Unit 1: Neuropharmacology Flashcards
What are drugs?
Drugs =
- a chemical substance—either naturally occurring (eg. nicotine from tobacco) or synthesized in a lab (eg. fentanyl)
- when consumed, will change an organism’s physiology and/or psychology
- have a defined chemical structure
- a 3D object with (+) and (-) charge—it will fit into cell receptors with the same 3D size, shape and electrical charge(s)
- developed based on pre-existing, naturally-occurring receptors
How do drugs work?
All drugs have a target—they bind to receptors (proteins) and change their shape and activity
Change in receptor activity = change in neuron activity = change in brain function
Orphan Receptors
Cell receptors whose purpose = unknown
What does ADME stand for?
Administration: the method of administration will affect the rapidness of a drug’s onset
- intraveinously/inhalation: rapid onset
- intramuscular/ingestion: slower onset
Distribution: once a drug reaches the bloodstream, it is distributed fairly evenly throughout the body
Metabolism: enzymes exist to break down nutrients and to eliminate toxins—some drugs (pro-drugs) depend on the body’s metabolism to work
- (eg. codeine = a pro-drug wherein the body converts it to active morphine)
Elimination: a drug will stop working once it is eliminated from the body
Cell Receptors
A receptor is a protein
Receptors are located at the surface of the cell—they signal to the cell by changing shape when they bind their ligand or drug
When the neurotransmitter/drug binds to the channel, it opens a pore allowing ions to flow in or out of the cell
Lock and Key analogy
Lock = a receptor
Key = a drug
If the key (drug) is the right size and shape, it can turn the lock (receptor) and influence the activity of that receptor.
How long do drugs act?
How long do drugs act?
- depends on the drug and dosage
- drug binding is usually transient (reversible)
- once unbound, a drug can bind to another receptor or be eliminated from the body
- some drugs bind irreversibly—only way to stop their action is to make a new receptor (hours)
Drug Presence
- if a drug is continuously present, the cell will adapt
- receptor upregulation: more protein made (when the drug is an antagonist)
- receptor downregulation: less protein made (when the drugs is an agonist)
What is an agonist?
An agonist is a medication that mimics the action of a signal ligand by binding to and activating a target receptor
What is an antagonist?
An antagonist is a medication that binds to a target receptor without activating it, and instead inhibits the receptor’s ability to be activated by another ligand
Agonist/Antagonist
≠
Excitatory/Inhibitory
The agonist/antagonist labels ARE NOT necessarily indicative of the polarization action of a neuron.
The inhibitory/excitatory characteristic is determined by what ions are influencing electrical charge.
Positive ions (Na+, Ca+, K+) = excitatory effect
Negative ions (Cl-) = inhibitory effect
eg.
- agonist = activator of a receptor
- alcohol = agonist of GABA receptors (inhibitory neurotransmitter) – alcohol stimulates GABA, which
Analogy for Neurons: The Battery
(pt 1)
Neurons are like rechargeable batteries that are continually storing and releasing energy:
Batteries have two chambers that separate chemicals with opposite charge
- negative charge (-) = molecules with extra electons
- positive charge (+) = molecules lacking electrons
Electrons are drawn to the positive chamber by electrostatic attraction—energy is only released when a conductive wire connects both chambers, allowing (-) electrons to flow to the (+) chamber. When all neg charged chemicals are gone, the battery is dead.
Analogy for Neurons: Neuron Battery
(pt 2)
Neurons are like batteries that store energy by continuously pumping charged ions like (Na+), (Ca+) and (Cl-) out of the cell—meaning there are more (+) ions outside than inside
Positive and negative ions are drawn to each other by electrostatic attraction, but are prevented from interacting by the cell membrane—when the membrane opens, (+) ions rush into the cell, equalizing the electrical gradient, creating an electrical current. Like a battery, the neuron loses its stored energy
Analogy for Neurons: Recharging the Neuron Battery
(pt 3)
The neuron battery must be recharged by pumping charged ions back across the membrane—using energy in the form of ATP, generated by mitochondria in the neuron
ATP = adenosine triphosphate
This is why the brain consumes more energy than any other organ—it is constantly recharging the billions of batteries in our brain
Positive Ions
Sodium (Na+), Calcium (Ca+), Potassium (K+)
Negative Ions
Chloride (Cl-)
Resting Membrane Potential
(Polarized Neuron)
A neuron that is in the charged state and ready to fire
Polarized neuron: (+) and (-) ions are kept separate
Depolarization
A rapid rise in potential. A neuron is depolarized when an excitatory neurotransmitter opens the voltage-gated sodium channel, allowing (Na+) ions to flood into the neuron.
If enough depolarization happens, the neuron will fire, sending an action potential (electrical current) down the axon.
A neuron will remain polarized if enough inhibitory neurons reach the dendrites at the same time—hyperpolarization counteracts depolarization.
Action Potential
An action potential is a rapid change in voltage across a membrane caused by the depolarization of a neuron.
This electrical current begins at the axon hillock, travels down the myelinated axon, and ends at the axon terminal. When the potential reaches the terminal, this triggers calcium (Ca+) channels to open—(Ca+) causes synaptic vessicles to release their neurotransmitter.
Repolarization
Once a neuron is depolarized and has fired, it can’t fire again until it is recharged. Repolarization is the process of re-establishing a membrane potential by using ATP to push ions out of the cell.
Hyperpolarization
A hyperpolarized neuron is one that is less likely to fire. A neuron becomes hyperpolarized when inhibitory neurotransmitters offsets the amount of positive ions in the membrane.
Presynaptic Neuron
A presynaptic neuron is the cell that sends information (releases neurotransmitters upon depolarization)
Postsynaptic Neuron
A postsynaptic neuron is the cell that receives information (collects neurotransmitters as a result of depolarization).
Neurotransmitters bind to receptors on the postsynaptic neuron. If the transmitter is:
Excitatory : the postsynaptic neuron will generate a new action potential.
- eg: glutemate, acetylcholine
Inhibitory : the postsynaptic neuron is quieted and becomes less likely to generate an action potential
- eg. GABA, glycine
Pharmacology
Pharmacology: the study of drugs and their actions on the body
Target
The specific protein that a drug physically interacts with and changes its function
Mechanism of Action
The specific biochemical interaction through which a drug substance produces its pharmacological effect
A current understanding of a drug’s target, and how the interaction between a drug and receptor facilitates a change in neuron activity/brain function
Drug Potency
Concentration or amount of drug required to produce a defined effect
Drugs with higher potency:
- have better affinity for their receptors
- are usually selective for one type of receptor
Drug Affinity
The extent or fraction to which a drug binds to receptors // the strength of attraction between a drug and receptor
- “goodness of fit”
- how much energy is needed to pull the drug away from the receptor
High Affinity drugs:
- have a shape that hugs the contours of the protein and makes numerous electrostatic contacts to hold in place
- less drug required to achieve defined effect
- high effectiveness and longer duration
- are usually very selective, interacting with one specific target
Low Affinity drugs:
- more drug required to achieve defined effect
- have low effictiveness and short duration
- usually non-selective about their target
Drug Selectivity
Refers to how many proteins (target receptors) are affected by the drug
Highly Selective “clean” drug: only binds to one or a few proteins—has a high affinity for its target
Non-Selective “dirty” drug: has many targets that it interacts with; similar affinity for any target
