MIDTERM Flashcards
Pharmacokinetics
How does a drug get to its target?
“How do we get the drug out of the body too”
Pharmacodynamics
When a drug binds to its target, what is the effect?
“Once it’s binded, how does it affect the body?”
What is the time course of drug action in the body?
4 Key processes:
Absorption
- Getting the drug into the body
Distribution
- Where does the drug go once it’s in the body?
Metabolism
- How is the drug broken down
Elimination
- How do we get rid of it?
ADME = acyroym for bioavailability
Absorption (list the different ways it gets into the bloodstream)
How does a drug get into the bloodstream?
Enternal (through the GI tract)
Oral
Rectal
Parenteral (non GI)
Injection
Inhalation
Topical (skin)
Mucousal/Sublingual
Enteral Administration - ORAL
Requirements:
Water soluble -> liquids absorbed faster than solids
Stable, resistant to stomach acids/enzymes and liver enzymes
“First-pass metabolism” in liver (meaning we lose some of the effects due to metabolism)
Hepatic portal vein
Sometime a prodrug is administered, and then is metabolized by enzymes into the desired drug (ex: lisdexamfetamine/Vyvanse)
Acidic drugs absorbed in stomach: basic drugs absorbed in small intestin
Lipid soluble (at least partially)
Pass through GI lining
Oral Administration
Advantages: easy, non-invasive
Disadvantages: stomach upset/nausea, actual concentration in blood stream less accurate compared to parenteral, many drugs cannot withstand the GI tract
- Newer “enteric coatings” help with this
Enteral Administration - RECTAL
Advantages:
Faster absorption/onset/peal
Shorter duration
Higher % of drug gets into circulation
Distal ⅓ of rectum highly vascularized; blood does not pass through liver
Good for pxts with GI tract issues, or who have trouble swallowing
Disadvantages:
Painful, unpleasant, messy
Methods:
Suppository, enema (micro/macro), catheter
Parenteral Administration - Injection
Types: Intravenous (IV), intramuscular (IM), intraperitoneal (IP), subcutaneous (SC), intrathecal (IT), intradermal (ID)
Advantages
More accurate dosing, can have faster absorption than enteral routes
Disadvantages
Easy to overdose, especially with IV, requires sterile techniques so as not to introduce harmful agents into the bloodstream, unable to remove drug once injected (e.g. vomiting won’t help)
Parenteral Administration - Injection - INTRAVENOUS ADMINIATRATION
Drug administered directly into bloodstream
Advantages:
Very rapid, large volumes, extremely accurate dosing
Disadvantages:
Very rapid, risk of infections, not suitable for drugs that are not completely solubilized
Parenteral Administration - Injection - INTRAMUSCULAR ADMINISTRATION
Drug injected into muscle
Advantages:
Can vary the rate of absorption/action depending on diluent
Drugs disscoled in water are absorbed rapidly, and have a short duration of action
Drugs disscoled in oil are absorbed more slowly, and have a longer duration of action
Disadvantages:
Cannot inject large volumes, may irate muscle tissue
Parenteral Administration - Injection - SUBCUTANEOUS ADMINISTRATION
Drug injected under the skin into the subcutaneous fat layer
Advantages: fairly rapid
Disadvantages: large volumes not recommended, skin irritation
Inhalation - Administration of Drugs
Drug inhaled into lungs
Advantages: extremely rapid (can be even faster than IV), rapid accumulation in brain
Disadvantages: extremely rapid, lung irritation, possible lung disease with repeated administration
If you have taken too much, there’s nothing you can do about it.
Mucosal - Administration of Drugs
Drug placed on mucosal membranes (gums, under tongue, nasal, vaginal)
Insufflation, sublingual
Advantages: fairly rapid
Disadvantages: may irritate mucous membranes
SUBLINGUAL/BUCCAL ADMINISTRATION
Sublingual = under the tongue. Buccal = side of the mouth, like on the cheek
Advantages: non-invasive, relatively easy, does not go through GI system (more drug gets into system)
Disadvantages: may be unpleasant, have to be able to hold substance in mouth and not swallow
Children are not good at this. And the taste has to be okay.
TOPICAL ADMINISTRATION OF DRUGS
Drug applied directly to skin
Adhesive patches, creams, ointments
Advantages: slow, continuous absorption, can be localized to application spot
Disadvantages: skin irritation, not fast
SLOWER IN = SLOWER OUT
What is the distribution of drugs?
Once in the bloodstream, the drug travels throughout the body until it reaches its target (receptor)
Desired-target effects = “therapeutic effects”
Extra-target effects = “side effects”
Majority of drug is not interacting with target
Must pass through (several) membranes to reach target
Only around 2% of the drug makes it to the target tissue
Other areas it goes: Fat, plasma protein, tissue, and plasma
Protein Binding
WHEN IT IS BOUND TO SOMETHING ELSE, THEN IT IS STUCK THERE.
Plasma, tissue, cell
Plasma
Albumin, lipoproteins, alpha1-acid glycoprotein (AAG)
Drug is inactive when bound
Distribution
Larger molecule; harder to cross cell membranes
Elimination
Protein-bound drug serves as a “reservoir”
Bound drug cannot be metabolized or eliminated
Capillary Membranes and Drugs
Drugs exit capillaries through small pores called fenestra
90-150 angstroms wide
Most drug molecules are smaller
Blood cells and plasma proteins cannot pass through
Move via diffusion until equilibrium with surrounding fluid is established
If drug binds to plasma proteins, it will not be able to leave capillaries
Rate of drug entry into specific tissues is determined by:
- Rate of blood flow through tissue
- Ease of passage through fenestra
i.e. plasma binding
What is the Blood-Brain Barrier?
Combination of “tight junctions” of capillary endothelial cells (no fenestra) and “astrocytic sheth”
Astrocytic sheath becomes more permeable with age
Rate of drug passage into the brain determined by:
Size of molecule, lipid solubility
What are the principles of ADME?
Absorption: How it will go in
Distribution: Where will it go
Metabolism: hos it is broken down?
Excretion: How does it leave?
What is the volume of distribution? (Vd)
Theoretical value
The volume necessary to contain the total amount of administered drug at the same concentration observed in plasma.
A small Vd (<10 L) indicates that the drug is staying in the circulatory system, not diffusing into tissue
Medium Vd (10-25 L) indicates the drug is primarily in the blood and extracellular fluid.
High Vd (>25 L) indicates the drug is going into tissue
In general, higher Vd is associated with:
Longer excretion time
More drug needed to get into brain
Longer time to get into brain
What are metabolites?
Water soluble
Larger
Less lipid soluble
What is the brand name and use for Chlorpromazine?
Chlorpromazine treats mental health conditions, like schizophrenia and bipolar disorder. It regulates your mood. In addition, it can also help you relax before a procedure and treat nausea, vomiting, prolonged hiccups and more. The brand name of this medication is Thorazine®.
What is capillary membranes?
WHEN IT IS BOUND TO SOMETHING ELSE, THEN IT IS STUCK THERE.
Drugs exit capillaries through small pores called fenestra
90-150 angstroms wide
Most drug molecules are smaller
Blood cells and plasma proteins cannot pass through
Move via diffusion until equilibrium with surrounding fluid is established
If drug binds to plasma proteins, it will not be able to leave capillaries
Rate of drug entry into specific tissues is determined by:
Rate of blood flow through tissue
Ease of passage through fenestra
i.e. plasma binding
What is extra target binding ?
MOVE VIA DIFFUSION
Only unbound drug molecules can interact with their targets
Protein binding (in blood stream)
Albumin – mainly acidic molecules
α1-acid glycoprotein
lipoproteins
Tissue binding (intra cellular)
Proteins
Phosopholipids
Nucleic acids
Fat binding
Lipid solubility
Poorly vascularized
Extra Target Binding: Occasionally, drugs may also bind to other molecules besides their intended targets. This can happen due to similarities between the drug’s structure and other molecules in the body, leading to unintended interactions. These extra interactions can sometimes cause side effects or impact the drug’s efficacy.
Understanding extra target binding is important in drug development and pharmacology because it helps researchers anticipate and mitigate potential side effects or off-target effects of medications. By studying a drug’s interactions with various molecules in the body, scientists can better optimize its therapeutic profile while minimizing adverse effects.
What is binding tissue sequestration?
typically refers to the phenomenon where drugs or substances become trapped or sequestered in certain tissues of the body due to binding interactions. This can affect the distribution and elimination of the substance, potentially altering its pharmacokinetic profile.
The degree of binding effects:
The initial concentration of drug available to bind to target (onset and strength of effect)
The concentration of drug in the bloodstream over time (duration of effect)
Example:
Thiopental (anesthetic) is lipid soluble and does not bind very much to albumin in the blood, thus it has rapid initial effects. However, the effect wears off quickly as it is redistributed to fat tissue, and moderate effects are long-lasting as it is slowly released from fat.
Binding: When a drug is administered, it circulates through the bloodstream and may bind to various tissues in the body. This binding can occur due to specific interactions between the drug molecules and molecules present in the tissues.
Sequestration: After binding to tissues, the drug may become trapped or sequestered within these tissues. This means that the drug accumulates in certain areas of the body rather than being evenly distributed throughout.
Effects: Tissue sequestration can impact the concentration of the drug in the bloodstream and other tissues. It can also affect the drug’s effectiveness and duration of action. Additionally, sequestration may prolong the drug’s presence in the body, leading to a slower elimination rate.
How are drugs eliminated from the body?
Routes:
Kidneys
Lungs
Bile
Skin
Sweat
Saliva
Breast milk
Kidney is most common route of elimination, once a drug is metabolized
Made up of units called nephrons
Molecule must be water-soluble, and large
What is a drug’s half life?
Drug concentration will be higher for longer IN OLDER ADULTS
Allows for optimal dosing regimen
What dose should be given?
How often?
Maintenance of therapeutic levels over time
Time required to completely clear system
How long until you will pass the drug test?
NOT necessarily the amount of time it takes for ½ the initial concentration to be metabolized!
Determined by a concentration curve -> WHERE ITS FLATTENED OUT, AND MORE CONSISTENT
Once drug is in the elimination phase (flat part of curve), how long does it take for the concentration in the blood to decrease by half?
TIME is consistent, not the amount of drug metabolized
Independent of initial concentration
Allows us to estimate how long the drug will stay in the body
The longer the half-life, the longer it takes to eliminate the drug from the body
“drug hangover” -> the effects are less, but there’s still drugs in the system
Effected by age
Older adults are slower to metabolize drugs
Drug concentration will be higher for longer.
Effected by other drugs
Some drug combinations can increase/decrease the rate at which one or both drugs are metabolized.
What is drug accumulation? GIVE AN EXAMPLE
If a second dose of drug is given before the first dose is eliminated, the overall concentration in the blood will be greater than that of the first dose alone.
With repeated administrations, concentrations are additive.
If 100 mg of a drug with a half-life of 4 hrs is given at noon, at 4:00pm there will be 50 mg in the blood.
If another 100 mg of drug is given at 4:00pm, how much drug will be in the blood at 8:00pm?
75 mg = 25mg (1st dose; 2nd half-life) + 50mg (2nd dose; 1st half-life)
25 is the half-life of the first dose, and 50 mg is the half life of the second dose
What is a steady state concentration?
Consistent level of drug in body achieved by repeated, regular-interval dosing
~4-6 half-lives
1st = 50%
2nd = 75%
3rd = 87.5%
4th = 93.75%
5th = 96.875%
6th = 98.44%
At steady state the amount of drug eliminated per unit time is equal to the amount of drug absorbed per unit time
Continuous Dosing: When you take medication regularly, whether it’s once a day or several times a day, the drug is being constantly introduced into your body.
Absorption and Elimination: After taking a dose of medication, the drug is absorbed into your bloodstream. At the same time, the body works to eliminate the drug through processes like metabolism and excretion.
Steady State: After repeated doses, there reaches a point where the amount of drug being absorbed into the bloodstream equals the amount being eliminated. This results in a stable concentration of the drug in the body, known as steady state concentration.
Maintaining Steady State: To maintain steady state concentration, it’s important to consistently take the medication as prescribed. If doses are missed or if the dosing schedule is irregular, it can disrupt steady state and lead to fluctuations in drug concentration.
What is Therapeutic Drug Monitoring (TDM)?
Estimation of the amount of receptor interaction required to maintain a therapeutic response
Based on large scale clinical studies that compare plasma levels to therapeutic effects
Allows doctors to accurately prescribe optimal doses
Depends on the client’s individual reaction to the drug
What is Drug Tolerance?
A progressive decline in response with repeated usage of a drug.
Metabolic tolerance
Usually due to upregulation of enzymes
Pharmacodynamic tolerance
Down-regulation of receptors or sensitivity
Behavioral conditioning (learning)
Homeostatic theory
Physiological processes can be conditioned to specific stimuli or environments
Just being in the environment can cause your body to release dehygrenous
What is Drug Dependence?
Related to tolerance, but different
Administration of drug is required to avoid withdrawal symptoms
Abstinence syndrome
This is why it is important to slowly wean off a drug, rather than stopping it abruptly
Also why addicts continue to use even though experience is no longer pleasurable
What are other considerations for drugs consumed between females versus males?
Gender
Females
Smaller
Less water
Higher fat percentage
Hormone fluctuations
E.g. estrogen influences pain perception
Slower gastrointestinal motility
Less intestinal enzymatic activity
E.g. Females produce less dehydrogenase
Lower glomerular filtration rate
Males
Larger
Bigger organs (liver, kidneys)
More water
More muscle mass
What is the placental membrane?
Not really a “membrane”
Blood supply is contiguous between mother and child
Small, lipid-soluble molecules cross readily
Concentration of drug in fetus about the same as in mother
What are the pregnancy categories?
Established by the FDA to indicate the potential of a drug to cause birth defects if used during pregnancy. They do not take into account any risks from pharmaceutical agents or their metabolites in breast milk.
Category A - Well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters).
Examples: levothyroxine, folic acid, magnesium sulfate, liothyronine
Category B - Animal reproduction studies have failed to demonstrate a risk to the fetus (there are no well- controlled studies in pregnant women).
Examples: metformin, hydrochlorothiazide, cyclobenzaprine, amoxicillin, pantoprazole
Category C - Animal reproduction studies have shown an adverse effect on the fetus, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
Examples: tramadol, gabapentin, amlodipine, trazodone, prednisone
Category D – Positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
Examples: lisinopril, alprazolam, losartan, clonazepam, lorazepam
Category X - Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.
Examples: atorvastatin, simvastatin, warfarin, methotrexate, finasteride
Category N - FDA has not classified the drug.
Examples: aspirin, oxycodone, hydroxyzine, acetaminophen, diazepam
Dr. Preggo is on a mission to explore Pregnancy Land, but she needs to know which paths are safe for her and her little one. Luckily, she has her trusty guidebook with the FDA pregnancy categories to help her navigate!
Category A: 🚼 “Absolutely Safe Avenue”
Dr. Preggo skips down “Absolutely Safe Avenue” where she finds levothyroxine, folic acid, and magnesium sulfate. These are like magical potions that pose no risk to her little one, even in the first trimester!
Category B: 🦄 “Baby Unicorn Boulevard”
Next, Dr. Preggo glides along “Baby Unicorn Boulevard,” where she discovers metformin, hydrochlorothiazide, and cyclobenzaprine. These are like rare baby unicorns because while animal studies show no risk, there haven’t been enough human studies to confirm their safety.
Category C: 🐾 “Courageous Cub Cave”
Dr. Preggo ventures into the “Courageous Cub Cave,” where she meets tramadol, gabapentin, and amlodipine. These are like brave little cubs because they may have some risks, but the potential benefits might still make them worth using during pregnancy.
Category D: 🌟 “Dangerous Dragon Dungeon”
Oh no! Dr. Preggo encounters the “Dangerous Dragon Dungeon” where she faces lisinopril, alprazolam, and losartan. These are like fiery dragons because they have shown evidence of risk to the little one, but in some cases, the benefits might outweigh the dangers.
Category X: 🚫 “eXtreme Danger Zone”
Finally, Dr. Preggo tiptoes into the “eXtreme Danger Zone,” where she sees atorvastatin, simvastatin, and warfarin. These are like forbidden treasures because studies have shown they pose serious risks to the little one, and it’s best to avoid them altogether during pregnancy!
Category N: 🎈 “Not Yet Classified Neighborhood”
Dr. Preggo stumbles upon the “Not Yet Classified Neighborhood” where she finds aspirin, oxycodone, and hydroxyzine. These are like mystery balloons because the FDA hasn’t classified them yet, so it’s a bit uncertain whether they’re safe or not.
With her adventure complete, Dr. Preggo can now safely navigate Pregnancy Land, armed with knowledge from the FDA pregnancy categories! 🌈🤰
What are the drug schedules?
Designated by the DEA
Schedule I
No currently accepted medical use and a high potential for abuse. Considered to be the most dangerous drugs with potentially severe psychological or physical dependence.
Heroin, lysergic acid diethylamide (LSD), marijuana (cannabis), ecstasy, methaqualone (quaaludes), peyote
Schedule II
Drugs with a high potential for abuse, with use potentially leading to severe psychological or physical dependence. Also considered dangerous.
Cocaine, methamphetamine, methadone, hydromorphone (Dilaudid), meperidine (Demerol), oxycodone (OxyContin), fentanyl, Dexedrine, Adderall, Ritalin
Schedule III
Drugs with a moderate to low potential for physical and psychological dependence.
Combination products with less than 15 milligrams of hydrocodone per dosage unit (Vicodin), products containing less than 90 milligrams of codeine per dosage unit (Tylenol with codeine), ketamine, anabolic steroids, testosterone
Schedule IV
Drugs with a low potential for abuse and low risk of dependence.
Xanax, Soma, Darvon, Darvocet, Valium, Ativan, Talwin, Ambien
Schedule V
Drugs with the lowest potential for abuse.
Cough preparations with less than 200 milligrams of codeine or per 100 milliliters (Robitussin AC), Lomotil, Motofen, Lyrica, Parepectolin
What is neurotransmitter synthesis, storage, and release?
Neurotransmitter synthesis
Increasing concentration of precursors (starting molecules)
Decreasing concentration of synthetic enzymes
Neurotransmitter storage
VMAT
Neurotransmitter release
Ca++
Receptors and Channels
Reuptake and enzymatic deactivation
Transport molecules, degrading enzymes
What are metabotropic receptors?
A recognition site extends into the extracellular fluid, and a special protein called a G protein on the receptor’s intracellular side.
G proteins can open nearby ion channels or activate second messengers
Actions can be DIRECT or INDIRECT
DIRECT -> G-protein can activate an ion channel
INDIRECT -> stimulates the production of cyclic AMP (cAMP) which, in turns, activates several ion channels simultaneously
2nd messenger
Signal amplification
1st messenger
Neurotransmitters
Drugs
2nd messenger
Adenylate cyclase
IP3 (inositol triphosphate)
MAPK
DAG/DG (diacylglycerol)
3rd messenger
PKA
PKB
4th messenger
DNA transcription factors
Fun:
So, in Metabotropic Land, metabotropic receptors are like the operators of the roller coasters. They don’t directly open the gates for excitement like the ionotropic receptors do in other parts of the park. Instead, they take their time, triggering a series of events that eventually lead to the fun and excitement happening all around the theme park.
What’s the difference between competitive versus noncompetitive binding?
Competitive Binding
Drug occupies the same binding site on the receptor that the NT occupies
Noncompetitive Binding
Drug occupies a different binding site on the receptor than the NT
What do enzymes regulate?
the availability of neurotransmitters
Synthetic
Tyrosine hydroxylase, dopa decarboxylase, etc.
Degrading
Acetylcholine esterase, monoamine oxidase, etc.
Drugs that effect the synthesis/degradation of NTs can have broad and powerful effects
Inhibiting tyrosine hydroxylase will decrease DA, NE and E!
What are optical isomers?
Optical Isomers
Isomers that are mirror images of each other
Enantiomers
Rotate a beam of light in opposite directions
Clockwise, or to the right = “+”, “R”, or “D”
Counter-clockwise, or to the left = “-”, “S”, or “L”
The distinction is important, as often only one form will be biologically active, or the different forms will produce different effects
Most substances contain both isomers in equal proportions (50% L and 50% D)
Racemic mixture or racemate
Only ½ the molecules are biologically active
By purifying a racemic mixture so that the drug only contains the biologically active isomer, a drug’s potency can be increased.
Potency is a measure of the drug’s ability to achieve a desired effect at a given dose. If a 10mg dose of Drug A produces the desired effect, and a 5mg dose of Drug B produces the desired effect, Drug B is more potent than Drug A.
Example: Celexa – citalopram, racemic mixture
Lexapro – escitalopram, S-citalopram
What is an isomer?
Molecules that have the same molecular formula, but a different shape
Example C4H10
What exactly are side effects? (the true meaning with receptors)
Many drugs have actions at more than one type of receptor
Tricyclic antidepressants increase 5-HT, NE and block ACh receptors
Actions at certain receptors might be responsible for the therapeutic effects
Increased 5-HT and NE receptor binding relieve depression
Actions at other receptors produce unwanted effects (side effects)
Blocking ACh receptors produces sedation, dry mouth, blurred vision.
Side effects can have different rates of tolerance than therapeutic effects
What is dose-response curves?
Population curves versus Single individual surves
Potency
Amount of drug required to elicit response
Efficacy
Maximum effect obtainable
Slope
The difference in concentration required between a minimal and maximal effect
Variability
Individual differences in response
In terms of drug safety, what are predictalbe side effects, versus unpredictable side effects?
Potential to cause adverse effects (side effects)
Predictable
Side effects that are expected given the various pharmacodynamic actions of the drug.
May or may not be tolerable to individual patients.
Most predictable side effects are mild.
Unpredictable
Allergic reactions, genetic-variance reactions.
Can be mild or serious.
What are the placebo effects (definition, general, what percent of clients experience it?)
Placebo
In drug trials a treatment that is similar in preparation and administration to the actual drug, but missing the active ingredients
Different from “no treatment”
Placebo Effect
Pxt exhibits therapeutic response in absence of actual treatment
Lasagna et al., (1945) estimated that it occurs in 30-40% of pxts.
What is schizophrenia?
Characterized by perceptual, emotional, and intellectual deficits; loss of contact with reality; and inability to function in life.
The term means “split-mind,” and refers to a distortion of thought and emotion; it is not the same as multiple personality.
Incidence
1% of general population (1 in 100)
~2.5 million Americans suffer from schizophrenia
Seen throughout history, across cultures
Most common dissociative disorder
Cost to society is greater than cost of all cancers COMBINED
Slightly more prevalent in M than F (1.4:1)
Onset
Late teens, early twenties (males earlier)
Usually diagnosed by 30 5
What are the positive symptoms of schizophrenia?
Hallucinations
Usually auditory, sometimes olfactory (e.g. poisonous gas)
NOT NEEDED TO HAVE A SCHIZOPHRENIA DIAGNOSIS
Delusions
False beliefs not shared by others
Persecution – feelings that one is being watched, spied upon, that one’s thoughts are being broadcast
Grandeur – beliefs that one is important, patient may adopt a historical persona
Very resistant to reason
Disordered Thoughts
Loosening of associations, thoughts jump around and are only tenuously connected to one another
“Racing thoughts”
Disorganized Behavior
Sudden mood changes
Inability to focus
Inappropriate sexual behavior
Inappropriate Affect
Laughing at sad things, crying at happy things
Picture the “positive” symptoms as things that are added on or exaggerated, like extra excitement on a roller coaster ride. These are things that shouldn’t be there but are added on. Examples of positive symptoms include hallucinations (seeing or hearing things that aren’t there), delusions (believing things that aren’t true), and disorganized thinking or speech.
What are the negative symptoms of schizophrenia?
Flat affect
No facial expressions or emotions
Lack of movement
Will not move
Maintain odd postures for long periods of time (catatonia)
Social withdrawal
Don’t talk to people, even when spoken to
Poverty of speech
Don’t speak much
Monosyllabic
Poor hygiene/grooming
Nucleus accumbens and Schizophrenia, what’s the link?
Nucleus accmbens is involved in reward processes. Some symptoms of schizophrenia may be related to a faulty reward system
Dopamine Dysfunction: One of the key neurotransmitters associated with the nucleus accumbens is dopamine. In schizophrenia, there is evidence of dysregulation in the dopamine system, particularly an overactivity of dopamine transmission in certain brain regions, including the nucleus accumbens. This dysregulation is thought to contribute to the development of positive symptoms like hallucinations and delusions.
Reward Processing Abnormalities: The nucleus accumbens plays a central role in the brain’s reward circuitry. Dysfunction in this circuitry, including abnormalities in the nucleus accumbens, has been implicated in the motivational deficits often observed in schizophrenia. Individuals with schizophrenia may experience reduced motivation and anhedonia (reduced ability to experience pleasure), which could be related to dysfunction in the nucleus accumbens.
Antipsychotic Medications: Many antipsychotic medications, which are commonly used to treat schizophrenia, work by blocking dopamine receptors, including those in the nucleus accumbens. By reducing dopamine transmission in this brain region, these medications can help alleviate positive symptoms of schizophrenia.
Amygdala and Schizophrenia, what’s the link?
Amygdala is involved in conditioned emotional responses, especially to aversive stimuli
Overall, while the precise mechanisms linking the amygdala to schizophrenia are complex and multifaceted, dysfunction in this brain region is thought to contribute to the emotional disturbances, social impairments, and psychotic symptoms characteristic of the disorder.
Why do drugs differ in their effectiveness?
Different mechanisms
i.e. reducing amount of NT produced vs. blocking receptor vs. increasing metabolic destruction
Lipid solubility
Affects how quickly the drug reaches its target
Affinity for site of action
How attracted the drug is to its target
The higher the affinity, the lower the dose needed to produce an effect
What is the therapeutic index?
-ED50; the dose at which a 50% response is achieved
-LD50; the dose at which 50% of subjects die
-TI = LD50/ED50
-The larger the TI, the safer the drug
-If there is overlap between the curves, the safest estimate is LD1/ED99
What is Phenothiazines?
any of a group of derivatives of phenothiazine with tranquilizing properties, used as tranquilizers in the treatment of mental illness.
List of Phenotiazines:
Promethezine
Chlorpromazine (Thorazine)
Prochlorperazine(Compazine)
Fluphenazine (Prolixin)
Trifluoperazine (Stelazine)
Perphenazine (Trilafon)
Acetophenazine (Tindal)
Carphenazine (Proketazine)
Trifulpromazine (Vesprin)
Mesoridazine (Serentil)
Thioridazine (Mellaril)
What is the ROA for Phenothiazines?
ROA: usually oral, sometimes given IM initially. Oral absorption is initially inconsistent, however with repeated dosing blood levels stabilize (steady state).
What is the distribution and half-life of Phenothiazines?
Distribution: Highest in lungs, liver, adrenals, spleen. Fairly low in brain.
Half-life: 24-48 hrs, metabolized slowly by liver, and slow to leave tissues.
What is the binding profile and sites of action for phenothiazines?
Binding Profile: Primarily block DA D2, but also AChM1, H1, NEα1
Blockade of AChM produces dry mouth, pupil dilation, blurry vision, cognitive impairment, constipation, urine retention, tachycardia (Sympathetic NS)
H blockade produces sedation, antiemesis
NE blockade produces sedation and hypotension
Sites of Action
Medulla
Suppresses behavioral activation and vomiting.
Reduces response to environmental stimuli.
Limbic System/Frontal Lobes
Blocks DA input from VTA. Decreases hallucinations, delusions, and improves cognitive function. Decreases restlessness and behavioral hyperactivity.
Hypothalamus/Pituitary
Changes in appetite, metabolic rates, sex drive, sleep patterns, body temp.
Increases prolactin production.
Produces sexual dysfunction and infertility.
Basal Ganglia
DA blockade in BG leads to motor deficits similar to PD.
Akasthesia, bradykinesia, gait disturbance, tremor.
Dystonia – involuntary muscle contractions, sustained contractions (particularly trunk and upper body)
Tardive Dyskinesia – involuntary hyperkinetic movements (face, tongue, trunk, upper limbs). Presents after chronic use, cannot be resolved by stopping the antipsychotic.
Possible txt with VMAT2 blocking drugs.
What is the side effects and tolerance/dependence for phenothiazines?
Side Effects
Affinity for D2 receptors predicts incidence of extra-pyramidal symptoms (EPS) and tardive dyskinesia (TD)
Affinity of AChM, H and NE predicts sympathetic effects, memory impairment, sedation and hypotensive effects.
Pigment alterations, including retinal pigments which can produce visual problems
Neuroleptic Malignant Syndrome (NMS); fever, muscle rigidity, autonomic fluctuations, alterations in consciousness
Can lead to death.
Tolerance and Dependence
Not prone to abuse
Blockade of DA receptors can lead to increases in DA-ergic tone (Neuroleptic Malignant Syndrome)
Fever
Muscular rigidity
Autonomic dysfunction
Altered mental status (agitation, delirium)
Otherwise does not create dependence and/or tolerance
What is the list of thioxanthenes?
Thioxanthenes
List of Thiocanthenes:
Thiothixene (Navane)
Chlorprothixene (Taractan)
Clopenthixol (Sordinol)
Flupenthixol (Depixol)
Zuclopenthixol (Acuphase)
Similar to phenothiazines
D2 antagonists
5-HT, NE, H effects as well
What is Butyrophenones?
Butyrophenone is synthetic agents containing the phenyl-1-butanone group, most Butyrophenones are neuroleptic (antipsychotic) drugs, such as haloperidol, droperidol, or azaperone, that control schizophrenic symptoms (hallucinations, delusions, dementia).
List of Butyrophenones
Haloperidol (Haldol)
Droperidol (Inapsine)
Used to control post-operative nausea and vomiting
What is the ROA, Distribution, Half-Life, binding profile, sites of action, and side effects of Butyrophenones?
ROA: usually oral, sometimes given IM (Haldol Decanoate) initially.
Distribution: Equal throughout tissues.
Half-life: 18 hrs (oral), 3 weeks (decanoate), metabolized slowly by liver, and slow to leave tissues.
Binding Profile: very similar to phenothiazines
Primarily block DA D2, but also AChM1, H1, NEα1
Sites of Action: brain stem, basal ganglia, limbic system/frontal lobe, hypothalamus
S
ide Effects
High incidence of EPS, particularly PD-like symptoms, dystonia, TD
Anticholinergic effects
Neuroleptic Malignant Syndrome (NMS)
Fever, cognitive problems, muscle rigidity, autonomic dysfunction
Life threatening
Tolerance and Dependence
Not prone to abuse
Does not produce tolerance/dependence
What is Lozapine?
Another type of first-generation antipsychotic (FGA)
Loxapine (Loxitane)
Similar in structure to clozapine
High affinity for D2 and 5-HT receptors
Antipsychotic, antiemetic, sedative effects
Induces EPS
An inhaled version (Adasuve) approved by FDA in 2012
