographic (EEG) signals of the cortex and plays a role in memory by
maintaining neuronal excitability. Alzheimer’s disease is related to the death of
cholinergic (ACh-containing) neurons in the cortex. There are two types of ACh
receptors: muscarinic and nicotinic. Muscarinic ACh receptors are G-protein coupled
receptors whereas nicotinic ACh receptors are ion channels.
Biosynthesis: ACh is made from acetyl-CoA and choline by the enzyme
cholineacetyltransferase (ChAT). Although acetyl-CoA is derived from the Krebs cycle in
mitochondria, choline is only obtained from the diet and transported into neurons.
Termination of signal: After action at the synaptic cleft, ACh is eliminated by the enzyme
acetylcholinesterase (AChE) that breaks down the neurotransmitter into choline and
acetate.
Drugs: organophosphate-containing insecticides (like Malathion) and nerve gases (like
Sarin) are irreversible AChE inhibitors. Reversible AChE inhibitors are used for treating
Alzheimer’s symptoms. Nicotine is an ACh receptor agonist whereas scopolamine is an
ACh receptor antagonist.

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Catecholamines (dopamine, norepinephrine, epinephrine)

Back 72

Catecholamines are a family of neurotransmitters that contain a “catechol” nucleus.
Although derived from a common biosynthetic pathway, each catecholamine
(dopamine, norepinephrine and epinephrine) has unique roles in the nervous system.
Dopamine is involved in regulation of motor activity, motivation and reward, mood,
sleep, learning, attention, etc. Parkinson’s disease is related to the death of
dopaminergic neurons in the substancia nigra (part of the subthalamus). Reduced levels
of dopamine may be related to attention deficit hyperactivity disorder (ADHD). Too
much dopamine may be related to schizophrenia. Norepinephrine is involved in
alertness, focus, positive feelings of reward. Epinephrine (also referred to as adrenalin)
is involved in alertness and, together with NE, is part of the “fight-or-flight” stress
response.
Biosynthesis: catecholamines are derived from the amino acid tyrosine by a series of
enzymatic steps that convert tyrosine into dopamine, then into norepinephrine, then into
epinephrine.
Termination of signal: catecholamines are eliminated from the synaptic cleft by either
reuptake transporters or by degradation enzymes (like monoamine oxidase [MAO] or
catechol-O-metyltransferase [COMT]).
Drugs: cocaine and amphetamines disrupt reuptake transporters. MAO inhibitors are
used as antidepressants.

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Serotonin

Back 73

Serotonergic systems are involved in regulating aggression, emotional processing,
mood, sleep, sexuality, appetite and metabolism. Increases in levels of serotonin are
related to obsessive-compulsive disorder and schizophrenia. Decreases in levels of
serotonin are related to depression.
Biosynthesis: serotonin is made from the amino acid tryptophan in two enzymatic steps.
Because tryptophan is an essential amino acid, it must be obtained from the diet and
transported to neurons for use in serotonin biosynthesis.
Termination of signal: serotonin is eliminated from the synaptic cleft by either reuptake
transporters or by degradation enzymes (like monoamine oxidase [MAO]).
Drugs: cocaine and amphetamines also disrupt serotonin reuptake transporters. MAO
inhibitors can also be used but there are “selective serotonin reuptake inhibitors”
(SSRIs) like Prozac that are specific to serotonin.

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Glutamate and GABA

Back 74

The neurotransmitters mentioned so far (ACh, catecholamines and serotonin) are made
in a small subset of neurons by specific biochemical pathways. In contrast, glutamate
and GABA are made in most neurons and are also universal cellular constituents.
Glutamate is the major excitatory neurotransmitter in the brain whereas GABA is the
major inhibitory neurotransmitter in the brain. Together, glutamate and GABA maintain
the balance between excitation and inhibition in the brain. Defects in either pathway can
lead to epilepsy and seizures.
Biosynthesis: glutamate is synthesized from the amino acid glutamine by the enzyme
glutaminase; it can also be derived as a byproduct of the Krebs cycle. GABA is
synthesized from glutamate by the enzyme glutamic acid decarboxylase (GAD).
Termination of signal: both glutamate and GABA are eliminated from the synaptic cleft
by either reuptake transporters or by degradation enzymes (GABA-transaminase) in
neurons or glia.
Drugs: several well-known sedatives (barbiturates & benzodiazepines) act as agonists
of the GABA receptor. Alcohol also acts as an agonist of the GABA receptor.

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Peptide Neurotransmitters: Opioids

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Opioid type of peptide neurotransmitters are made of small chains of amino acids
(polypeptides) derived from cleavage of larger precursor proteins made in the nucleus
of appropriate neurons. Endorphins are chains of 16 to 30 amino acids of specific
sequence. Enkephalins have shorter chains (about 5 amino acids). Opioid
neurotransmitters are involved in pain perception and reward mechanisms. Natural
opiates made from the opium poppy (like morphine and codeine) or derived from these
(like heroin and oxycodone) are agonists of endogenous opioid receptors. The synaptic
signal initiated by these neurotransmitters is terminated by specific peptidases.