Term
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Definition
Study of the changes produced in living animals by chemical substances, especially the actions of drugs, used to treat diseases
(chem consumed, effects on the body)
Or
Branch of medicine that deals w/ the interaction of drugs w/ the systems and processes of living animals, in particular, mechanisms of drug action as well as the therapeutic and other uses of the drug. |
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Term
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Definition
Broadly defined as any chemical that has an effect on living processes.
- Affects the processes of mind or body
- Used in the diagnosis, treatment or prevention of diseases or other abn. Conditions
- Used recreationally for its effects on CNS |
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Term
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Definition
| Originally it meant "magic charm" but it eventually came to mean "remedy or drug" |
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Term
| Earliest known salves contained what common herb? |
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Definition
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Term
Which receptors in the heart belong to the adrenergic (sympathetic) neurosystem?
When activated, what is their action? |
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Definition
Beta-1 receptors
When beta-1 receptors are activated, the force and rate of contraction increases |
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Term
| The beta receptors are found in which branch of the nervous system and what does the activation of each one cause? |
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Definition
Beta receptors are a part of the sympathetic branch of the automatic nervous system.
Beta-1 receptors -- found in the heart, cause an increase in contraction rate and force.
Beta-2 receptors -- found in the bronchial smooth muscle (found in smooth muscle)
Beta-3 receptors -- |
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Term
| Which receptors are innervated by the sympathetic nervous system? |
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Definition
Beta and alpha receptors.
Beta-1 (heart) beta-2 (bronchial smooth muscle) beta-3 (?)
Alpha-1 (blood vessels, vasoconstriction) |
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Term
| How do you treat hypertension? |
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Definition
You can use alpha-1 blockers (which causes vasodilation, as activation of alpha-1 causes constriction)
Or you can use beta-1 blockers (which causes a decrease in the force and rate of heart contractions)
Both of these reduces blood pressure. |
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Term
| Who was the person who started pharmacology? |
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Definition
| Pedanius Dioscorides -- wrote the first pharmacopia |
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Term
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Definition
| A book containing an official list of medicinal drugs together with articles on their preparation and use. |
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Term
| A patient is in shock and is found to have dangerously low blood pressure. What would you give to treat them? |
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Definition
| You would treat them with either an alpha-1 agonist (increasing vasoconstriction) or a beta-1 agonist (increasing heart contraction rate and force) |
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Term
| What are the receptors of the parasympathetic nervous system? |
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Definition
| Muscarinic and nicotinic receptors. |
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Term
| What is the result of excessive stimulation of the heart? |
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Definition
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Term
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Definition
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Term
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Definition
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Term
| How were most drugs discovered? |
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Definition
| Isolation of pure drug compounds from natural sources. |
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Term
| What was the first drug to be isolated from a plant? |
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Definition
| Morphine (in 1804) was isolated from opium. |
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Term
| Who started the first medical school pharmacology laboratory? |
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Definition
| Rudolf Buchheim in Estonia. |
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Term
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Definition
- established the first pharmacology department @ the Uni of Michigan and is considered the father of american pharmacology.
- isolated adrenalin from the adrenal gland. |
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Term
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Definition
- Increase blood pressure by increasing vasoconstriction of blood vessels
- Reduces release of histamine
- Steroid and NT properties |
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Term
| What are the two main neurotransmitters in the body? |
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Definition
Acetylcholine (parasympathetic)
Norepinephrine (sympathetic) |
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Term
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Definition
1) Proprietor names (can have more than 1)
- Given by the company
2) Generic name (**worth remembering*)
- Will be released as the "main ingredient"
3) Pre-market manufacturer code
4) Chemical name |
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Term
| How much tylenol can an individual take before harmful effects and why? What causes the harmful effects? |
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Definition
They can take up to 4g before the side effects begin to occur.
When tylenol is metabolized by CYP enzymes it creates a reactive chemical, NAPQI, which can cause damage to RNA and DNA if it is not neutralized.
There is an antioxidant, glutathione (DSH), neutralizes many harmful chemicals in the body *including NAPQI* but when dosages exceed 4g the production of the reaction chemical uses up the NAPQI, leaving toxic chemicals in the system. |
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Term
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Definition
- Absorption
- Distribution
- Biotransformation
- Excretion
Pharmacokinetics determines how long a drug will stay in the system and what metabolism processes the drug undergoes. |
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Term
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Definition
| Mechanism and magnitude of drug effect. |
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Term
| Which organs receive the major fraction of blood supply? |
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Definition
| The kidneys and the brain. |
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Term
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Definition
Kinetics: doseofdrug-->resulting drug concentration in body over time due to absorption/distribution/biotransformation/excretion of drug.
Pharmacodynamics --> resulting [drug] stimulates some mechanism that has a measurable magnitude of drug effect in the body.
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Term
| What are the sites where drug exchange takes place? |
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Definition
| Capillary beds in each organ |
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Term
| True or false: lipid soluble drugs can reach practically any part o the body |
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Definition
True. It's concentration will be almost the same in all parts of the body.
Other drugs that are highly lipid soluble can saturate the adipose tissue, leading to increased levels of drug concentration over time. |
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Term
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Definition
Generally secondary effect, mostly due to a known mechanism, which may be harmful or beneficial.
It can have adverse effects due to interactions or some unknown mechanism. |
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Term
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Definition
| An adverse effect or complication caused by a physician, resulting from a medical treatment or device. |
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Term
| What are the limitations in taking drugs orally? |
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Definition
- Action of peptidases in stomach limits use of peptide-drugs (insulin)
- Drugs need to cross several layers (GI tract epithelium) to reach circulation.
- GI epithelium is rich in enzymes, so only a fraction of the drug reaches circulation before the rest is metabolized. |
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Term
| What are the main organs in metabolization of drugs? |
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Definition
First: The GI tract epithelium (brush-border enzymes)
Second: Liver |
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Term
| True or false: most drugs, when absorbed across the GI epithelium, remain free from plasma proteins in circulation. |
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Definition
| False, most charged molecules end up being bound to plasma proteins. (many drugs are charged). |
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Term
| True or false: drug molecules that are bound to plasma proteins can still exert their effect |
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Definition
False. Only free-drug can exert their effect.
As the free drug decreases, more drug is released from the plasma proteins. |
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Term
| True or false: drug molecules that are irreversibly bound to plasma proteins. If not, how so? |
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Definition
| They are reversibly bound to plasma proteins based on the levels of free drug in the circulation. When the fraction of free-drug begins to drop, more will be released from the plasma proteins. |
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Term
| Which organ receives the lowest blood supply? |
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Definition
The skin.
Adipose tissue also receives very little blood supply. |
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Term
| Is the distribution of drug concentration going to be even if the drug is administered orally? |
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Definition
No. Due to the difference in fenestrations, some organs may receive a higher concentration of drug then others. For example, the brain has tight-junctions meaning that mainly only lipophilic (or drugs taking advantage of transport machinery) cross the barrier. In another example, the liver has extremely fenestrated capillaries so it ends up receiving a higher concentration of the drug.
Nails, which have almost no blood flow, will have the lowest concentration of drug. |
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Term
| Why is it difficult to treat infections of the CNS? |
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Definition
| Because of the blood-brain-barrier, it is very difficult to have non-lipophilic drugs cross that barrier. Often patients must have the antibiotic injected directly in the CSF in hospital for treatment. |
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Term
| What are the routes for administering a drug? |
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Definition
Enteral (GI tract)
Oral
Sublingual
Rectal
Parenteral (other than GI tract)
Intravenous
Intramuscular
Subcutaneous
Intra-arterial
Intrathecal
Intraperitoneal |
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Term
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Definition
Refers to the passage of drug from the site of administration into the general circulation (except for those drugs that are applied directly to the target tissues).
Drugs given intravenously are 100% absorbed. |
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Term
| Which types of molecules are better absorbed? |
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Definition
Non-ionized molecules
Small molecules
Lipid-soluble drugs |
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Term
| Which types of molecules are either slowly absorbed or not absorbed at all? |
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Definition
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Term
| What factors effect oral absorption? |
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Definition
- Drugs that are destroyed by stomach acid or digestive enzymes
- Chelation to components of food
- So polar that they will not cross membranes |
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Term
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Definition
| Should be taken on an empty stomach to achieve maximal absorption. However, it can cause gastric upset. In such cases should be taken with food. |
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Term
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Definition
The precursor molecule to dopamine that is lipid soluble and not digested by the GI tract.
Since it is lipid-soluble it can cross the blood brain barrier, where it is still not metabolized.
It is then converted to the active form, dopamine, by an enzyme @ the site of a neuron. |
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Term
| Which NT's have re-uptake as their major method of action-termination ? |
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Definition
| Norepinephrine(NE), dopamine(dopa), serotonin (5-HT). |
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Term
| What kind of drug would be used to potentiate the action of NE, dopa or 5-HT? |
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Definition
| Reuptake blockers would potentiate their effect as they would remain in the synaptic cleft for a longer duration. |
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Term
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Definition
Works on either muscarinic or nicotinic receptors.
Broken down by enzyme acetylcholinesterase |
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Term
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Definition
| Enzyme located in the post-synaptic membrane that breaks down acetyochline into an acetyl and a choline group. |
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Term
| What kind of drug would be used to potentiate the effect of acetylcholine? |
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Definition
| Enzyme inhibitors. These would limit the breakdown of acetylcholine by AChE |
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Term
| If you have an excess of neurotransmitters, what can you do? |
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Definition
| You can use receptor blockers. |
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Term
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Definition
Condition characterized by skeletal muscle weakness.
There are too few receptors for ACh present so muscle contraction is very weak.
*can be treated by limiting the breakdown of ACh and potentiating its action. |
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Term
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Definition
| Defined as the pH at which half of the drug is ionized. |
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Term
| True or false: most drugs are weak acids or weak bases |
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Definition
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Term
| True or false: the deprotenated form of acid drugs is the more easily absorbed form. |
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Definition
| False. A deprotenated acidic drug carries a negative charge, making it less readily absorbed. |
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Term
| True or false: the deprotenated form of a basic drug is the more easily absorbed form. |
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Definition
| True. Deprotenated basic drugs do not carry a charge and therefore can more easily cross membrane barriers. |
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Term
| Weak acid and basic drugs |
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Definition
Acidic drugs:
The protenated form (HA) is better absorbed
Basic drugs:
The deprotenated form (B) is better absorbed. |
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Term
| Acidic drug + alkalyne medium =? |
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Definition
| An acidic drug will ionize in an alaklyne medium, resulting in a charged molecule and reduced absorption. |
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Term
| Acidic drug + acidic medium=? |
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Definition
| An acidic drug will remain protonated within an acidic medium, resulting in maximal absorption. |
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Term
| Basic drug + acidic medium=? |
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Definition
| A basic drug would ionize within an acidic medium, resulting in reduced absorption. |
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Term
| Why should you never take delayed-release aspirin? |
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Definition
| Aspirin is a weakly acidic drug and therefore is best absorbed from the stomach or the very beginning of the duodenum where it is most acidic. Delayed release aspirin make it so that the aspirin is being released in later, more basic, parts of the small intestine, rendering it basically useless as the drug is highly ionized in the basic environment. |
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Term
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Definition
Ion trapping refers to the phenomenon where an uncharged molecule can cross a membrane, but if ionized on the other side it will be unable to cross back, causing an increase in concentration of that molecule on the other side of the membrane.
Ie if an acidic molecule cross from an acidic environment to a more basic one, the acidic molecules will become ionized and be unable to move back.
This is important in cases like fetuses who may injest drugs from mother's milk and potentially end up with dangerous doses of those chemicals.
Basically, ion trapping leads to different concentrations in different body departments. |
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Term
| Clinical significance of ion trapping |
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Definition
- Basic drugs taken by mother can accumulate in fetal circulation/breast milk leading to harmful effects in the fetus/breastfed baby
- Ion trapping can be utilized to acidify/alkalyze urine and accelerate excretion of basic/acidic drugs that have reached toxic levels |
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Term
How would you increase the excretion of phenobarbital or salicylates?
What other common drug could be excreted this way? |
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Definition
These are weakly acidic drugs.
If you want to alkalyze the urine (which would increase the excretion of these drugs) then you would give sodium bicarbonate to the patient.
Aspirin. |
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Term
| How would you increase the excretion of amphetamine? |
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Definition
It is a weakly basic drug.
To acidify the urine, you give ammonium chloride or ascorbic acid. |
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Term
| What is the purpose of drug metabolism with relation to urine excretion? |
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Definition
The goal is to ionize the drugs (give them a charge) so that they are not readily reabsorbed by the kidney after being filtered through the glomurulus' fenestrated capillaries.
Nonionized drugs can be reabsorbed, therefore extending their mechanism of action and potentially increasing the risk for toxicity. |
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Term
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Definition
| The phenomenon where most drugs are first metabolized by either the enzymes of the GI epithelium or the liver. This is why most drugs cannot be taken orally, as they are subject to the first-pass effect and very little or no drug reaches the general circulation. |
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Term
| True or false: nitroglycerine, insulin and noreadrenalin cannot be given orally because they are subject to the first-pass effect. |
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Definition
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Term
| Pathway of the drugs taken orally |
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Definition
Drugs must first cross the GI tract epithelium and deal with the enzymes that are there. If they are not broken own by the enzymes (first pass effect) they enter into the portal circulation.
From there they enter the liver, which also has powerful enzymes (first pass effect) that can break down drug molecules. If the drug can make it past those enzymes then it will enter general circulation. |
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Term
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Definition
Tyramine, a sympathomimetic found in cheese and wine, is normally metabolized by the monoamine oxidase enzymes found in the wall of the GI tract and liver.
When a patient is taking MAO inhibitors, tyramine can be absorbed and release nerve terminals where it causes a release of NE.
NE will stimulate adrenergic receptors, causing tachycardia and an increase in blood pressure by stimulating beta-1 and alpha-1 receptors. |
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Term
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Definition
Enzyme found in the wall of the GI tract, in the liver and @ the presynaptic terminal whos job is to metabolize amine neurotransmitters (like dopamine and NE).
Most importantly: It metabolizes Tyramine, the metabolite found in cheese and wine, thereby eliminating the potential for tyramine's circulatory effect, which is to stimulate the release of NE (tachycardia/hypertension).
If someone is taking a general MAO inhibitor because they need increased activity of one of the amine-NT's (dopamine/NE) in the brain, then they will have the potential for the "cheese-wine reaction" to occur. |
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Term
| True or false: most blood vessels have only parasympathetic innervations, resulting in vasodilation. |
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Definition
| False. Most have sympathetic innervations, leading to vasoconstriction when NE is released. |
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Term
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Definition
| The fraction of an orally given drug that reaches the circulation. It is a comparison between the amount that would reach the circulation given absorption over the GI tract or given intravenously. |
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Term
| How do you test for bioavailability? |
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Definition
Drug is given intravenously to some volunteers and the concentration is taken. After some time, the concentration becomes zero. (100-0)
The same drug is given orally after some time. (0-x-0) you reach maximal concentration in the plasma before levels begin to fall again.
You take the fraction of these two values (oral/iv)*100=bioavailability |
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Term
| What feature enables the binding of drug molecules to plasma proteins? |
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Definition
Plasma proteins are highly charged molecules.
They are also non-specific, so they can bind a wide range of drug molecules. |
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Term
| What are the plasma proteins? |
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Definition
Albumin
Alpha-1-acid glycoprotein |
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Term
| What plasma protein would acidic molecules bind to? |
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Definition
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Term
| Which plasma protein would basic molecules bind to? |
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Definition
| Alpha-1-acid glycoprotein |
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Term
| True or false: drugs compete for the binding sites on plasma proteins. Therefore, those proteins are saturable. |
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Definition
| True. There is competition for the binding sites on plasma proteins between drug molecules. |
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Term
| True or false: displacement of a drug from plasma protein binding will generally cause a distinct change in its overall effect or adverse effects |
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Definition
False.
Displacement of a drug from plasma protein binding will generally NOT cause a distinct change in its overall effect or adverse effects (extravascular), except in the case of those that have a very small volume of distribution (intravascular)(example, warfarin)). |
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Term
| What is the danger of warfarin? |
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Definition
Warfarin is an anticoagulant drug that binds readily to plasma proteins (90% is bound, 10% is exhibiting therapeutic effects). However, it is an intravascular drug - meaning that it does not leave the vascular compartment. Therefore, it can produce significant effects (as its change in concentration can be severe) if displaced from the plasma proteins.
This leads to severe bleeding or hemorrhaging. |
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Term
| Drug-drug interaction, plasma proteins. |
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Definition
If a patient is taking two drugs at the same time that both bind to plasma proteins, there will be competitive binding where their concentrations will effect which proportion is most bound to the plasma proteins.
This can cause a drug-drug interaction where the increase in concentration of one of the drugs can have adverse physiological effects. |
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Term
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Definition
| The reversible movement of a drug between body compartment. |
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Term
| What factors effect drug distribution from the circulation to the other tissue compartments? |
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Definition
Ionization
Capillary permeability (high in kidney + liver and spleen, low in brain)
Blood flow (kidneys/brain/liver = highest first)
Plasma protein binding |
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Term
| Where are the "leakiest" capillaries? |
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Definition
Liver and spleen = highest degree of fenestration.
Kidney (glomeruli) |
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Term
| True or false: drugs that are polar, poorly lipid soluble or charged cannot easily cross fenestrated capillaries |
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Definition
False.
As you increase the degree of fenestration, you make it easier for the movement of charged, ionized, or poorly lipid soluble drugs to cross to the other side of capillaries.
There is a high degree of fenestration in the capillaries of the liver, spleen and kidneys and there are basically no fenestrations in the brain capillaries.
Everywhere else is varying levels of selective permeability in between those two extremes. |
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Term
| What things can cross the blood brain barrier? |
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Definition
Very little.
Amino acids/glucose by specific carrier-mediated transport.
Only lipophilic drugs can diffuse across the brain capillaries unless those drugs utilize the active-transport mechanisms. |
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Term
| What are the clinical implications of the blood-brain barrier? |
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Definition
| Because of its tight junctions, most drugs are unable to cross the barrier from the systemic circulation to the brain-circulation. Therefore, the degree to which the drug can penetrate the blood-brain barrier is extremely important for treatment. |
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Term
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Definition
| L-dopa is a precursor molecule to dopamine. It is the clinically used molecule for use it treatments that require dopamine (parkinsons, alzheimers) as dopamine cannot cross the blood-brain barrier, but the lipid-soluble L-dopa can. |
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Term
| True or false: dopamine can't cross the blood-brain barrier because it is too hydrophilic. |
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Definition
False.
It cannot cross the blood-brain barrier because it is broken down by enzymes in the blood-brain barrier. |
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Term
| What can make the blood-brain barrier easier to cross? |
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Definition
Infections (meningitis) or injury or brain tumors.
Brain tumors - tumors undergo vascularization and the new capillaries do not have tight junctions. **radioactive iodine-labeled albumin penetrates normal blood tissue slowly, but vascularized tissue rapidly. This aids in |
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Term
| How are brain tumors diagnosed? |
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Definition
| Radioactive iodine-labeled albumin is injected into the patient. It slowly penetrates normal brain tissue, but rapidly penetrates vascularized tissue allowing for the identification of tumors. |
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Term
| How does blood flow effect drug delivery? |
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Definition
The tissues that receive more blood, receive more drug.
The rate at which drugs distribute from the bloodstream into the various tissues depends on the relative blood flow to the various tissues.
Brain, liver, kidneys have comparatively more blood flow > skeletal muscle > fat, skin (comparatively little blood flow). |
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Term
| Volume of distribution (Vd) |
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Definition
The theoretical (or apparent) volume in which the total amount of administered drug should be uniformly distributed to account for its plasma or blood concentrations.
Vd = dose administered/plasma concentration
It gives us an idea of how much drug is present in the body and in which compartment it has accumulated.
A drug with a high Vd indicates that most of the drug is in the extravascular compartments.**(lipophilic drugs)...some may concentrate in the liver, bone marrow, etc.
A drug with a high Vd also takes longer to excrete from the body, having a slower clearance value and longer half-life.
This is important for trying to figure out a dosage-schedule for a patient. |
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Term
| A drug has a high Vd. What is the significance of this? |
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Definition
| A high Vd is an indication that the drug has distributed out of the vascular compartment into the surrounding tissues. It also means that the drug will have a longer half-life and will have a slower clearance value. |
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Term
| A drug has a low Vd. What is the significance of this? |
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Definition
| A low Vd is an indication that much of the drug is located within the vascular compartment. Therefore, it will have a higher clearance value as well as a shorter half-life. |
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Term
| Explain how blood-flow is important in anesthesia |
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Definition
Tissues that receive a higher fraction of blood flow (brain, liver) will receive a higher initial concentration of drug from the circulation.
They introduce agents that induce anesthesia very quickly and then a gas is used to maintain unconsciousness.
Over time, tissues like the adipose tissue accumulate the drug due to high storage capacity and plasma concentrations fall.
Now the plasma has very little drug and the drug will be redistributed from the brain/liver to equilibrate with low plasma concentrations. |
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Term
| What is thiopental used for? |
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Definition
Thiopental is a drug that is used to induce anesthesia intravenously.
- Induction/recovery are rapid
- A lower concentration is given to take advantage of redistribution
○ Using the regular concentration would draw out anesthesia/recovery as well as limit redistribution. |
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Term
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Definition
| Refers to the phenomenon where a higher concentration of drug is deposited into the organ/tissues that receive the highest fraction of initial blood flow. After several passes, the drug accumulates in other compartments (like adipose tissue) leading to a lower plasma level. As plasma levels drop, the drug is removed from the brain/liver and the physiological response ends (important in anesthesia). |
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Term
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Definition
| The main purpose of drug metabolism is chemical modification of drugs by enzymes, to make them more polar (less lipid soluble) and therefore readily excretable by the kidneys. |
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Term
| Where are drug metabolizing enzymes found (from highest concentration to lowest) |
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Definition
1) The liver
2) Gastrointestinal wall
3) Lungs
4) Kidneys (excretion)
5) Skin
6) Blood
7) brain |
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Term
| What is needed to happen to drugs before they can be excreted by kidneys? |
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Definition
| They have to be ionized. Uncharged molecules can cross back over the kidney capillaries and be reabsorbed in the tubules whereas charged molecules cannot. |
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Term
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Definition
| Prodrugs are inactive (or partially active) forms of drugs that are not affected by drug metabolism if taken orally. Therefore it can be easily absorbed and reach the site of action where there are enzymes that can covert it into the active-form. (some can be partially active while others r inactive) |
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Term
| What are omeprazole and iansoprazole? |
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Definition
| They are proton-pump inhibitor pro-drugs. |
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Term
| The release of histamine in the stomach causes an increase in acid secretion. Can you take a general antihistamine to treat stomach pH issues. Why or why not? |
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Definition
You cannot take a general antihistamine to block acid secretion in the stomach. You have to take selective H2 blockers.
H1 receptors are the histamine receptors which are involved in bronchial dilation/allergen responses and those are blocked by the general antihistamines. |
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Term
| Are there any drugs that are given alongside L-dopa, or is it enough to be administered alone? |
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Definition
Carbidosa is another drug that is given alongside it.
It limits the metabolism of L-dopa into dopamine outside of the brain. It cannot cross the blood-brain barrier itself, however, so its effects are limited to the periphery. |
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Term
| Describe the two-phase biotransformation. |
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Definition
Phase 1- functionalization reactions:
Oxidation, reduction and hyrdolytic reactions make the drug more polar but not necessarily inactive… exposes vulnerable functional groups.
A small amount of drugs (prodrugs) are activated by this phase.
Phase 2 - conjugation reactions:
Conjugation to polar groups: glucoronidation, sulfation, acetylation most often result in drug inactivation and increased excretion in the kidneys. |
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Term
| True or false: most drug-drug interactions are due to Phase-2 enzymes. |
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Definition
| False. Most of the drug-drug interactions are most often involving enzymes from phase I reactions. |
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Term
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Definition
Microsomal cytochrome P450 monooxygenase family of enzymes.
Transfers electrons from NADPH to an oxygen molecule and thus oxidizes drugs (mostly hydroxylations and dealkylations)
-act on structurally unrelated drugs (widest range of drugs, almost 90%)
-located within the endoplasmic reticulum of a cell
-enzymes most often involved in drug-drug interactions. |
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Term
| Which type of enzyme would we expect to be involved in most drug-drug interactions? |
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Definition
| Cytochrome p450 enzymes or, CYP enzymes. |
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Term
| Which CYP isoforms metabolize the majority of drugs? |
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Definition
CYP1A2
CYP2C9
CYP2C19
CYP2D6
CYP2E1
CYP3A4 (**primary enzyme for metabolism of about half of all drugs and is inhibited or induced by many drugs, leading to drug-drug interactions). |
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Term
| What factors effect drug biotransformation? |
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Definition
Drugs (including herbals) and other substances (food) and stimulate or inhibit the expression of some metabolizing enzymes, specifically the CYP p450 enzymes.
Inducers
inhibitors |
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Term
| Which CYP enzyme is most often involved drug-drug interactions? Why is this? |
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Definition
CYP3A4 is most often involved.
This is because it is the enzyme that metabolizes about half of all drugs. Therefore, if you are taking two drugs that are metabolized by the same enzyme then you will likely see some form of drug-drug interaction. |
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Term
| St. john's wort is an example of what? |
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Definition
| It is an example of an inducer that increases the product of CYP enzymes, resulting in faster elimination of drugs. |
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Term
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Definition
| Inducers are compounds that can cause an increase in genetic expression. |
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Term
| What is the effect of inducers on CYP enzymes and give some examples of inducers |
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Definition
Inducers cause an increase in the production of those enzymes, thereby increasing the biotransformation of suceptible drugs and increasing the rate that they are eliminated.
This can bring the concentration of the drug to below therapeutic levels and leading to treatment failure. |
|
|
Term
What are inhibitors?
Give some examples |
|
Definition
Inhibitors inhibit enzymes. Most importantly for the purpose of this class, they inhibit the CYP enzymes that metabolize most drugs. Inhibiting the activity of CYP enzymes reduces the elimination of substrate drugs. However, it can also inhibit the CYP enzymes that metabolize other molecules like hormones in the body, leading to other side effects.
Grapefruit juice (flavonoids inhibit CYP)
Cimetidine (H2 blocker - stomach acid inhibitor) |
|
|
Term
| Name the most important examples of CYP inhibitors |
|
Definition
Grapefruit juice (flavonoid)
Cimetidine (stomach acid inhibitor) |
|
|
Term
| What is CYP polymorphism? Example? |
|
Definition
It describes how the CYP enzymes could come in different forms across the population.
The most common example of p450 polymorphism is in the expression of CYP2D6. Many lack the expression of this enzyme.
In patients who lack the expression of the CYP2D6 enzyme, codeine is almost completely ineffective as an analgesic as it must be metabolized by CYP2D6 into morphine for analgesic effect. |
|
|
Term
| What is the most common kind of CYP polymorphism and what is the effect of this? |
|
Definition
A lack of expression of CYP2D6 is the most common type of polymorphism.
Patients who lack this enzyme are unable to metabolize codeine into morphine and therefore do not receive its analgesic effect. |
|
|
Term
|
Definition
-conjugation reactions
- A chemical group such as glucornic acid, sulfate, glutathione, amino acids or acetate is added to the drug
-conjugated drug is highly polar and in most cases inactive
-polar drugs are rapidly excreted
-enzymes for phaseII are mostly located in the cytosol. |
|
|
Term
| What are slow acetylators? |
|
Definition
Slow acetylators refers to a group of people who have reduced expression of an acetylating enzyme, NAT (N-acetyl transferase).
There is an NAT1 and NAT2. the mutation occurs in NAT2.
Examples of drugs slowly metabolized due to this:
Caffeine is the most recognizable. |
|
|
Term
|
Definition
A situation in which a substance affects the activity of a drug.
Most often it's an instance of increased effect/toxicity or decreased effect/treatment failure. Very rarely are new effects discovered.
Drug-drug interactions
Drug-food interactions (inhibitor/inducer actions)
Drug-herb interaction |
|
|
Term
| True or false: if an individual is taking two drugs, we can anticipate that there will be some fort of drug-drug interaction |
|
Definition
| False. While this could be true in some instances, the likelihood of having a drug-drug interaction from two drugs is low unless those drugs are metabolized by the same enzyme. |
|
|
Term
| True or false: if an individual is taking 3+ drugs we can anticipate that there will be drug interactions |
|
Definition
| Yes. We can anticipate that an individual taking 3+ drugs will have some form of drug interaction produced. |
|
|
Term
| Where is drug use greatest? |
|
Definition
Amongst:
Elderly
Hospital patients
Nursing home residence* |
|
|
Term
| Pharmacodynamic interaction |
|
Definition
| Two drugs affecting the same system. One drug can effect the effect of the other drug in the body. |
|
|
Term
| Pharmacokinetic interaction |
|
Definition
| One drug effects the absorption, distribution, metabolism and excretion of another drug (ADME) |
|
|
Term
| Calcium supplements reduce the absorption of what? |
|
Definition
| Thyroxine. That is a derivitive of thryoid hormones. |
|
|
Term
| How do drug interactions impact distribution? |
|
Definition
Competition for plasma proteins can impact the distribution of drugs if both drugs bind to plasma proteins.
Example: warfarin and aspirin. |
|
|
Term
| What is the most common reason for drug-drug interactions? |
|
Definition
One drug affecting the metabolism of another drug.
Two drugs metabolized by the same enzyme (example CYP) can compete for the enzyme |
|
|
Term
| How can someone reduce the excretion of penicillin and how does it work? |
|
Definition
By giving someone probenecid.
Probenecid is in competition for the kidney tubule transport system, thereby reducing the excretion of penicillin. |
|
|
Term
| What is the number one drug that interacts with other drugs? |
|
Definition
|
|
Term
| Describe the DDI that occurs between warfarin and NSAIDs that causes direct GI injury |
|
Definition
| NSAIDs inhibit COX enzymes, which are responsible for forming prostaglandins, which increase mucus secretion in the stomach. In inhibiting prostaglandin formation, you also reduce the amount of mucus produced potentially leading to ulceration when the mucus layer is lost. |
|
|
Term
| Describe the NSAIDs and warfarin interaction. |
|
Definition
*an NSAID greatly increases the risk of warfarin toxicity because of the following interactions:
1) P-bound warfarin is displaced, increasing [warfarin] and causing toxicity.
2) NSAIDs suppress platelet function that adds to anticoagulant properties of warfarin
3) Some NSAIDS prevent warfarin metabolism by competition for the metabolizing enzyme.
4) NSAIDs can cause direct gastric injury and warfarin can cause gastric bleeding. |
|
|
Term
| What is the clinical significance of drug-drug interactions? |
|
Definition
-when a patient is taking two or more drugs, DDI resulting from metabolism should be considered
-a single drug metabolized by CYP enzymes, interactions with food items/herbs should be considered
-in cases of drug toxicity or treatment failure, genetic variation of metabolizing enzymes should be considered. |
|
|
Term
| Which drug types should be most concerned about DDI's if you are pairing them with other drugs? |
|
Definition
1) Warfarin
2) NSAIDs
3) Antiplatelets
4) Statins (anticholesterol meds)
5) Thyroxine (thyroid medication)(calcium reduces absorption) |
|
|
Term
|
Definition
An energy dependent, mostly non-specific efflux pump that carries drugs from the interior of the cell to the exterior. It is responsible for many cases of DDI and cases of resistance to anti-cancer drugs.
The same drugs that are handled by the CYP enzymes can be transported by p-glycoprotein.
Located in many sites: *cancer tissue*, colon/small intestine, kidney tubules, brain, liver, placenta |
|
|
Term
| How is P-glycoprotein involved in cancer-drug resistance? |
|
Definition
| There is a higher expression of P-glycoprotein in cancer tissues, therefore the drug is removed from the affected cells very rapidly. |
|
|
Term
| How can they overcome the resistance to cancer drugs caused by the activity of p-glycoprotein? |
|
Definition
| The expression of P-glycoprotein can be induced or inhibited. |
|
|
Term
| What is the role of P-glycoprotein in the brain? |
|
Definition
| It's role is at the blood-brain barrier where it protects the CNS from a variety of structurally diverse compounds through efflux mechanisms. |
|
|
Term
| What do calcium channel blockers do to P-glycoprotein? |
|
Definition
They inhibit the efflux activity of P-glycoprotein.
This may be useful to reverse resistance to certain drugs (cancer treatment, for example) |
|
|
Term
| What is the enterohepatic circulation and what is its significance in drug therapy? |
|
Definition
A compound will be conjugated in the liver (phase II) and excreted into the intestines in bile, deconjugated in the intestine (deconjugase) and reabsorbed into the circulation.
**this phenomenon prolongs the duration of action (half life) of the drug. |
|
|
Term
| What is the therapeutic significance of enterohepatic recycling? |
|
Definition
| 1) Reducing the cholesterol synthesis and plasma levels by interrupting the bile-acid enterohepatic recycling by binding conjugated bile-salts. |
|
|
Term
| What are bile salts conjugated to, other than drugs? |
|
Definition
|
|
Term
| Describe the clinical significance of taking birth control at the same time as taking antibiotics. |
|
Definition
| Estrogen is a molecule that is part of enterohepatic recycling. If antibiotics kill the gut flora responsible for deconjugation, the estrogen that would normally be reabsorbed is actually secreted and plasma estrogen levels can be reduced to below therapeutic levels therefore reducing the effectiveness of the birth control. |
|
|
Term
|
Definition
The volume of blood in which a drug is irreversibly removed per unit time.
Unit: ml/min (/kg) |
|
|
Term
| What are clearance values important for? |
|
Definition
In figuring out what the maintenance dose would be that would keep the drug at a steady state.
Rate of administration (maintenance dose) = rate of elimination |
|
|
Term
| Name three processes in the kidney which determine the amount of drug that enters the urine. |
|
Definition
1) Filtration of the free drugs at the glomerulus
2) Some drugs added to urine through secretion from the tubular capillaries (strong acids/bases)
3) Nonionized/lipid soluble drugs are reabsorbed
Net removal = filtered + secreted - reabsorbed |
|
|
Term
| How do you figure out the net removal of a drug by the kidneys? |
|
Definition
| Net removal = filtered + secreted - reabsorbed |
|
|
Term
| Which order (0, first, second) kinetics are most drugs generally eliminated according to? |
|
Definition
First order.
This means that a constant fraction of drug is eliminated per unit time.
The rate of elimination is proportional to the plasma concentration… this means that as plasma concentrations fall, the rate at which the drug is excreted also falls. |
|
|
Term
| Which order (0, first, second) kinetics are drugs generally eliminated according to given that their enzymes have been saturated? |
|
Definition
Zero order.
Occurs when the metabolic mechanism has been saturated, but those doses are not common therapeutically.
A constant amount of drug is eliminated per unit time, independent of plasma concentration. |
|
|
Term
|
Definition
| The time it takes for the plasma concentration of a drug to be reduced by 50% (applies to drugs that are eliminated by first order kinetics) |
|
|
Term
| How many half lives does it take for a drug to be basically removed from circulation? |
|
Definition
It takes about 5 half-lives for more than 90% of the drug to be effectively removed from circulation.
It also takes about 5 half-lives for a drug to reach steady state in the plasma if it is given in a fixed dose, at fixed intervals. |
|
|
Term
| If a drug is given at fixed intervals and at a fixed dose, how many half-life's does it take for it to reach steady state? |
|
Definition
| Approximately 5 half-lives. |
|
|
Term
|
Definition
| A macromolecule whose biological function changes when a drug binds to it. |
|
|
Term
|
Definition
| A measure of the propensity of a drug to bind to a receptor; the force of attraction between and drug and receptor. |
|
|
Term
| True or false: the binding of a drug to its receptor causes a cascade of reactions intracellularly. The entire process is known as signal transduction. |
|
Definition
|
|
Term
| Where are nicotinic receptors found? |
|
Definition
| Ganglionic sites and in skeletal muscle |
|
|
Term
| True or false: the nicotinic receptor is a g-protein coupled receptor |
|
Definition
| False. The nicotinic receptor is an ion channel. |
|
|
Term
| Describe drug-receptor interaction |
|
Definition
-most cases the binding is transient
-each binding triggers a signal
-two structurally similar drugs will compete for the same receptor due to transient binding
-an equilibrium is reached between a drug and its receptor |
|
|
Term
|
Definition
kd = dissociation constant
K2/K1 = kd (SMALL kd)
K2 = rate constant in reverse direction
K1 = rate constant in forward direction
The lower the Kd, the more affinity the drug has for the receptor. |
|
|
Term
| How do we measure or quantify a drug-reaction interaction |
|
Definition
Dose-response curve.
A log dose-response graph is useful because it transforms a hyperbolic curve into a sigmoid (straightens the line), compresses the dose scale, proportionate doses occur at equal intervals. This makes it easier to analyze mathematically. |
|
|
Term
| Is the dose-response curve more useful then the log dose response curve |
|
Definition
No.
A log dose-response graph is useful because it transforms a hyperbolic curve into a sigmoid (straightens the line), compresses the dose scale, proportionate doses occur at equal intervals. This makes it easier to analyze mathematically. |
|
|
Term
|
Definition
| The dose or concentration of a drug that produces 50% of maximal response |
|
|
Term
|
Definition
| Maximal effect produced by a drug. It is a measure of the efficacy of a drug. |
|
|
Term
| Efficacy (or intrinsic activity) |
|
Definition
| Ability of a bound drug to change the receptor in a way that produces an effect; some drugs possess affinity but not efficacy. |
|
|
Term
|
Definition
| Concentration of a drug that occupies 50% of the total number of receptors at equilibrium. |
|
|
Term
|
Definition
Given by the relative position of the dose-effect curve along the dose axis. **
If it is more left on the x-axis then it is a more potent drug
If it is more right on the x-axis then it is less potent.
Generally compared between two or more drugs with the same mechanism of action
A more potent of two drugs is not clinically superior.
Potency is determined by the affinity plus intrinsic activity of the drug. |
|
|
Term
| If EC50 = Kd then what does this mean in terms of receptors? |
|
Definition
The significance of EC50 (the quantity of drug it takes to produce 50% max response) and Kd (the quantity of drug it takes to fill 50% of total receptors) being equal is that it means that there are no "spare receptors" (Ie intravesicle receptors) as it takes all receptors to elicit a max response.
This is valid when all receptors must be occupied for a full response. |
|
|
Term
| What does it suggest if EC50 < Kd? |
|
Definition
It suggests the existence of spare receptors (intravesicle receptors)
**this is the case with most organs in the body. |
|
|
Term
Which is the case with most organs in the body:
a) EC50 > Kd
b) EC50 < Kd
c) EC50 = Kd |
|
Definition
| EC50 < Kd, meaning that there are spare receptors for most organs of the body. |
|
|
Term
|
Definition
Refers to receptors that are either internalized within vesicles or within tissues but not being used much.
Advantages:
Allows for maximal response without total receptor occupancy -- increase sensitivity of the system
Spare receptors can bind (and internalize) extra ligand, preventing exaggerated responses when too much ligand is present. |
|
|
Term
|
Definition
A drug which binds to the receptor and produces an effect…
As such, it has both affinity and efficacy (intrinsic activity) |
|
|
Term
|
Definition
An type of agonist that has affinity for the receptor but less intrinsic activity.
It has a lower Emax (maximal response) |
|
|
Term
|
Definition
A drug that binds but does not activate the receptor. It thus competes for binding with other ligands.
It has no affinity or intrinsic activity.
Can be competitive (reversible) or non-competitive (irreversible = poisons) |
|
|
Term
| Why are partial agonists useful? |
|
Definition
-produces less than the full effect of the agonist, but still elicits response (excess NE,
-acts as an antagonist in the presence of a full agonist (blocks full effect of agonist)
-therapeutic use of a partial agonist
Ie: buprenorphine, an opioid analgesic |
|
|
Term
|
Definition
An alternative opioid analgesic which is a partial agonist.
-has lower abuse potential, lower level of physical dependence and greater safety in overdose compared to a full agonist such as morphine. |
|
|
Term
| When does a partial agonist act as an antagonist? |
|
Definition
| When in the presence of a full agonist. |
|
|
Term
| What is pindolol used to treat? |
|
Definition
| High blood pressure in patients who have too high of a concentration of NE. This is an example of a partial agonist acting as an antagonist when in the presence of the full agonist as the receptors will still be stimulated, but blood pressure will lower. |
|
|
Term
| What is competitive antagonism? |
|
Definition
| In the presence of a competitive antagonist, a HIGHER DOSE of agonist is required to produce the same effect - but those agonists CAN still produce the same effect given a high enough dose. |
|
|
Term
| How do you treat excessive ACh? |
|
Definition
| You treat it with Atropine, a competitive antagonist for the same receptors as ACh |
|
|
Term
| A competitive agonist will cause a shift in which direction in a dose-response curve? |
|
Definition
| The presence of a competitive antagonist will right-shift the curve (meaning that a higher concentration of the agonist will be required to produce the same effect) |
|
|
Term
| Non-competitive antagonism |
|
Definition
In the presence of a non-competitive antagonist, even a higher dose of agonist cannot produce maximal effect.
An agonist cannot exert the maximal effect in the presence of a non-competitive antagonist and therefore Emax is reduced. |
|
|
Term
|
Definition
When the binding of ligand B has an effect on agonist A who's binding site is nearby. It can have an effect on binding and/or response to agonist A.
Ligand B can potentiate the response for agonist A.
Ligand B can also reduce or completely inhibit the response or binding of agonist A to the receptor.
EXAMPLE: GABA receptors and the difference between its interaction with barbituates and its interactions with benzodiazepam. Benzodiazepam requires the allosteric binding of GABA in order to activate the channel (causing potentiation) whereas barbituates can activate the GABA receptors without the presence of GABA. |
|
|
Term
| What is the clinical relevance of non-competitive and competitive antagonists? |
|
Definition
Competitive antagonists (or enzyme/receptor blockers) are easier to treat. You have to increase the concentration of the agonist at the receptor site while inhibiting the enzymes that break the agonist down.
Non-competitive antagonists (or irreversible antagonists) are much harder to treat. |
|
|
Term
|
Definition
| It means that a response is either there or it is not. |
|
|
Term
| Quantal dose response curve |
|
Definition
Indicates the varying sensitivity of a given population to the doses of a drug for a given effect.
Different doses of a drug are given to a group and a defined response is noted.
Helps you to define the therapeutic index |
|
|
Term
| dose response - frequency distribution and cumulative frequency distribution |
|
Definition
Frequency distribution - shows the number of people responding to that specific dose
Cumulative frequency distribution - each bar shows the number of people responding to that dose and to lower doses. |
|
|
Term
|
Definition
Defined with the help of a quantal dose response curve.
Therapeutic index = toxic dose in 50% of people/effective dose in 50% of people
TI = TD50/ED50 OR LD50/ED50 (LD = lethal dose)
**this formula very important
The higher the ratio (higher TI) the safer the drug. |
|
|
Term
| Which cells are most affected by anti-cancer drugs? |
|
Definition
The rapidly dividing cells of the body:
GI tract epithelium
Germ cells
Hair cells |
|
|
Term
|
Definition
| It is the difference between the minimum effective concentration of a drug for a desired response and an adverse response. (the plasma concentration range that provides efficacy without toxicity) |
|
|
Term
|
Definition
| The activation of multiple enzymes within a cell starting with the activation of a receptor located (most often) at the cells surface. |
|
|
Term
| The serial activation of enzymes within a cell is known as what? |
|
Definition
|
|
Term
| What are common responses in the body to signal transduction? |
|
Definition
-transient increase in Ca levels (muscle contraction)
-activation of enzymes for various biochem reactions
-neurotransmission
-secretion of NT's and hormones (Ca) |
|
|
Term
| What are the fundamental mechanisms of signal transduction? |
|
Definition
1. g-protein coupled receptors
1. Half of known drugs work through GPCR
2. Ion channel receptors
3. Enzymes as receptors
1. Tyrosine or serine/threonine kinase
4. Nuclear receptors
1. Cytosolic receptors |
|
|
Term
| Which secondary messenger is involved in the relaxation of bronchial smooth muscle? This same second messenger is present in the heart - does it have the same reaction? |
|
Definition
cAMP.
In the heart it causes contraction, not relaxation. |
|
|
Term
| Can there be absolute blocks for GPCRs? |
|
Definition
| No. the reason is because receptors often interact downstream and therefore just because you have blocked one receptor does not mean that the response will not occur through some other receptors signal transduction. |
|
|
Term
| What are the major secondary messengers for GPCRs? |
|
Definition
cAMP (activate protein kinase A)
IP3 (increase Ca)
DAG (activate protein kinase C, leading to increase Ca) |
|
|
Term
| What action can activated GPCR's take? |
|
Definition
1) Activate K+ channels directly
2) Activate phospholipase C-b, breaking down PIP2 into IP3 and DAG.
1. IP3 increases intracellular calcium
2. DAG activates PKC, leading to increase in calcium
3) Activate adenylyl cyclase, increasing cAMP and activating protein kinase A. |
|
|
Term
|
Definition
Example: tyrosine kinase receptor = insulin receptor, tyrosine channel receptor = growth factor receptors
They are enzyme-linked receptors that often are involved in phosphorylation of secondary messengers and other enzymes, thereby activating them and beginning signal transduction. |
|
|
Term
|
Definition
An enzyme receptor that consists of a pair of monomers which are separate when inactive.
Agonist binding causes them to form a dimer and this action phosphorylates tyrosines @ the interior of the receptor, activating it.
The active enzyme then goes on to activate a number of other enzymes that interact with the activated receptor. |
|
|
Term
|
Definition
Agonist causes channel to open, allowing specific ions across the membrane.
Eg. Nicotinic acetylcholine receptor - allows for movement of sodium (Na+)(excitatory)
GABA receptors - allow for movement of chloride ions (Cl-)(inhibitory) |
|
|
Term
|
Definition
Found in the cell cytosol, so an agonist must enter the cell to bind to the receptor.
Drug-receptor complex then enters the nucleus and stimulates gene transcription.
e.g. receptors for steroids, retinoids, thyroid hormones
This is the slowest type of receptor response |
|
|
Term
| True or false: agonists tend to sensitize receptors |
|
Definition
False. Constant stimulation by an agonist will desensitize receptors by the following:
--receptor sequestration
--receptor down-regulation
--receptor inactivation
--inactivation of signaling protein
--production of inhibitory protein |
|
|
Term
| True or false: antagonists lead to up-regulation of receptors |
|
Definition
True. Basically the body attempts to insert more receptors in an attempt to achieve the homeostatic response and increase stimulation.
This can be a danger due to the fact that if you were to half the medication abruptly, there would be a "rebound effect" and an overstimulation response. |
|
|
Term
| Why is drug therapy in children difficult? |
|
Definition
-few studies done in children for ethical reasons, meaning that pharmakinetics of most drugs in children is not well defined
-some differences in clearance compared to adults
-hepatic enzyme systems are not fully developed in infants (especially premies)
-**extra caution needed for premature infants** |
|
|
Term
|
Definition
Rarely occurs in newborn infants following IV administration of the antibiotic chloramphenicol.
It causes blue discoloration of the skin/lips and cardiovascular collapse.
Why?
The UDP-glucoronyl transferase enzyme system in infants, especially premies, is immature and is incapable of metabolizing the excessive drug load. |
|
|
Term
| Why does gray baby syndrome occur? |
|
Definition
| IV administration of the antibiotic chloramphenicol can cause gray baby syndrome. This is because the UDP-glucoronyl transferase enzyme (phase II) system in those infants are immature. This is especially common in premies (so this drug is not given to them). |
|
|
Term
|
Definition
An antibiotic that can cause gray-baby syndrome after IV administration.
This is due to the immaturity of the UDP-glucoronyl transerase enzyme system |
|
|
Term
| UDP-glucoronyl transferase enzyme |
|
Definition
A phase II enzyme.
It is involved in gray-baby syndrom where the immaturity of this enzyme leads to the inability to metabolize the antibiotic chloramphenicol, leading to blue discoloration of the lips/skin and cardiovascular collapse. |
|
|
Term
| What are the physiological changes that we see in elderly people that changes treatment parameters? |
|
Definition
-reduced gastric acidity and GI motility
- Decreased absorption of some drugs/nutrients (b12)
-increased body fat
- Increased Vd (especially for lipid soluble drugs)
-reduced GFR (0.5% per year approximately)
- Decreased clearance (water soluble drugs)
-reduced hepatic blood flow
- Decreased clearance of some drugs |
|
|
Term
| What are the phases in drug development? |
|
Definition
Preclinical - see whether or not drug is safe enough for volunteers (animal studies)(1-5yrs)
Clinical (human trials broken down into three phases)(2-10 yrs)
Phase 1 - done in normal volunteers or special populations by clinical pharmacologists. Sussing out safety/biological effects/metabolism/kinetics/drug interactions
Phase 2 - done in selected patients.
Sussing out therapeutic efficacy, dose range, kinetics, metabolism
Phase 3 - large sample of selected patients by clinical investigators
Sussing out safety and efficacy
New Drug Application submission (12 months) to regulatory committee
Marketing + looking for least common side effects
Drug available in generic form |
|
|
Term
| How long does a patent last for a company? |
|
Definition
| 20 years. The other companies can begin making their own versions of the drug. |
|
|
Term
| In what phase of drug development do the majority of rare side-effects become apparent? |
|
Definition
| During phase 4, marketing, reveals the rarest of side effects. |
|
|
Term
| In what phase of drug development do the majority of the most common side effects become apparent? |
|
Definition
During the clinical stage, during phase 2 and 3.
Phase 2 = clinical pharmacologists (small test size)
Phase 3 = practicing physicians giving to patients (much larger sample size) |
|
|
Term
| After which phase in drug development can the drug be submitted for approval by the regulatory body? |
|
Definition
| After the 3rd phase of drug testing (after physicians have been given their "experimental treatment" to patients for long enough to see if any other SEVERE side effects arise) |
|
|
Term
| Who received the nobel prize for the discovery of insulin? |
|
Definition
| Banting and Macleod, then they shared it with Best and Collip |
|
|
Term
| Who received the nobel prize for the discovery of nitric oxide |
|
Definition
| Furchgott, Ignarro and Murad |
|
|
Term
|
Definition
Discovered the angiotensin --> angiotension II conversion in the lung and hypothesized that that could be taken advantage of in the treatment of hypertension if you could block that enzyme and process.
Also found that aspirin inhibited the production of certain prostaglandins that cause inflammation (involved in discovering ASPIRIN!) |
|
|
Term
| What are the divisions of the nervous system? ALL of them. |
|
Definition
The nervous system is divided up into two main branches:
The central nervous system, which consists of the brain and spinal cord
The peripheral nervous system, which consists of the somatic nervous system (sensory and motor neurons) and the autonomic nervous system, which can be further broken down into its own classes of sympathetic nervous system, parasympathetic nervous system and enteric nervous system. |
|
|
Term
| Basic details about the autonomic nervous system |
|
Definition
-involuntary branch of the peripheral nervous system
-innervates all organs that contains smooth muscle, skeletal muscle, visceral organs, blood vessels, exocrine glands. |
|
|
Term
|
Definition
| Neurons that are located within the CNS (brain/spinal cord) |
|
|
Term
|
Definition
Relay between pre and post-ganglionic nerves.
They are aggregation of nerve cell bodies located in the PNS |
|
|
Term
|
Definition
| Neurons that terminate on the effector organs/tissues |
|
|
Term
| Describe, very basically, the autonomic structure anatomy (ganglion etc) |
|
Definition
Signal originates from brain or spinal cord.
Travels down to ganglia site, where it releases ganglionic NT, leading to AP in the ganglia.
The ganglia AP travels down and it releases the neuroeffector NT that innervates the effector organ/tissue. |
|
|
Term
| True or false: the neurotransmitters are the same for the pre- and post- ganglia within the sympathetic nervous system |
|
Definition
False.
In the sympathetic nervous system, the NT that innervate the ganglia is different from that which innervates the effector organ. |
|
|
Term
| True or false: the neurotransmitters are the same for the pre- and post- ganglia within the parasympathetic nervous system |
|
Definition
|
|
Term
| Where does innervation originate from in the parasymapthetic nervous system? |
|
Definition
| The brain and the sacrum. "craniosacral" innervation. |
|
|
Term
| What does craniosacral innervation refer to? |
|
Definition
| It refers to the parasympathetic nervous system who's innervation originates from the craniosacral region (from the brain and the sacrum). |
|
|
Term
The parasympathetic nervous system has:
a) Short pre-ganglionic neurons, short post ganglionic neurons
b) Long pre-ganglionic neurons, short post-ganglionic neurons
c) Short pre-ganglionic neurons, long post-ganglionic neurons
d) Long pre-ganglionic neurons, long post-ganglionic neurons |
|
Definition
| B - the parasympathetic nervous system has long pre-ganglionic neurons and short post-ganglionic neurons. |
|
|
Term
| Which are the different cranial nerves that have motor function? Which ANS system does it belong to? |
|
Definition
They belong to the parasympathetic nervous system (craniosacral system)
III-occulomotor
VII-facial
IX-glossopharyngeal
X-vagus |
|
|
Term
| Where are the ganglia found in the sympathetic nervous system? |
|
Definition
| They are found as part of a paravertebral ganglionic chain (found on either side of the spinal cord.) |
|
|
Term
| Where does the innervation for the sympathetic nervous system originate from? |
|
Definition
| It originates from the thoracic and lumbar section of the spinal cord. |
|
|
Term
| Thoracolumbar origin describes which nervous system? |
|
Definition
| The sympathetic nervous system is innervated from the thorax and the lumbar region. |
|
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Term
The sympathetic nervous system has:
a. Short pre-ganglionic neurons, short post ganglionic neurons
b. Long pre-ganglionic neurons, short post-ganglionic neurons
c. Short pre-ganglionic neurons, long post-ganglionic neurons
d. Long pre-ganglionic neurons, long post-ganglionic neurons |
|
Definition
| C - short preganglionic neurons and long post ganglionic neurons. |
|
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Term
| Which are the pre-vertebral ganglia, which ANS system are they a part of and what organs do they innervate? |
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Definition
|
|
Term
| Splanchnic nerves innervates which ganglion/organs? |
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Definition
| The celiac ganglion is innervated by the splanchnic nerves. It then goes on to innervate the stomach, liver, spleen, and small intestine |
|
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Term
| True or false: There are ganglion within the adrenal gland. Therefore, the ganglionic chain leads to ganglia within the adrenal gland. |
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Definition
True! The chromaffin cells = the ganglia of the adrenal gland = NE and E producers
It is an exception for the sympathetic nervous system |
|
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Term
| True or false: blood vessels are innervated by both parasympathetic and sympathetic nervous systems. |
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Definition
FALSE.
Blood vessels are generally only innervated by the sympathetic nervous system.
Since sympathetic nervous system causes vasoconstriction, the parasymp- would cause vasodilation. This does not occur as it could cause a dramatic drop in blood pressure (which just "lessening" the vasoconstriction will do anyways, in a safer fashion). HOWEVER there are PS receptors there. |
|
|
Term
| Which organ is innervated by only the sympathetic nervous system? |
|
Definition
Blood vessels
Spleen
Adrenal gland |
|
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Term
|
Definition
Thoracolumbar origin
Pre-ganglionic fibers are short, post ganglionic fibers are long.
Ganglia: 2 paravertebral chains along the spinal cord
Action: diffuse on effector organs (fight/flight/fright) |
|
|
Term
|
Definition
Cranio-sacral origin
Preganglionic fibers are long, post ganglionic fibers are short
Action: localized to specific effector organs (rest and digest) |
|
|
Term
| Which neurotransmitters are involved in the sympathetic outflow |
|
Definition
Preganglionic neurons release ACh
Post ganglionic neurons release NE onto an adrenergic receptor |
|
|
Term
| Which neurotransmitters are involved in the parasympathetic outflow? |
|
Definition
Preganglionic fibers release ACh
Post ganglionic fibers also release ACh |
|
|
Term
| True or false: NE action of termination is by reduction by NEreductase @ the level of the synaptic cleft |
|
Definition
False.
The ways that the action of NE is terminated is by a reuptake mechanism in the presynaptic membrane and an enzyme in the post synaptic membrane (catechol-O-methyl-transferase) |
|
|
Term
| True or false: Acetylcholine is broken down by acetylcholinesterase at the level of the synaptic cleft. |
|
Definition
True.
Acetylcholine esterase is part of the post-synaptic membrane. It breaks down acetylcholine into choline (which is taken back up into the pre-synaptic membrane) and acetate (diffuse/reused) |
|
|
Term
| What is the receptor type that is activated @ the level of the ganglia in both the sympathetic/parasympathetic nervous system |
|
Definition
|
|
Term
| What type of receptor is found at the effector organ in the parasympathetic nervous system |
|
Definition
|
|
Term
| What type of receptor is at the effector organ for the parasympathetic nervous system |
|
Definition
|
|
Term
| How do nerve cells communicate? |
|
Definition
| Through neurotransmitters |
|
|
Term
| What is the sequence in neurotransmission? |
|
Definition
AP arrives at nerve ending
AP triggers Ca+ influx
CA influx causes fusion of synaptic vesicles w/ pre-synaptic membrane and exocytosis of NT
NT diffuses across the cleft & acts on receptors on post-synaptic membrane |
|
|
Term
| What are the primary NT's of the ANS? |
|
Definition
| Acetylcholine and norepinephrine. |
|
|
Term
| Summary of sympathetic ANS neurotransmission |
|
Definition
-Ach is released @ preganglionic nerve terminal, acts on nicotinic cholinergic receptors @ the level of the ganglia, activating post-ganglionic neurons.
-Post-ganglionic neurons release NE @ post ganglionic nerve terminal
-NE acts on adrenergic (alpha or beta, dopamine or muscarinic) receptors in effector organs and tissues. |
|
|
Term
| Summary of parasympathetic ANS neurotransmission. |
|
Definition
-Ach is released @ parasympathetic ganglia, acting on ganglionic nicotinic receptors, activating the post-ganglionic neurons.
-the post ganglionic neurons also release ACh onto muscarinic receptors at the effector organs. |
|
|
Term
| True or false: the sympathetic nervous system can activate either alpha, beta, dopaminergic or muscarinic receptors @ the level of the effector organ |
|
Definition
|
|
Term
| True or false: the parasympathetic nervous system can activate either alpha, beta, dopaminergic or muscarinic receptors @ the level of the effector organ. |
|
Definition
False.
The parasympathetic only innervates muscarinic receptors at the level of the effector organ. |
|
|
Term
| For the sympathetic nervous system, which receptors does it act on at the level of the effector organ |
|
Definition
| Either alpha, beta, dopaminergic or muscarinic receptors |
|
|
Term
| For the parasympathetic nervous system, which receptors does it activate at the level of the effector organ? |
|
Definition
| Only muscarinic receptors. |
|
|
Term
| Where does the sympathetic nervous system act on muscarinic receptors? |
|
Definition
|
|
Term
| True or false: sweat glands are innervated ONLY by the sympathetic nervous system |
|
Definition
|
|
Term
| The sweat glands are innervated by which NS? |
|
Definition
| The sympathetic nervous system |
|
|
Term
| For renal vascular smooth muscle, which NS innervates it and what is its NT? |
|
Definition
The sympathetic nervous system innervates smooth muscle
Dopamine is the NT |
|
|
Term
| What is the effect of the parasympathetic nervous system? Divide it into head region, chest region, GI tract and lower abdomen. |
|
Definition
Head:
Eyes = miosis (constriction of pupils)
Accommodation (changes lens shape to see better close up)
Lacrimation (increased tear production)
Nose = mucus secretion
Mouth = salivation
Chest:
Bronchoconstriction
Mucus secretion (lungs)
Decreased heart rate
Decreased atrioventricular conduction.
GI tract:
Increased HCl secretion
Increased motility
Lower abdomen:
Micturition - increased urination
Erection |
|
|
Term
| What is the effect of the sympathetic nervous system? Divide it into head, chest, GI tract and lower abdomen. |
|
Definition
Head:
Pupil dilation (mydriasis)
Vasoconstriction (eyes, nose, mouth)(reduced mucus secretion)
Salivation
Sweating
Chest:
Bronchodilation
Tachycardia
Increased AV conduction
Increased contractility
Gi tract:
Glycogenolysis
Decreased motility
Renin secretion
Lower abdomen:
Urinary retention
Uterine relaxation
Ejaculation |
|
|
Term
|
Definition
| Drugs that mimic the effect of transmitter substances of SNS/PSNS |
|
|
Term
|
Definition
| Having to do with adrenaline/epinephrine/choline |
|
|
Term
|
Definition
| Drugs which inhibit the postganglionic functioning of symapthetic/parasympathetic |
|
|
Term
|
Definition
| Innervations by receptors. |
|
|
Term
| Describe acetylcholine synthesis |
|
Definition
Choline and sodium are brought into the cell by a Na/choline cotransporter.
Choline acetyltransferase catalyzes choline+acetyl CoA into acetylcholine |
|
|
Term
| Describe acetylcholine release |
|
Definition
ACh is released by exocytosis at the synapse.
Botulinum toxin blocks this. |
|
|
Term
| Describe how acetylcholine is stored |
|
Definition
| ACh is packaged into synaptic vesicles by vesical associated transporter |
|
|
Term
| What is the rate limiting step in acetylcholine synthesis? |
|
Definition
| The transporting of choline into the synaptic terminal. |
|
|
Term
| What is the blocker for the rate limiting step in acetylcholine synthesis? |
|
Definition
Hemicholinium
It blocks the choline/sodium cotransporter. |
|
|
Term
| What blocks the storage of acetylcholine? |
|
Definition
| Vesamicol blocks the vesical associated transporter that is responsible for the storage or ACh |
|
|
Term
| What toxin blocks the release of ACh |
|
Definition
|
|
Term
| What does botulinum toxin do? |
|
Definition
| It blocks the release of ACh and causes rigid skeletal muscle paralysis. |
|
|
Term
| Where is acetylcholine esterase found? |
|
Definition
|
|
Term
|
Definition
A substance that blocks the choline/sodium cotransporter involved in acetylcholine synthesis.
This transporter is the rate limiting step of ACh synthesis. |
|
|
Term
|
Definition
| Blocks the storage of ACh in vesicles |
|
|
Term
| where is butyrylcholesterase found? |
|
Definition
| In the plasma and liver. It is a non-specific esterase that also breaks down ACh |
|
|
Term
| True or false: we have clinically used uptake blockers for ACh |
|
Definition
| FALSE. ACh is broken down by an enzyme, acetylcholine esterase (or butyrylcholesterase) and choline is taken back up into the cell to be turned back into ACh. |
|
|
Term
| Why can you not administer acetylcholine parentally? |
|
Definition
Because Ach is hydrolyzed nearly immediately by the enzyme butyrylcholesterase which is found in the plasma and liver.
We do use structurally related molecules that are broken down more slowly |
|
|
Term
| What enzyme breaks down ACh |
|
Definition
| ACh is broken down by acetylcholinesterase and butyrylcholesterase. AchE is found in the post-synaptic membrane and effector organs, whereas butylrylcholesterase is found in the plasma and liver. |
|
|
Term
| How quickly does hydrolysis of ACh occur? |
|
Definition
| Approximately 10000 ACh molecules/second by a single enzyme molecule. |
|
|
Term
| How does acetylcholine act in regulating itself? |
|
Definition
| There are acetylcholine autoreceptors located on the presynaptic membrane. When acetylcholine binds to it, it regulates the release of acetylcholine. |
|
|
Term
|
Definition
They are receptors that, when bound to their ligand, limit the release of that ligand.
For example, there is an ACh autoreceptor that limits the release of ACh. |
|
|
Term
| True or false: there are no drugs available to act on pre-junctional autoreceptors for the PSNS, but there are for SNS. |
|
Definition
True.
SNS has alpha-2 agonists which reduce NE release and reduce sympathetic activity. |
|
|
Term
| Botulinum can be used to treat what ailments |
|
Definition
1) Strabismus (unaligned lines of vision between a pair of eyes)
2) Blepharospasm (contracted eyelid)
3) Hemifacial spasms
4) Cosmetic use to remove wrinkles
5) Marginally effective for prophylaxis against chronic migraine headaches (not approved for treatment of episodic migraine headaches). |
|
|
Term
| What are the different important cholinoreceptors and where are they predominantly found? |
|
Definition
Nicotinic receptors
N_N=ganglia, CNS, adrenal medulla
N_M=muscles
Muscarinic receptors
M1 = brain
M2 = heart
M3 = exocrine / vascular endothelial cells
M4 = everywhere
M5 = everywhere |
|
|
Term
| Muscarinic receptors are what type of receptor |
|
Definition
| g-protein coupled receptors |
|
|
Term
| Nicotinic receptors are what type of receptor |
|
Definition
|
|
Term
| Describe the structure of the nicotinic receptor* |
|
Definition
Polypeptide PENTAMER composed of subunits 2 alpha, beta, delta, epsilon
**there are different subunit compositions at autonomic ganglia and in the brain |
|
|
Term
| What is a nicotinic receptor? |
|
Definition
It is an acetylcholine gated sodium channel.
Polypeptide pentamer composed to 2 alpha subunits, beta subunit, delta subunit and epsilon sub unit. |
|
|
Term
| What does activation of a nicotinic receptor do? |
|
Definition
| It causes sodium influx, membrane depolarization, Ca release from the SR and muscle contraction. |
|
|
Term
| What are the major drug classes for cholinergic drugs? |
|
Definition
Muscarinic (M) receptor agonists
Cholinesterase inhibitors
Muscarinic (M) receptor antagonists
Nicotinic (N) receptor agonists
Ganglionic (nicotinic) antagonists |
|
|
Term
| Parasympathomimetic drugs |
|
Definition
Muscarinic receptor agonists:
Cholin esters: (structurally similar to ACh) selective for muscarinic receptors*
Acetylcholine
Bethanechol (added methyl and amine group)
Carbachol (treatment for GI tract/nervous system conditions) (added amine group)
Methacholine (added methyl group)
Plant alkaloids:
Muscarine
Pilcarpine (commonly used in eye conditions) |
|
|
Term
| What is the differences in structure between the different cholin ester drugs |
|
Definition
They are derivatives of acetylcholine that selectively activate muscarinic receptors.
Bathanechol* -- has added methyl (ch3) and amine (nh2) group instead of the terminal methyl group
Carbachol (added amine group instead of terminal methyl group)(carbamic acid ester deriv)
Methacholine (added methyl group) (carbamic acid ester deriv) |
|
|
Term
| What functional groups are added to acetylcholine to reduce the rapidity of their breakdown by AChE and butarylcholesterase |
|
Definition
| Methyl and terminal amine groups are added. |
|
|
Term
|
Definition
| A muscarinic (parasympatheticomimetic) agonist which is used in the treatment of glaucoma |
|
|
Term
| What will parasympatheticomimetic agents do to the heart? |
|
Definition
Bradycardia
Decreased AV conductivity
**DOES NOT EFFECT VENTRICULAR CONTRACTION (IE the strength of contraction)
Ventricles DO NOT have sympathetic innervation. |
|
|
Term
| What will parasympatheticomimetic agents do to the GI tract |
|
Definition
|
|
Term
| What will parasympatheticomimetic agents do to the urinary bladder |
|
Definition
| Increase contraction of the bladder causing increased urination |
|
|
Term
| If an individual is having problems with passing food or urine, what would you treat them with? |
|
Definition
| A parasympatheticomimetic agent |
|
|
Term
| What will parasympatheticomimetic agents do to the GI tract, urinary bladder and eye |
|
Definition
When applied topically,
They increase GI motility and urinary bladder contractility |
|
|
Term
| If you have a disease of the CNS that requires treatment with a parasympatheticomimetic, which would you choose to treat them with? |
|
Definition
| Carbachol -- activates nicotinic receptors |
|
|
Term
| What are the therapeutic uses of parasymatheticomimetics or cholinomimetics |
|
Definition
-reduce ocular pressure in glaucoma
-increase motility of GI and increase urinary tract motility
-to diagnose Asthma by using Methacholine |
|
|
Term
|
Definition
| A compound used in the diagnoses of asthma. It innervates muscarinic receptors found on bronchial smooth muscle. When activated, they cause vasoconstriction. |
|
|
Term
|
Definition
| Parasymatheticomimetic that is used to treat GI disorders and urinary bladder disorders (where urinary is retained) |
|
|
Term
|
Definition
A parasympatheticomimetic drug that is used to topically treat glaucoma (eyedrops) and xerostomia (dry mouth). However, it can cause excessive sweating.
Bethanechol is an alternative that does not |
|
|
Term
| Muscarinic receptor agonists therapeutic uses |
|
Definition
1) Xerostomia (dry mouth) - salivary and lacrimal secretions are reduced. Treated with PILOCARPINE (but causes sweating) or BETHANECHOL (which does not)
2) Glaucoma (increased intraocular pressure) - |
|
|
Term
|
Definition
| An M3 agonist, similar to pilocarpine, but it has a longer duration of action and fewer side effects. |
|
|
Term
| in which type of glaucoma is pilocarpine the best treatment? |
|
Definition
| Pilocarpine reduces intraocular pressure in narrow angle glaucoma to cause pupillary constriction (miosis) and facilitate drainage of aqueous humor. |
|
|
Term
| What can overdoses of parasympathetomimetic drugs be treated with? |
|
Definition
| Atropine (a muscarinic receptor antagonist) |
|
|
Term
| What is the first line of treatment in glaucoma? |
|
Definition
| Pilocarpine eye drops, which are parasymapthetomimetic drugs which are muscarinic agonists. |
|
|
Term
| Cholinesterase inhibitors |
|
Definition
Used to increase the duration of action of the released ACh @ the synapse and amplifies the effects of ACh at all sites.
These are also called indirectly acting parasympathetomimetics
**cholinesterase inhibitors need to have a limited duration, otherwise the effects will quickly become toxic |
|
|
Term
|
Definition
Located in plasma/liver
Metabolizes certain drugs...some local anesthetics (dental procedures), succinylcholine (muscle relaxant) |
|
|
Term
| True or false: most acetylcholine esterase inhibitors can discriminate between AChE and BuChE |
|
Definition
| False. Most enzyme inhibitors cannot discriminate between the two. |
|
|
Term
| What are the active sites of cholinesterase? |
|
Definition
The choline subsite (chol)
Catalytic subsite (cat)
The acyl subsite (ac)
The acetate group of ACh forms a covalent bond with the Cat subtype and choline and acetate are released . |
|
|
Term
| What is used in the treatment of myasthenia gravis? |
|
Definition
You treat this by using a cholinesterase inhibitor.
Carbamates are used, which bind to the active site in a cholinesterase enzyme and form a carbamoylated enzyme. Carbamoylated enzymes are slowly hydrolyzed by cholinesterase.
(Neostigmine, physostigmine and pyridostigmine) |
|
|
Term
| Describe the metabolism of ACh? |
|
Definition
Broken down by acetylcholine esterase
The enzyme has three different active sites - chol ,cat and ac
The enzyme will attack on the acetate (acetylcholine) once it attaches to the cat site, converting it to an acetylated enzyme, removing the choline part from ACh.
Once it has separated, the enzyme releases choline and acetate molecules. |
|
|
Term
| What are the methods of cholinesterase inhibition? |
|
Definition
1) Using carbamates to make a carbamoylated enzyme, which hydrolyzes ACh much more slowly
2) Using organophosphates to form a strong covalent bond with the catalytic site on AChE. It is very slowly hydrolyzed by the enzyme. **phosphorylated enzyme releases hydrofluoric acid however. |
|
|
Term
| Describe the action of organophosphates. |
|
Definition
| Organophosphates are a type of AChE inhibitor, which covalently bind to the catalytic site on the AChE molecule, rendering those enzymes incapable of completing their job and making it so the body has to produce more before it can hydrolyze ACh again. |
|
|
Term
| Rivastigmine and galantamine are used in the treatment of what? |
|
Definition
| Alzheimers disease. They are reversible acetylcholine esterase inhibitors. |
|
|
Term
| Neostigmine, physostigmine and pyridostigmine are used in the treatment of what? |
|
Definition
Myasthenia gravis
Pyridostigmine - duration of action 3-6H
Neostigmine (shorter acting) |
|
|
Term
|
Definition
| DRUG used for the diagnosis of myasthenia gravis {autoimmune condition where there is auto-antibodies against the nicotinic receptors, so acetylcholine cannot stimulate nicotinic receptors at neuromuscular junctions) |
|
|
Term
|
Definition
| A cholinesterase inhibitor that is used in the treatment of alzheimers disease |
|
|
Term
|
Definition
A type of cholinesterase inhibitor that is used in the treatment of alzheimers.
Also: tacrine, rivastigmine, galatamine are used in the same way. |
|
|
Term
| Neostigmine, physostigmine |
|
Definition
| Carbamic acid ester derivatives (carbamate inhibitors) which are reversible AChE inhibitors. They bind to AChE and are hydrolyzed at a relatively slow rate. A carbamylated enzyme takes 3-4 hours to decarbamylate |
|
|
Term
| What are the main conditions in which cholinesterase inhibitors are used therapeutically? |
|
Definition
| Myasthenia gravis(treatment+diagnosis), Alzheimer's disease, glaucoma, |
|
|
Term
|
Definition
| A reversible cholinesterase inhibitor which has rapid renal clearance and a brief duration of action (around 10 min) so it is used in the diagnosis of myasthenia gravis. |
|
|
Term
|
Definition
| Reversibly binding cholinesterase inhibitors used in the treatment of alzheimers, which have higher affinities are partition into lipids and longer duration of action when compared to edrophonium, which is used in the diagnosis of myasthenia gravis, so they can cross the blood-brain barrier. |
|
|
Term
| True or false: irreversible cholinesterase inhibitors are also known as indirect sympathetomimetics |
|
Definition
| False: they are also known as indirect parasympathetomimetics |
|
|
Term
| What are the types of irreversible ChE inhibitors |
|
Definition
Organophosphorous compounds
Toxic nerve gas
Insecticides
Therapeutic agents |
|
|
Term
| What kind of symptoms would we see in a patient affected by irreversible ChE inhibitors? |
|
Definition
DUE TO EXCESSIVE STIMULATION OF MUSCARINIC CHOLINERGIC RECEPTORS
Eyes: miosis, accommodation respnose, increased lacrimations
Mouth: increased saliva
Bronchial constriction
Bradycardia / loss of contraction force
Increased GI motility (diarrhea)
Increased urinary tract motility
Skeletal weakness/paralysis (depressed respiration) |
|
|
Term
| How do irreversible ChE inhibitors work? |
|
Definition
They phosphorylate the serine in the active site of ChE - the phosphorylated enzyme is ext. stable
-dephosphorylation can take hours, if at all, and in instances where it is not dephosphorylated new enzyme must be created to take its place
**many organophosphates ChE inhibitors irreversibly phosphorylate and inactivate OTHER serine hydrolases, including trypsin and chymotrypsin. |
|
|
Term
| Organophosphorus ChE inhibitors |
|
Definition
| Irreversibly binding inhibitors that also inactivate other serine-hydrolases including trypsin and chymotrypsin. |
|
|
Term
| What are the main principles in treating poisoning by organophosphorous compounds or nerve gases? What are the actions of oximes? |
|
Definition
As the poisoning comes from excessive stimulation of muscarinic receptors, repeated administration of the muscarinic receptor antagonist - ATROPINE - can treat the symptoms of muscarinic overstimulation until the poison is removed.
Respiratory support is also required
Neuromuscular paralysis is treated w/ attempts to reactivate the inhibited enzyme with oximes |
|
|
Term
|
Definition
Such as pralidoxime or obidoxime or HI-6
They are nucleophilic and are used to reactivate enzymes (choline esterases) that have been irreversibly bound by insecticides or toxic nerve gasses.
They dephosphorylate the inactivated enzyme, reactivating it.
*oximes must be administered before the phosphorylated enzyme undergoes aging.
Aging takes place when an alkoxy or alkyl group from the phosphorylated enzyme is removed. |
|
|
Term
|
Definition
Reversible acetylcholine esterase inhibitor.
Used as a prophylactic against threats of nerve gas in combat.
30mg every 8 hr has been tried |
|
|
Term
| True or false: anti-cholinesterase agents will reverse the antagonism created by competitive NM blockers. |
|
Definition
|
|
Term
|
Definition
| Competitive neuromuscular blocker that causes paralysis |
|
|
Term
| Duration of action for pyridostigmine |
|
Definition
3-6 hours.
ChE inhibitor. Used to treat myasthenia gravis. |
|
|
Term
|
Definition
| Longer acting AchE inhibitor tht is used in the treatment of myasthenia gravis. |
|
|
Term
| What effect do ChE inhibitors have on heart rate, cardiac output and ventricular contraction |
|
Definition
They are indirect parasymapthetomimetics.
Therefore, bradycardia, decreased cardiac output. No influence on ventricular contraction as the ventricles do not have parasymp. Innervation. |
|
|
Term
| What is the effect of ChE on blood pressure |
|
Definition
Moderate doses of chE inhibitors have little effect on blood pressure (vessels have innervation, mostly, from sym. System).
High doses of ChE inhibitors decreases blood pressure. |
|
|
Term
| What's the difference in the way that acetylcholine acts on endothelial cells and smooth muscle cells? |
|
Definition
Endothelial cell = smooth muscle contraction:
ACh activations muscarinic (3) receptor
Activates PLC --> IP3 / DAG --> Ca --> eNOS --> L-Argenine + NO and NO goes to the smooth muscle cell and stimulates an increase in cGMP levels, leading to relaxation.
Smooth muscle cells = contraction
ACh activates muscarinic (1 or 3) receptor
Activates PLC --> IP3 / DAG --> ca --> contraction |
|
|
Term
| Effects of muscarinic receptor antagonists |
|
Definition
(sympathetomimetics…)
Eye: mydriasis (dilation) and paralysis of accommodation reflex
Relaxation of broncial, GI tract, and urinary bladder smooth muscle
Inhibition of exocrine gland/mucus/lacrimal secretion
In moderate to high doses: increase heart rate (blocks effects of Ach on the heart) |
|
|
Term
| What is the most commonly used muscarinic blocker? |
|
Definition
Atropine.
It is used in the treatment of AChE poisoning. |
|
|
Term
|
Definition
Parasympathetic antagonists, muscarinic receptor antagonists.
Scopolamine - compound able to cross the blood-brain barrier and innervate muscarinic (1) receptors in the vestibular apparatus, thereby lessening motion sickness.
When applied directly to the eye they bind to the pigments in the iris, which slowly releases the drug over time. |
|
|
Term
| Therapeutic uses for muscarinic receptor antagonists |
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Definition
Motion sickness (scopolamine) - blocks M1 receptors of the vestibular aparatus in the brain.
Used in exmination of pupils - mydriases (dilation)
Used to reduce excessive motility of GI (IBS), decreases acid secretion
To treat urinary incontinence
Treat chronic obstructive pulmonary disease (COPD)
To treat parkinsons disease (bentropine adjunct with L-dopa) (treatment of antipsychotic side-effects)
Example: atropine |
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Term
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Definition
| Often used alongside atropine as a pre-anesthetic agent. @ low dosses supresses lacrimal/mucus/salivary and bronchial secretions and also can increase the heart rate (whereas most anesthetics supress it) but keep it lower than atropine would alone. |
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Term
| What's the difference in structure between atropine and scopolamine? |
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Definition
Atropine = ester of tropic acid and a tertiary amine
Scopolamine = addition of epoxide group which enables it to enter the brain more readily than atropine
Both are well absorbed by the gut. |
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Term
| When should you never use atropine or scopolamine? |
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Definition
| In the treatment of glaucoma patients. You would ruin their eyes. |
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Term
| True or false: low doses of atropine are more sedative than low doses of scopolamine |
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Definition
| False. Low doses of scopolamine are more sedative. |
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Term
| How do you treat atropine toxicity? |
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Definition
| Repeated doses of physostigmine (ChE inhibitor) , diazepam (anesthetic) for sedation and control of convulsions. |
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Term
| What makes scopolamine better for treating motion sickness and CNS illnesses? |
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Definition
It is able to cross the blood bran battier because of an epoxide group. As such, it's pKa is around 7.53, so a greater fraction of it is found in the unionized form @ physiological pH than atropine.
*this is why you can use a scopolamine transdermal patch for behind the ear to treat motion sickness (lasting up to 3 days) |
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Term
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Definition
| Synthetic muscarinic receptor antagonist. Relaxes intestinal smooth muscle (IBS) and serves as an antispasmodic agent. |
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Term
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Definition
Muscarinic receptor antagonist that is selective for M1 receptors.
-reduces gastric acid secretion in patients with peptic ulcers by blocking M1 receptors on paracrine cells and inhibiting the release of histimine.
-available in Ca but not US |
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Term
| Uroselective muscarinic blockers are selective for which muscarinic receptor? |
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Definition
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Term
| What are the primary uroselective muscarinic blockers? |
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Definition
| Oxybutynin, tolterodine, darifenacin, solifenacin, trospium |
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Term
| What are the major symptoms of overreactive bladder |
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Definition
Daytime urination frequency
Nocturia (frequent night urination)
Urgency
Incontinence |
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Term
| Which muscarinic receptor antagonists are used in chronic obstructive lung diseases and why are they advantageous |
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Definition
Ipratropium and Tiotropium (Quat amine derivitives of atropine).
Advantageous because it isnt absorbed into the systemic circulation across the pulmonary mucosa.
ALSO does not impair the ciliary clearance of secretions from the airways.* |
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Term
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Definition
| Muscarinic receptor antagonist that is used topically in the eye as a mydriatic (dilator) agent to facilitate the examination of the peripheral retina. Has a short duration of action and so is used for shrt term mydriasis. |
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Term
| Trihexphenidyl and benztropine |
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Definition
| Muscarinic receptor antagonists that are used in the treatment of parkinsons disease. |
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Term
| What compounds have prominent antimuscarinic side effects |
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Definition
Antihistamines
Tricyclic antidepressents
Antipsychotics |
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Term
| What are the side effects of muscarinic receptor antagonists |
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Definition
Eye = excessive dilation
Salivary glands = decreased secretion
Lungs = vasodilation
Heart = tachycardia
GI tract = decreased motility, distention of abdominal wall/constipation
Urinary tract = decreased motility
Sweat glands = decreased secretion of sweat |
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Term
| In which situations can you not treat with muscarinic receptor antagonists given that doin so will actually exacerbate the situation |
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Definition
Atony of the bowel and prostatic hypertrophy
Narrow angle glaucoma |
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Term
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Definition
Hexamethonium
Trimethaphan
Mecamylamine
Used durin hypertensive crisis |
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Term
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Definition
Has effects only in PNS
Selective blocks nicotinic receptors @ autonomic ganglia but NOT at the NM junction. |
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Term
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Definition
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Term
| What is generally used instead of ganglionic blockers in hypertensive emergencies these days? |
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Definition
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Term
| Nicotinic receptor agonists |
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Definition
Carbachol - has both nicotinic / muscarinic receptor agonist activity
Nicotine - activates at NM Junction
Also acts at parasympathetic and sympathetic ganglia
Its effects on the vascular system are primary sympathetic
On the GI tract it's parasympathetic |
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Term
| What does nicotine do to blood pressure and heart rate |
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Definition
| Nicotine is a nicotinic receptor agonist that increases blood pressure and heart rate. |
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Term
| When would ganglionic blockers be used |
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Definition
| During hypertensive crisis |
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Term
| What are the kinds of NM blocking agents? |
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Definition
Competitive and depolarizing agents.
Competitive:
Antagonizing actions of ACh @ nicotinic receptors. Structure is different to that of ACh however - much more bulky and rigid.
e.g. CURARE causes flacid paralysis due to continual depolarization
Depolarizing: occupies and activates the nicotinic receptor for prolonged period of time, preventing repolarization, known as a "depolarizing block". Structure is similar to that of acetylcholine.
e.g. succinylcholine |
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Term
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Definition
A depolarizing neuromuscular blocker. The only one of its kind!
It binds to and activates nicotinic receptors.
Is not metabolized by AChE but IS metabolized by butyrylcholinesterase.
*it causes persistent receptor stimulation and FLACID paralysis, but it has a short duration of action.
Clinical problem: certain patients exhibit a varient of this enzyme which lead to prolonged and potentially dangerous durations of neuromuscular block (respiratory block included). Side effect can be malignant hyperthermia
Therapeutic use: in surgical anesthesia to obtain brief relaxation of skeletal muscle, particularly in the abdominal wall. Orthopedic procedures. To facilitate tracheal incubation.
Licensed anesthesiologists only can utilize it. Facilities for respiratory cardiovascular arrest should be available. |
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Term
| True or false: The hunters who killed their prey using curare had to wait several days bfore they could eat their pray to allow for the curare to dissipate |
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Definition
| False. Curare does not have any effect if you taken orally - you have to be injected with it or given intravenously. |
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Term
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Definition
Isolated from the Strychnos species, turned into Curare and neuromuscular competitive blocker that causes flacid paralysis by repeated depolarizations.
Earlier was used for treatment of spastic disorders as well as a muscle relaxant in general anesthesia. |
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Term
| Whats the danger in NM blocking agents, other then paralysis |
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Definition
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Term
| Which ChE inhibitors are used clinically to reverse NM block caused by competitive blockers? |
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Definition
| Neostigmine, edrophonium, pyridostigmine |
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Term
| If you want muscular contraction, what percentage of nicotinic receptors needs to be occupied? |
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Definition
| 90-95% of nicotinic receptors need to be occupied by NM blockers in order to produce muscular relaxation. |
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Term
| Sequence of muscle paralysis for competitive neuromuscular blockers (IV) |
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Definition
Rapidly moving muscles first (eyes, jaw, larynx)
Limbs, trunk
Intercoastal muscles
Diaphragm*
*recovery occurs in reverse order. |
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Term
| What type of paralysis is caused by competitive neuromuscular blockers? |
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Definition
| Flacid, due to continual depolarizations |
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Term
| Are there side effects caused by competitive neuromuscular blockers? Why is this? |
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Definition
There are.
Neuromuscular blockers also effect the nicotinic receptors located in the ganglionic junctions.
- blocking the parasympathetic NS's nicotinic receptors, increased heart rate
-blocking sympathetic NM junctions, causing a fall in blood pressure
Blocking of vagal response |
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Term
| What is the toxicity caused by NM blockers? |
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Definition
HISTIMINE is released and causes
-bronchospasm
-hypotension (vasodilation)
-increased bronchial and salivary secretions |
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Term
| Are there many depolarizing neuromuscular blockers? |
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Definition
NO.
There is only one, succinylcholine |
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Term
| True or false: succinylcholine is metabolized by AchE and butyrylcholinesterase |
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Definition
FALSE.
It is not metabolized by AChE. Only by butyrylcholinesterase. |
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Term
| What are the side effects of depolarizing neuromuscular blockers? |
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Definition
Hyperkalemia (K+ release from intracellular site)
(dangerous in heart failure patients on digoxin or diuretics)
Rahbdomyolysis -- lysis of skeletal muscle
Cardiac arrest - due to increase in potassium lvls |
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Term
| In which people should depolarizing neuromuscular blockers be avoided in? |
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Definition
Due to the hyperkalemia, patients in heart failure or on digoxin/diuretics
In patients with any type of tissue damage (histimine already being released)
ANY skeletal muscle injury
Paraplegia or quadriplegia
Not given to children under 8 years of age. |
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Term
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Definition
Caused by neuromuscular blocker (succinylcoa) paired w/ certain anesthetics (inhalants).
It is seen as a serial increase in temperature.
It is due to a genetic abnormality in a RYANODINE (SR Ca channel) receptor 1:3000 mutations.
Increased Ca released from SR causes contracture/rigidity/heat production from skel muscle.
Symptoms: hyperthermia, accelerated muscle metabolism, metabolic acidosis, tachycardia
Treatment: dantrolene (ryanodine blocker) |
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Term
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Definition
| Calcium channel usually found on the sarcoplasmic reticulum of the cytoplasm |
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Term
| True or false: d-tubocurarine is a non competitive neuromuscular blocker. |
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Definition
| FALSE. It is a competitive NM blocker. |
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Term
| True or false: succinylcholine is a competitive NM blocker. |
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Definition
| FALSE. It is a noncompetitive NM blocker. |
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Term
| What is the action of D-tubocurarine? |
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Definition
| It is a competitive NM blocker. It blocks ACh actions @ nicotinic receptors, causing flacid paralysis. Paralyzes small, rapid acting muscles first and diaphragm last. Many of the derivatives cause histamine release. |
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Term
| What is the action of succinylcholine? |
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Definition
| It is a noncompetitive NM blocker. It stimulates nicotinic receptor causes persistent depolarization. Blocks chest and abdominal muscle with transient apnea. Malignant hyperthermia is a potential side effect. |
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Term
| Which mimetic category do you generally use to treat ocular ailments |
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Definition
| Parasympathetomimetics but sometimes u use symapthetomimetics |
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Term
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Definition
| Increase in intraocular pressure that can lead to damage to the retina and the optic nerve. Can lead to complete blindness. |
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Term
| Which can be a cause of glaucoma: a decrease in the draining of aqueous humor, or an increase in the production of aqueous humor |
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Definition
BOTH!
Both cause an increase in intraocular pressure. |
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Term
| Which is more common, narrow or wide (open) angle glaucoma? |
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Definition
| Wide (open) angle glaucoma is more common. Narrow angle glaucoma is less common. |
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Term
| What is the pathway for the drainage of aqueous humour? |
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Definition
Produced in the ciliary bodies, flows from the posterior chamber through the pupil into anterior chamber leaving the eyes primarily by the trabecular meshwork and canal of Schlemm. Drains into episclaral venous (90-95% of AH drains this way) *are the target for cholinergic drugs
Uveoscleral route = target for prostanoid drugs which flowers thru ciliary muscles and into the subarachnoid space. |
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Term
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Definition
| Pressure from the aqueous humor in the posterior chamber pushes the iris against the trabecular meshwork, closing the ocular angle and preventing the drainage of aqueous humor. |
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Term
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Definition
Controls lens curvature. M3 M2 receptors.
Contraction of ciliary muscles focuses the lens for near vision. |
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Term
| Contraction of which, circular or longitudinal ciliary muscle, facilitates the drainage of aqueous humour |
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Definition
| Contraction of the longitudinal ciliary muscle stretches open the trabecular meshwork and facilitates the drainage of aqeous humor which reduces intraocular pressure in glaucoma. |
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Term
| What do the ciliary muscles control? |
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Definition
Contraction of those muscles control lens curvature
Longitudinal: stretches open ciliary muscles stretches open the trabecular meshwork and facilitates the drainage of aqueous humor and reduces intraocular pressure in glaucoma.
Circular: contraction makes the lens more spherical, making focus on near objects easier. This is known as the spasm of accommodation (parasympathetic effect) |
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Term
| Occular sympathetic innervation causes which: accommodation or reduced accommodation (distance vision) |
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Definition
| Sympathetic innervation in the eye is of the Beta-2 receptors. It causes near vision to become blurry and far vision to become clear by relaxing the circular ciliary muscles by reducing the curvature of the lens. |
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Term
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Definition
More common form. Treatment aimed at decreasing aqueous hmor production/increasing outflow.
Surgical iridectomy preferred but cholinergic miotics are used for short-term management. (miotics = pupil dilators) |
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Term
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Definition
iridectomy
First line of drug treatment
Prostaglandin PGF2-Alpha analogues ^ outflow through uveoscleral pathway.
latanoprost and travoprost due to fewer side effects + longer duration of action.(increases drainage)
Second line of treatment
Beta-receptor antagonists are 2nd line of choice = non selective = timolol and levobunolol. They decrease the production of aqueous humor by reducing secretion as well as by reducing blood flow.(decreases production)
Third line of treatment
Alpha-2 agonists - alpraclonidine (doesn't cross bloodbrain barrier) brimonidine to reduce aqueous production by reducing cAMP - may also increase outflow through uveoscleral pathway
Carbonic anhydrase inhibitors - dorzolamide, brinzolamide (topically used) inhibit carbonic anhydrase III form thus reduce fluid transport and intraocular pressure. *inhibits the enzyme required
Muscarinic agonists -- contraction of ciliary pupil, opening trabecaular meshwork and facilitate acqeuous outflow but does not effect production. Opens the angle.
Pilocarpine commonly used (orally) but is very irritating to the eye/scleral region.
Cholinesterase inhibitors are indirect actin parasympathetomimetic agents (physostigmine, echothiophate, isofluorophate) can be used by over long-term can cause glaucoma. Used only in aphakic patients or when other agents are ineffective. (irreversible esterase inhibitors) |
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Term
| Would atropine help in the treatment of glaucoma? |
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Definition
| No! it is a muscarinic receptor antagonist. It would not help. It will exacerbate the issue. |
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Term
| What is atropine used for occularily. |
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Definition
It is a muscarinic receptor antagonist used for inflammatory uveitis (reduce the pain and photophobia) and in dilating the pupil / relax the ciliary muscle for retinal examination.
Also useful for breaking the adhesions between lens and iris tht may be produced by inflammation. |
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Term
| What is the rate limiting step in the production of dopamine/NE and E |
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Definition
| Tyrosine hydroxylase (the first enzyme) is the rate limiting enzyme. |
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Term
| Where does most of the synthesis of the NT's dopamine, NE and epinephrine occur? |
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Definition
| In the presynaptic terminal |
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Term
| What are the steps in the synthesis of dopamine, epinephrine and norepinephrine |
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Definition
1) Tyrosine molecule
1. Tyrosine hydroxylase
a. Blocked by metyrosine
2) DOPA (3,4 Dihydroxyphenylalanine)
1. L-aromatic amino acid decarboxylase
3) Dopmine
1. Dopamine-beta hydroxylase
4) Norepinephrine
1. Phenylethanolamine N-methyl transferase (adrenal gland)
5) Epinephrine |
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Term
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Definition
| Converts tyrosine molecule into DOPA molecule. Blocked by metyrosine. |
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Term
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Definition
Molecule that blocks the molecule Tyrosine Hydroxylase. It is the rate limiting step in the conversion of tyrosine into the catecholamines like epinephrine, dopamine, NE.
Used in the treatment of pheochromocytoma (cancer of adrenal gland) |
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Term
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Definition
| Blocks storage of NE (dopamine/Epinephrine) into vesicles. This decreases sympathetic activity. |
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Term
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Definition
| Molecules that prevent the release of NE from the presynaptic membrane. |
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Term
| What do tricyclic antidepressants and cocaine block |
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Definition
| Blocks the NE transporter. If this is blocked then it will increase sympathetic activity. |
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Term
| How can you increase sympathetic activity at the level of neurojunctions? |
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Definition
| By blockin the NE transporter |
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Term
| Describe the feedback inhibition of NE at the synaptic junction. |
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Definition
There are alpha-2 receptors located on the presynaptic membrane.
When NE binds to these alpha-2 receptors, it prevents further release and it causes a reduction in the production of NE. |
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Term
| If you use an alpha-2 blocker, what response would you see? |
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Definition
| You would see a reduction in the sympathetic physioloical response from a reduction in the production and release of NE into the synaptic cleft. |
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Term
| What does cocaine do/block? |
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Definition
| What does cocaine do/block? |
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Term
| Describe the metabolism of catecholamines. |
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Definition
| Catecholamines (E, NE, DOPA) are metabolized by monoamine oxidase (mitochondrial enzyme, expressed in most neurons + GI tract + liver) into DOMA (dihydroxymandelic acid) then by COMT (catechol-o-methyl transferase) into VMA (vanillymandelic acid) OR they could be converted by COMT into some intermediates, then by MAO into VMA. |
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Term
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Definition
| Urine VMA levels are an indication of the degree of sympathetic activity occuring as they are a major catecholamine metabolite. Oral drugs are metabolized and produce this metabolite. |
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Term
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Definition
A neuronal drug which is a member of the class of drugs known as nitrocatechols.
It is an COMT (catechol-o-methyl transferase) inhibitor used in the treatment of Parkinsons disease. It is administered along with dopaminergic agents such as L-dopa. It's for the inhibition of the conversion of L-dopa into 3-methoxy-4-hydroxy-L-phenylalanine in the periphery. |
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Term
| Effect of agonists on alpha-1 receptors |
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Definition
Eyes: mydriasis (dilation of pupil) by contraction of iris smooth muscle
Vascular vasoconstriction and increased blood pressure.
Glycogenolysis and glyconeogenesis
Intestinal smooth muscle relaxation
Smooth muscle contraction of the genitourinary smooth muscle. |
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Term
| Effect of agonists on alpha-2 receptors |
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Definition
Alpha-2 agonists reduce the NE release and therefore sympathetic activity. It is used to treat hypertension.
Vasoconstriction of vascular smooth muscle
Aggregation of platelets
Decrease in insulin secretion
Present in ciliary processes in treatment of glaucoma |
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Term
| Effect of agonists of beta-1 receptors |
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Definition
Heart - increased heart rate, increased force of contraction, increased AV node conduction
Kidney - increased renin secretion |
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Term
| Effect of agonists on beta-2 receptors |
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Definition
Bronchial smooth muscle - relaxation (agonists = asthma treatment)
Liver and skeletal muscle - glycogenolysis and gluconeogenesis
Uterus - relaxation -- prevent uterine hypermotility and prevent premature labour during pregnancy. |
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Term
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Definition
D1 - renal & splanchnic blood vessels - vasodilation and natriuresis, so D1 agonists are used for treatment of renal failure associated with shock.
D2 - (more significant in the brain) - suppresses NE release |
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