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378 Cards in this Set
- Front
- Back
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What is the definition of Pharmacology? |
The science of drugs |
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What is the definition of a Drug? |
Any chemical structure that has an effect on a living system |
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What are some therapeutic applications of drugs? |
1. Treat specific disease (e.g. HIV) 2. Permits diagnosis and treatment (e.g. local anesthetic) 3. Alter physiological function (e.g. contraceptives) 4. Prevent disease (e.g. prevention of bone strength decrease) 5. Veterinary medicine (i.e. treating animal illnesses) 6. Performance alteration (e.g. athlete doping) |
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What is the difference between a pharmacist and a pharmacologist? |
A pharmacist goes to business school and is legally permitted to sell drugs whereas a pharmacologist studies the science of drugs. |
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What is toxicology? |
Toxicology is the study of poisons: -> subdivision of pharmacology |
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What 3 types of names does a drug have?
Give an example. |
1. Chemical Name: based on chemical formula (e.g. N-acetyl-para-aminophenol) 2. Generic Name: simple, universally known (e.g. Acetaminophen) 3. Trade Name: company's (e.g. Tylenol) |
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Is Aspirin the acetylsalicylic acid's generic or trade name? |
It is both!
It was originally the trade name but soon became the generic name. |
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What is the difference between pharmacokinetics and pharmacodynamics? |
Pharmacokinetics: What your body does to the drug (i.e. liberation, absorption, distribution, metabolism, excretion) Pharmacodynamics: What the drug does to the body (i.e. effect on different target cell components - receptors, ion channels, immune system) |
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What are Therapeutic Indications and Contraindications? |
Indications: The basis for initiation of a treatment for a disease Contraindication: The basis for stopping or preventing the initiation of treatment |
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What are the 7 methods of drug administration? |
1. Oral (enteral) 2. Parenteral 3. Intraperitoneal 4. Inhalation 5. Topical 6. Sublingual 7. Rectal |
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What are the benefits of each of the 7 methods of drug administration? |
1. Oral - Cheap, easy, convenient, modifiable release 2. Parenteral (injection) - Fast, accurate, no first pass 3. Intraperitoneal - Large fluid replacement 4. Inhalation - Very rapid system effects 5. Topical - Acts on skin surface 6. Sublingual - Rapid absorption, no first pass 7. Rectal - Fast onset, high bio-availability |
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Explain the pharmacokinetics of each of the 7 methods of drug administration? |
1. Oral - Absorbed in small intestine -> liver (1st) 2. Parenteral - Can be subcutaneous, intramuscular, intravenous -> all bypass liver 3. Intraperitoneal - Delivered in to the peritoneal space 4. Inhalation - Alveoli -> capillaries 5. Topical - Stays on skin (impermeable barrier) 6. Sublingual - Mucosa in mouth -> blood vessels 7. Rectal - Rectum -> blood vessels |
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Out of the following drug administration routes, what is the order of absorption rates (high to low)? 1.Oral 2. Intravenous 3. Rectal |
1. Intravenous 2. Oral 3. Rectal |
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What 2 forms of drug administration have only recently been developed? |
1. Drug insertion in to a lipid carrier (liposome) -> insertion in to nose 2. Drug insertion in to slow releasing implant |
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What is the selectivity of a drug? Give an example of a drug that is selective and one that is not. |
A property of a drug which allows it to target a certain cell type, without adverse side effects. Iodide is a very selective drug -> Only concentrates in the thyroid Epinephrine is not selective -> Receptors for epinephrine all over the body (generalized effects everywhere) |
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What is an Agonist? |
An agonist is a drug that stimulates a receptor by binding to its active site |
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What is an Antagonist? |
An agonist is a drug that blocks the signal of a receptor by binding to its active site
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What is an Allosteric Site? |
An allosteric site is a region on a receptor away from its active site, to which an effector may bind
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List the 6 types of transmembrane signalling mechanisms. |
1. R-activated ion channel
2. R-activated enzyme 3. R-activated protein kinase 4. Intracellular receptor 5. G-protein coupled receptor 6. Enzymes |
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Explain the difference between: - Autocrine - Endocrine - Paracrine - Juxtacrine |
Autocrine -> Self receptors Endocrine -> Blood stream dissemination Paracrine -> To nearby non-self cells Juxtacrine -> Also to nearby cells, but requires close contact |
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Can an ion channel allow more than 1 type of ion to flow through? |
Yes
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What are the 3 states of an ion channel? |
1. Open 2. Closed 3. Inactivated |
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What 2 properties of a cell's membrane determine a drug's affinity?
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1. Membrane potential
2. Channel cycling frequency (how often channels open/close) |
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What molecules do transport proteins usually carry? Why are they important in pharmacology? |
1. Glucose 2. Large Proteins 3. Large Amino Acids They can act as a site for drug action |
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How many times does a G-Protein Coupled Receptor pass the cell membrane? |
7 Pass |
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How many functional units does a G Protein have? Name them all. |
1. Alpha Subunit 2. Beta Subunit 3. Gamma Subunit |
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In what form is the alpha subunit of G Proteins active/inactive? |
Active = GTP Inactive = GDP |
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Is the trickle down effect of G Protein activation stimulatory or inhibitory? |
It can be either. |
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Do receptors last for a long time, or are they replaced quickly? |
They can have a high turnover rate, and their type and number is often determined by environmental demand. |
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What type of receptor does insulin and growth factor act on? |
Tyrosine Kinase Receptor |
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Give at least 2 examples of intracellular receptors. What are their primary function and how do they achieve this? |
E.g. 1. Estrogen receptor 2. Progesterone receptor 3. Glucocorticoid receptor Any steroid receptor really. They can alter gene transcription -> protein synthesis. They do this by translocating in to the nucleus and binding to specific DNA domains to cause their transcription. |
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What is an enzymatic receptor? Give an example. |
An enzymatic receptor or enzyme-linked receptor is a transmembrane receptor which received extracellular input to cause intracellular enzymatic activity. Receptor tyrosine kinase and ser/thr kinase are both examples. |
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In terms of response times, list the following from fastest to act to slowest. 1. DNA-Linked (intracellular) Receptor 2. G-Protein Receptor 3. Ion Channel Receptor 4. Enzymatic Receptor |
1. Ion Channel 2. G-Protein 3. Enzymatic 4. Intracellular |
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How can the magnitude of a drug's effect be graphically represented? What is the use of such graphs? |
1. Histogram (dose vs no. responding)
2. Cumulative (dose vs no. responding) 3. Dosage vs. degree of response |
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What is the threshold dose? How does this compare with the ceiling dose? |
The threshold dose is the lowest dose, for which no therapeutic response can be seen if below. The ceiling dose on the other hand is the dose at which the highest therapeutic response is observed. |
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When is the maximal response of a drug observed? Why is the maximal response rarely achieved? |
The maximal response of a drug is achieved when all receptors targeted are occupied. This is rarely possible as there are commonly spare receptors left. Thus the maximal effect is usually achieved before the maximal response. |
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What are the purpose of spare receptors? |
The play a safety factor (prevention of complete drug saturation) and are also used for receptor turnover. |
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What is the difference between full and partial agonists? What is the purpose of the latter in drug development? |
Full agonists provides a large stimulus and thus invokes a large cellular response. Partial agonists are weaker at activating the receptor, meaning they only invoke a partial response. In drug development, partial agonists that mimick an addictive substance can be given to occupy similar receptors, but provide less receptor stimulation. |
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Would a lower affinity or a lower efficacy cause a drug to have a lower maximal response? |
A lower efficacy would cause a lower maximal response (i.e. no matter how much dosage is increased, receptor saturation only causes so much response) |
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What is the ED50 of a drug? |
The dosage needed to get 50% of the maximal response. |
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Would the presence of a competitive antagonist or a noncompetitive antagonist decrease the maximal response of an agonist? |
A noncompetitive antagonist (shifts curve down). Competitive antagonist effects can be overcome by increasing dose (only shifts curve right). |
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What is the LD50 of a drug? |
The dosage at which 50% of animal subjects die. |
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How do you calculate the Therapeutic Index (TI) of a drug? |
TI = LD50 / ED50 High TI is good |
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What is the Therapeutic Window? |
The range in which you get a useful therapeutic response in the majority of individuals, but you're still below the dose at which toxic effects are significant. |
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How do you calculate the safety factor of a drug? |
SF = TD1 / ED99 High SF is good |
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What happens to weak acids when they are placed in an acidic environment like the stomach? |
They are largely non-ionized (lipid soluble) thus they can pass the plasma membrane and be absorbed.
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What happens to weak bases when they are placed in an acidic environment like the stomach? |
They are largely ionized (non-lipid soluble) thus they can't pass the plasma membrane and can't be absorbed. |
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What area of the body is the majority of all drugs absorbed in to the blood stream? |
The small intestine |
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Once absorbed in to the blood stream what organ must drugs pass? With regards to drugs, what purpose does this organ achieve? |
The liver. It breaks down a significant portion of certain drugs (first pass effect) but can be avoided given different routes of administration. |
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Why are orally administered drugs often given on an empty stomach? |
A stomach which isn't full will empty faster allowing faster absorption via the small intestine.
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What is the bio-availability of a drug? |
The fraction of an administered drug that reaches systemic circulation. |
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Rank the following in terms of blood distribution (highest to lowest): 1. Brain, heart, liver and kidneys 2. Bone, teeth, hair 3. Muscles |
1.Brain, heart, liver and kidneys 2. Muscles 3. Bone, teeth, hair |
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What is the MEC of a drug? |
The minimum effective concentration of a drug. |
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What is the duration of action of a drug? |
The time period through which the drug has a positive effect. |
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What are the 3 blood-brain barrier transport mechanisms? |
1. Diffusion (highly lipid soluble) 2. Facilitated diffusion 3. Active transport |
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Is the rate of decrease of a drug in the blood concentration higher when the drug is being distributed or when the drug is being eliminated? |
It is higher during the distribution of a drug, and slower when it is being eliminated. |
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What does the 2 compartment model of drug distribution suggest? |
That immediately after injection, organs with a higher blood flow will have high concentrations of the drug whereas the low blood flow tissue will only slow grow in concentration. Thus, there are effectively 2 compartments, not 1 compartment (body as a whole). |
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What is the volume of distribution (VD) of a drug? |
Also known as the apparent volume of distribution. It represents the degree to which a drug is bound to tissue vs. its concentration in the blood plasma. Vd = X / Cp Where X = injected amount Cp = concentration in plasma |
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What 5 processes happen to a drug after it's administration (pharmacokinetics)? |
LADME 1. Liberation 2. Absorption 3. Distribution 4. Metabolism 5. Excretion |
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Where is the primary location of drug metabolism in the body? |
The liver |
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Aside from the liver, what 5 areas of the body also have drug metabolizing enzymes? |
1. Small intestines
2. Lungs 3. Kidneys 4. Skin 5. Brain |
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When it is said that the liver has a large 'functional reserve', what does this mean? |
It means that a large portion of the liver can be lost, yet it can continue functioning.
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How does the blood from the GI organs enter the liver?
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The portal venous system |
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How does the liver get its personal blood supply? |
Via the hepatic artery |
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What are the 2 phases of drug metabolism?
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1. Oxidation/Reduction/Hydrolysis
-> frequently produces a metabolically inactive drug 2. Conjugation -> usually addition of water-soluble functional groups |
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Where are Cytochrome P450 enzymes found within the body? |
Located within hepatocytes (liver cells) -> attached to the smooth ER. |
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Using the given CYP450 enzyme example, explain the nomenclature: CYP2C19*8 |
CYP = Cytochrome P450 2 = Genetic Family C = Genetic Sub-Family 19 = Specific Gene *8 = Allele gene is situated on |
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How many families of CYP450 Enzymes are there? |
17 Families
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Which CYP genetic families are involved with the breakdown of foreign substances, like drugs? |
1, 2 & 3 |
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What 2 CYP enzymes account for the majority of drug metabolizing in the body? |
1.CYP3A 2. CYP2D6 |
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Considering how drugs are metabolized in the body, what is a reason there are different drug effects for different individuals? |
1. Genetic Factors -> Often there are CYP450 Enzyme polymorphisms 2. Environmental Factors -> Enzyme levels may be altered with exposure to other drugs as well as nutrition |
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What are 3 environmental factors that can affect drug elimination in the body? |
These all serve to reduce metabolic enzyme levels 1. Malnourishment 2. Smoking or alcohol 3. Illness (e.g. GI disease) |
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What are enzyme induction and inhibition? |
Induction -> The triggering of the liver or other organ to produce more enzyme Inhibition -> The impairment of enzyme function or production |
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Why is it dangerous to take both Warfarin and Ketoconazole? |
Ketoconazole inhibits the action of the enzyme that normally breaks down Warfarin -> Can lead to fatal concentration of Warfarin |
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With regards to drug metabolism, what must be considered when giving drugs to young children? |
It must be noted that CYP450 levels may be low in infants because their liver is not fully developed yet. Hence, they may not be able to fully metabolize the drug. |
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Aside from variations in enzyme levels in the body and environmental factors, what is another reason different drugs will have different effects on different individuals? |
Completely different enzymes may be used in different individuals to metabolize the exact same drug. |
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What sort of enzymes are responsible for the conjugation of water-soluble functional groups on to drugs for metabolism? |
Transferase enzymes |
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What 2 chemical groups are typically transferred on to drugs in phase 2 of metabolism? |
1. Glutathione 2. Glucuronic Acid Groups |
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What is the drug clearance rate? |
The volume of body fluid cleared per unit time (L/h or mL/min). Clearance = filtration + secretion - reabsorption |
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How many half lives does it take for a drug to be considered 'eliminated'? |
4 Half lives ( < 6.4%) |
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In what situation would drugs be eliminated through zero-order kinetics, and not first-order kinetics? |
For certain drugs, when they are saturated, a constant amount of drug will be eliminated per unit time (0th order), whereas for the majority of drugs which haven't reached saturation, a constant fraction is eliminated per unit time (1st order) |
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When attempting to reach a steady state of drug concentration, at what intervals should a drug be administered? |
Drugs should be administered at every half-life, for a total of 4 half-lives to reach a steady state. |
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What are the 2 types of drug tolerance? Give a brief description of each. |
1. Acute -> Body counteracts effects of drug after only 1 dose 2. Chronic -> Repeated administration causes decreased response to normal dose |
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What are the 3 mechanisms through which tolerance can be formed? |
1. Pharmacokinetics -> Body metabolizes drug faster 2. Pharmacodynamics -> At site of action, cells biologically adapt to drug 3. Behavioral -> Behavioral adaptation counteracts the effects of the drug |
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In response to increased tolerance, would a dose-response curve for a drug shift left or right? |
It would shift to the right as only a higher dose would produce the same response. |
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How would you distinguish between pharmacokinetic and pharmacodynamic drug tolerance? |
You need to analyze a blood concentration-response curve. For pharmacokinetic tolerance, the curve does not change as the same blood concentration is still needed to achieve the same effect in the cells. For pharmacodynamic tolerance, the curve shifts to the right as the cells have adapted, meaning a higher blood concentration is needed to get the same effect. |
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What are 4 model systems for the study of drug tolerance? |
1. Animal models 2. Isolated organs 3. Tissue cultures 4. Subcellular functions |
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Is drug dependence mostly related to pharmacodynamic or pharmacokinetic tolerance? |
Pharmacodynamic tolerance
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If you have a drug withdrawal effect, are you most likely to exhibit the same symptoms as when on the drug, or the opposite symptoms? |
You are likely to experience the opposite symptoms as your body has adapted to overcome the original symptoms. |
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Why is the post synaptic cell a good target for cell adaptation in response to drug use? |
Because there is constant turnover of receptors on the post synaptic cell -> Easy modification of number of receptors present |
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What is the difference between surmountable and insurmountable chronic tolerance of drugs? |
Surmountable -> Taking more drug can overcome tolerance Insurmountable -> Tolerance cannot be overcome, no matter how much drug is administered |
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What is cross tolerance? |
Where tolerance mechanisms are the same between drugs of the same family, meaning tolerance to one drug will infer tolerance to another. E.g. morphine and morphine derivatives |
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What is differential tolerance? |
Where tolerance for a drug may not be the same for all the tissues it affects (i.e. you may become tolerant towards the therapeutic effects of a drug, but not its toxic effects). |
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What is behavioral tolerance? |
The alteration of behavior in order to adapt or compensate for the presence of a drug. E.g. You have less of a drunk behavior if you drink in a bar setting than if you drink at home because you're accustomed to it. |
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What is conditioned tolerance? |
Where there are immediately activated physiological mechanisms that act to counteract an expected administration of drugs.
E.g. Mice who expected to receive a dosage of heroin responded much better to its administration |
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Do drugs with short, medium or long half-lives produce the worst withdrawal effects? Explain why |
Drugs with a medium half-life causes the worst withdrawal effects. Low -> concentration doesn't last long so body has time to recover High -> concentration takes a long time to drop down, and as the concentration drops the body has already begun to remove tolerance mechanisms |
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What treatment method for drug dependence is typically used to prevent relapse? |
Slowly decreasing the dose, using antagonists or substituting the agonist with a partial agonist |
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What pathway in the brain does the pharmacodynamic mechanism of addiction act on? |
The dopaminergic pathway |
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What is the main area of the dopaminergic pathway that is affected by addiction? Why is this? |
The ventral tegmental area. Neurons from the ventral tegmental area project to the nucleus accumbens which, when stimulated, releases dopamine. |
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What is the mesolimbic dopamine pathway otherwise known as? |
The reward pathway
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Out of the following drugs, which one has the highest withdrawal effect, and which one the lowest? 1. Heroin 2. Alcohol 3. Cocaine 4. Nicotine |
Alcohol has the most withdrawal effect, and cocaine the least |
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What is the difference between mainstream and sidestream smoke? |
Mainstream = what is being directly inhaled by the smoker Sidestream = what comes out of the burning section of the cigarette (accounts for 85% of 2nd hand smoke) |
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Does inhaled nicotine pass through the liver? |
No, it bypasses it |
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How long does it take for nicotine to get from the lungs to the brain? |
7 seconds |
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How many people alive on Earth currently will nicotine kill? |
600 million |
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What percentage of smokers will die from chronic lung disease? |
20% |
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Why is the vasoconstriction caused by nicotine a major health problem? |
It can caused increased hypertension of the heart and reduce blood flow to areas of the body such as the nose, thus causing asphyxiation of cells in those areas. |
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What percentage of smokers will die from smoking? |
50% |
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What are the 2 areas of the body nicotine is absorbed through? |
1. Oral Mucosa 2. Lungs |
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Is Nicotine a weak acid or a weak base? Does this mean they will ionic or non-ionic in a basic environment? And does this mean they will diffuse more rapidly or less rapidly? |
Nicotine is a weak base -> Weak bases are non-ionic in basic environments -> Non-ionic species are more lipid soluble |
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How does a smoker control the bioavailability of nicotine? |
Often unconsciously, if their body detects a lower concentration of nicotine with every puff, they smoke more rapidly. The opposite is true for cigarettes with high concentration. |
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If ingested, where will the nicotine in a cigarette be absorbed? Is absorption rapid or slow? |
The nicotine will be absorbed in the GI tract very rapidly. However, there is often a trigger to vomit when this occurs (nicotine gets in to the chemoreceptor trigger zone). |
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Which enzyme is responsible for the metabolism of nicotine? |
The Cytochrome P450 enzyme, more specifically CYP2A6 |
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What is the half-life of nicotine? |
2 Hours |
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After nicotine is metabolised by CYP2A6, what is the product? |
Continine |
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If the CYP2A6 enzyme is defective, what happens to the amount of cytotoxic and genotoxic metabolites produced following nicotine inhalation? |
It decreases. CYP2A6 produces procarcinogens that are activated by the enzyme. |
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Why is bladder cancer so frequent in smokers? |
Because the urine of a smoker contains many carcinogenic compounds. Also, if the urine is alkaline, nicotine with be non-ionized meaning the kidney will reabsorb it in to the system. |
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What are the 2 main types of cholinergic receptors? What type of receptor is each? |
1. Muscarinic -> GPCR for K (hyperpolarization) 2. Nicotinic -> Ligand gated ion channel for Na & Ca (depolarization) |
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Is Ach an agonist or antagonist for cholinergic receptors? |
Cholinergic receptors are actually named so because Ach is the one neurotransmitter which causes universal agonism of all receptors. |
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Is nicotine and agonist or antagonist for nicotine receptors? |
Depending on the type of nicotine receptor, it can be either. |
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What is the structure of a nicotine receptor? |
- Composed of 5 units - Pore in the middle - Some combination of any of 9 alpha subunits and 3 beta subunits |
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What is difference between a homomeric and heteromeric nicotine receptor? |
Homomeric contain either all alpha or all beta subunits whereas heteromeric is a combination of both. |
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What is the most common nicotine receptor? |
α4β2 receptor -> allows passage of both Na & Ca |
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Is Ach an agonist or antagonist of the nicotine receptor? |
An agonist. Ach is always an agonist of any type of cholinergic receptor. |
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What is the effect of a nicotine ligand binding to a nicotinic receptor? |
It has much of a similar effect as ACh. Binding causes the opening of Na channels, followed by a desensitization of the receptor. However, once the ligand leaves the receptor, it goes in to a state of long term inactivation. The receptor does not degrade and it is useless, so the cell will make more to compensate. |
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In what particular area of the brain do smokers have more nicotinic receptors? |
In the prefrontal cortex |
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Does nicotine's effect on the nicotinic receptors of the autonomic nervous system cause sympathetic or parasympathetic physiological responses? |
It can cause both |
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In what areas does nicotine cause the respective release of epinephrine and norepinephrine? |
Epinephrine = adrenal medulla Norepinephrine = sympathetic nerve endings |
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What are some consequences of epinephrine and norepinephrine release following nicotine inhalation? |
- Initial stimulation followed by sedation - Decreased skin temperature - Skeletal muscle relaxation - Increased salivation - Thermogenesis - Increased basal metabolism |
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What is the most common homomeric nicotinic receptor in the brain? |
α7 -> allows the passage of Ca |
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Where on a heteromeric nicotinic receptor does nicotine bind? |
Between the alpha and beta subunits |
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How can one experimentally study the effect of certain nicotinic receptor subunits? |
We can make knockout mice which are defective in a certain type of subunit only. |
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Monoamine oxidase inhibitors are found in cigarette smoke. What effect do they have? |
Monoamine oxidase is responsible for the breakdown of transmitters in neurons. An inhibitor causes constantly higher transmitter levels. They can thus act as psychoactive substances. |
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What is the effect of presynaptic α7 nAChRs when stimulated by nicotine? |
They enhance glutamate release, which can stimulate dopaminergic neurons which commonly have the α7 receptors. |
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Is nicotine's effect on dopaminergic neurons more stimulatory or inhibitory? |
Whilst it is both stimulatory and inhibitory, glutamate release is higher and stays higher for a longer period of time causing more overall stimulation. |
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Where are non-α7 nAChRs commonly found in the brain and what is their effect when stimulated by nicotine? |
Non-α7 nAChRs are typically found in the ventral tegmental area and serve to increase the release of GABA transmission, causing slight inhibition of dopaminergic neurons. |
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When does the withdrawal reaction of smoking peak? |
About a week after stopping |
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What is the main effect of ethanol on the body? |
It is a CNS depressant |
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Can the CNS depressant effects of ethanol be reversed with stimulants? |
No, they cannot (e.g. you can't get 'undrunk' by drinking coffee)
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What fraction of people who die driving, die due to alcohol consumption?
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At least 1/3rd |
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Which receptors and ion channels does ethanol target? |
It targets many of them, including glutamate (excitatory), GABA (inhibitory), Na, K, Ca, 5HT and ACh |
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Does ethanol consumption increase or decrease dopamine neurotransmission in the reward pathway? |
It increases it |
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What is the main inhibitory neurotransmitter in the nervous system? |
GABA A |
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What is the main method through which ethanol causes general CNS depression? |
There are receptor sites on GABA receptors for ethanol. Binding causes increased GABA release or agonism of the GABA receptors. When GABA receptors are stimulated, they cause influx of Cl- ions which cause hyperpolarization, and thus inhibition. There is also extra synaptic GABA receptors which mediate the tonic level of inhibition which ethanol can also influence. |
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What is the relationship between ethanol and glycine in the body? |
Ethanol consumption causes presynaptic glycine release and enhances the postsynaptic response to inhibition. |
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What are the 3 ways through which ethanol can cause CNS depression? |
1. GABA stimulation 2. Glycine stimulation 3. Glutamate inhibition |
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What are NMDA receptors? |
Excitatory receptors that allow the influx of positive ions, in response to glutamate binding |
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What subtype of NMDA receptor will be upregulated in response to chronic ethanol consumption? |
The N2B subtype |
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Are serotonin and ACh levels lowered or increased in response to ethanol? |
They are both lowered |
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What chemical substances are respectively linked to ethanol addiction and ethanol dependence? |
Addiction = elevated dopamine Dependence = elevated endorphin |
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What behavioral responses result from decreased serotonin levels, following ethanol consumption? |
Increased aggression and impulsiveness |
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Is ethanol lipid-soluble? |
Yes, it is highly lipid-soluble. |
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How long does it take for ethanol to be detected in the blood following consumption? |
5 minutes |
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What percentage of ethanol is absorbed through the stomach?
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20% -> High level of ADH (alcohol dehydrogenase) |
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Why does ethanol consumption cause vomiting? |
Ethanol passes the chemoreceptor trigger zone in the brain, which causes the vomiting reflex. |
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Is metabolism of ethanol 1st or 0th order? |
At low doses, its is 1st order, however once high levels are reached and there is saturation of enzymes, this becomes 0th order. |
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What are the 2 steps of alcohol metabolism? |
1. Ethanol + ADH -> Acetaldehyde 2. Acetaldehyde + Acetaldehyde dehydrogenase -> Acetate |
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What is the main factor which causes variance in tolerance levels for ethanol, between different people? |
There are 6 categories of ADH and also different varieties of acetaldehyde dehydrogenase. |
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Where is ADH found in the body? |
In the liver and the gastric mucosa |
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Are ADH levels higher or lower in males, when compared to females? |
Higher in males |
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What is the structure of ADH and how can it vary? |
ADH is a dimer with 6 potential subunits. 5 genes encodes these subunits and there are polymorphisms of each. |
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Acetaldehyde is toxic. Why then doesn't ethanol consumption, and subsequent acetaldehyde production cause significant damage to the liver? |
Because the acetaldehyde intermediate product is short lived, and quickly converted in to harmless acetate through acetaldehyde dehydrogenase found in the liver. |
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Compared to other populations, do Asians have a more active or inactive acetaldehyde dehydrogenase? What does this mean for these individuals? |
They have less active acetaldehyde dehydrogenase meaning they are less likely to drink alcohol due to the unpleasant effects |
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What percentage of alcohol is metabolised by the P450 system? |
10% -> higher levels can be induced through chronic consumption |
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What percentage of alcohol is exhaled? What changes have occurred this exhaled alcohol? |
5% of alcohol is exhaled. This alcohol remains unchanged and unmetabolized. |
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What is the therapeutic index for alcohol? |
4 -> Lethal dose is only 4 times higher than recreational dose |
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What is cirrhosis? |
A lethal disease of the liver caused by chronic alcohol consumption. |
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How can chronic ethanol consumption cause neurodegeneration? |
Alcohol consumption uses up vitamin B. A lack of vitamin B can cause neurodegeneration. |
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What is the progression of alcohol induced liver damage? |
1. Accumulation of fat (fatty liver) 2. Cell death 3. Scar tissue (cirrhosis) |
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What consequences can occur as a result of impaired liver function, due to alcohol consumption? |
1. Blood that would otherwise pass through the liver can be diverted to other pathway such as the esophagus and the rectum, leading to diseases such as esophageal varices 2. There is no longer a first pass effect, meaning detoxification of other drugs is severely impaired |
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With regards to alcohol consumption, what is rebound excitation? |
As ethanol is a CNS depressant, the body tries to counteract its effect by producing excitatory neurotransmitters. The alcohol typically wears off faster than these excitatory neurotransmitters, meaning that you can be come excited many hours after drinking. |
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What are the pharmacokinetic, pharmacodynamic and behavioral tolerance changes in response to alcohol? |
Pharmacokinetic = increased P450 Pharmacodynamic = increased NDMA receptors Behavioral = people who drink a lot learn how to counteract the effect (e.g. drinking in the bar) |
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What is the general effect of cocaine and mephamphetamines? |
They are strong CNS stimluants |
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What are two places that cocaine acts on neurotransmitters? |
1. The nerve impulses coming down the neuron 2. At the synapse of the reuptake of transmitters |
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What pharmacodynamic effects does cocaine have on the body? |
1. Blocks Na+ voltage gates - Stops axonal conduction all over the body - CNS is excited first before inhibited 2. Blocks neurotransmitter reuptake - Acts on a family of neurotransmitter/sodium symporter (NSS) for dopamine, noradrenaline and serotonin - Leads to constantly elevated levels of these neurotransmitter - Dopamine (reward), noradrenaline (sympathetic fight or flight) |
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What type of receptor are dopaminergic receptors? Where in the brain do they have a particularly high density of distribution? |
They are all GPCRs. They have high density in the cerebral cortex. |
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Is the rate of drug absorption proportional or inversely proportional to the potential for addiction? |
It is proportional, the higher the rate, the larger the potential for addiction. |
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Would smoking or snorting cocaine have a higher rate of absorption? |
Smoking cocaine is not only cheaper, it also has a higher rate of absorption. |
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What is the main enzyme that metabolizes cocaine? Where is this enzyme found in most high concentrations in the body? |
Human carboxylesterase 1 -> Mainly in the liver |
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What happens when you take cocaine the same time as alcohol? |
Human carboxylesterase 1 will produce a different derivative -> cocaethylene. This is a highly toxic product |
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How can cocaine exposure be detected in newborns? |
Metabolites of cocaine can be detected in hair follicles |
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Why does cocaine have such a great effect on the cardiovascular system, often causing such diseases as cardiac arrhythmia? |
Cocaine blocks Na+ voltage gated channels, preventing action potential transmission -> prevention of heart contractions |
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How does cocaine cause generalized hypertension? |
It increases noradrenaline (fight or flight), leading to increased blood pressure and generalised hypertension |
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What is a brain aneurysm? How can cocaine consumption cause one? |
A localized enlargening of an artery in the brain caused by the weakening of the artery wall. Cocaine can inflame and weaken these walls. |
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What is agitated delirium? |
A side effect of cocaine use. It causes individuals to be extremely aggressive. It involves variation of a D2 dopamine receptor, linked to temperature control -> Individuals rapidly get hyperthermia |
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Why does chronic cocaine consumption cause depleted dopamine in neurons? |
As dopamine is not reuptaken, new dopamine must be constantly synthesized and pumped out of the cell, leading to a depletion of dopamine actually in the neuron. |
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What are the 2 reaction phases of cocaine withdrawal? |
1. Crash -> Immediate reactions that appear within hours or days after cessation, high cravings and withdrawal symptoms 2. Withdrawal -> Even further increase of cravings, especially when present at a certain location where the body has been conditioned to accept the drug |
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What happens to the dendrite composition of neurons with cocaine use? |
Once you withdraw from chronic cocaine use, actin filaments will rearrange themselves, and will do so again once even more cocaine is take, |
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What does amphetamine use cause the release of? |
It increases dopamine and noradrenaline release. |
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Does amphetamine use induce tolerance for motor abilities? |
No, no matter how much and prolonged the usage of amphetamines is, there will be no tolerance effect on motor abilities. |
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What important chemical does amphetamine block the release of? |
It blocks monoamine oxidase release (stops the break down of neurotransmitters) |
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What is ecstasy a derivative of? |
It is a derivative of amphetamine |
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Does ecstasy have hallucinogenic or stimulant effects? |
It has both |
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On what structure does ecstasy have most of its effect on? |
5HT serotonin transporters |
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Is absorption of caffeine rapid or slow? When does it reach its peak concentration? |
It has a rapid absorption and reaches its peak concentration 0.5-2 hours after consumption |
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|
What is the half-life of caffeine? |
It depends on the age of the individual -> Newborns are 65 - 102 hrs -> Adults are 3 - 7.5 hrs |
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What is the pharmacodynamic effect of caffeine? |
Caffeine is a competitive antagonist of adenosine receptors -> adenosine is a neuromodulator which regulates the release of other transmitters -> it usually blocks the activity of cholinergic stimulatory pathways -> inhibition of adenosine cause cholinergic stimulation |
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What is the lethal dose of caffeine (based on the average amount per cup of coffee)? |
100 cups |
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What is psychopharmacology the study of? |
It is the study of drugs used to treat mental diseases and conditions. |
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What percentage of the general population is affected by schizophrenia? |
Around 1% |
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What is a psychosis? |
Where someone has a mental disease that renders them no longer in touch with reality |
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Is there a genetic factor associated with schizophrenia? |
Yes, studies with identical twins shows that there is a significant chance the other twin will develop the disease if one does. |
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What pathway of the brain does schizophrenia typically affect? |
The dopaminergic pathway |
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What is the main receptor of interest when it comes to treating schizophrenia? |
The D2 receptor -> blocking these receptors can reduce the symptoms of schizophrenia |
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What is the function of chlorpromazine? What is the main problem of drugs such as chlorpromazine? |
It is a neuroleptic (psychoactive) drug that blocks the D2 receptor (treatment of schizophrenia). The main problem is that it is not specific in blocking D2 receptors -> It also acts on histamine, 5HT, noradenaline... |
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What is the main physiological cause of depression? |
Decreased levels of amine neurotransmitters: - dopamine - noradrenaline - serotonin |
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|
What do drugs that are used to treat depression aim to do? |
They aim to inhibit the reuptake or interfere with the metabolism of dopamine, noradrenaline and serotonin |
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What are the 3 main drug categories used to treat depression? |
1. Selective Serotonin Reuptake Inhibitors (SSRIs) 2. Monoamine Oxidase Inhibitors (MAOIs) 3. Tricyclic Antidepressants (TCAs) |
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What is the function of Tricyclic Antidepressants (TCAs)? |
These drugs interfere with the reuptake of transmitters to increase their synaptic concentration. They block receptors for noradrenaline, histamine and acetylcholine. |
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|
What drug is typically the first choice used in the treatment of depression? |
Selective serotonin reuptake inhibitors (SSRIs) |
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Why aren't Tricyclic Antidepressants typically used as the first option in treating depression? |
TCAs act on many other systems in the brain therefore use will cause a number of side effects like GI problems, blurred vision (muscarininc acetylcholine receptor), sedation (histamine receptor) and vascular problems (andrenergic receptor). |
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What is Fluoxetine (trade name: Prozac)? |
A common SSRI that blocks the 5HT reuptake receptor |
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|
What type of receptor are 5HT receptors? |
They are all GPCRs except 5HT3 which is a ligand gated ion channel |
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|
What is seasonal affective disorder? |
Depression associated with altered light cycle and colder weather |
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Are hierarchal or diffuse systems of neuronal communication typically found in the CNS? |
Diffuse systems. Hierarchal systems are more commonly found in the PNS. It is why the brain is often so complicated to understand. |
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What are benzodiazepines mainly used to treat? |
They are mainly used to treat anxiety. |
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|
What are the 6 types of anxiety? |
1. Stress-related 2. Generalized anxiety disorder 3. Panic attacks 4. Phobias 5. Secondary (pathological) anxiety 6. Drug induced |
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|
What are benzodiazepines named after? |
Their chemical structure: Benzo - benzene ring Diaz - 2 nitrogen atoms Epine - Nitrogen containing ring structure |
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Aside from the treatment of anxiety, what are some effects of benzodiazepines? |
1. Insomnia treatment 2. Anticonvlsant 3. Muscle relaxant 4. Impaired memory formation |
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Why are benzodiazepines such wonderful drugs? |
There are many variations to treat a number of different cases, and they are incredibly safe (TI of 500 - 1000) |
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|
Why do musicians often take beta-blockers before a performance? |
They serve to act on the autonomic nervous system -> decrease tremors and palpatations |
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|
What is the main pharmacodynamic effect of benzodiazepines? |
Attach to allosteric sites on GABAa receptors, causing the opening of pores which allow Cl- influx, meaning there is hyperpolarisation and inhibition. |
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How many different types of units does a GABA receptor have? |
5 different types of units, each with different variations |
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What is the most common GABAa receptor? Are they subsynaptic or extrasynaptic? |
2 β2 2 α1 1 γ2 Subsynaptic receptors |
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What is the difference between subsynaptic and extrasynaptic GABAa receptors? |
Extrasynaptic receptors are more sensitive to lower levels of GABA that didn't get reuptaken. They maintain the tonic inhibition as opposed to the synaptic which maintain phasic inhibition. |
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For a dose-response curve of the action GABA, would the addition of benzodiazepines shift the curve left or right? |
Left -> Less GABAa is needed to achieve the same influx of Cl- as benzodiazepines assist the opening of the pore |
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What will the addition of benzodiazepines (alone) do to a GABAa receptor? |
Nothing, it only enhances the function of GABAs ligands. |
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In regards to their effect on GABAa receptors, how do benzodiazepines and barbiturates differ? |
Benzodiazepines: - increase opening frequency - No direct action - Much safer (more selective) Barbiturates: - Increase opening duration - Act directly on receptor - Not as selective |
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Why are barbiturates more dangerous than benzodiazepines when trying to stimulate GABAa receptors? |
Benzodiazepines maximum effect is related to the concentration of GABA in the cell which is naturally controlled so there is less of a chance of overdose. The maximum effect of barbiturates relates to the concentration of barbiturate so it is possible to overdose. |
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Where is the GABAa binding site located on the GABAa receptor? |
Between the alpha 1 and beta 2 subunits |
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What types of drugs are α1-GABAa receptors primarily the target of? |
They are the main target for drugs which act on sedation and sleep |
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What types of drugs are α2-GABAa receptors primarily the target of? |
The are the main target for drugs that are used for analgesia and also to treat anxiety. |
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Will antagonistic drugs that attach to the benzodiazepine site on GABAa receptors cause inhibition? |
No, they don't have much effefct on the influx of Cl- despite being considered antagonistic. |
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What is flumazenil used for? |
It is an antagonist for the benzodiazepine site on GABAa receptors. |
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What is the difference between a benzodiazepine antagonist and inverse agonist? |
A benzodiazepine antagonist just block the effect of the benzodiazepines and will not change the GABA dose-response curve whereas inverse agonists will actually cause the effect of the GABAa receptor to dip below baseline. |
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What is the main role of GABAb receptors? |
They are not involved in anxiety or insomnia, they allow efflux of K+ and are mainly modulators in the inhibition of other neurotransmitters. |
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|
How are benzodiazepines typically absorbed? |
Absorb easily through the oral route, highly lipid-soluble, peak blood concentration in 1 hour. |
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Do benzodiazepines have a long or short half-life? Are it's intermediates active or inactive? |
A long half-life. Intermediates are active. |
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How are benzodiazepines metabolised? |
They are broken down by P450 enzymes (CYP3A in particular). |
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|
What are the 2 important intermediate metabolites formed from the breakdown of diazepam and chlordiazepoxide? What are these chemicals further broken down to? |
Nordiazepam and desmethyldiazepam -> Oxazepam |
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Are desmethyldiazepam and its metabolite, oxazepam, biologically active? |
Yes they are both biologically active. They also have a long half-life meaning frequent use of benzodiazepines can cause toxic build up. |
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How long can withdrawal symptoms of benzodiazepines last? What are some of these symptoms? |
Can last for up to a week. Include anxiety attacks and insomnia. |
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Does benzodiazepine suppress REM or Deep sleep? |
It suppresses REM sleep |
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When treating insomnia with benzodiazpines, should you choose ones with short or long half-lives? |
Short half-lives, optimally wearing off just before one wakes up. However, the drawback with short half-life drugs is that there will be more of a withdrawal reaction. |
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What are non-benzodiazepines and why are they being increasingly utilized? |
They are drugs that also act on the GABAa receptors. They are even more selective than benzodiazepines, only binding to α1 subunits causing sedation. |
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|
What is the non-benzodiazepine mentioned in lectures? |
Zolpidem |
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|
What are the 2 main structures in the brain which are involved in endocrine signalling? |
1. Hypothalamus 2. Pituitary |
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Does the hypothalamus control the following structures through direct neural connection or via hormonal signalling?
1. Anterior pituitary 2. Posterior pituitary |
1. Anterior = hormone 2. Posterior = neural |
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|
Starting with the hypothalamus, explain the process of cortisol production. |
1. Hypothalamus releases corticotrophin releasing factor (CRH) 2. CRH acts on the anterior pituitary 3. Anterior pituitary produces POMC 4. POMC is processed in the anterior pituitary and ACTH is release 5. ACTH acts on adrenal cortex 6. Increases the transcription of steroidogenic enzymes 7. These enzyme increase cholesterol levels in the inner mitochondrial membrane 8. Increased cholesterol availability allows adrenal cortex synthesis and release of cortisol |
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CRH is a pro-hormone. What does this mean? |
It means it is a larger peptide which will be further processed and cleaved to give the active part. |
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|
What are the 2 types of corticosteroids? |
1. Mineralocorticoid -> Salt retention (aldosterone) -> Produced in the outer layer of adrenal cort 2. Glucocorticoid -> Intermediary metabolism (cortisol) -> Involved in main anti-inflammatory action |
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Are glucocorticoid levels high or low during sleep? |
They are low, and peak after breakfast, returning to low levels at 10AM. |
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|
How are glucocorticoids transported to their target organ? |
As they are lipophilic, they require transport proteins -> transported through circulation bound to corticosteroid binding protein (CBG) |
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What is the effect of a glucocorticoid on its target tissue/cell? |
Enters the cell where it will bind to a glucocorticoid receptor. Ligand-receptor complex enters the nucleus and binds to DNA. Increases or represses transcription of specific glucocorticoid receptor responsive genes. This will affect the cell's function in different ways. |
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What are Nuclear factor kB and Activator protein 1? What is their relation with glucocorticoids? |
They are proteins highly involved in the inflammatory and stress response -> glucocorticoids may repress their expression thereby downregulating the response |
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|
How does feedback control for cortisol work? |
Negative feedback where cortisol inhibits the production of CRF (hypothalamus) and ACTH (anterior pituitary) |
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What are the 4 metabolic (fight or flight) effects of endogenous glucocorticoids? |
1. Increased glycogenolysis & gluconeogenesis 2. Increased lipolysis and lipgenesis 3. Increased protein catabolism 4. Decreased osteoblast formation and activity (increased osteoporosis) |
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What are the 4 anti-inflammatory effects of endogenous glucocorticoids? |
1. Decreased production of prostaglandins & leukotrines (affects the activity of phospholipase A2 which is needed to make arachidonic acid, the precursor for prostaglandins & leukotrines, also represses cyclooxygenase 2 which converts arachidonic acid to them) 2. Represses the synthesis of interleukins 3. Represses the synthesis of platelet activating factor (PAF) 4. Cause inflammatory cell apoptosis |
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|
What are 5 things glucocorticoid drugs can be used to treat? |
1. Adrenal insufficiencies 2. Inflammatory responses 3. Immune responses 4. Myeloproliferative diseases (excess cell division, glucocorticoid causes apoptosis) 5. Respiratory distress syndrome (induces surfactant production in lung of infant) |
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|
What is dexamethasone? |
A cortisol with fluorine and a methyl group added. It is optimised to enhance glucocorticoid activity and reduce mineralocorticoid activity. |
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How does fluorine addition alter the glucocorticoid and mineralocorticoid effects of cortisol? |
It increases both activities |
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How does a methyl group addition alter the glucocorticoid and mineralocorticoid effects of cortisol? |
It minimizes mineralocorticoid effects if a fluorine group is also present. |
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|
What is cushing's syndrome a result of? |
Excessive short-term cortisol levels -> infertility and reproductive problems |
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|
What can result from long-term, high dosage use of exogenous steroids? |
Adrenal atrophy |
|
|
What are the respective benefits of steroidal drugs vs. NSAIDs? |
Steroidal drugs are useful for treating large acute inflammatory responses, whereas NSAIDs can be taken chronically because they do not have serious side effects.
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|
What is aspirin a derivative of? |
It is a derivative of salicin
|
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|
What is the fundamental building block of both prostaglandins and leukotrienes? |
Arachidonic acid |
|
|
How is arachidonic acid liberated from the cell membrane in the production of prostaglandins? |
Via phospholipase A2 |
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|
What enzyme converts arachidonic acid to prostaglandins? |
Cyclooxygenase enzymes (COX) |
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|
What are roles of prostaglandins in the body? |
1. Pain 2. Inflammation 3. Stomach acid protection 4. Platelet aggregation (thromboxane) |
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|
Do prostaglandins act in an autocrine, paracrine or endocrine fashion? |
They can be both autocrine and paracrine. Rarely act on cells at a distance. |
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|
Where is cyclooxygenase found? |
It is embedded in the endoplasmic reticulum. |
|
|
Aside from prostaglandins, what does COX also produce? |
Thromboxane A2 |
|
|
What is the general pharmacodynamic effect of NSAIDs? |
They block the cyclooxygenase -> Less production of prostaglandins |
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|
Does COX-1 or COX-2 have more of a pathological role in inflammation and pain? |
COX-2 is more pathological whereas COX-1 is more physiological |
|
|
On what types of receptors do prostaglandins act on? |
They act on prostanoid receptors (GPCR) |
|
|
How are prostanoid receptors coded? |
They are coded to correspond to the specific type of prostaglandin that activates them (e.g. Prostaglandin E will active prostaglandin E receptors) |
|
|
How do we register pain? |
Injury to cells causes prostaglandin (and other chemicals) release, which sensitizes and stimulates nerve endings that create an impulse relayed to the brain. |
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|
What is acetaminophen (tylenol) used to treat? |
Pain (very weak anti-infllammatory). |
|
|
What is the difference of effect between prostaglandins and bradykinin on nociceptors? |
Both cause direct activation of nociceptors to send pain impulses to the brain but PGs also sensitize the nociceptor to other mediators.
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|
What is the difference between osteoarthritis and rheumatoid arthritis? |
In rheumatoid arthritis, there is an autoimmune disease causing degradation of cartilage whereas osteoarthritis is caused by general wear & tear. |
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|
Where do pyrogens go to in the brain? |
They travel to the hypothalamic temperature-regulating center |
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|
Once pyrogens are detected by the hypothalamic temperature-regulating center in the brain, what happens? |
PGE2 is produced in the hypothalamus, which then causes an increase in body temperature in the periphery through shivering or vasoconstriction. |
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|
What is the major enzyme that produces PGE2 in the brain?
|
COX-2 |
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|
What is the major side effect of chronic NSAID consumption? What are the 2 minor side effects? |
Due to a decrease prostaglandin level, the lining of the stomach mucosa can thin, and there can also be a decrease in bicarbonate production which would otherwise neutralize the acidic environment.
Can also cause renal dysfunction and interfere with platelet aggregation in coagulation. |
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|
What are the 4 uses of aspirin? Which one is the reason it commonly used in NA today? |
1. Analgesic 2. Anti-inflammatory 3. Antipyretic 4. Antithrombotic It's antithrombotic effects are the main reason it is used today |
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|
What is the pharmacodynamic effect of aspirin? |
The acetyl group of aspirin binds irreversibly to the serine on a COX enzyme, effectively killing it (new COX must be synthesized). Also it prevents the production of new thromboxane A2 by activated platelets, thus stopping aggregation of platelets. |
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|
What are the 2 ways in which aspirin can be metabolized? |
It is first deacetylated in to salicylic acid, then it can either be conjugated with glycine or oxidized. |
|
|
What is the half-life of aspirin? |
Low-dose: 3 hours High-dose: 15 hours (saturation causes high half-life) |
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|
Will salicylic acid be ionized or unionized in alkaline urine? Would it be lipid-soluble or insoluble? |
In alkaline urine, it would be ionized meaning it would be non lipid-soluble (excreted more rapidly). |
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Why would you give someone who's overdosed on aspirin some bicarbonate? |
Because bicarbonate is alkaline, meaning it would make aspirin become ionized and thus cause it to be lipid-insoluble leading it to be excreted faster. |
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|
What is the term for aspirin toxicity? |
Salicylism |
|
|
What is Reye's syndrome? |
A rare disorder that affects cells in the brain and liver -> caused when children have viral infections and are given aspirin at the same time. |
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|
What is the difference between aspirin and other traditional NSAIDs such as ibuprofen? |
Traditional NSAIDs have reversible inhibition of COX whereas aspirin is irreversible. |
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|
Is the anti-thrombotic effect of aspirin due to COX-1 or COX-2 inhibition? |
COX-1 inhibition. |
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|
Aside from pain and inflammation, COX-2 also is involved in certain "housekeeping" actions in the body. What are these? |
COX-2 is involved in renal electrolyte homeostasis and renal blood flow maintenance. It also has physiological effects in the brain, ovary and uterus. |
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|
What is the pharmacodynamic effect of the NSAID 'Celecoxib'? |
It acts specifically on COX-2 enzymes so there are less platelet aggregation inhibition side effects. It can be specific because the COX-2 enzyme site is larger than COX-1, so it can't fit. |
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|
COX-2 is involved in the production of prostacyclin. What does prostacyclin cause? What does this mean if you selectively inhibit COX-2 only? |
Prostacyclin can cause vasodilation. This means if a NSAID selectively inhibits COX-2, there will be promotion of both platelet aggregation and vasoconstriction which can lead to clots. |
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|
What percentage of acetaminophen is conjugated and excreted by the body? |
75% |
|
|
What are the therapeutic uses of acetaminophen? |
It is an analgesic and antipyretic but not an anti-inflammatory
|
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|
What happens if you overdose on acetaminophen? |
You saturate the enzyme which is involved in conjugating the toxic derivative of acetaminophen, leading to hepatotoxicity. |
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|
What happens when you combine ethanol and acetaminophen? |
1. Ethanol can induce the P450 enzymes which convert acetaminophen in to toxic metabolites that cause liver injury 2. Ethanol depletes glutathione stores which slows the removal of metabolites |
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|
What are the 2 major locations of the body associated with pain sensation? What types of drugs target the respective locations? |
1. Peripheral Nervous System
- NSAIDs 2. Central Nervous System - Opioids |
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|
What are the 2 ways in which pain suppression of the central nervous system can be achieved through opioids? |
1. Endogenous opioid peptides -> can be released through stress and exercise -> neurons that make opioids widely distributed 2. Ingested opioids -> Pharamaceuticals |
|
|
What are the naturally occurring alkaloids found in opium poppies? |
Morphine and codeine |
|
|
What was the original use of opioids? |
They were used to treat diarrhea. |
|
|
What are the 3 most common type of opioids? |
1. Morphine 2. Codeine 3. Heroine |
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|
Explain the pharmacodynamic mechanisms of opioids in the reduction of pain? |
At the synapse between the nociceptive nerve ending and the spinal cord, opioids can bind to presynaptic opioid receptors which reduce the influx of Ca2+ which means less neurotransmitter is released. On the postsynaptic receptors, opioids will also cause hyperpolarization. In addition, opioids will activate a descending pain-inhibitory pathway. |
|
|
What are A delta and C fibers? |
Nerve fibers which are stimulated by nociceptors and carry the impulses to the spinal cord. |
|
|
What are the 3 different subtypes of opioid receptors? |
1. Mu (μ) 2. Delta (δ) 3. Kappa (κ) |
|
|
Which of the 2 opioid receptors are very similar in protein sequence? |
Delta (δ) & Kappa (κ) |
|
|
What types of receptor are opioid receptors? What does binding of opioids on to these receptors cause? |
They are all GPCRs. Ligand binding causes either K+ channel opening or Ca2+ channel closing. |
|
|
Where are Mu opioid receptors most strongly concentrated? |
In postsynaptic neurons |
|
|
What are the 3 ways pain can be classified? |
1. Nociceptor pain - Peripheral injury 2. Neuropathic pain - Nerve injury 3. Psychogenic pain - Complex psychological reasons |
|
|
What type of opioid receptor do modern opioids (heroin, morphine, methadone) have a preference for? |
Mu receptors (pain relief) |
|
|
What effects do delta receptors agonist have? |
Analgesic effects (not much is known) |
|
|
Give a definition of analgesia. |
The relief of pain without impairment to other sensory modalities. |
|
|
What are the 6 physiological effects of opioids? |
1. Analgesia 2. Gastrointestinal motility inhibition 3. Cough suppression 4. Euphoria 5. Respiratory depression 6. Miosis (pupil constriction) |
|
|
If morphine is administered orally, where in the body is it absorbed? |
It would be absorbed in the gastrointestinal tract |
|
|
What is the most common route of morphine administration? |
Intramuscular/Subcutaneous/Intravenous |
|
|
What is the benefit of intramuscular vs. intravenous opioid administration? |
Although the concentration will rise slower with intramuscular administration, it will also fall slower, allowing a longer range of time within the therapeutic window |
|
|
What percentage of administered morphine typically crosses the blood brain barrier? |
Around 20% |
|
|
Why isn't oral administration of morphine recommended for chronic use? |
When morphine is swallowed, a large amount is metabolized to normorphine which is a psychoactive neurotoxic compound. Chronic use causes tolerance, which means larger amounts of opioid is needed, meaning larger doses of toxic normorphine. |
|
|
What percentage of injected morphine is metabolized in to an inactive compound? |
60% |
|
|
How can opioid consumption cause constipation as a side effect? |
Opioids bind to mu receptors in the GI tract (myenteric plexus), causing circular muscle contraction more than longitudinal contraction. This means there is less propulsion and more contraction. Also, there is increased water retention and rectal sphincter tone. |
|
|
How does opioid consumption cause nausea and vomiting? |
Morphine stimulates the chemoreceptor trigger zone -> stimulates gastric mucose -> acts on vomiting center Morphine also acts on the labyrinthine apparatus of the inner ear -> acts on vomiting center |
|
|
Does morphine consumption increase or decrease antidiuretic hormone? |
It increases antidiuretic hormones meaning more water retention (can cause constipation but can also treat diarrhea) |
|
|
What happens when you combine codeine with an NSAID? |
You get a synergistic effect which allows a much greater analgesic effect |
|
|
What is the difference between codeine and morphine? |
Codeine is just methyl-morphine -> metabolized to morphine by CYP2D6 in the body -> huge genetic variation in ability to metabolize codeine |
|
|
Genetic variation in which enzyme determines an individuals ability to receive an analgesic effect from codeine? |
CYP2D6 (converts codeine to biologically active morphine) |
|
|
Why is morphine highly addictive? |
Its structure is diacetyl-morphine meaning it is highly lipid soluble and passes the blood brain barrier easily. |
|
|
What is the function of methadone? |
It is a weak agonist of opioid receptors, meaning it can be used to treat addiction and cravings. |
|
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What is diethyl ether and why isn't it used today? |
It is an effective anesthetic drug however it is highly flammable meaning the presence of electronic equipment could trigger an explosion. |
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What effects does general anesthesia have? |
1. Lose sensation and consciousness
2. Amnesia 3. Relaxation of skeletal muscle and suppression of reflexes |
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What are the 2 stages of anesthesia use in surgery? |
1st stage is the induction agent where the patient is rendered unconscious very quickly 2nd stage involves the maintenance of keeping the patient unconscious |
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Why must analgesics be administered with anesthetics? |
Because anesthetics don't take pain away, they only render the patient unconscious. |
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What are the 2 types of general anesthetics used? |
1. Inhalation anesthetics (end in -ane) 2. Intravenous anesthetics potent opioids |
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What determines the partial pressure of a gaseous drug? Why is this important when administering inhaled anesthetics? |
The fractional concentration of drug determines its partial pressure. This is important as the partial pressure of an anaesthetic is what determines the concentration of the drug in the blood stream, and the partial pressure of the drug in the blood stream is what determines its concentration in the brain. |
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What does a time vs. arterial anesthetic tension graph show? |
Curves on this graph describe the solubility of the general anesthetic. Low solubility drugs will get in to brain very fast as it can cross the blood brain barrier (they are less blood soluble but more lipid soluble) |
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Is nitrous oxide more or less soluble than halothane? Does it pass the BBB faster or slower? |
It is less soluble and passes the BBB faster. |
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Is the solubility of a drug proportional or inversely proportional to its partial pressure? |
Inversely proportional |
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What 3 factors affect the rate of anesthesia induction? |
1. Concentration of mixture 2. Alveolar ventilation 3. Solubility |
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When considering the desired effect of anesthesia, would we want a higher or lower cardiac output when we administer it? |
A lower cardiac output -> reduces blood flow to undesired peripheral tissue (main target is brain) |
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What is the minimum alveolar concentration (MAC) of an anesthetic? |
The MAC is the concentration that will produce a surgical level of general anesthesia in 50% of patients. |
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What is considered a safe minimum alveolar concentration of anesthesia when conducting surgery? |
1.3 however this may change depending on specific patient needs |
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What are 2 the major side effects of general anesthetics? |
They are CNS depressants so they can cause repression of respiration and cardiac function. Also they depress the blood pressure dramatically which can cause tissue death if insufficient blood flow results. |
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What is isoflurane? |
A general anesthetic |
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What are the 2 benefits of NO as a general anesthetic and what is its drawback? |
It is a good analgesic because it doesn't lower blood pressure and doesn't repress respiration. However, it is a poor muscle relaxant. |
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Why is important that an anesthetic is compatible with epinephrine? |
Because if blood pressure drops, you will need to administer epinephrine to boost it back up. |
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Why is NO often combined with other anesthetics? |
You can't achieve a surgical level of anesthesia with NO alone, so it is often combined with small amounts of more potent but dangerous drugs. |
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What is the benefit of isoflurane over NO as an analgesic? |
Isoflurane has more of a muscle relaxant effect. |
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In comparison with inhalation anesthetics, do IV anesthetics have more or less cardiac and respiratory depression? |
It has less cardiac and respiratory depression. |
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Why is thiopental a good barbiturate anesthetic for unconsciousness induction but not for continuous use? |
It rapidly reaches the brain (within seconds). However, if it is constantly administered, the patient will be unconscious for too lang as it accumulates in muscle and adipose tissue and is not exhaled out. |
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Do benzodiazepines or barbiturates have a faster rate of induction as IV anesthetics? |
Barbiturates have a faster rate of induction. |
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What is the most frequently used anesthetic benzodiaepine? |
Midazolam |
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What does an opioid paired with midazolam achieve? |
Conscious sedation -> great for short term procedures |
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Do opioids as intravenous anesthetics cause respiratory depression? |
Yes they do |
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What is Fentanyl? |
An extremely powerful opioid that can be used as an intravenous anesthetic. |
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For what purposes would ketamine be the anesthetic of choice? |
Where a patient is at risk of hypotension, is an asthmatic or there is no reliable ventilation equipment to use. This is because it causes much less repiratory and cardiac depression when compared to other anesthetics, however it causes severe hallucinations and a senses of dysphoria. |
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What are some common pharmacodynamic effects shared between different anesthetics? |
They generally act on the presynaptic side of neurons to decrease neurotransmitter release. Also they generally increase inhibition via GABAa and decrease excitation by acting on cholinergic receptors (muscle relaxant). All of them act on more than one ligand gated ion channel. |
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Why are NO and ketamine the odd ones out when it comes to general anesthetics? |
They are the only ones not involved with GABAa receptors |
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What kinds of receptors does ketamine act on? |
Does not act on anything related to inhibition - acts mainly on NMDA (prevention of glutamate binding) and nACh receptors to decrease excitation |
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What are neuromuscular blocking agents? |
Drugs that cause paralysis of affected skeletal muscle by stopping neurotransmission at the neuromuscular junction. |
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How do non-depolarizing blockers work as muscle relaxants in surgical procedures? |
They are competitive inhibitors of ACh action -> bind to ACh receptor site |
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What are the 2 general types of neuromuscular blocking agents? |
1. Non-depolarizing 2. Depolarizing |
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What is the only depolarizing neuromuscular blocker currently in use for surgery? |
Succinylcholine |
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What is the parmacodynamic action of depolarizing neuromuscular blockers like succinylcholine? |
They cause initial depolarization at the neuromuscular junction causing twitching. However, this is short lived and the blocker then goes on to stay on the receptor and block further depolarization (desensitization). |
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How can the action of neuromuscular blockers be terminated? |
Anti-cholinesterase drugs can be administered causing larger ACh amounts in the synapse which can overcome the effect of the competitive binding neuromuscular blocker. |
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Where do neuromuscular blockers act? |
They act only in the periphery (don't cross BBB) |
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How is succinylcholine metabolized at the neuromuscular junction? |
By succinylcholinesterase |
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What are the 3 different types of nociceptive fibres that local anesthetics work on? |
A, B and C fibres |
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What is the pharmacodynamic action of local anesthesia? |
They block the opening of Na+ channels along the A, B and C nociceptive fibers. |
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Why is adrenaline often administered alongside local anesthetics? |
In high enough amounts, adrenaline can cause vasoconstriction which slows down the rate of anesthetic absorption allowing the anesthetic to stay at the injected site for longer |
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Why is tissue inflammation an important factor to consider when administering local anesthetics? |
Local anesthetics work on the inside of the cell (need to cross plasma membrane). If there is tissue inflammation, there can be an acidic external environment which means the local anesthetic will be more ionized, and less likely to cross the membrane. |
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What are the properties of a local anesthetic with an ester as the intermediate chain? |
They are metabolized easily by plasma cholinesterase (very short half life) |
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What are the properties of a local anesthetic with an amide as the intermediate chain? |
They are metabolized by the liver and have a longer half-life than the ester intermediate. As they are metabolized by the liver, they have to get in to systemic circulation which means there is a risk of crossing the BBB. |
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What is lidocaine? |
A local anesthetics that can have systemic effects like cardiovascular collapse and respiratory arrest -> used for treatment of arrhythmias |
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When is it useful to use a combination of lidocaine and prilocaine? |
They are both local anesthetics which, when combined, create a product with highly lipid-soluble and can be absorbed through the skin (useful for children who are afraid of needles). |
