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85 Cards in this Set

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What does Hemicholinium do?
Limits entry of Choline into the cell, by inhibiting its transporter (competitive).
What do Vesamicol do?
Inhibits transoprter B, that transports acetylcholine into the vesicles.
What does Butulonium toxin do?
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).
Where do you find AChe?
BChE?
AChE: post-synpatic membrances.
BChE: blood (which is why ACh cannot function as a drug).
What is the structure of the Nicotinic ACh receptor?
Ligand-gated ion channel.
Not selective- but overall Na flows in so there is depolarization.
What types of Nicotinic receptors are there?
Nn: In neurons and postganglion neurons of ANS.
Nm: In skeletal muscle.
What is the structure of the muscarinic receptor?
GPCR- second messengers!
M1-M5: uneven number are excitatory, even numbers are inhibitory.
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.
What is the mechanism of excitatory muscarinic ACh receptors?
GPCR causes breakdown of PIP2 to IP3 and DAG.
IP3- hydrophilic- release Ca from inside cell.
DAG- hydrophobic- activates PKC.
What does M3 cause?
* Contraction of SMC.
* Excretion of glands that receive sympathetic cholinergic.
* On endothelial cells- cause secretion of NO that relaxes.
What is the mechanism by which ACh causes relaxation of blood vessels through M3 receptors?
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.
How does IP3 recruit Ca from intracellular storage in SMC?
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.
What do we use NO for?
Dilation of BV by relaxation of SMC.
Used in angina pectoris, Viagra.
What are the sources of NO during an erection?
> NO is released from NANC
> NO is released from activated endothelial cells.
How does NO cause dilation of BV?
NO activated guanylate cyclase to creap cGMP from GTP.
cGMP activates PKG, that dephosphorylates myosin- relaxation..
How does Viagra work?
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.
What does M2 do, both in heart and neurons (negative feedback)?
Its GPCR causes opening of K channels (beta-gamma subunits) and lowering of cAMP (a-subunit).
Do you have voltage-gated Na channels in the SA node?
Nope- only Ifunny and voltage-gated Ca channels.
What does cAMP do in the SA node?
Makes Ifunny more sensitive.
Causes phosphorylation of Ca channels by PKA.
Where do you find ATP in vesicles?
ACh, Noradrenalin etc.
It is a coreceptor.
What receptors does ATP have?
P2y: negative feedback on pre-synapse.
P2x: post-synpase (causes contraction of muscles).
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.
What happens after activation of M3 receptors?
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.
What is the main function of M2 in the heart?
Decrease sympathetic activity.
What does M1 do?
Increase secretion of Histamine, that causes secretion of acid from parietal cells.
What are two agonists to Muscarinic Cholinergic receptors?
Bethanecol and Pilocarpine.
DON'T degrade quickly.
What does Bethanecol do?
Doesn't pass BBB!
Used for problems in GI and bladder (when they can't contract).
What does Pilocarpine do?
Passes BBB!
Used for glaucoma and increase of saliva.
Glaucoma: causes CONTRACTION of the ciliary muscle- enables better drainage.
What is Atropine?
Muscarinic antagonists.
What is the unique activity of Atropine?
Dilation of BV in skin.
What are the effects of Atropine and other anti-muscarinic?
Confusion, delirium.
Cycloplegia (loss of accomodation).
Mydriasis.
Inhibits sweating- increase in body temp.
Inhibits secretion of tears and saliva.
High pulse.
What is Ipratropium Bromide?
Muscarinic antagonist.
Similar to Atropine, but doesn't pass BBB.
Used for asthma.
What do you use muscarinic antagonists for?
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).
What is nerve gas?
Indirect cholinergic agnoists.
What are the symptoms of nerve gas poisoning?
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.
What do you use for nerve gas poisoning?
1. Muscarinic antagonist- like Atropine.
2. Oximes, like Toxinogen, that reactivate AChE. MUST USE QUICKLY.
What can't you use nicotinic agonists?
Too many side effects.
What are the effects of nicotine?
PARA: increase secretion- GI, bladder, bronchi constriction.
SYMPA: increase. Tachycardia -> Bradycardia, high BP.
SKELETAL MUSCLE: Increase contraction.
CNS: Alertness, hyperventilate.
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.
What happens in Myasthenia Gravis?
Antibodies against nicotinic receptors.
The drugs can increase functioning at the begininng, but overall hopeless.
What do you use for treatment of Myasthenia Gravis?
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.
What is Physostigmine? What do you use it for?
Indirect Competitive Cholinergic Agonist- inhibits AChE.
Crosses BBB.
Used for atropine poisoning.
What do Parasympathetic agonists do?
Lower HR.
Constriction of bronchi.
Increase GI, bladder.

on sympa: increase sweating, NO CHANGE IN BP.
skeletal muscle: contract.
What happens to the HR when you apply nicotinic antagonists?
HR is controlled by the vagus- when the vagus is inactive, HR goes up.
Name two nicotinic antagonists
Curare (Tubocurarine)
Succinylcholine (Suxamethonium)
What does Curare/Tubocurarine do?
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.
What does Succinylcholine/Suxamethonium do?
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.
Who is innervated by the sympathetic system?
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.
How are dopamine/nor/ad created?
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.
How is dopamine transported into the vesicle?
They take out H+ and insert dopamine (or noradrenaline- it's not specific).
In the vesicle, it is bound to ATP.
What is released along with noradrenaline etc?
ATP-
P2y: negative feedback.
P2x: activated ligand-gated Na channels, that cause depolarization (can add to constriction of BV).
How are catecholamines removed from the synpase?
1. Reuptake (85% of nor).
2. Uptake- into the post-synpase.
3. Diffusion to blood.
How are the catecholamines degraded in the cells?
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).
How do you decrease amount of catecholamines in synapse?
alpha-methyltyrosine: inhibits synthesis, does not enable Tyrosine -> DOPA.
Reserpine: Inhibits entry into vesicles, so it accumulates in cytoplasm and is degraded by MAO.
How do you increase amount of catecholamines in synpase?
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.
What does Cocaine do?
Reuptake inhibitor- competitive.
Cross BBB.
Can cause fibrillation in people with heart problems.

Blocks voltage-gated Na channels- causes sedation.
What increases מוקדים אקטופיים?
Adrenergic activity.
What do amphetamines do?
(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.
What does Ephedrine do?
Increase release of catech, also acts as direct agonist to adrenergic receptors.
Constricts BV.
Cross BBB.
What does Tyramine do?
Release of noradrenaline.
Adrenergic receptors- which is activated by adrenaline? Noradrenaline?
Adrenaline: all.
Noradrenaline: all but beta2.
Adrenergic receptors?
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.
What does a1 do?
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.
What does a2 do?
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).
What does b1 do?
Heart - increase BOTH contractility (muscle) and HR (nodes).
Kidney- secretion of Renin- increase CO and blood volume.
What does b2 do?
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).
What is Ventolin?
b2 agonist- relaxes SMC around bronchi.
Overdose causes beta tremor.
What is unique about b2?
Only activated by adrenaline- not noradrenaline.
There is no direct innervation- picks up adrenaline from blood flow.
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.
List of noradrenergic agonists (=Sympathomimetics)?
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)
What does Noradrenaline do?
-Increase CO and peripheral resistance- high BP.
-Reflex bradycardia.
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.
What does Isoprenaline do?
Selective to b.
b1- increaes CO.
b2- decrease peripheral resistance.
Overall, no change in BP.
What does Phenyephrine do?
Selective to a1- in high doses, also a2.
What does Clonidine do?
Selective to a2.
Used for hypertension.
What does Salbutamol do?
Selective to b2.
Ventolin! Can cause Tachycardia and beta tremor in high doses.
What does Dopamine do?
Selective to D receptors.
In high doses, also works on a amd b receptors.
What does Dobutamine do?
Selective to b1.
Given for severe heart failure.
List two a-adrenergic antagonists (Sympatholytics/sypathoplegics)?
Daxazosin (a1)
Phenoxybenazmine (a1, some a2). Stronger, usually given.
What are typical side effects of a1-adrenergic antagonists?
Orthostatic BP drop- usually the sympathetic system kicks in when we stand up.
Tachycardia reflex- lowering BP causes tachycardia.
List two b-adrenergic antagonists
Propanolol (b1, b2). CLASSIC B-BLOCKER.

Atenolol- selective antagonist to b1 (angina pectors).
What do you use b-adrenergic antagonists for?
- 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.
What do you use a-adrenergic antagonists for?
- 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).
What are typical side effects of b-adrenergic antagonists?
Low HR.
Heart failure (overdose).
Trouble breathing in asthma patient- CANNOT GIVE B-BLOCKERS TO ASTHMA PATIENTS!
What do you use b2 antagonists for?
- Glaucoma (b2 increases creation of fluid).
- b-tremor.
- Migraines.
- Anxiety attacks.