Exam 1 Flashcards
What is pharmacology?
scientific discipline that investigates the interactions between living organisms and drugs; includes several subdisciplines that investigate different aspects of these interactions (e.g., pharmacokinetics, pharmacodynamics, etc.)
When did pharmacology become the primary way to understand drugs in Western Medicine?
19th century
What are the two primary branches of pharmacology that analyze drug-body interactions?
- Pharmacokinetics
- Pharmacodynamics
What are drugs?
- chemical substances used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental wellbeing
- can vary greatly in complexity from simple organic molecules to large and complex organic molecules
- use by humans pre-dates earliest historical records
drugs vs. poisons
Drugs - chemical substances used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental wellbeing
Poisons - chemical substances that cause injury, illness, or even death in living organisms
Drugs can act as poisons when the level of the drug in the body exceeds a toxic threshold
What is toxicology?
sub-discipline of pharmacology that investigates the adverse effects of chemicals on living organisms
Where does tobacco (nicotine) originate?
New World
Where does caffeine originate?
Coffee from Ethiopia
Tea from China
Cocoa from the New World
Where do beer and wine (ethyl alcohol) originate?
Unsure, widespread in pre-history
How is Chinese medicine an example of a pre-pharmalogical success?
“The Divine Farmer’s Herb-Root Classic” is a book that lists 365 medicines derived from natural sources, many of which are still medicines today
The most prominent of these is Ephedra sinica (now known as ephedrine), which is used as a stimulant to improve breathing
How is Peruvian Indian medicine an example of a pre-pharmalogical success?
Peruvian Indians used bark extracts from the cinchona tree (now called quinine) to treat fever and malaria; this is still used today for the same purposes
How is Eastern Mediterranean medicine an example of a pre-pharmalogical success?
Eastern Mediterranean people used opium (which contains morphine and codeine) for pain relief; both are on the WHO’s list for essential medicines, and codeine is thought to be the most commonly used drug today
Why were many pre-pharmacological “medicinal drugs” ineffective and/or dangerous?
Marketed/used without evidence for efficacy and often compounded in the home
Who was Francois Magendie?
19th century scientist who rejected theory-only based explanations for drugs in favor of facts gathered through experimentation; established the value of experimental animals and established experimental approaches such as IV injection
2 advances in other sciences that facilitated 19th century pharmacology
- Chemists isolated active drug compounds from plant-based medicines
- New instruments were invented that aided investigation of the responses to drugs (e.g., mercury manometer to measure blood pressure changes)
Who was Claude Bernard?
19th century scientist known as the “father of experimental medicine;” his research on curare and carbon monoxide poisoning pioneered the concept of investigating the mechanism of action for drugs
Claude Bernard’s 4 thoughts on the scientific method
- Goal is to discover new facts and formulate new theories to explain diseases and the responses to drugs and poisons
- Theories should try to explain cause and effect relationships
- Theories should be testable and continuously tested by experimentation
- Observable reality is the ONLY AUTHORITY and theories must be reformulated if contradicted by experimentally observed facts (the common practice before this was to rely on the authority of past physicians, like Hippocrates)
How is Aspirin an example of a 19th century pharmacological success?
Extracts of willow and similar plant had been used to treat fever and pain for thousands of years, but in the 19th century, salicylates (the active compounds in these plants that are chemically related to Aspirin) were isolated and studied
3 common features of non-steroidal anti-inflammatory drugs (NSAIDs)
- Anti-inflammatory effects
- Analgesic effect: reduction of pain
- Antipyretic effect: lowering of a raised temperature
What was the 1937 Elixir Sulfanilamide disaster, and why was it significant to pharmacology?
Sulfanilamide was an early antibiotic used to treat infections, and S.E. Massengill Co. created an elixir of sulfanilamide using diethylene glycol (a poison similar to antifreeze) as the solvent, causing hundreds of painful deaths from kidney failure.
This prompted passage of the 1938 Federal Food, Drug, and Cosmetic Act that remains the basis for FDA regulation of drugs
What is the role of pharmacology in the 21st century?
central role in the development and improvement of medicines (e.g., discovery of cyclooxygenase inhibitors)
How are cyclooxygenase inhibitors an example of a 21st century pharmacological success?
Aspirin was discovered to act as a cyclooxygenase inhibitor, and other NSAIDs have been developed as cyclooxygenase inhibitors such as celecoxib, which has several advantages over Aspirin for long-term pain management
What are international non-proprietary names (INN)?
Generic names for drugs that are set by the WHO, are the same worldwide, and are in the same public domain (e.g., celecoxib)
Drugs with similar structures and actions tend to have similar INN names
5 main questions that pharmacology experiments try to answer
- What routes can be used to administer the drug (oral, injection, inhalation, etc.)?
- How long does the drug last in the body?
- What are the molecular targets of the drug?
- What doses are effective to treat a medical condition?
- What doses cause unacceptable side effects?
4 benefits of laboratory based pre-clinical research in pharmacology
- Pharmacologist has more complete control over the experimental subjects
- Human safety not at risk
- Animal experimentation can predict safe and effective drug dosing for human trials
- Mechanism based studies can lead to better drugs
What is clinical pharmacology?
the science of using drugs in humans; subjects must provide informed consent to be part of clinical research and the work of clinical pharmacology is usually based on laboratory science and seeks to understand if and how a drug should be used in medical practice
What are Phase I clinical trials?
Phase I clinical trials are usually the first time the drug has been evaluated in human subjects, and its purpose is to evaluate the SAFETY of a drug and the maximum dose that does not cause unacceptable side effects. May also evaluate the interactions between the drug, food intake, and metabolism.
Usually conducted on a small group (tens) of healthy volunteers who are paid to participate.
What are Phase II clinical trials?
Phase II clinical trials continue safety testing and provide the first test of DRUG EFFICACY. Efficacy often judged in a randomized and blinded trial which compares the drug to a placebo.
Usually conducted on an intermediate sized group (tens to hundreds) of volunteers who have a medical condition that may be treatable by the drug.
What is the placebo effect?
a psychological phenomenon where individuals experience real changes in their health or symptoms after receiving a treatment that has no therapeutic effect; this outcome occurs because the person believes the treatment is real and expects it to work, which can trigger physiological responses in the body
What are Phase III clinical trials?
Phase III clinical trials are designed to be a DEFINITIVE TEST OF DRUG EFFICACY, providing the final required tests needed in support of an application for FDA approval of a new drug.
Studies a large total patient population (often thousands) usually at multiple medical centers around the country or world; involves the majority of the total costs to bring a new drug to the market
What is a Phase IV clinical trial?
Phase IV clinical trials are additional human trials for a drug that is already approved in the marketplace.
These can occur for several reasons:
1. Additional evaluation of drug safety and side effects
2. Study of long-term risks and benefits
3. Investigation of a drug efficacy for new medical conditions or in patient populations not enrolled in initial clinical trials (e.g., pregnant women)
High profile example is the withdrawal of rofecoxib (Vioxx) from the market following phase IV trials.
What is rofecoxib (Vioxx)?
COX2-selective NSAID that was approved as an arthritis drug in 1999 until a phase IV trial investigating Vioxx in colon cancer uncovered a 2-fold increased risk for heart attakcs and strokes for patients taking the drug.
Likely caused ~100,000 heart attacks while on the market from 1999-2004.
3 requirements for informed consent in clinical trials
- Must be mentally competent
- Must be informed of the details of the study, its benefits, and its risks
- Must agree to be part of the trial and able to withdraw consent
What is the Belmont Report, and what are its 3 main principles?
A report used to provide research subjects with protections, based on past subject abuses like the Tuskegee Syphilis Experiments
Principles:
1. Respect for persons - voluntary and informed participation
2. Beneficence - study must have the possibility of producing good for subjects, society, etc.
3. Justice - subjects must not be chosen to selectively provide benefit or put at risk selected social groups
What was the TGN1412 phase I clinical trial?
TGN1412 was a candidate drug for arthritis and leukemia that had been evaluated in non-human primates. In the phase I trial with humans, all 6 who took the drug became extremely ill, and 4 developed multi-organ failure. All 6 survived, but one was hospitalized for three months, one developed cancer, and one had his toes and parts of his fingers amputated.
How many cells are in the human body?
10^14 (or 100,000,000,000,000) cells
What is the composition of a cell by weight?
30% chemicals (proteins, DNA, RNA, ions, etc.)
70% H2O
From where does most of a cell’s “dry weight” derive?
Most of a cell’s “dry weight” derives from 4 families of organic biomolecules:
1. Polyaccharides (carbs)
2. Lipids, membranes
3. Proteins
4. Nucleic acids
What are ionic bonds?
relatively weak bonds occurring between atoms that can easily become charged (ions); water-soluble
What are covalent bonds?
strong chemical bonds made by the sharing of a pair of electrons between two atoms (vs. donating ionic bond); can be non-polar or polar based on equal or unequal distribution of electrons that may result in partial charges
What are hydrogen bonds?
form between molecules because of the attraction between areas of partial negative and positive charge that result from polar covalent bonds; very weak compared to covalent bonds
Common examples are water (H2O) molecules
What are hydrophobic interactions?
arrangements of molecules that minimize interaction with water (non-polar molecules, AKA hydrophobic molecules)
What bonds typically form interactions among biomolecules and between cells and their environment?
Mostly hydrogen and ionic bonds (chemical interactions), but hydrophobic interactions are also important
Prokaryotic cell (bacterial cell) vs. Eukaryotic cell (plants, animals, people)
What is the chemical basis for cell membranes?
Phospholipids with a hydrophilic head and two hydrophobic tails compose the semipermeable lipid bilayer cell membrane
How do drugs cross the cell membrane (phospholipid bilayer)?
Hydrophobic molecules can freely cross (some drugs)
Many molecules are hydrophilic (many drugs), and proteins help transport such molecules into the cell
Why are proteins on the phospholipid bilayer important?
Many serve as receptors and transporters that can be important for drug availability and action
What are the respective functions of DNA, RNA, and proteins within cells?
Together, DNA, RNA, and proteins are responsible for the flow of biological information within cells…
DNA: function is long-term storage of information
RNA: function is short-term transmission of information and sometimes catalysis
Protein: functions include providing physical structure, transmission of information, transport of materials, and catalysis
Drugs could target any of these, but mostly target proteins
What type of bonds hold the two strands of DNA together in a double helix?
Hydrogen bonds; this is how complimentary base pairing works
What drugs damage DNA?
Some chemotherapy drugs chemically damage DNA by mimicing subunits and disrupting replication
What is the role of mRNA?
Provides a template for protein synthesis in translation (RNA –> amino acid sequence)
What is transcription?
RNA is synthesized from a DNA template based on complementary base pairing
What drugs disrupt transcription and translation of RNA?
Some antibiotic drugs, specifically in bacteria
How are proteins formed?
Initially formed as a linear polymer, and the amino acid sequence is directly determined by mRNA based on information in DNA (AKA translation)
How many amino acids make up the proteins found in the human body?
20
How many proteins are in the human body?
> 20^300 potential proteins, but probably a few hundred thousand actually found in humans
What is the primary cellular target of most drugs?
most drugs target or mimic proteins
What are carbohydrates?
The class of organic molecules characterized by a ratio of 1:2:1 carbon:hydrogen:oxygen (e.g., glucose C6H12O6)
Functions are composition of structural elements, communication (ABO blood type), building blocks (nucleotides contain a carb compound), ENERGY SOURCE
Certain drugs (e.g., type 2 diabetes drugs) mimic carbohydrates to alter nutrient absorption
4 protein-based processes in cells that make good drug targets
- Receptor-Ligand binding: drugs can bind the receptor to mimic or block the ligand
- Enzymes and the process of catalysis: drugs can block catalysis by mimicking the enzyme substrate
- Ion channels: drugs can change the conformation to open or close the channel
- Macromolecule synthesis: drugs can mimic the monomer subunits to poison the process
What is the role of enzymes in cell metabolism?
Cell metabolism is organized by enzymes, which accelerate, or catalyze, a chemical reaction
What is the implication of drugs in catalysis (+ statin example)?
Enzymes are often organized into networks to achieve their purpose, and drugs can target any of the enzymes to stop the process.
An example is statin drugs, which target an enzyme network that leads to cholesterol synthesis. Hydrogen bonds that normally form between the catalytic site and the enzyme’s substrates can’t occur because the enzyme forms hydrogen bonds with the statin drug instead. This is known as competitive inhibition.
How does an enzyme act as a catalyst for a chemical reaction?
The catalytic site often makes hydrogen and/or ionic bonds with the substrate to promote a chemical reaction
Why is x-ray crystallography important with regard to biomolecule interactions?
X-ray crystallography can be used to observe the 3-dimensional atomic structure and interations among biomolecules (and between biomolecules and drugs)
What is the implication of competitive inhibitors and enzyme catalytic sites?
Drugs that bind enzyme catalytic sites are often competitive inhibitors that inhibit catalysis by competing with natural enzyme substrates for binding to the catalytic site.
This is usually a reversible process that ceases when concentration of a drug falls (e.g., stop taking drug), but can be irreversible for some drugs that covalently modify their target.
How does Aspirin act on catalytic sites?
Aspirin is an irreversible competitive inhibitor of COX-1 and COX-2, as it causes acetylation near the catalytic sites
What is pharmacokinetics?
the branch of pharmacology that examines the distribution and fate of drugs administered to the body; includes altered kinetics caused by drug interactions and/or disease status and is important for designing a drug-based therapy that will keep the levels of a drug within therapeutic range
What 2 things does drug fate depend on?
- Route of Administration
- Formulation
4 important pharmacokinetic parameters
- Absorption of drug
- Distribution of drug
- Metabolism of drug
- Excretion of drug
How do most drugs reach their target tissues?
Through the circulatory system by way of one of many routes of administration
What is the role of capillaries in drug action?
Absorb drugs at sites of delivery and release drugs into tissues throughout the body
What does the area under the curve (AUC) measure in pharmacokinetics?
The level and duration of a drug in systemic circulation; it is a measure of extent of exposure of the body to the drug.
AUC is proportional to bioavailability and inversely proportional to clearance.
`What is bioavailability (F), and how is it calculated for different routes of administration?
Fraction of a drug dose that reaches systemic circulation; directly proportional to AUC
For IV injection: F = 1
For oral dosing: F = (fraction absorbed)(fraction escaping first-pass clearance)
At equal doses, F= oral AUC / IV AUC
When can a drug be given orally on the basis of bioavailability (F value)?
Drugs with higher F value (closer to 1) can easily be given orally.
Drugs with F value < 0.01 cannot be given orally and typically require injection.
Why might a drug be delivered by IV injection instead of orally or topically?
With IV injection, absorption is immediate and complete, and IV injection gives 100% bioavailability (F=1).
Good for drugs that need to act quickly (critical care) and drugs that can’t survive the digestive tract or first-pass metabolism or have F < 0.01.
What is a formulation?
Concoction of the drug together with other chemicals to control the pH and act as preservatives; in liquid form for IV injection and pill/capsule form for oral.
Oral formulation can control the rate and location of absorption from the digestive tract.
Why might a drug be given orally instead of via IV injection or topically?
Less invasive, very convenient for patients and good for drugs that can survive the digestive tract and first-pass metabolism
Why might a drug be given topically instead of via IV injection or orally?
Good for small hydrophobic drugs that can be formulated to pass through the skin or other body surfaces (e.g., steroids, nicotine, antibiotics).
Good for local drug delivery.
Can achieve very slow and sustained drug absorption.
How do the pharmacokinetic curves differ between a drug injected via IV and a drug taken orally?
IV injection has faster time to effect (immediate) and a much greater peak concentration
Describe skin epithelium and how drugs are implicated
In the skin…
1. Epithelium has multiple cell layers
2. Thin layer of dead cells
Abosrption barrier = high, epithelial cells create a barrier between the environment and circulation, and drugs must cross this barrier if they are not injected or are not small hydrophobic drugs (classic in topical administration); they are held tightly together by protein-based junctions so most drugs must pass through the cells rather than around them, limiting drug absorption
What are the types of epithelium?
- Simple: one layer
- Stratified: many layers
Can also be subdivided by shape:
1. Squamous
2. Cuboidal
3. Columnar
Describe the lung epithelium and how drugs are implicated
In the lungs…
1. Epithelium is one layer of very thin cells
2. Blood vessels are in very close contact with epithelial cells
Absorption barrier = very low, so for drugs that can be delivered as an aerosol or gas, inhalation is a very fast and efficient route for drug absorption; it also avoids first-pass metabolism in the liver
Describe drug absorption from the GI tract
Drug absorption in the GI tract affected by…
1. Epithelial barrier that varies along GI tract
2. pH changes significantly along the GI tract:
- neutral pH in mouth/esophagus
- very acidic pH in stomach
- moderately basic pH in small intestine
Drug formulations can often be designed to prevent absorption prior to the small intestine using pH-sensitive materials
Describe mouth and esophagus epithelium and how drugs are implicated
In the mouth and esophagus…
1. Epithelium is many layers
2. Also contains flattened cells but NO dead cells
Absorption barrier = moderate
Describe stomach epithelium and how drugs are implicated
In the stomach…
1. Single layer of columnar cells
2. Specialized for secretion
Abosrption barrier = low; the stomach is very acidic (low pH), but drug coatings can be made to resist the low pH environment
Describe small intestine epithelium and how drugs are implicated
In the small intestine…
1. Single layer of columnar cells
2. Many capillaries near the epithelium
3. Specialized for absorption of nutrients
Absorption barrier = very low, macroscopic villi and microscopic villi give the epithelium a very high surface area, and most oral drug absorption takes place in the small intestine
What is first-pass metabolism?
All drugs absorbed in the GI tract pass through the liver capillary bed prior to reaching general circulation. The liver has several enzyme systems that chemically modify drugs, and liver-modified drigs are often inactive and easy for the body to eliminate.
First-pass metabolism is why oral drugs have reduced potency.
What is clearance (CL)?
One of two primary pharmacokinetic parameters that describes the efficiency of irreversible elimination of a drug from the body, and is defined as the volume of blood cleared of drug per unit time
A CL value can be determined for the whole body or for a single organ like the liver
5 main types of irreversible elimination of a drug
Irreversible elimination can be by excretion of the drug into…
1. Urine
2. Gut contents
3. Expired air
4. Sweat
5. or by metabolic conversion of the drug into another chemical in the liver or other tissues
How are most drugs cleared from the body?
MOST clearance results from drug metabolism in the liver and/or drug and metabolite excretion in the kidneys
What is cytochrome p450 (CYP)?
Family of enzymes in the liver responsible for first-pass metabolism of drugs; most metabolic transformation of drugs (~75% of drugs) due to CYP450 actions
What determines the dosing needed to achieve a desired level of drug in the body?
Clearance; at steady state, the amount of the drug administered per unit time (dose rate) must equal the amount of drug eliminated per unit time (elimination rate)
A drug with higher CL value will achieve a lower steady state drug concentration for any given dose rate, meaning more drug must be given to achieve the same concentration
What determines the elimination rate of a drug?
Determined by the plasma drug concentration and the whole body clearance (CL) value
elimination rate = clearance*plasma drug concentration
What is the significance of serum albumin?
Each drug has an inherent tendency to interact with components of the blood (especially serum albumin) and/or other tissue types
I.e., serum albumin binds many drugs
What is volume of distribution (V)?
One of the two primary pharmacokinetic parameters, describes the relationship between the amount of drug in the plasma to the total amount of drug in the body; determined by the relative tendency of a drug to stay in the blood vs. reside in tissues of the body
V = total amount of drug in body / plasma drug concentration
Small V means most of the drug stays in the bloodstream
Large V means most of the drug resides in the tissues of the body
V can be used to plan a “loading dose” when medical care requires a drug to rapidly reach a therapeutic level
What is half life (t1/2)?
A pharmacokinetic paramter that can be derived from clearance (CL) and volume of distribution (V) that can be described as the length of time for the drug plasma concentration to fall by 50%; also determines the length of time to reach a steady state plasma concentration (e.g., 1 dose per 24 hours can be established based on half life)
Half life applies for drugs with a plasma concentration that declines as exponential decay (most drugs), and may not apply when drug metabolizing enzymes are saturated (like alcohol during heavy drinking)
3 ways individualized medicine is pertinent to pharmacokinetics
- Half life of a drug for a given person may be longer or shorter than the population average, requiring differing doses and/or dose timing
- Individuals with diseases of the liver or kidneys (where metabolic alteration and excretion of drugs occurs) can have dramatically altered pharmacokinetics
- Individual polymorphisms for drug-metabolizing enzymes can also radically alter responses to drugs
In sum, pharmacokinetics can be variable between individuals
What is pharmacodynamics?
Branch of pharmacology concerned with what drugs do to the body (whereas pharmacokinetics is what the body does to drugs)
How do drugs do what they do?
“the pharmacological, physiological, or behavioral effects induced by a drug follow from their interaction with receptors”
What is a receptor?
a protein that is 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; they are “sense organs” of a cell
How are receptor-ligand interactions like a “molecular switch?”
Ligand binding activates the receptor, allowing it to be turned “ON” like a light switch
Is receptor-ligand binding reversible?
Ligand binding is often reversible, and is more likely to be reversible if it binds with less affinity (more loosely)
2 determinants of signal intensity in receptor-ligand interactions (modulated signal intensity)
- Binding affinity (and subsequently time bound)
- how tight or loose a ligand binds, which affects how long it is bound - Number of receptors bound
How are receptor-ligand interactions like a “lock and key” mechanism?
Ligands are like a key in that they are specially shaped to fit with a given “lock,” or receptor; the ligand binds and “turns” like a key to flip the molecular switch
This is known as binding specificity, and the strength of binding (affinity) is structural
What determines a ligand’s receptor selection?
Ligand binding specificity, which is based on the structure of the ligand (think of the lock and key analogy)
How can binding affinity differ between a drug and its endogenous ligand?
A drug may be more specific to a given receptor than its endogenous ligand (higher binding affinity), which is how drugs can “win” competition with naturally produced compounds
What are side effects with regard to drugs?
Any result other than the therapeutic (or recreational) purpose of the drug
What is an agonist?
A ligand that binds to a receptor and triggers a response, often a drug mimicking the action of a naturally occurring substance
Agonists can either…
1. Mimic - act as an endogenous ligand
2. Facilitate - help the endogenous compound carry out its effects (called allosteric agonists)
What is an antagonist?
A ligand that binds to a receptor and blocks it, preventing the triggering of a response
4 types of drug targets (receptors) that regulate neuronal function
- Ion channels
- G-protein coupled receptors (GPCRs) (metabotropic receptors)
- Carriers or transporters
- Enzymes
How do drugs take effect at ion channels?
Ligand binding to an ion channel changes the voltage of the cell, inducing cellular action
How do drugs take effect at G-protein coupled receptors (GPCRs) (metabotropic receptors)?
Ligand binds to receptor, activating a G-protein. The G-protein then moves and triggers signal inside the cell.
How do drugs take effect at carrier or transporter proteins?
Ligand binds to transporter molecules and directly manipulates carrier/transporter action (e.g., cocaine binds and prevents the transporter from eliminating neurotransmitters, leading to neurotransmitter accumulation)
How do drugs take effect at enzymes?
Ligand binds to enzyme and can trigger the creation or disruption of neurotransmitter/molecule production (e.g., some drugs can bind to enzymes and catalyze ACh neurotransmitter breakdown)
What does the y-axis of a dose response curve describe?
Drug efficacy, or the intensity of drug response; this can plateau, meaning additional doses no longer have an effect
What does the x-axis of a dose response curve describe?
Drug potency, or the increasing dose of drug; drugs that bind more strongly (higher affinity) are more potent and require a smaller dose to yield efficacy
What is drug potency?
A measure of how well drug molecules bind their receptor (binding affinity or strength of receptor-drug binding)
More potent drugs bind more strongly and require lower dose for same effect
Can different drugs bind the same receptor?
Yes, but with different affinities (strength of binding)
What is drug efficacy?
A measure of how well a drug produces the desired response; it is the maximum effect obtainable, with additional doses producing no additional effect
A drug that is more efficacious (effective) can produce a greater peak, or maximum, effect than a drug that is less efficacious
How do the dose response curves (potency and efficacy) of methamphetamine, speed, and caffeine differ?
5 reasons why using the most potent, efficacious drug is not always the best option
Must consider…
1. Variability in responses
2. Drug toxicity
3. Therapeutic index
4. Drug interactions
5. Placebo effects
I.e., safety and tolerability reasons
What is ED50?
The effective dose for 50% of subjects; there is variability in dose response, and ED50 helps us understand that
What is drug toxicity?
Represents unwanted effects of a drug
Related to principal and predictable drug action, not related to unpredictable side effects
What is therapeutic index?
The margin of safety, essentially a window between the ED50 (effective dose) and LD50 (lethal dose)
Answers how much of a drug is needed for efficacy while avoiding toxicity
Why is a narrow therapeutic index especially important?
Drugs with a narrow therapeutic index are easier to overdose on or induce toxic effects due to the ED50 (efficacious dose) and LD50 (toxic dose) being close together
What are drug interactions?
Describes how the effects of one drug may be modified by simultaneous use of another; these are usually pharmacodynamic interactions and/or pharmacokinetic interactions
central nervous system (CNS) vs. peripheral nervous system (PNS)
CNS contains:
1. Brain
2. Spinal cord
PNS contains:
1. Nerves from brain and spinal cord
2. Sensory neurons
What is the function of the spinal cord?
- Carries and modulates sensory information from skin, muscles, joints, and internal body organs to brain
- Organizes and modulates motor outflow to muscles (coordination) via motor neurons
What is functional specialization?
Term used to describe how different parts of the brain are specialized to carry out specific functions; CNS functions are spatially distributed
What is the function of the brain stem?
- Acts as a bridge of communication between the brain and the rest of the body
- Regulates vital bodily functions (respiration, blood pressure, heart rate, GI function, sleep and wake, alertness, attention, arousal)
Site of action for depressant drugs (barbituates)
What is the function of the cerebellum?
Controls movement and posture
Site of action for ethyl alcohol
What is the function of the hypothalamus (+ limbic system)?
- Responsible for integration of the involuntary (autonomic) nervous system
- Links the nervous system to the endocrine system via the pituitary gland
The limbic system controls primitive behaviors (emotions and reward) and interacts with the hypothalamus
What is the function of the midbrain?
It is one of our motor systems and contains the substancia nigra
Parkinson’s patients have dopamine deficiencies in this brain region
What is the function of the cerebral cortex, and what are its 4 lobes and their respective functions?
Cerebral cortex is the largest part of the human brain and the center of highest functions
4 lobes:
1. Frontal: conscious thought
2. Parietal: body sensations
3. Temporal: smell and sound
4. Occipital: vision
What is the body motor/sensory “map?”
Somatosensory map in the parietal lobe resembled by a “homonculus;” that is, specific regions of the parietal lobe correspond to body sensations in specific bodily areas
What is the neural “connectome?”
Refers to the comprehensive map of neural connections in the brain; it’s essentially the wiring diagram of the brain, encompassing how neurons are interconnected and communicate with each other through synapses
How many neurons are in the brain?
~100 billion neurons, plus support cells
What is the speed of neuronal transmission?
Neurons transmit nerve signals at up to 200 mph
3 parts of the neuron
- Soma: the cell body (nucleus)
- Dendrites: receive input from other neurons
- Axons: send output to other neurons
How many neurons does a single neuron receive input from?
A typical neuron receives input at dendrites from thousands of other neurons
In simple terms, what is a nerve?
a bundle of axons
What is myelin?
made by Schwann cells and coat axons to increase transmission speed
What are synapses?
sites of signal transmission from one neuron to another (drugs act at synapses)
What type of process is synaptic transmission?
Chemical process: neurotransmitters to receptors
7 steps in synaptic transmission
Synthesis and loading of neurotransmitters:
1. Producing NTs from precursors
2. Loading NTs into vesicles
3. Quality control (degrading enzymes
Release of NTs and receptor binding:
4. Action potential causes vesicle fusion
5. Autoregulation of release
6. NTs bind postsynaptic receptors
Termination of synaptic transmission:
7. NT re-uptake or breakdown
What steps in synaptic transmission are disrupted by botox?
Release of NTs and receptor binding:
4. Action potential causes vesicle fusion
5. Autoregulation of release
6. NTs bind postsynaptic receptors
Botox disrupts this process
What steps in synaptic transmission are disrupted by SSRIs?
Termination of synaptic transmission:
7. NT re-uptake or breakdown
What are structural differences between peripheral capillaries and CNS capillaries (i.e., blood-brain barrier), and how are drugs implicated?
CNS capillaries have tighter junctions and astrocyte “foots” that provide an additional barricade
Drugs in the circulatory system attempting to cross the blood-brain barrier to access CNS capillaries encounter more challenges; many drugs cannot enter the brain due to the BBB
What are the characteristics of the blood-brain barrier with respect to drugs (what drugs can enter, etc.)?
The BBB severely restricts access to the brain, as entry requires diffusion through two membranes
Hydrophobic drugs can cross the barrier
Hydrophilic drugs have difficulty crossing the barrier
What is tolerance?
Tolerance occurs when the person no longer responds to the drug in the way that person initially responded, requiring a higher dose of the drug; this is the mechanism behind withdrawal, and thus, addiction
What is pharmacokinetic tolerance?
Increase in the ability of the body to dispose of the drug through increased excretion or degradation
Contributes ~20% to tolerance and is not a factor in physical dependence
What is cellular tolerance?
An adjustment in brain neurochemistry in response to the chronic presence of a drug that offsets the effects of the drug
It is a factor in physical dependence, as absence creates withdrawal
What happens in the brain when we build cellular tolerance to an agonist?
Decrease in number of postsynaptic receptors, resulting in subsensitivity; normal neurotransmitter levels no longer enough
Example is marijuana
What happens in the brain when we build cellular tolerance to an antagonist?
Increase in number of postsynaptic receptors, resulting in supersensitivity; normal neurotransmitter levels are too much
7 major neurotransmitters
- Acetylcholine (ACh)
- Dopamine (DA)
- Norepinephrine (NE)
- Serotonin (5-HT)
- Glutamate
- GABA
- Endorphins
4 criteria neurotransmitters have to meet
- They are synthesized in neurons
- Present and released from presynaptic neuron
- Exogenous application mimics action of released NT
- Have specific mechanisms for removal or elimination
Are neurotransmitters evenly distributed throughout the brain?
No, different NTs have different projection pathways because different neurons use different NTs (e.g., there are distinct cholinergic, dopaminergic, and serotonergic projection systems)
What determines whether a neuron is active or inactive?
receptor activation
Do drugs have target-specific effects?
We usually assume that a drug is aimed at a specific receptor, in a specific region of the brain, to produce a target-specific effect, BUT few currently available drugs possess such specificity
7 “small molecule” neurotransmitters
- Acetylcholine (ACh)
- Dopamine (DA)
- Norepinephrine (NE)
- Epinephrine
- Serotonin (5-HT)
- Glutamate
- GABA
2 peptide/opioid neurotransmitters
- Endorphins
- Substance P
These are classified as both peptide and opioid neurotransmitters
3 catecholamine neurotransmitters
- Dopamine (DA)
- Norepinephrine (NE)
- Epinephrine
The catecholamines are within the broader “small molecules” NT classification
4 monoamine neurotransmitters
- Dopamine (DA)
- Norepinephrine (NE)
- Epinephrine
- Serotonin (5-HT)
The monoamines are within the broader “small molecules” NT classification, and the first 3 are catecholamines
2 amino acid neurotransmitters
- Glutamate
- GABA
The amino acid neurotransmitters are within the broader “small molecules” NT classification
What is acetylcholine (ACh)/cholinergic system, and what is its role?
The cholinergic systems:
1. Maintain the EEG signals of the cortex
ACh:
1. Used as the NT in neuromuscular junctions (motor control role)
2. Plays role in memory by maintaining neuronal excitability (for this reason, Alzheimer’s is thought to be related to the death of cholinergic neurons in the cortex)
2 types of acetylcholine (ACh) receptors
- Muscarinic (GPCR)
- Nicotinic (ion channel)
How is acetylcholine (ACh) synthesized?
- Acetyl-CoA is generated by mitochondria in the Krebs cycle
- Choline comes from diet (not synthesized)
- ACh then generated from acetyl-CoA + choline by cholineacetyltransferase enzyme (ChAT)
How is acetylcholine (ACh) removed/degraded?
After action in synaptic cleft, acetylcholinesterase (AChE) breaks down ACh into acetate + choline
What drugs act on cholinergic (ACh) pathways?
- AChE inhibitors: reversible (e.g., cognitive enhancers, Alzheimer’s treatments), irreversible (e.g., nerve gas (sarin), pesticides)
- ACh receptor agonists: nicotine, muscarine
- ACh receptor antagonists: scopolamine (treats addiction and motion sickness)
How are catecholamines synthesized?
Formed as part of an enzymatic pathway; DA, NE, and epinephrine are all part of the same pathway and can be created via distinct enzymes
What are the functions of the dopaminergic (DA) systems?
Motor activity, motivation and reward, mood, sleep, learning, etc.
Parkinson’s thought to be related to death of dopaminergic neurons in the substancia nigra (in midbrain)
Too much dopamine may be related to schizophrenia
What are the dopamine (DA) receptors?
Several types: D1-5
How is dopamine (DA) removed/degraded?
2 options:
1. Removal/re-uptake from synaptic cleft by dopamine transporter
2. Enzymatic degradation by monoamine oxidase (MAO) or catechol-O-methyl transferase (COMT)
What drugs act on dopaminergic (DA) pathways?
- Dopamine transporter inhibitors: cocaine (blocks pump), amphetamine/speed (reverse pump)
- MAO inhibitors: used as antidepressants
What are the functions of the serotonergic (5HT) systems?
Involved in:
1. Regulating aggression
2. Emotional processing
3. Mood
4. Sleep
5. Sexuality
6. Appetite
7. Metabolism
Increases are related to OCD and schizophrenia
Decreases are related to depression
What are the main sources of serotonin (5-HT)?
Raphe nuclei
How is serotonin synthesized?
Made from the amino acid tryptophan in two enzymatic steps (tryptophan is an essential amino acid, meaning we do not synthesize it and it must come from diet)
Does serotonin (5-HT) cross the blood-brain barrier?
No, but 5-hydroxytrytophan, its precursor does; therefore, serotonin is often synthesized after it crosses the BBB
How is serotonin (5-HT) removed/degraded?
- Serotonin signal is terminated primarily by the serotonin re-uptake transporter
- Monoamine oxidase (MAO) breaks down serotonin in glial cells
Mechanisms similar to those of dopamine
What drugs act on serotonergic (5-HT) pathways?
- Serotonin transporter inhibitors: SSRIs, MDMA, cocaine, amphetamines
- Serotonin receptor agonists: LSD, psilocybin
glutamate vs. GABA
Glutamate is the major excitatory neurotransmitter in the brain
GABA is the major inhibitory neurotransmitter in the brain
Both are used by most neurons, and together they maintain the balance between excitation and inhibition in the brain
Both receptors can be ion channels or GPCRs
Defects in either can lead to epilepsy and seizures
How is glutamate synthesized?
From the non-essential amino acid glutamine by glutaminase or from the Krebs cycle
How is GABA synthesized?
From glutamate by glutamic acid decarboxylase (GAD)
How are glutamate and GABA removed/degraded?
Both signals terminated by re-uptake transporters on neurons or glia
GABA can also be degraded by GABA-transaminases (GABA-T)
What drugs act on GABA pathways?
GABA agonists (depressants): barbiturates, benzodiazepine, ethanol
4 types of opioids
- Endogenous opioids: endorphins
- Natural opiates (from opium poppy): morpheine, codeine
- Semi-synthetic opiates (from natural opiates): heroin, oxycodone
- Synthetic opiates: fentanyl
How are opioid transmitters removed/degraded?
Signal terminated by peptidases (for endogenous opioids only, like endorphins)
What are the psychological effects of anxiety?
Feelings of unease, fear, and worry in situations that don’t warrant these feelings
What are the physiological effects of anxiety?
May include heart palpitations, fatigue, nausea, chest pain, shortness of breath, stomach aches, or headaches
Where in the brain does anxiety exert its effects?
Neural circuits in the amygdala and hippocampus
What is the overlap between anxiety drugs and sleep drugs?
Many of the anxiolytic drugs can be used for sleep disorders
What is the mechanism of anxiety’s effects in the brain?
Lack of activation of the GABA pathway, which causes the amygdala to be over-active; we know this because activation of the GABA pathway (causing inhibition) reduces amygdala action
What is anxiety, and what are its 4 major forms?
Most frequent psychological disorders, characterized by both psychological and physiological effects
4 major forms of anxiety disorders:
1. Generalized anxiety disorder
2. Panic disorder
3. Social anxiety disorder
4. PTSD
How prevalent are anxiety symptoms, and how prevalent is anxiety treatment?
Symptoms may effect 30% of the general population
Only 15-36% of affected individuals are treated
2 types of insomnia
- Acute: sudden onset in people without a history of insomnia
- Chronic
3 symptoms of insomnia
- Trouble falling asleep
- Trouble staying asleep
- Sleep not restorative
Considered insomnia if any of these symptoms last >1 month
5 causes of insomnia
- Physical issues like pain or illness
- Response to use of drugs
- Response to strenuous exercise
- Result of psychological issues
- Poor sleep environment (e.g., noisy)
What is the prevalence of insomnia in the U.S.?
affects ~64 million each year
What is the approach to treating both anxiety and insomnia?
combination of pharmacotherapy (e.g., benzodiazepines) and psychological therapy
5 pharmacodynamic effects of benzodiazepines (effects on the brain and body)
- Anxiolytic (antianxiety)
- Sedative
- Anticonvulsant
- Amnesic
- Muscle relaxant
Benzodiazepine sites of action are different for different responses
How addictive and dangerous are benzodiazepines?
Middle of the road; moderately addictive and somewhat dangerous
6 common benzodiazepine drugs (no idea if we actually have to memorize this)
- Diazepam (Valium) - long-acting agent
- Chlorodiazepoxide (Librium) - long-acting agent
- Clonazepam (Klonopin) - intermediate-acting agent
- Lorazepam (Ativan) - intermediate-acting agent
- Triazolam (Halcion) - short-acting agent
- Alprazolam (Xanax) - short-acting agent
How are different benzodiazepines named?
Defined by chemical structure…chemical core is common to all while changes in side groups or slightly modifying the basic structure creates different drugs
What is the mechanism of action for benzodiazepines?
- Act as receptor agonists at the GABA-benzodiazepine-chloride receptor
- Facilitate the binding of GABA but do not directly stimulate the receptor (simply increase the affinity of the receptor for GABA)
- This increases the influx of chloride and hyperpolarization
Different GABA-benzodiazepine receptors yield different effects
What do the different GABAa subunits (alpha1, alpha2, alpha3, alpha5) do when benzodiazepine binds?
alpha1: mediate sedation, amnesia, and ataxic effects
alpha2 + alpha3: involved in anxiolytic and muscle-relaxing actions
alpha5: involved in some memory impairment
Are benzodiazepines likely to lead to death in the case of an overdose?
No, as dose increases, CNS depressant effects taper off
Risk of death is low unless combined with other drugs
What are benzodiazepines?
CNS depressant drugs used to treat anxiety and depression; also common treatment for epilepsy/seizures
What are the effects of benzodiazepines at the amygdala and orbitofrontal cortex?
moderate anxiety, agitation, and fear
What are the effects of benzodiazepines at the cerebral cortex and hippocampus?
mental confusion and amnesia
What are the effects of benzodiazepines at the spinal cord, brain, and cerebellum?
muscle relaxation
What are the effects of benzodiazepines at the cerebellum and hippocampus?
antiepileptic actions
What are the effects of benzodiazepines at the cerebral cortex and brain stem?
sedation, increased seizure threshold, cognitive impairment, muscle relaxation
Describe the metabolism and excretion of benzodiazepines
Long-acting agents are typically metabolized to active intermediates that remain longer
Short-acting agents are typically metabolized to inactive metabolites
Describe the absorption and routes of administration of benzodiazepines
All 15 U.S. benzodiazepines are absorbed well in about an hour
All may be given orally except midazolam which is given only by injection
What is unique about benzodiazepines in the elderly?
- Elderly have reduced ability to metabolize long-acting benzodiazepines and active metabolites
- Half-lives are greatly increased in the elderly
- Increased incidence of falls and fractures
For how long are benzodiazepines typically used?
short periods, few days up to 3-4 weeks
Short-term therapy may be all that is needed or as a prelude to long-term treatment with other drugs with a slower onset of action (antidepressants are used for longer term treatment of anxiety and insomnia)
2 limitations of benzodiazepines
- Act as anxiolytics but not antidepressants
- Adverse effects and dependency potentially limit usefulness
5 main clinical uses of benzodiazepines
- Anxiety
- Insomnia
- Anterograde amnesia for medical procedures
- Treatment of alcohol withdrawal
- Antiepileptic action
3 situations in which benzodiazepines should be avoided
- Situations requiring fine motor control, cognitive skills, or mental alertness
- Situations involving alcohol or other CNS depressants
- Elderly, children, or people with a history of abuse
Describe benzodiazepines as date rape drugs
Benzos cause physical and mental impairment as well as memory loss, and combination with alcohol can enhance these effects
Rohypnol (roofies) is a date rape benzodiazepine that is not FDA approved
Do benzodiazepines cause tolerance and dependence?
Tolerance and dependence develop with long-term use but most withdrawal symptoms subside in 1-4 weeks; there may be rebound increases in anxiety and insomnia with cessation
What is flumazenil (Romazicon)?
Benzodiazepine receptor antagonist that binds the GABA-benzo receptor with high affinity but produces no effect on GABA signaling (doesn’t do much on its own)
It reverses the antianxiety and sedative effects of benzodiazepines (like a benzodiazepine antidote or counter)
Has a short half-life
What are benzodiazepine receptor agonists (BZRAs)?
Drugs that act at GABA receptors and facilitate GABA action; these drugs have variable chemical structures and can be classified into two groups:
1. Benzodiazepines
2. Nonbenzodiazepines (Z-drugs)
What are Z-drugs?
Called nonbenzodiazepines, these are benzodiazepine receptor agonists (BZRAs) that are widely used to improve the quality of sleep and manage insomnia…they are prescribed as hypnotics, NOT as anxiolytics like benzodiaepines
Z-drugs vary in chemical structure and are chemically distinct from benzodiazepines
How do Z-drugs work for insomnia?
Z-drugs (AKA nonbenzodiazepines) are benzodiazepine receptor agonists (BZRAs) that treat insomnia by binding more selectively only with GABAa receptor isoforms that contain the alpha1 subunit
Recall that the alpha1 subunit mediates sedation, amnesia, and ataxic effects
What is the main difference between the different types of Z-drugs (zolpidem, zaleplon, eszopiclone)?
half-life
What is zolpidem (Ambien)?
Z-drug (nonbenzodiazepine) used for short-term treatment of insomnia; no anxiolytic, anticonvulsant, or muscle relaxant effects, just amnesic effects
What is zaleplon (Sonata)?
Z-drug (nonbenzodiazepine) used for short-term treatment of insomnia that is unique due to its very short half-life (less than 1 hour)…this short half-life is useful because:
1. Can be taken if there are difficulties falling asleep (no predicting)
2. No detrimental morning effects
3. No rebound effects since dependence is unlikely
What is eszopiclone (Lunesta)?
Z-drug (nonbenzodiazepine) used for short-term treatment of insomnia that has the longest half-life of the Z-drugs (5-7 hours)…this long-half life is noteworthy because it is probably the most effective for improving sleep latency and maintence BUT effectiveness is offset by sedation the next day
What is ramelteon (Rozerem)?
Melatonin receptor agonist that is used for insomnia with difficult sleep onset; it is nonaddicting and devoid of abuse potential, causes no rebound insomnia, and leaves little morning drowsiness while maintaining modest efficacy (has not been compared to Z-drugs, however)
I.e., it acts like a melatonin supplement
How might serotonin mediate anxiety?
Anxiety may be due in part to defects in serotonin neurotransmission and drugs that augment serotonin activity may aid in treatment (serotonin receptor agonists can be used as anxiolytics (SSRIs))
What are selective serotonin reuptake inhibitors (SSRIs)?
Serotonin receptor agonists that are the drugs of first choice to treat anxiety; activate 5-HT1A receptors that diminish neuronal activity and fear
Have a slow onset of action and are also used as antidepressants
What is buspirone (BuSpar)?
SSRI that is a selective 5-HT1A agonist with unique anxiolytic properties and an additional antidepressant effect…no sedation or hypnosis even in overdosages so it is ineffective in promoting sleep, but causes minimal amnesia, mental confusion, and psychomotor impairment
Also does not potentiate CNS depressants and has no cross-tolerance or cross-dependence with benzodiazepines, and has little potential for abuse or addiction
Has a much slower onset of action than benzodiazepines
3 general effects of CNS depressants
- Sedative effects: calming effect
- Hypnotic effects: promote drowsiness and sleep onset
- Anesthesia and coma: higher doses
What is the general site/mechanism of action for CNS depressants?
Augment GABA activity, and some may reduce glutamate excitatory activity (NMDA)
4 features of abused general CNS depressants
- Cause intoxication
- Overdoses serious (e.g., alcohol poisoning)
- Tolerance (and cross-tolerance) can develop
- Dependence (and cross-dependence) can develop
What is ethyl alcohol (ethanol)?
CNS depressant that is used as a recreational drug; it is the second most widely used psychoactive substance, is generated by fermentation, and consumption of alcohol by man dates back to at least about 10,000 BC
What is “proof” in liquor?
Double ABV%
Example: 1.5oz liquor that is 80 proof…1.5*0.40 = 0.6oz pure ethanol
Describe alcohol absorption (where/how)
Alcohol is rapidly absorbed from the gastrointestinal tract…10-20% is absorbed in the stomach and 80-90% absorbed in the upper intestine
Cells in the stomach contain alcohol dehydrogenase (ADH), and men have more stomach ADH than woman; also, slowed gastric emptying decreases the amount of alcohol absorbed into the blood stream
How does alcohol absorption compare between an empty stomach and after food consumption?
Significantly more alcohol is absorbed on an empty stomach
Describe alcohol distribution in the body
Distribution depends on blood supply to tissue…for example, alcohol rapidly crosses the blood-brain barrier, where the CNS is highly vascularized
Also depends on body fat, because higher body fat % means less body water, and less body water means BAC will be higher; women tend to have more body fat, therefore BAC of women is higher than men for a given amount of alcohol
Alcohol can freely cross the placenta, which is why fetal alcohol spectrum disorders (FASD) are a thing
5 ways alcohol is metabolized
- Alcohol dehydrogenase (ADH) metabolizes about 90-95% of the ethanol ingested, up to 15% of this is performed in the stomach and about 85% of this is performed in the liver
- The lungs also excrete a small amount, as an exhaled air:BAC ratio of 1:2300 exists (this is how breathalyzers work)
- A small amount is also secreted in other fluids, like urine
- Microsomal ethanol oxidizing system (MEOS) in the liver can also contribute to metabolism (induced by chronic alcohol consumption
- Catalase may metabolize ethanol in fasted state
What is the microsomal ethanol oxidizing system (MEOS)?
System in the liver consisting of CYP450 family members that metabolizes alcohol in chronic consumption as well as other drugs; metabolizes acetaminophen (Tylenol) to toxic metabolite, which is why people say Tylenol is bad for the liver
What is the ADH pathway of alcohol metabolism?
Alcohol dehydrogenase (ADH) metabolizes about 90-95% of the ethanol ingested, up to 15% of this is performed in the stomach and about 85% of this is performed in the liver
ADH degrades ethanol into acetaldehyde, which is further metabolized in the liver by aldehyde dehydrogenase
What are the kinetics of alcohol metabolism?
Most alcohol metabolism shows zero order kinetics; that is, metabolism does not depend on alcohol concentration and alcohol metabolism rate is similar in most people
What is the nutritional value of alcohol?
Alcohol metabolism results in production of about 7 calories per gram (not counting mixers), and alcohol has no other nutritional value
What are the effects of alcohol on appetite?
Lower doses = appetite stimulant
Very high doses = appetite suppressant
How is blood alcohol concentration (BAC) expressed?
as g% (grams of ethanol/100mL of blood) and assumes the specific gravities of alcohol and blood are equal (1g = 1mL)
What is the BAC level for automatic legal intoxication?
0.08%
What is the BAC level at which blackouts tend to occur?
can vary - begins around 0.16%
What is the BAC level that is life threatening?
can vary - ~0.31-0.45%
How quickly is alcohol metabolized in terms of BAC?
Each hour ethanol is metabolized at a rate that causes about a 0.015% drop in BAC
4 influences that cause BAC to differ between people
- Differences in gastric ADH levels: levels in men greater than in women, so lower BAC in men
- Differences in body fat: women have higher body fat percentage, so higher BAC in women
- Differences in weight: higher weight generally means more body water, so lower BAC
- Food in stomach: slight delay in absorption and increased exposure to stomach ADH in those who have eaten, so lower BAC
What counts as “one drink?”
12 fl oz beer = 8-9oz malt liquor = 5 fl oz wine = 1.5oz shot of 80 proof hard liquor
What is the mechanism of action of ethanol?
- Binds to GABAa and potentiates GABA-mediated increase in Cl- ion flow
- Binds to glutamate (NMDA) receptors and inhibits glutamate ability to open channel
Ethanol is a CNS depressant, so both of these facilitate inhibition
What are the dose-related physical and behavioral effects of alcohol (low dose, moderate dose, high dose)?
Low dose:
1. Disinhibition (relief from anxiety)
2. Small fall in blood pressure
3. Loss of motor coordination
4. Transient stimulation of respiration
Moderate dose:
1. Progressive depression of respiration
2. Sleep
3. Muscle relaxation
High dose:
1. Amnesia
2. Unconsciousness, coma, death from respiration and cardiac depression
3. Large drop in blood pressure
4. Hypothermia
3 cardiovascular effects of alcohol
- Dilates blood vessels in skin (heat loss)
- Low doses reduce risk of cardiovascular disease (good/bad cholesterol ratio)
- Low doses reduce strokes (good cholesterol/platelets)
Note that these 2 protective effects are lost at higher doses
2 sexual effects of alcohol
- Lower doses can cause disinhibition of sexual behavior
- Depresses body function and interferes with sexual performance
Why do we have to frequently urinate when drinking alcohol?
Alcohol has diuretic effects by inhibiting vasopressin release
What is the metabolic (pharmacokinetic) mehanism behind alcohol tolerance?
Liver increases alcohol metabolizing enzymes (MEOS)
What is the tissue or functional (pharmacodynamic) mechanism behind alcohol tolerance?
Neurons adapt to drug; causes people to appear less intoxicated but still have cognitive and memory defects
What is the behavioral (learned) mechanims behind alcohol tolerance?
People become conditioned to adjust to drug effects
Describe physical (physiologic) dependence on alcohol
Adverse physical symptoms caused by alcohol withdrawal; these symptoms are often directly opposite to those caused by alcohol (e.g., anxiety)
Describe psychological dependence on alcohol
Alcohol gives feelings of pleasure, and drug abstinence causes dysphoria and cravings; this is caused by effects on the dopaminergic reward pathway
dependence vs. addiction
Dependence: person needs a drug to function normally
Addiction: compulsive use of a substance, despite its negative or dangerous effects
What are the symptoms of alcohol withdrawal?
Can be both psychological and physical, like anxiety and headaches; symptoms are largely directly opposite to the effect of the drug
What is considered excessive alcohol use (what is considered binge, heavy, and high intensity drinking)?
Excessive alcohol use: binge drinking or heavy drinking any alcohol consumption by pregnant women or those <21 years old
Binge drinking: 4 or more drinks on an occasion by woman, 5 or more by man
Heavy: more than 3 per day or 7 per week for women, more than 4 per day or 14 per week for men
High intensity: 2 or more times binge threshold
What are the impacts of excessive alcohol use in the U.S.? (no way we have to remember this shit, just give it a 5 tbh)
140,000 deaths per year, 1 in 5 deaths of people 20-49 years of age
$249+ billion in economic costs
In 2019, 14.5 million had alcohol use disorder (AUD)
9.5% of pregnant women reported alcohol use in past month (can lead to fetal alcohol spectrum disorders (FASD))
5 impacts of long-term use or abuse of alcohol on the brain
- Neuronal death
- Deficits in executive function
- Deficits in cognition
- Changes in brain morphology and volume
- Tissue tolerance
3 potential effects of withdrawal from chronic use of alcohol
- Withdrawal seizures (usually within 12-48 hours)
- Alcoholic hallucinosis (usually within 12-24 hours, resolve by 48 hours)
- Delirium tremens (usually 48-96 hours after last drink, but can occur 7-10 days later): characterized by delirium and hyperthermia, hypertension, and tachycardia
What is alcohol use disorder (AUD)?
Chronic relapsing brain disease characterized by compulsive alcohol use, loss of control over alcohol intake, and a negative emotional state when not using
Requires at least 2 of like 20 criteria to be met in the same 12 month period, and can be mild (2-3 criteria), moderate (4-5 criteria), or severe (6 or more criteria)
5 factors that increase risk of developing alcohol use disorder (AUD)
- Alcohol misuse over time (e.g., binge, heavy use)
- Drinking at early age
- Genetics, family history
- Mental health conditions
- History of trauma
5 treatment options for alcohol use disorder (AUD) (again, no way we need to know this shit, probably should delete it)
- Reverse acute alcohol effects (limited to IV fluids, nutrition, etc.)
- Limit withdrawal effects and psychomotor agitation (benzodiazepines)
- Treat co-existing conditions
- Limit neuronal injuries during detox
- Eliminate/reduce alcohol use (our focus, specifically pharmacotherapy)
3 FDA approved pharmacotherapies to reduce alcohol relapse
- Naltrexone (ReVia, Vivitrol)
- Acamprosate (Campral)
- Disulfiram (Antabuse)
What is naltrexone (ReVia, Vivitrol) (goal, mechanism of action, who should avoid, side effect)?
Goal: reduce craving for alcohol
Mechanism of action: opioid antagonist, thought that reinforcing properties of alcohol involve opioid systems
ReVia - brand name of oral formulation
Vivitrol - brand name of extended release, injectable
Who should avoid: people taking opioids or those with certain liver conditions
Most common side effect: nausea
What is acamprosate (Campral) (goal, mechanism of action, who should avoid, side effect)?
Goal: stop drinking
Mechanism of action: not completely understood, but thought to restore balance of GABA/glutamate neurotransmission; also has actions at some glutamate receptors
Who should avoid: those with severe renal impairment
Most common side effect: diarrhea
What is disulfiram (Antabuse) (goal, mechanism of action)?
Goal: alcohol sensitizing drug, alcohol ingestion causes build up of acetaldehyde (i.e., indirectly reduces motivation to drink)
Mechanism of action:
1. Inhibit aldehyde dehydrogenase (not alcohol dehydrogenase!)
2. Also may work by modulating neurotransmitters involved in addiction
1st FDA approved drug for alcohol abuse, but not 1st line now
What are barbiturates?
CNS depressants that were formerly used to treat anxiety and insomnia, but have mostly been replaced by safer drugs like benzodiazepines due to some serious issues
4 issues with barbiturate use
- Lethal in overdose
- Narrow therapeutic-to-toxic range
- High potential for tolerance, dependence, and abuse
- Can have dangerous drug interactions
4 clinical uses of barbiturates
- Anticonvulsants
- Anesthetics
- Treat insomnia or to cause sedation
- Death-inducing agents (i.e., euthanasia)
What is the mechanism of action of barbituates?
- Act to facilitate GABAa activity; specifically, increase the duration of the chloride channel openings caused by GABA
- At high doses may open the GABAa channel in the absence of GABA
- Can also depress the actions of the excitatory neurotransmitter glutamate
What is gamma hydroxybutyrate (GHB) (what does it do, receptors, half life, therapeutic window)?
CNS depressant that is structurally similar to GABA, found endogenously in mammals, and acts as a neurotransmitter/neuromodulator to cause euphoria, disinhibition, relaxation, and increased libido
Receptors: GABAb, GHBR, GABAa
Half-life: relatively short
Therapeutic window: narrow
Also called “liquid ecstasy,” it is a common drug of abuse (date rape drug)
What are the clinical uses of gamma hydroxybutyrate (GHB)?
Narcolepsy and idiopathic hypersomnia (name brands: XYWAV and XYREM)
What is narcolepsy, and how can it be treated?
Chronic sleep disorder, cataplexy, characterized by dirsupted sleep at night
Treated with XYWAV or XYREM (gamma hydroxybutyrate (GHB)), and is taken in 2 doses at night - bedtime and 2.5-4 hours later…these promote sleep in 5-15 minutes and treat daytime sleepiness
Other drugs (stimulants) can be used to treat narcolepsy
What is idiopathic hypersomnia (IH), and how can it be treated?
Rare disorder characterized by:
1. Excessive daytime sleepiness even if good night’s sleep
2. Difficulty waking up
3. Naps aren’t refreshing
Treated with XYWAV or XYREM (gamma hydroxybutyrate (GHB)), which is dosed either once or twice nightly
Other drugs (stimulants) can be used to treat IH
5 issues with XYWAV and XYREM (gamma hydroxybutyrate (GHB))
- Potential for misuse/abuse
- Issues associated with CNS depressant actions
- Small % of patients experienced psychiatric adverse events (e.g., depression, suicidality, anxiety, confusion)
- Small % of patients experienced parasomnias (e.g., sleep walking)
- REMS
