Exam II Flashcards
What types of drugs are most relevant in relation to pharmacogenomics?
Antineoplastics.
What class of drug is 6MP? What is its mechanism of action?
- 6-mercaptopurine is a Purine Analog.
- Interference w/ nucleic acid synthesis.
What conditions/diseases do purine analogs treat?
- Lymphoblastic leukemia
- Autoimmune diseases
- IBS
- Post-Transplant
What limits the usage of Purine Analogs? Why?
- Toxicity (poor Therapeutic index) and myelosuppression.
6-mercaptopurine is metabolized into 6-methyl-mercaptopurine by what enzyme?
TPMT (Thiopurine S-Methyl-Transferase)
What would a deficiency in TPMT (Thiopurine S-Methyl Transferase) cause?
Toxicity with Purine Analogs (specifically 6MP)
What is the pathway of Azathioprine?
Azathioprine → 6 Mercaptopurine → TPMT → 6-Methyl-Mercaptopurine
What therapy would be needed for someone with a TPMT deficiency who needed to receive 6MP to treat a lymphoblastic leukemia?
- A new drug would need to be found or…
- A much smaller dose of the 6MP would need to be given.
What drug ranks #1 in total mentions on death certificates for drug related deaths? What about emergency room visits?
Warfarin
What is the major bleeding side effect range for warfarin?
2-16% of patients
What does genetic analysis allow in regards to giving warfarin? How many bleeding events are avoided by genetic analysis? Is genetic testing for warfarin administration required by the FDA?
- Allows for better therapeutic dose determination
- 4500 - 22000 serious bleeding events?
- No, it is recommended.
What are the two enzymes that metabolize warfarin?
- CYP2C9
- VKORC1
What do variant alleles of CYP2C9, such as CYP2C9*2 or CYP2C9*3, do to the metabolism of warfarin?
They inhibit metabolism leading to ⇡ warfarin concentrations.
60-70% of breast cancers express what receptors?
- Estrogen Receptors (ERs)
- Progesterone Receptors (PRs)
- HER2
What breast cancer receptors indicated a less aggressive breast cancer?
- Estrogen Receptors
- Progesterone Receptors
Which breast cancer receptors indicate a more aggressive cancer?
HER-2 receptors.
What deprivation treatment is used for breast cancer?
Estrogen Deprivation
What drugs are used in Estrogen Receptor + tumors?
- Tamoxifen
- Aromatase Inhibitors
What happens to the number of HER-2 receptors in 15-25% of breast cancers? What is the result?
- HER-2 is 2-20x more prevalent on the cell surface.
- More receptors means greater cell proliferation.
What drug do HER2 cancers respond to? How does this drug work?
- Herceptin (Trastuzumab)
- Trastuzumab (a monoclonal antibody) binds to HER2 receptor and shuts it down.
Name 3 purine analogs?
- Azathioprine
- 6-Mercaptopurine
- 6-Thioguanine
What are examples of solute carrier (SLC) proteins? What percentage of membrane proteins are SLC’s?
- Couple transporter, Exchanger, Passive transporter, etc.
- 15-30% of all membrane proteins are SLC’s
How were drug efflux transporters discovered? What are some characteristics of drug efflux pumps? Why do they exist?
Drug efflux transporters were found by researching people developing resistance to antineoplastics (anti-cancer drugs).
- Broad substrate specificity ( Works on lots of different drugs)
- Cellular survival mechanism
What is the most common family of Drug Efflux Transporters? Is there a lot of research in this area?
- ATP-Binding Cassette (ABC) Transporters
- Yes, very intense area of research.
What are the three major ABC family drug efflux transporters?
- ABCB
- ABCC
- ABCG
What substrate specificity does ABCB1 have? Where are these transporters located? Maintenance of what critical system is enforced by ABCB1 transporters?
- The broadest specificity ( everything from antineoplastics and antibiotics to opioids and HIV drugs)
- GI, Kidney, Liver, Testes (They’re spread out in a lot of places)
- Blood Brain Barrier.
Why are there no CNS effects when loperamide (an opioid) is given? What happens if Quinidine is given in conjunction with loperamide?
- ABCB1 moves loperamide out of the system before it can be converted to morphine.
- Quinidine is an ABCB1 inhibitor → Loperamide becomes systemic → CNS affected & respiratory depression.
What class of ABC transporters is the largest? What drugs does it efflux?
ABCC’s. These transporters efflux antineoplastics.
What led to the discovery of ABCG2? What drugs does the ABCG2 transporter efflux? What vitamin is influxxed by this transporter? Why?
- ABCG2 was discovered for being a breast cancer antineoplastic resistant protein (but it does more than just work with breast cancer cells.)
- Antineoplastics, toxins, and food borne carcinogens.
- Folate is influxed by this transporter so that the cancer cell can grow.
What’s the most important non-ABC Drug Efflux Transporters? What is the important sub-type associated with this family?
- SLC21 family which includes:
- OATPs (organic anion transporter proteins)
What are the physical components of the blood brain barrier that prevent drugs from entering the brain tissue?
- Astrocytes
- Podocytes (effectively a macrophage)
- Tight junctions in the capillaries preventing leaking.
- Protein Efflux Barrier
Is the blood brain barrier weaker than the Spinal CSF barrier? Can drugs be administered into the CSF? What about antineoplastics in the CSF?
No, The Spinal CSF barrier has less effluxive proteins.
Yes, intrathecal drugs like bupivicaine.
No, Anti-cancer drugs administered in the CSF have been infeffective.
What is the most common transporter in the GI tract? Where are your GI tract transporters localized and how many things do they let in?
- ABCG2
- These transporters are in the microvilli and let most things in.
Which ABC transporter moves out glucuronidated drugs from hepatic metabolism? Give an example.
ABCC Transporters
Acetaminophen absorbed past ABCC → Glucuronidation → Glucuronide+Acetaminophen effluxed by ABCC.
What type of protein transports are found in the liver?
- SLC Type OATPs
- ABCs (all types)
Which ethnic group has ABCB1 polymorphisms affecting Fentanyl efflux?
Ethnic Koreans
What ABC Transporter has the broadest substrate specificity and what does this mean? What are other names for this specific ABC? Where is this ABC found?
- ABCB1, broad specificity means it works on a bunch of different things
- MDR1 and p-Glycoprotein
- Everywhere (GI, Kidney, liver, testes, etc.)
Which ABC Transporter is critical in maintaining the blood brain barrier?
ABCB1
What is the most important thing that separates brain vascular endothelial cells from other vascular endothelial cells? How?
Tight Junctions. These prevent the movement of things out of the vascular endothelium from between the endothelial cell space.
What transporter proteins are located in the liver? Where are effluxed drugs/toxins/etc dumped?
- SLCs (essentially OATPs)
- ABCs (all)
Effluxxed drugs/toxins/etc are dumped into the bile where they will be passed into the feces.
Muscarine is highly charged, this means that effects are seen where? Does Muscarine affect the ganglia?
Effects are seen at PNS rather than CNS (hydrophilicity prevents passage through BBB)
No, only the effector tissue.
Nicotine affects the __________ and the _______ rather than ________.
Autonomic Ganglia. - Skeletal Muscle NMJ. - Effector tissue.
What makes nicotine able to cross the BBB?
Lipophilicity
Which muscarinic receptors are stimulatory? Inhibitory?
Stimulatory = M 1,3,5
Inhibitory = M 2,4
What are the esters of choline? What is a major characteristic of these cholinomimetics?
- ACh
- Methacholine
- Carbachol
- Bethanechol
All Esters of Choline are charged and thus unable to cross the BBB.
What is ACh as a drug used for? Why is not used for anything else?
Pupillary Constriction
ACh is broken down too quickly by AChE.
What is the use of Methacholine?
Asthma Diagnosis by bronchoconstriction
If Forced Vital Capacity is decreased after methacholine is given then = asthma
What is Carbachol used for?
Decreasing Intraocular Pressure
What is Bethanechol used for?
Urinary retention
What is the order of Choline Ester metabolism from shortest excretion to longest excretion?
- ACh (rapid)
- Methacholine (fast)
- Carbachol/Bethanechol (slow)
What should be known about betel nuts?
Addictive nut to chew similar to nicotine.
leaves mouth red
parasympathetic agonist
Where are alkaloids excreted? What would enhance excretion?
Kidneys
Urine acidification (alkaloids are basic)
What are the two sub-groups of Direct-acting Cholinergic Drugs?
- Esters of Choline
- Alkaloids
What is an alkaloid in regards to cholinoceptor drugs? Which drugs should be known?
Alkaloids = Basic pH and plant-based
- Muscarine
- Nicotine
- Pilocarpine
- Lobeline
What are the effects of muscarinic agonists in regard to the eye? What is the result of this?
Myosis (pupillary constriction)
⇡ aqueous humor drainage
What are the cardiac effects of muscarinic agonists?
⇣ SVR with reflexive ⇡ HR
How many cases of glaucoma are open angle? How many are closed angle? What drug can never be given in closed angle glaucoma? Why?
90% open angle
10% closed angle
Atropine can never be given as it relaxes the ciliary muscle and blocks flow of aqueous humor out of the canal of Schlemm.
Will direct-acting cholinergics have CNS effects? What is the exception?
No, too charged to cross BBB.
Nictotine is exception due to lipophilicity.
What neurotransmitters does Nicotine release? What could large-toxic doses of nicotine cause?
Dopamine (thus addictiveness), Serotonin, GABA, and NE
Larger Doses = Ingestion = Tremor, emesis, convulsions, coma.
What Nicotinic Receptor Agonist causes paralysis? How? What is this drug’s structure?
Succinylcholine.
Immediate Muscular Depolarization that causes the muscle to “fasciculate”.
Two ACh molecules end to end.
What are the three Cholinomimetics in order of duration of action?
- Simple alcohols - 5-15 min
- Carbamic acid esters of alcohols - 0.5 - 6 hours
- Organophosphates - Days to weeks
What is the rapid-acting cholinomimetic? What is its use?
Edrophonium - used in diagnosis of myasthenia gravis
What are the 3 Cholinomimetics with an intermediate duration of action? What is the main use of these drugs?
- Neostigmine -
- Pyridostigmine
- Physostigmine
Reversal of paralysis from -curare derivatives.
What makes organophosphates duration of action so long? What are they used for?
Covalent bond forming at the active site.
As insecticides
Is there a reversal for organophosphate poisonings? What are considerations?
Yes, Pralidoxime (strong nucleophile)
Has to be given within the first 1-2 hours of poisoning to break bond.
What is “aging” in regards to organophosphates?
This concept refers to organophosphate bonding getting stronger over time.
Pralidoxime becomes ineffective after aging occurs.
What is the pathophysiology of myasthenia gravis? What are the symptoms? What is the treatment?
Progressive loss of ACh receptors.
Muscle weakness, worsens with exercise.
AChE inhibitors to produce more ACh at NMJ sites.
What drug is used as a diagnostic test for Myasthenia Gravis? How is this done?
Edrophonium
- Baseline muscle strength test
- Edrophonium is given.
- Muscle strength is reassessed, if improved then test is + for MG.
What two AChE inhibitors are given for reversal of paralytic ileus? Which one is generally avoided?
Neostigmine and Physostigmine
Physostigmine is generally avoided because of CNS effects.
What are the symptoms of parasympathetic toxicity? What is the antidote?
SLUDGE-M
- Salivation
- Lacrimation
- Urination
- Defecation
- Gastroenteritis
- Emesis
- Myosis
Atropine is antidote
What are the signs of Cholinesterase inhibitor toxicity? What are the 3 steps in treating Cholinesterase inhibitor toxicity? What is the most common cause?
SLUDGE-M
- Vital sign maintenance
- Decontamination
- Atropine, then Pralidoxime (if organophosphate toxicity)
Insecticides
What two drugs are given as auto-injectors to military personnel for Sarin gas exposure?
Atropine and Pralidoxime
What is the most important anticholinergic drug? What is this drug derived from? How potent is this plant?
Atropine
Derived from Atropa Belladona (Nightshade)
Plant isomer is 100x more potent than racemic drug
What anticholinergic crosses the blood brain barrier? This makes it useful for what?
Scopolamine; useful for motion sickness.
What AChE inhibitor is useful for its bronchodilating effects?
Atrovent (Ipratropium Bromide)
What drug is used for pupillary dilation? What is its duration of action?
Tropicamide for Mydriasis (dilation of pupil)
Duration of action is 4 hours
What are contraindications to atropine use?
Closed Angle Glaucoma
Benign Prostatic Hyperplasia
What are the signs/symptoms of anticholinergic toxicity?
Hot, blind, dry, red and mad
What paralytic agent is characterized by continuous end-plate depolarization?
What are the indications for this drug?
Describe the two phases of this drug.
Succinylcholine
RSI and electroconvulsive therapy
Phase I = continuous depolarization causing relaxation
Phase 2 = repolarization occurs, ⇡ risk of ⇡K+ if more succ is given
What is the mechanism of action of -curare derivatives?
Competitive Antagonism of ACh at binding sites
Why would succinylcholine be given over the -curare derivates?
Very short duration of action. Essentially only to facilitate intubation
What drugs reverse Neuromuscular Blocking agents?
Neostigmine
Sugammadex (only for Vec and Roc, traps drugs like an ionophore)
Why would a drug be given that causes prolonged mydriasis?
To promote relaxation of ciliary muscle for healing.
Where is blood shunted away from in a sympathetic response?
Non-vital organs and systems (ex. endocrine, GI, and urogenital)
What is the scientific term for the “rest and digest” phenomenon of the parasympathetic nervous system?
Trophotropic
Long pre-ganglionic with short post-ganglionic nerve fibers is indicative of what branch of the ANS?
Parasympathetic Branch
Short pre-ganglionic with long post-ganglionic is indicative of which branch of the ANS?
Sympathetic Branch
Which two groupings of spinal nerves innervate the parasympathetic system? Which specific cranial nerve innervates 75% of the parasympathetic system?
Cervical and Sacral nerves.
Cranial nerve X (Vagus nerve)
Which two groupings of spinal cord nerves innervate the sympathetic system?
Thoracic and Lumbar
What is the primary feature of chain ganglia? Which portion of the ANS do these work with?
Chain Ganglia allow for rapid activation of multiple spinal nerves at once.
Sympathetic Nervous System
What nerve is responsible for 75% of all parasympathetic output?
Vagus Nerve (CN X)
What are the neurotransmitters of the GI tract?
- Serotonin
- Substance P
- Endorphins
What organ system contains more serotonin that the CNS?
GI Tract
Sympathetic input is _______ to the Enteric Nervous System?
Inhibitory
Do we have drugs that target the enteric nervous system?
No
What neurotransmitter(s) are released by the post-ganglionic fibers of the Autonomic Nervous System? What effects do the neurotransmitter(s) have? What is the effect dependent on?
- ACh and NE
- Effect can be inhibitory or stimulatory
- Effect is dependent on receptor type
What are some examples of direct-acting sympathomimetics? What makes these drugs “direct-acting”?
- Epinephrine, Isoprotenerol, Albuterol, etc.
- The drugs are direct-acting because they bind directly to the α and β receptors of the SNS.
What drugs are examples of indirect sympathomimetics? What makes these drugs “indirect-acting” sympathomimetics?
- Ephedrine, Amphetamines, Cocaine, etc.
- These drugs do not bind directly to α or β sites directly.
How do indirect-acting sympathomimetics cause an effect?
Release stored NE and/or Replace NE on NET → ⇡ circulating NE available at synapse.
What are 4 common effects of direct and indirect-acting sympathomimetics?
- Vasoconstriction
- Inotropy and Chronotropy
- Bronchodilation
- Uterine relaxation. (suppress premature labor).
How do sympatholytic drugs differ from sympathomimetic drugs?
Sympatholytic drugs inhibit the transmission of neurotransmitters in the SNS.
What’s an example of an α-specific sympatholytic drug? What is the effect of giving this drug?
Phentolamine - peripheral vasodilation
What’s an example of a β-specific sympatholytic drug? What is the effect of giving this drug?
Propanolol - suppressed inotropy and chronotropy.
What enzyme breaks down ACh?
ACh esterase
What are the two types of cholinergic receptors? What neurotransmitter binds to cholinergic receptors?
- Muscarinic
- Nicotinic
ACh binds to cholinergic receptors
What are the 3 types of Adrenergic receptors?
- α - receptors
- β - receptors
- Dopamine - receptors
How many Muscarinic receptors are there (that we need to know about)?
5 total (M1 - M5)
How many Nicotinic receptors are there?
NM and NN
aka
Nicotinicmuscle & Nicotinicneuronal
Where do we find NM receptors?
The Neuromuscular Junctions
Where do -curare derivates work to produce paralytic effects? How? Where were these drugs derived from originally?
-curare derivates induce paralysis by blocking ACh at the Nn receptors, preventing skeletal muscle contraction.
Poison dart frogs.
Where are α-1 receptors located primarily?
Peripheral Vasculature
Where are α-2 receptors located primarily?
CNS
Where are β-1 receptors located primarily?
Heart
Where are β-2 receptors found?
Lungs
Where are β-3 receptors found?
Adipose tissue.
How many Dopamine receptors are there? Where are these primarily located?
5 Receptors (D1 - D5)
Brain and Renovascular capillary bed.
What general type of receptor are all α and β receptors?
GPCRs
What is the signal transduction pathway for α-1?
α-1 → GQ → PLC → IP3 and DAG
α-1 → GPCR α-subunit Q → phospholipase C → IP3 and DAG
What is the signal transduction pathway for α-2 receptors?
- α-2 → GI (inhibitory)
- → Inhibition of adenylate cyclase, Ca++, and K+
- → ⇣ cAMP
What is the signal transduction pathway for all β receptors?
β-1,2,3 → GS → stimulation of adenylate cyclase and Ca++ channels → ⇡cAMP
What is the signal transduction pathway for M1 M3 and M5 receptors?
M1,3,5 → GQ → Phospholipase activation w/ DAG and IP3
What is the signal transduction pathway for M2 and M4 receptors in a cardiac myocyte?
M2 → Gi → Inhibition of AC → ⇣cAMP = ⇣ Inotropy & Chronotropy
What are NANC neurons? What neurotransmitters do these neurons use?
- Non-adrenergic, non-cholinergic neurons.
- NOS, Substance P, Somatostatin, etc. (there are lots)
In α-1 receptors MLCP is _______, and MLCK is ______, Thereby causing _____.
- Inhibited
- Potentiated
- Vasoconstriction
In a β-2 receptor of the lungs cAMP is released and ______ MLCK, producing ______.
- Inhibits
- Bronchodilation
Myosin Light Chain Kinase (MLCK), in general, will cause _______.
Smooth Muscle Contraction
Myosin Light Chain Phosphatase (MLCP), in general, wil cause ______.
Smooth muscle relaxation.
What receptor is going to inhibit continued activation of β-1 and β-2 receptors by NE? Where is this receptor located?
α-2 will inhibit continued β stimulation through a negative feedback loop
the α-2 receptor is located on the sympathetic nerve that is delivering NE to the tissue site.
What is the signal transduction pathway for β receptors in a cardiac myocyte?
- NE binds to β-receptor
- Gs → cAMP
- cAMP → PK (Protein Kinase)
- PK → ⇡Ca++ → Contraction
What is the scientific term for our “Fight or Flight” response?
Ergotropic Response
Where do baroreceptors send their signals?
Hypothalamus Vasomotor center
What response would be elicited from activation of an M3 receptor on the Bronchiolar smooth muscle? What would be the purpose of this response?
Bronchiolar Contraction
This helps keep debris from getting deep into the lungs.
Overstimulation of the M3 receptor would have what effect on the GI tract?
Increased secretions = Diarrhea.
A β-1 receptor activation would have what response on the kidneys?
Renin release
A β-2 receptor activation would have what response on the bladder?
Relaxation
Activation of which receptor would cause decreased inotropy and chronotropy?
M2
Activation of which receptor would cause smooth muscle in the peripheral vasculature to contract? How about dilate?
α1 = Contraction
M3 = Relaxation
Activation of which receptor would cause contraction of the GI lining (stomach, intestines, etc.) ?
Which receptors, if activated, would have the opposite effect ?
M3 activation = GI contraction & food movement
α-2 , β-2 activation = GI relaxation & food stasis
If GI muscle is contracted what happens to corresponding sphincters? Why?
Sphincters are relaxed, this is to allow for passage of food.
GI sphincter relaxation = PSNS
GI sphincter contraction = SNS
Cholinomimetics will potentiate the _______.
Parasympathetic system
Parasympatholytics (or Antimuscarinics) will inhibit the ________.
Parasympathetic system
What is the defining characteristic of En Passant synapses? Where do we primarily find these?
En Passant synapses are synapses interacting with other neurons that occur along the length of the axon.
CNS
What two organelles are often found at the terminal end of a neuron at the synapse?
Mitochondria for ATP
Endoplasmic Reticulum for neurotransmitter creation
What are the 4 “fates” that end a neurotransmitter’s life?
- Diffusion away from synapse
- Enzyme degradation (ACh esterase)
- Re-uptake into pre-synaptic cell
- Uptake into target cell
What are the 6 Neurotransmitter classes and what is an example of each?
- Esters (ACh)
- Monoamine (Epi, Dopamine, etc.)
- Amino Acids (GABA)
- Purines (Adenosine)
- Peptides (Substance P, Endorphins, etc.)
- Inorganic Gasses (Nitric Oxide)
Which of the Amino Acid neurotransmitters is inhibitory? Excitatory?
GABA = Inhibitory
Glutamate = Excitatory
NM receptors utilize what kind of membrane protein?
Ion channels
NN utilize what kind of membrane channel?
GPCR’s
What food is high in choline?
eggs
What CNS effects are commonly associated with dopamine?
Reward and Pleasure
Low levels of this transmitter are associated with depression. What is given to counteract the low levels?
Serotonin
SSRI’s
What is the most important excitatory amino acid neurotransmitter in the brain? What brain functions is it necessary for? What are its receptor types and their corresponding transmembrane channel type?
Glutamate
Learning and Memory
- AMPA = Ion channel
- NMDA = Ion channel
- Metabotropic = GPCR + Ion channel
Which inhibitory amino acid neurotransmitter is associated with strychnine poisoning? How?
Glycine
- Glycine is inhibitory to contraction
- Strychnine antagonizes Glycine
- Excessive contraction = Convulsions
What is the most important inhibitory neurotransmitter? How does this relate to general anesthetics?
GABA
Many general anesthetics increase GABA activity
What class of drug is given for a lack of NE in the CNS?
SNRI’s
(Serotonin/Norepinephrine Reuptake Inhibitors)
What are the two neuropeptide pain signaling neurotransmitters?
Substance P and CGRP
What endogenous neuropeptide is involved with pain control? What are the two subgroups?
Endogenous opioids
Endorphins and Enkephalins
Excitatory neurotransmitters cause ________. What is the number 1 excitatory neurotransmitter of the CNS?
Depolarization
Glutamate
Inhibitory neurotransmitters cause ________. What are the two most important inhibitory neurotransmitters?
Hyperpolarization
GABA and Glycine
What are the two components of ACh? What enzyme combines these two?
Acetyl-CoA and Choline
ChAT (Choline Acetyl-transferase)
How many molecules of ACh are present in each secretory vesicle present at a synapse?
1000 - 50,000 ACh molecules
How does Acetylcholinesterase (AChE) split an ACh molecule? What are the two binding sites?
- Anionic Site - Ionic Bonding of the Nitrogen on the Choline.
- Esteric Site - H-Bonding of the ester group
What transporter brings Choline into a pre-synaptic cell? What else is brought in? This makes it a what?
ChT (Choline Transporter)
Na+ and Choline
Symporter or Co-Transporter
What transporter pulls ACh into the secretory vesicle?
VAT
What are the 3 main steps of vesicular exocytosis of ACh? Summarize each step.
- Docking - getting ACh into vesicle
- Priming - SNAPs + VAMPs = Vesicular Anchoring
- Fusion - Action potential → Ca++ release → Exocytosis
What are the two components that allow for fusion to occur between a secretory ACh vesicle and the presynaptic membrane?
Ca++ and Synaptotagmin?
Need to verify
What happens if ACh is not broken down by AChE?
Flaccid paralysis
What organelle is Acetyl-CoA found in?
Mitochondria
What are the two primary SNARE proteins? What is the purpose of a SNARE protein?
Syntaxin and SNAP-25
Located on the presynaptic cell membrane and “anchor” the vesicle to the membrane.
What protein, located on the secretory vesicle, interacts with the cell membrane to anchor the vesicle? What proteins does this specific protein bind to?
VAMP (Vesicular associated Membrane Protein)
SNAP’s
What molecule binds to Ca++ and allows for rapid exocytosis of a secretory vesicle?
Synaptotagmin
What does Vesamicol inhibit?
VAT (preventing ACh from entering secretory vesicle)
What does Botulinum Toxin (Botox) inhibit?
SNAPs and VAMPs
What is the lethal does of botulinum?
1 ng/kg
What does Sarin (nerve gas) inhibit? What is the result of this?
AChE
Convulsions, flaccid paralysis, and eventual suffocation
What drug class blocks CHT and is essentially only used for research purposes?
Hemicholiniums
What is the pathophysiology of Myasthenia Gravis?
- Autoimmune disease destroys ACh receptors.
- Fewer receptors → muscle weakness → paralysis
How is myasthenia gravis treated?
AChE inhibitors → more ACh available for the fewer receptors
What amino acid is a precursor to almost all adrenergic neurotransmitters?
Tyrosine
What is the largest difference between adrenergic and cholinergic transmission, in regards to how the neurotransmitter for each is broken down?
ACh broken down in synapse by AChE
NE broken down inside presynaptic cell by MAO
What transporter pulls adrenergic neurotransmitters into their secretory vesicles?
VMAT (Vesicular MonoAmine Transporter)
Which adrenergic inhibitors are no longer widely used?
Metyrosine - Inhibits tyrosine conversion
Reserpine - Inhibits VMAT
Bretylium / Guanethedine - Inhibits exocytosis
What is the mechanism of action of cocaine and tricyclic antidepressants?
Inhibition of NET (and inhibit reuptake of serotonin too)
How do indirect-acting adrenergic agonists elicit an effect?
By increasing NE at the synapse
A Catecholamine’s organic chemistry structure is characterized by a benzene ring with hydroxyl groups at ___ and ___ as well as an ____ side chain.
3 position, 4 position, amine group
What enzyme are catecholamines inactivated by? Where is this enzyme found that makes this route of administration essentially useless?
COMT (catechol-O-methyltransferase)
GI tract, catecholamines not given via PO because they are broken down too quickly in the gut.
Does norepinephrine have a bronchodilating effect?
No, NE has no β-2 activity
Agonist binding of an α-1 receptor elicits?
- Release of Ca++
- VasoConstriction
β agonist binding produces what effect? How does this affect the Heart vs the Lungs?
β-agonist binding = ⇡ cAMP
increased cAMP = ⇡ Inotropy
increased cAMP = bronchodilation
α-2 binding produces what effects?
- ⇣cAMP
- increased contraction (CNS effects drop BP past this)
- decreased Inotropy
What is the mechanism of action of methamphetamine?
Methamphetamine reverses reuptake of NE at the synapse increasing available NE.
(It also does the same with dopamine, 80% addicted on first dose)
What is the mechanism of action of cocaine?
Cocaine blocks reuptake of NE at the synapse increasing available NE.
(20% addicted on first dose)
What is the formula for cardiac output? What numbers are normally used?
CO (ml/min) = SV (70ml/beat) x HR (75beats/min)
What effect do these drugs have on the eye?
- α-1 agonist
- β-agonist
- β-antagonist
- α-1 agonist = dilation
- β-agonist = little effect
- β-antagonist = decrease aqueous humor
What are CNS effects of catecholamines?
Nervousness and feelings of doom ONLY in large doses
Little effect in lower doses.
What makes dopamine triphasic?
- Low dose = Renal dilation and diuresis
- Moderate dose = Inotropy
- High dose = Vasostriction
What is the main difference between norepinephrine and epinephrine?
Norepinephrine has no β-2 activity
Which potent β-agonist has vasodilatory effects?
Isoproterenol
Which β-1 agonist has indication for acute heart failure and cardiogenic shock?
Dobutamine
What is phenylephrine and its mechanism of action?
Phenylephrine is a non-catecholamine pure α1-agonist.
What is a “TET” spell?
What is a non-pharmacologic treatment?
What is the pharmacologic treatment?
Tetralogy of Fallot hypoxic episode.
“Squatting” forces blood back into RV
Phenylephrine
What is midodrine and what is it’s indication?
α-1 receptor indirect-agonist (metabolite binds to α)
Utilized for orthostatic hypotension
What is ephedrine? What is its mechanism of action? Does this drug cross the BBB?
Orally active non-catecholamine
- Releases stored catecholamine and mimics epinephrine.
- No.
What class of sympathomimetics readily enters the CNS and has much greater CNS effects compared to PNS effects? What are general effects from these drugs when given in proper dosages?
Amphetamines
Improved focus, attention, and mood.
What mild sympathomimetic has high concentrations in fermented foods? What metabolizes this compound? What drugs can increase BP significantly due to their interactions with this compound?
- Tyramine
- MonoAmine Oxidase (MAO)
- MAOI’s can ⇡ BP if taken in conjuction with eating fermenteed foods.
Which three organs are most dependent on consistent perfusion?
Brain, Heart, and Kidneys
What α-2 agonist is useful for sedation?
Dexmedetomidine
Which α-2 agonist is useful as a muscle relaxant?
Tizanidine
Which α-2 agonist is useful for treating HTN, diarrhea, and hot flashes?
What use might this drug have during anesthesia?
Clonidine
Treats hemodynamic instability in anesthesia
Which alpha antagonist is irreversible?
Phenoxybenzamine
Which α-antagonists are reversible?
- Phentolamine
- Tolazoline
- Prazosin
- Labetalol
What is a primary use for non-selective α-antagonists? What is a secondary use? What are the adverse effects of these drugs?
- Decreasing BP in people with pheochromocytoma
- Male erectile dysfunction and priapism.
- Abdominal pain (↑ GI motility), N/V/D, cardiac stimulation
Which α-antagonist drugs are useful for treating BPH?
-osin drugs (tamsulosin, prazosin, etc.)
What are the two non-selective α-antagonist drugs? Which is irreversible?
Phentolamine
Phenoxybenzamine (irreversible)
Which two α-2 selective drugs are marketed for penile blood flow but don’t really work?
- Ergotamine
- Yohimbine
What would happen if epinephrine and phentolamine were given at the same time?
HR would ↑ and BP would ↓
Which of the -osin drugs can be used for both HTN and BPH?
Prazosin
Chronic use of β-blocker therapy usually indicates usage of what other class of drug? Why?
Statins
Chronic β-blocker use ↑ VLDL, and ↓ HDL
What are the effects of β-blockers on asthma patients?
↑ bronchostriction = bad for asthma patients
What are the effects of β-blockers on eyes?
↓ intraocular pressure
What are the effects of β-blockers on metabolism?
Lipolysis inhibition (β3)
Glycogenolysis inhibition (↑ lipids)
What are the two main things that should be known about Propanolol?
- Non-selective β-blocker w/ long-acting form
- Extensive 1st pass metabolism
What should be known about metoprolol?
Cardio-selective β-blocker
Safer in COPD & Diabetes
What should be known about nebivolol?
most cardio-selective β-blocker
What should be known about Nadolol?
Long acting and non-selective
What should be known about Labetolol?
α and β activity
racemic mixture
What β-blocker is useful during surgery? Why? What does it treat?
Esmolol
- β-1 selective
- Ultra short acting
- Treats intraoperative SVT and tachycardia
What β-blocker requires weaning when switching to a new medication?
Propanolol
