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85 Cards in this Set
- Front
- Back
What does Hemicholinium do?
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Limits entry of Choline into the cell, by inhibiting its transporter (competitive).
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What do Vesamicol do?
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Inhibits transoprter B, that transports acetylcholine into the vesicles.
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What does Butulonium toxin do?
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Inhibits release of Acetylcholine from the cell, by cutting the docking proteins.
It is specific to cholinergic neurons (only has a receptor on them), and its duration is long and irreversible (~6 months). |
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Where do you find AChe?
BChE? |
AChE: post-synpatic membrances.
BChE: blood (which is why ACh cannot function as a drug). |
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What is the structure of the Nicotinic ACh receptor?
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Ligand-gated ion channel.
Not selective- but overall Na flows in so there is depolarization. |
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What types of Nicotinic receptors are there?
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Nn: In neurons and postganglion neurons of ANS.
Nm: In skeletal muscle. |
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What is the structure of the muscarinic receptor?
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GPCR- second messengers!
M1-M5: uneven number are excitatory, even numbers are inhibitory. |
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Muscarinic receptors- short list?
M1-M5 |
M1: In neurons/parietal cells in stomach.
M2: Heart muscle, neurons (negative feedback). M3: Smooth muscles and glands (contract), blood vessels (relax). M4: CNS neurons- negative feedback. M5: CNS neurons- POSITIVE feedback. |
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What is the mechanism of excitatory muscarinic ACh receptors?
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GPCR causes breakdown of PIP2 to IP3 and DAG.
IP3- hydrophilic- release Ca from inside cell. DAG- hydrophobic- activates PKC. |
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What does M3 cause?
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* Contraction of SMC.
* Excretion of glands that receive sympathetic cholinergic. * On endothelial cells- cause secretion of NO that relaxes. |
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What is the mechanism by which ACh causes relaxation of blood vessels through M3 receptors?
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a-subunit of M3 GPCR attaches to GTP and becomes active. It attaches to PLC in the membrane, that break down PIP2 to IP3 and DAG.
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How does IP3 recruit Ca from intracellular storage in SMC?
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IP3 opens ionic channels on SR membrane. The Ca that is released binds to Calmodulin, that activates MLCK, that phosphorylates myosin, that now attaches to actin.
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What do we use NO for?
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Dilation of BV by relaxation of SMC.
Used in angina pectoris, Viagra. |
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What are the sources of NO during an erection?
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> NO is released from NANC
> NO is released from activated endothelial cells. |
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How does NO cause dilation of BV?
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NO activated guanylate cyclase to creap cGMP from GTP.
cGMP activates PKG, that dephosphorylates myosin- relaxation.. |
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How does Viagra work?
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Since the erection is stopped by breakdown of cGMP by PDE5- Viagra inhibits PDE5.
It works everywhere- originally used for heart problems. Can cause lowering of BP. |
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What does M2 do, both in heart and neurons (negative feedback)?
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Its GPCR causes opening of K channels (beta-gamma subunits) and lowering of cAMP (a-subunit).
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Do you have voltage-gated Na channels in the SA node?
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Nope- only Ifunny and voltage-gated Ca channels.
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What does cAMP do in the SA node?
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Makes Ifunny more sensitive.
Causes phosphorylation of Ca channels by PKA. |
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Where do you find ATP in vesicles?
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ACh, Noradrenalin etc.
It is a coreceptor. |
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What receptors does ATP have?
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P2y: negative feedback on pre-synapse.
P2x: post-synpase (causes contraction of muscles). |
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What is VIP?
Where do you find it? What does it do? |
Vasoactive Intestinal Peptide.
Usually in GI, but also in some neurons that release ACh. Contained in DIFF vesicles than ACh. Released when neuron activity is high. Causes relaxation of SMC/glands- enables more oxygen and glucose to flow in. |
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What happens after activation of M3 receptors?
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SMC contraction:
-pupil constriction- myosis. -secretion of tears and saliva. -contractions of bronchi. -Contraction of stomach wall (less -important than M1). -Increased GI peristaltics. -Contraction of bladder and relaxation of inner sphincter by NANC stimulated by NO (stimulated by ACh). -Secretion of eccrine sweat glands. -erection. Release of NO, vasodilation. |
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What is the main function of M2 in the heart?
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Decrease sympathetic activity.
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What does M1 do?
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Increase secretion of Histamine, that causes secretion of acid from parietal cells.
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What are two agonists to Muscarinic Cholinergic receptors?
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Bethanecol and Pilocarpine.
DON'T degrade quickly. |
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What does Bethanecol do?
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Doesn't pass BBB!
Used for problems in GI and bladder (when they can't contract). |
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What does Pilocarpine do?
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Passes BBB!
Used for glaucoma and increase of saliva. Glaucoma: causes CONTRACTION of the ciliary muscle- enables better drainage. |
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What is Atropine?
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Muscarinic antagonists.
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What is the unique activity of Atropine?
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Dilation of BV in skin.
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What are the effects of Atropine and other anti-muscarinic?
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Confusion, delirium.
Cycloplegia (loss of accomodation). Mydriasis. Inhibits sweating- increase in body temp. Inhibits secretion of tears and saliva. High pulse. |
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What is Ipratropium Bromide?
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Muscarinic antagonist.
Similar to Atropine, but doesn't pass BBB. Used for asthma. |
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What do you use muscarinic antagonists for?
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1. Diagnostics in eye treatments.
2. GI issues. 3. Asthma. 4. Sinus bradycardia- to increase HR. 5. Incontinence. 6. Nerve gas poisoning- atropine (does not solve skeletal muscle problems). |
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What is nerve gas?
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Indirect cholinergic agnoists.
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What are the symptoms of nerve gas poisoning?
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PARA: Bradycardia, constriction of bronchi, secretion of saliva, diarrhea, urination.
SYMPA: sweating, lowering of BP (d/t desensitization of nicotinic receptors). SKELETAL MUSCLE: strong contraction at first, followed by relaxation d/t desensitization. CNS: seizures, inhibition of breathing. |
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What do you use for nerve gas poisoning?
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1. Muscarinic antagonist- like Atropine.
2. Oximes, like Toxinogen, that reactivate AChE. MUST USE QUICKLY. |
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What can't you use nicotinic agonists?
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Too many side effects.
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What are the effects of nicotine?
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PARA: increase secretion- GI, bladder, bronchi constriction.
SYMPA: increase. Tachycardia -> Bradycardia, high BP. SKELETAL MUSCLE: Increase contraction. CNS: Alertness, hyperventilate. |
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How much nicotine is toxic?
What are the symptoms of nicotine poisoning? How do you treat it? |
60mg.
High blood pressure -> low d/t desensitization. Arrhythmia, seizures, no breathing.. Treated by artifical respiration, Atropine for the muscarinic side effects. |
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What happens in Myasthenia Gravis?
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Antibodies against nicotinic receptors.
The drugs can increase functioning at the begininng, but overall hopeless. |
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What do you use for treatment of Myasthenia Gravis?
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Competitive indirect cholinergic agonists- that inhibits AChE and BChE.
Do no cross BBB. Edrophonium (tensilon): for diagnosis. 5-15 min. Pyridostigmin (Mastinon): for treatment. 3-6 hours. Physostigmine: Only in extreme cases- crosses BBB. Used for Atropine poisoning. |
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What is Physostigmine? What do you use it for?
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Indirect Competitive Cholinergic Agonist- inhibits AChE.
Crosses BBB. Used for atropine poisoning. |
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What do Parasympathetic agonists do?
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Lower HR.
Constriction of bronchi. Increase GI, bladder. on sympa: increase sweating, NO CHANGE IN BP. skeletal muscle: contract. |
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What happens to the HR when you apply nicotinic antagonists?
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HR is controlled by the vagus- when the vagus is inactive, HR goes up.
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Name two nicotinic antagonists
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Curare (Tubocurarine)
Succinylcholine (Suxamethonium) |
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What does Curare/Tubocurarine do?
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Nicotinic antagonist in muscle.
1-2 hours. Causes paralysis. side effects: -release of histamine (lowers BP, constricts bronchi). -in high doses, also works on the ganglionic receptor as antagonist. |
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What does Succinylcholine/Suxamethonium do?
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Non-selective inhibitor, both on ganglionic and muscle receptors.
It is an agonist that works as an antagonist d/t desensitization, because it does not break down by AChE (it does by BChE). 1st stage: depolarizing block- channels don't heal from inactivation. lasts a minute. 2nd stage: nondepolarizing block- d/t desensitization. |
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Who is innervated by the sympathetic system?
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Sweat glands- by ACh!
Heart, SMC, internal organs, BV, glands and nerve ends. Kidney - causes secretion of dopamine. Adrenal gland: INNERVATED BY PARA (actually by preganglionic- no ganglion), but releases noradrenaline/adrenaline. |
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How are dopamine/nor/ad created?
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Tyrosine enters the cells using a transporter.
by (Tyrosine hydroxylase) -> DOPA. by (DOPA decarboxylase) -> Dopamine. Dopamine enters vesicles. Can go further: by (Dopamine-b-hydroxylase) -> Noradrenaline. Can go further, to adrenaline. |
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How is dopamine transported into the vesicle?
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They take out H+ and insert dopamine (or noradrenaline- it's not specific).
In the vesicle, it is bound to ATP. |
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What is released along with noradrenaline etc?
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ATP-
P2y: negative feedback. P2x: activated ligand-gated Na channels, that cause depolarization (can add to constriction of BV). |
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How are catecholamines removed from the synpase?
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1. Reuptake (85% of nor).
2. Uptake- into the post-synpase. 3. Diffusion to blood. |
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How are the catecholamines degraded in the cells?
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MAO: On mitochondrial membrane.
Mostly in adrenergic neurons, but also in epithelium of liver and GI. COMT: In the CYTOPLASM of POST-synpase (not just neurons- target cells as well, a lot in GI and liver). |
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How do you decrease amount of catecholamines in synapse?
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alpha-methyltyrosine: inhibits synthesis, does not enable Tyrosine -> DOPA.
Reserpine: Inhibits entry into vesicles, so it accumulates in cytoplasm and is degraded by MAO. |
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How do you increase amount of catecholamines in synpase?
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on the outside- 1. Cocaine (reuptake). MAO sensitive.
on the inside- 2. Amphetamines (reuptake, increase release). Inhibit MAO and MAO insensitive. 3. Ephedrine (reuptake, increase release). MAO insensitive. 4. Tyramine (reuptake, increase release). MAO&COMT sensitive. ALL ARE COMT INSENSITIVE EXCEPT FOR TYRAMINE. |
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What does Cocaine do?
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Reuptake inhibitor- competitive.
Cross BBB. Can cause fibrillation in people with heart problems. Blocks voltage-gated Na channels- causes sedation. |
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What increases מוקדים אקטופיים?
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Adrenergic activity.
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What do amphetamines do?
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(enter the cell using the catecholamine transporter)
Increase release of catech: separate catcech from ATP so it diffuses out, reverse reuptake transporter so it secretes them. Inhibit MAO. |
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What does Ephedrine do?
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Increase release of catech, also acts as direct agonist to adrenergic receptors.
Constricts BV. Cross BBB. |
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What does Tyramine do?
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Release of noradrenaline.
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Adrenergic receptors- which is activated by adrenaline? Noradrenaline?
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Adrenaline: all.
Noradrenaline: all but beta2. |
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Adrenergic receptors?
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a1: SMC of BV.
a2: presynaptic negative feedback. [all b increase cAMP] b1: Heart. b2: SMC (NOT BV!), relaxation of bronchi. b3: Fat cells- lipolysis. |
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What does a1 do?
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Contraction of SMC by activating PKC, that breaks down PIP2 to IP3 and DAG- increase Ca.
-Causes high BP. -Prevents urination by contracting the sphincter (NOT related to relaxation of bladder) -Myosis -Create and secrete semen. -APPOCRINE sweat glands. |
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What does a2 do?
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Lowers cAMP, opens K channels:
Negative feedback in presynaptic adrenergic neurons (NOT TO CONFUSE WITH TRANSPORTER- this is a special receptor!). In the nose- constricts BV (usually causes relaxation). Aggregation of platelets. Inhibit release of insulin (a2 dominant). Inhibits lipolysis (but b3 wins). |
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What does b1 do?
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Heart - increase BOTH contractility (muscle) and HR (nodes).
Kidney- secretion of Renin- increase CO and blood volume. |
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What does b2 do?
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in SMC, causes phsophrylation- thus INactivation- of MLCK.
-RELAXATION of SMC in internal organs- bronchi, GI, BLADDER- prevents urination. -Relaxation of SMC in certain blood vessels- in skeletal muscle and CA, when amounts of adrenaline in blood are HIGH (BV in body are usually a1, but in skeletal muscle and coronary arteries are b2) -Increase glycogen breakdown in skeletal muscle (beta tremor) and liver. -increase insulin secretion by pancreas (but a2 wins). |
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What is Ventolin?
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b2 agonist- relaxes SMC around bronchi.
Overdose causes beta tremor. |
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What is unique about b2?
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Only activated by adrenaline- not noradrenaline.
There is no direct innervation- picks up adrenaline from blood flow. |
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What happens when you activate:
a1? b1? b2? |
a1: constriction of BV- high BP.
b1: Increase in contractility, thus increase in stroke volume. THAT will cause high BP. b2: decrease in BP. |
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List of noradrenergic agonists (=Sympathomimetics)?
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Noradrenaline (all but b2)
Adrenaline (all) Isoprenaline (b) Phenylephrine (a1, some a2) Clonidine (a2) Sulbatamol (b2- ventolin!) Dopamine (D receptors. in high does, also a and b) Dobutamine (b1) |
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What does Noradrenaline do?
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-Increase CO and peripheral resistance- high BP.
-Reflex bradycardia. |
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What does adrenaline do?
When do you use it? |
No massive increase in BP- combination of b1 and b2.
Used during anaphylactic shock- increases BP (a1) and relaxes bronchi (b2). Used to increase local sedatives- a1 does not enable the sedative to run away. |
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What does Isoprenaline do?
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Selective to b.
b1- increaes CO. b2- decrease peripheral resistance. Overall, no change in BP. |
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What does Phenyephrine do?
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Selective to a1- in high doses, also a2.
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What does Clonidine do?
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Selective to a2.
Used for hypertension. |
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What does Salbutamol do?
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Selective to b2.
Ventolin! Can cause Tachycardia and beta tremor in high doses. |
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What does Dopamine do?
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Selective to D receptors.
In high doses, also works on a amd b receptors. |
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What does Dobutamine do?
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Selective to b1.
Given for severe heart failure. |
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List two a-adrenergic antagonists (Sympatholytics/sypathoplegics)?
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Daxazosin (a1)
Phenoxybenazmine (a1, some a2). Stronger, usually given. |
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What are typical side effects of a1-adrenergic antagonists?
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Orthostatic BP drop- usually the sympathetic system kicks in when we stand up.
Tachycardia reflex- lowering BP causes tachycardia. |
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List two b-adrenergic antagonists
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Propanolol (b1, b2). CLASSIC B-BLOCKER.
Atenolol- selective antagonist to b1 (angina pectors). |
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What do you use b-adrenergic antagonists for?
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- Hypertension: they lower CO and DELAY RELEASE OF RENIN.
Make Baroreceptors MORE sensitive. - Angina pectors: ATENOLOL. Decrease workload on heart (works less hard. Since they also decrease BP, heart doesn't need to work as hard anyway. - Slight heart failure: increase the harming sympathetic activity. - Arrhythmia: **Sinus tachycardia- b1-antagonist. **ectopic מוקדים- adrenergic activity increases them. |
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What do you use a-adrenergic antagonists for?
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- hypertension.
- BPH: enlarged prostate, and problems urinating (the antagonists relax both prostate and sphincter). - Pheochromocytoma - tumor in adrenal medulla that causes secretion of adrenaline and noradrenaline, thus hypertension and high HR (HYPERTENSIVE CRISIS). |
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What are typical side effects of b-adrenergic antagonists?
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Low HR.
Heart failure (overdose). Trouble breathing in asthma patient- CANNOT GIVE B-BLOCKERS TO ASTHMA PATIENTS! |
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What do you use b2 antagonists for?
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- Glaucoma (b2 increases creation of fluid).
- b-tremor. - Migraines. - Anxiety attacks. |