MCMP407 Test 2
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Two Branches of the Nervous System
Central Nervous System and Peripheral Nervous System
Two subsets of the Peripheral Nervous System
Autonomic and Somatic Nervous Systems
Two Branches of the Autonomic Nervous System
Sympathetic and Parasympathetic
The Central Nervous System is made up by what?
The Brain and Spinal Cord
Function of Autonomic Nervous System
Automatic functions (ex respiration, digestion, cardiac)
Function of the Somatic Nervous System
Controls things under conscious control.
Function of Sympathetic
Gets ready for fight or flight.
Function of Parasympathetic
Rest and relaxation works in opposition to the sympathetic.
Neuron types in the parasympathetic
Acetylcholine, muscarine, nicotine
Neuron types in the ANS
Norepinephrine (noradrenaline) and Epinephrine (Adrenaline)
Characteristics of a Parasympathetic Ganglionic Synapse
1. Action Potential in Preganglionic neuron 2. Sodium moves in 3. Depolarization from Calcium influx. 4. Vesicles filled with Neurotransmitters (Ach) fuse with membrane 5. Release Ach to pass over to Postganglionic neuron 6. Binds to Nicotinic Receptor and Na+ moves into postganglionic (action potential) 7. Acetylcholineesterase is on postganglionic neuron.
Characteristics of Parasympathetic Organ Synpase (starting with Postganglionic)
1. Action potential moves from postganglionic neuron 2. Causes sodium influx leads to depolarization by Calcium influx 3. Ach vesicles fuse and release across synapse 4. Ach binds muscarinic receptor (gprotein) 5. Causes K efflux from the effector organ (also has acetylcholinesterase attached to organ membrane)
Summary of parasympathetic neurons and synapses: Preganglionic neurons
- 1) Long
- 2)Synapse with postganglionic neurons at or near organ
- 3)Release ACH to activate nicotinic receptors on postganglionic neurons
Summary of parasympathetic neurons and synapses: Postganglionic neurons
- 1) Short
- 2) Synapse on the target organ
- 3) Release ACH to activate muscarinic receptors on the target organ
Characteristics of Sympathetic Ganglionic Synapse
1) Action potential causes sodium influx 2) Calcium influx leads to depolarization 3) vesicles of ACH fuse 4) ACH binds to Nicotinic receptor allowing Na+ influx continuing the action potential in postganglionic
Characteristics of sympathetic Organ Synapse
1) Action potential comes through postganglionic neuron 2) Leads to Na influx and Ca influx (depolarization) 3) Fusing of vesicle with NE. 4) NE binds to Adrenergic Receptor in Effector Organ (Gprotein) 5)NO Acetylcholinesterase
Summary of Sympathetic Neurons and Synapse: Preganglionic Neurons
- 2)Synapse with postganglionic neurons near spinal cord
- 3) Release ACH to activate nicotinic receptors on postganglionic neurons
Summary of sympathetic neurons and synapses: Postganglionic neurons
- 1) Long
- 2) Synapse on Target Organ
- 3) Release Norepinpethrine to activate adrenergic receptors on target organs
Most ANS post ganglionic release what neurotransmitter?
Exceptions in the sympathetic nervous system
- 1) Sweat Glands
- 2) Kidneys
- 3) Adrenal glands
Characteristics of Sweat Glands
- 1) Postganglionic neurons involved with stress-related excretion release Norepinephrine "sweaty palms"
- 2) Postganglionic neurons involved with thermoregulation release ACH (the one exception where ACH release postganglionic in sympathetic)
ONE exception where ach released post ganglionic in sympathetic
Characteristics of the kidneys (exception in sympathetic nervous system)
1) Post ganglionic neurons to the smooth muscle of the renal vascular bed release dopamine (cause vasodilation)
Characteristics of Adrenal Gland (exception in the sympathetic nervous system.
- 1) Preganglionic neurons do not synpase in the paravertebral sympathetic ganglion
- 2) Preganglionic neurons synapse directly on the adrenal gland, release ACH, and activate nicotinic receptors on the adrenal gland
- 3) Adrenal galnds release epinephrine into systemic circulation (least selective)
Most postganglionic sympathetic neurons release what neurotransmitter
How do drugs influence the ANS?
- 1) Mimic or block the effects of the two primary neurotransmitters, ACH and NE/E
- 2) Drugs that mimic neurotransmitters are referred to as "receptor agonists" (activate receptor)
- 3) Drugs that block neurotransmitters are referred to as "receptor antagonists"
- -These drugs block the endogenous neurotransmitters from activating receptors
Mimic ACH = cholinergic = muscarinic agonists
Block acetylcholine = anticholinergic = muscarinic antagonist
Mimic norepinephrine = adrenergic = adrenergic agonist
Block Norepinephrine = antiadrenergic = adrenergic antagonist
Classes of Cholinergic Receptors
- 1) Nicotinic
- 2) Muscarinic
Locations of Nicotinic Receptors
- 1) Ganglionic
- 2) Skeletal muscle
- 3) Neuronal CNS
How is the skeletal muscle nicotinic receptor different other nicotinic receptors?
- 1) Under somatic control
- 2) This uniqueness allows drug delivery to be localized
Subclass of muscarinic receptors
Where are M1,3,5 found?
Found in glands and smooth muscle
Where are M2,4?
M2 is found in the hear MOST IMPORTANT
What kind of receptors are Nicotinic?
Ligand Gated Channels
What kind of receptors are Muscarinic?
What are muscarinic receptors?
7 Transmembrane domain, G protein coupled receptors
What sort of transduction system do M1,2,3 use?
Use signal transduction pathway known as Gq
Characteristics of the Gq pathway
- 7 transmembrane domain g protein
- 1) Gq activated by receptor
- 2) Gq activates effector enzyme (Phospholipase C)
- 3) PLC takes membrane lipids (PIP2) and uses to make biochemical substances (IP3 and DAG)
- 4) IP3 increases calcium concentration (triggers release of intracellular storage)
- 5) DAG activates PKC which phosphorylates many things (turns on/off processes)
Characteristics of Gi inhibitor
- 1) Activates G-protein which then activates Gi which:
- a) effects potassium channels (opens/activates), help regulated membrane potential usually more K in cell efflux out (leads to hyperpolarization (-90)
- 2) inhibits Adenylate Cyclase
- a) ATP is not converted to cAMP and reduces cAMP-Dependent Protein Kinase Activity
Overall can make heart muscle harder to fire so can slow heart rate
The different Adrenergic Receptor
a(alpha) 1, 2 , B
Types of a1 receptors
1a, 1b, 1d
Type of a2 receptors
A2a A2b A2C
Type of B receptors
B1, 2, 3
Most alpha 1 receptors are concerned with what?
Smooth muscle, particularly vasculature and arterioles
Where are most a2 receptors found?
Found in presympathetically (feed back receptor in cardiovascular control center in the brainste,. Have general control over sympathetic turn on or off the stem. Affects cardiovasculature.
Where are B1 receptors found?
in the heart
Where are B2 receptors found?
In the smooth muscle and some in the heart classified based on drug response but have started looking at genes.structure of each receptor.
Type of G-protein receptor used in the a1-adrenergic receptor
Gq follow same signal transduction as M1, 3 , 5
What type of signal transduction pathway do a2-adrenergic receptors follow?
Gi same pathway as m2,4 (coupled to Gi inhibitory)
What type of signal transduction pathway do B-adrenergic receptors follow?
Gs (coupled to Gs stimulatory) stimulate/activate adenylate cyclase.
Fuctional responses mediated by the ANS: Heart in sympathetic
- B1 Receptor - Rate of Contraction Increases (Chronotropic)
- B1 Receptor- Force of Contraction Increases (inotropic)
Functional Responses Mediated by ANS: Heart Parasympathetic
- M2 Receptor- Rate of Contraction Decreases (More pronounced effect on rate of contraction)
- M2 Receptor- Force of Contraction Decreases
Functional Responses Mediated by ANS: Arteries Sympathetic
Functional Responses Mediated by ANS: Arteries Parasympathetic
No direct activation (very little control)
Functional Responses Mediated by ANS: Veins Sympathetic
Functional Responses Mediated by ANS: Veins parasympath response
No direct activation
Functional Responses Mediated by ANS: Skeletal Muscle Symp.
Functional Responses Mediated by ANS: Skeletal Muscle Parasym
- M3- Release EDRF (Endothelial derived releasing factor)
- NO vasodilation but no direct effect
Functional Responses Mediated by ANS: Lung Sympath (bronchiolar smooth muscle)
B2- Bronchodilation (this is why asmatics use B2-agonists for brochodilation)
Functional Responses Mediated by ANS: Lung Bronchiolar Smooth Muscle Parasymp
Functional Responses Mediated by ANS: Genitourinary, smooth muscle Sympath
- B2- Bladder wall- relaxation
- B2- Uterus (pregnant) Relaxation
- a1- Uterus (pregnant) Contraction
- a1- Ureter contraction
- a1- Sphincter (bladder)
- a1- Penis/vas deferens Ejaculation *if patient takes drug that leads to sexual disfunct. will stop taking
If pregnany with premature contractions what would you give?
Functional Responses Mediated by ANS: Genitourinary, smooth muscle Parasympath
- M3- Bladder wall Contraction
- -Ureter relaxation
- - Spincter (bladder) Relaxation
- - Uterus (pregnant) variable
- - Penis/ vas deferens Erection
Functional Responses Mediated by ANS: GI tract Sympath
- a1- Salivary glands Increase Secretion
- a1- smooth muscle sphincter contract
- a2,B2- Smooth Muscle Walls Relax
- NO effect on GI secretion
Functional Responses Mediated by ANS: GI Tract Parasympath.
- M3- Increase in Salivary Secretion
- - Increase in Smooth Muscle Wall contraction
- - Smooth muscle sphincter relaxation
- - Increase in GI traction Secretion
Functional Responses Mediated by ANS: Skin and sweat glands sympath
- a1- Hair follicle contract
- - Smooth Muscle piloerection (goose bumps)
- M3- Sweat Glands Thermoregulation- Increase Secretion
- a1- Sweat Glands apocrine (stress) Increase Secretion
- ALL UNDER SYMPATHETIC CONTROL
One instance in which M3 receptors are found in the sympathetic response
Sweat Glands Thermoregulation Increase in secretion
Example of a time in which Para and Sympathetic do not act in opposition
Salivary Glands Both lead to increase in secretion
Functional Responses Mediated by ANS: Skin and Sweat Glands
Functional Responses Mediated by ANS: Eye Sympathetic
- -a1-Radial Muscle contraction
- - NO response on circular muscle
- Ciliary muscle
- -B2- Ciliary muscle relaxation
- Ciliary Epithelium
- -B2 Increase in secretion of aqueous humor
Functional Responses Mediated by ANS: Eye Parasympath
- -Contraction of circular muscle in the iris
- - Contraction of Ciliary muscle in eye
No effect on Iris Radial muscle and ciliary epithelium
- Spokes, dilator muscle
- -contracts in outward direction leading to mydriasis
Colored portion of the eye controls pupils
Circular run circle around iris
Ciliary muscle of eye
inside eye shape of lens control deals with accomodation (ability to see up close)
Canal of Schlemm
hole (like drain) cycles humor out if gets blocked increases interocular pressure
B2- Aqueous Humor production
connect muscle to lens
What controls the pupil?
Under radial/circular muscle control
How might one lose accomodation?
Accomodation - ability to see upclose
If use antimuscarenic to paralyze ciliary/circular muscles.
- -Constriction of pupil (makes smaller)
- -Caused by contraction of circular muscle.
- -M3 agonist promotes contraction Antagonist promotes dilation.
- Pupillary enlargement (dilation) caused by contraction of radial muscle. Mydriac drugs cause dilation of pupils.
- OF the two systems parasympathetic more dynamic. Preference usually not on a1. Anticholernergic preferred.
Functional Responses Mediated by ANS: Metabolic Function (Sympathetic)
- -Glycogenolysis (a1,B2)
- Fat Cells
- -Lipolysis (B1,B3)
- -Increase in renin secretion (B1)
- -Decrease insulin release (a2)
Importance of Kidney metabolic function regulation by sympath
Important because renin and angiotensin system control increase cardiac system. Hypertension patients have problem with this system.
To enhance or mimic the cholinergic system by pharmacologic manipulation
- 1) Nicotinic receptor agonist (might impact ganglia)
- 2) Muscarinic receptor agonist
- 3) AChE Inhibition (increase ACH in synapse longer effect so more opportunity for interaction. (Indirect parasympathomimetic)
To block or inhibit cholinergic system by pharmacologic manipulation must...
- 1) Inhibit choline uptake- Hemicholinium (blocks choline transporter)
- 2) Inhibit vesicular storage- Vesamicol (inhibits vesicular transport which decreases Ach in vesicle --> decrease action.
- 3) Inhibit release- Botulinum toxin (shuts down vesicle/membrane fusion)
- 4) Nicotinic receptor antagonist (block para and sympath)
- 5) Muscarinic receptor antagonist (Important because many drugs classes have anytimuscarenic functions)
Direct acting anticholernergic receptor agonists
Acetylcholine, carbachol, methacholine, bethanechol
*All have esters on one end and trimethylamine
These will not last long in plasma because chewed up short half life systemically.
Primary Characteristics of interaction between acetylcholine at Muscarinic receptors
- Hbonding at Tyr (VI) and thr (V) with carboxyl of ester on ACH
- Ion pairing between ASP (III) CA group and trimethylamine (can also hbrong with hydroxyl on asp)
Which form of acetylcholine is most stable in water?
The Cis Conformation
- Nicotinic receptors less stereoselective
Varenicline Tartrate (Chantix)
- Smoking cessation
- a4B2 Nicotinic receptor partial agonist
- activates nicotinic receptor much less than nicotine Blocks nicotine from binding
- Well Tolerated
- Side effects:
- GI related (Nausea, constipation, gas, vomitting)
- Altered dreams (black box depression suicide)
Clinical Pharmacology of cholinergic receptor agonists: Ach
- Receptor: M,N
- Cholinesterase sens: Yes
- Clinical Use: Intraocular use for miosis during surgery (eye drop)
Clinical Pharmacology of cholinergic receptor agonists: Carbachol
- Receptor: (M,N)
- Cholinesterase sens: No
- Clinical Use: Intraocular use for miosis during surgery. (carbomoyl group makes less sensitive),Glaucoma
Clinical Pharmacology of cholinergic receptor agonists: Pilocarpine
- Receptor: M
- Cholinesterase: No
- Clinical Use: Gluacoma
Clinical Pharmacology of cholinergic receptor agonists: Bethanechol
- Receptor: M
- Cholinesterase Sens: No
- Clinical Use: Urinary retention, post-operative ileus (oral use) muscaranic selective Carbomoyl/Bmethyl
*Post Operative Ileus: Intestine does not want to contract. Want to jump start. Most used intraocular not oral less affect more side effect.
Why are antimuscarinic drugs contraindicated in glaucoma?
Because will clock cilliary muscle contraction preventing the opening of the canal of schlemm draining so cannot decrease intraocular pressure.
Types of Cholinesterases
- -located in synapse
- - substrate selectivity (ach)
- Plasma Cholinesterase
- -Located in plasm (non-neural)
- -Substrate selectivity:
- -ACH, Succinycholine, Local Anesthetics (the half with esters not amines)
- -Any ester containing substrate
Characteristics of hydrolysis by AChE
- Esteratic site
- -Lots of action
- -comprised of triad (Glu, His, Ser)
- -Glu and His activate serine (leads to it acting nucleophilic)
- -Wants to interact with ester
- Anionic Site
- -But no (-charge)
- -comprised of Phe and Trp (two aromatic aa)
- - + charge of achetyl choline N(Ch3)3 interacts with aromatics --> Pi=cation interaction
Steps of AChE
- 1)Interaction with Esteratic Site Anionic site and Ach
- 2)Acetate transferred to the Ser
- 3)Choline then leaves from catalytic site
- 4)Water comes in and hydrolysis of acetate from Ser occurs
- 5)Acetate leaves (Rejuvenates cycle)
Effect of an inhibited AChE
- longer duration of action for Ach
- indirect acting parasympathomimetic
- Do not directly activate musc/nic
- Allows build up of Ach which then activates receptors due to Ach build up in synapse.
Characteristics of AChE inhibitors
- -Tetraalkylammounium (multialkyl)
- -Simplest structures
- -Bind to anionic site and block ACh binding
Relative potency of differing AChe Inhibitors
- 1)CH3 1.0
- 2)C2H5 5.0
- 3)C3H7 100
- 4)C4H9 50
Characteristics of Edrophonium
- -Quaternary ammonium alcohol
- -Simplest structures
- -Bind to anionic site and block ACh binding
- *diagnostic agent in myasthenia gravis (neuromuscular/degenerative disease)
- Skeletal CHolinergic break down.
- If Build up Ach levels can help bring function back.
Characteristics of Acetylcholinesterase inhbitors: carbamates
- Neostigmine, Pyridostigmine, physostigmine
- -Quaternary or tertiary ammonium groups
- -Covalent modification to AChE on serine
- -used in eye drops to treat glaucoma, myasthenthia gravis/ altheizmers
- Cross blood brain barrier
- -least absorption
- -increase SE profile
Characteristics of inhibition of AChE by Neostigmine
- 1) Glu and His activate Ser as nucleophile (this makes up the Esteratic site)
- 2)Esteratic site attacks carbomoyl group
- 3)Carbomyl group is transferred to serine.
- 4) Leaves free OH on drug
- 5) Carbamylation
- -presense of group resistant to hydrolysis (10^7 x slower then acetate hydrolysis)
- -Ties up enzyme prevents Ach from coming and interacting with enzyme (hydrolyzing)
- -inhibits enzyme due to slow hydrolysis not irreversible antagonism
- -Do not have to tie up long to cause pronounced impact on function
- 6) Hydrolyzed drug leaves catalytic site.
Characteristics of acetylcholinesterase inhibitor: Organophosphates
- -Isofluorophosphate; DFP, Echothiophate
- -Organophosphate (very strong electrophile; when serine activated becomes nucleophile want to get together. Draws phosphate to serine.
- -Covalent modification to AChE
- -Longer acting
- Used in the treatment of Glaucoma
Characteristics of AChE Inhibitor: Organophosphates (Nerve Gas)
- -Sarin, Soman
- -Nerve Gases (chemical warfare)
- -Covalent modification to AChE
- -Very lipophilic
- -absorbed through the skin
- -distribute across body.
Characteristics of AChE Inhibitors Oganophosphates (Insecticides)
- -Malathion, Diazinon
- -Insecticides (in insects actually activates compounds)
- -Covalent modification to AChE
- -Rapidly inactivated in mammals
Biotransformation of insecticides
- Malathion --> (cyt p450 insects) --> malaoxon Oxidize sulfur--> Active substance
- -Ex of prodrug
- -Activated by p450 --> more active version
-Malathion --> (carboxyesterase mammals, birds) Inactive
How do organophosphatic drugs selectively affect the cholinergic system?
- -At the Anionic site there is not a charge interaction ...strong electrophile
- -Structure that makes selective for AChE is that it looks similar to Ach strong electrophile. NOthing really else bringing in. Looks like seletive but not. Beacuse AChE inmportant over body. Will see affects quickly. Many other do so but AChE so important-->Rapid pronounced effect.
- -Nucleophile (Esteratic site) attacks electrophile and attaches (F leaves). Phosphorylation of serine.
- -Does not hydrolyze off (faster to just to make new AChE)
- -No very reversible (irreversible)
- -Aging may happen.
What is aging?
- -Partial hydrolysis so organophosphates strengthens bond.
- -Slows future hydrolysis makes treating hard.
What is the antidote or AChE "poisoning"?
- -Pralidoxime Chloride (strong Nucleophile) AKA 2-PAM
- -Antidote for pesticide or nerve gas poisoning
- -Most effective if given within a few hours of exposure because after aging it is harder to remove.
- -Nucleophile attacks phosphate
- -Phosphate goes onto inhibitor leaves attached.
- -Removes phosphate from serine (regenerates)
Type and Clinical Use of Edrophonium
- Diagnostic for Myasthenia Gravis
Type and Clinical use of Neostigmine
- Myasthenia gravis
- post-operative ileus-Trying to jump start smooth muscle
- bladder distention,
- surgical adjunct -allows Ach to build up in skeletal muscle, synapse to compete with muscle blocker.
Type and clinical use of Physostigmine
- Glaucoma, Alzheimer's disease, antidote to anticholinergic overdose
Type and Clinical Use Tacrine
REV Alzheimer's Disease
Type and Clinical use of Donepezil
Type and Clinical Use Isofluorophate
- Glaucoma eye drops contract cilliary muscle
Type and clinical use of Echothiphate
Contraindications to the use of parasympathomimetic drugs
- -Do not want to promote constriction
- -Peptic Ulcer (m3 receptors increase acid release)
- -Obstruction of the urinary or GI tract
- -promote contraction of smooth muscle YIKES
Cholinergic agent side effects and toxicity
- SLUD: Salivation, Lacrimation, urination, defecation
- -Increase sweating
- -Decreased heart rate
- -Pupils constricted
- CNS activation (Ach increase in brain (tremors, insomnia, convulsions)
- IF overdose of cholinergic agonist then just give atropine (or antagonist) but if irreversible order 2-pam
What is Alzheimer's Disease?
- -Atrophy of brain
- -Widening of sulci and thinning of gyri
- -Improper processing of B-amyloid precursor protein (B-APP) leads to toxic form (B-A42) that promotes apoptosis
- -On pathological exam:
- -Senile plaques B-amyloid
- -Nuerofibrillary tangles (neurons and areas around mesh)
- -Loss of cholinergic neurons in brain (play role in memory)
Name four different drugs used to treat Alzheimer's Disease
Characteristisc of Tacrine
- -Bind to anionic site and black ACh binding
- -enhances cognitive ability (improve symptoms)
- -Does not slow progression of disease (eventually get to point where not enough receptors to help anymore)
- -Newer agent (donepezil)
Characteristics of Rivastigmine
- -reversible carbamate AChE inhibitor
- -enhances cognitive ability by increasing cholinergic function
- -Loses effectiveness as disease progresses
- -Side effects: nausea, vomiting, anorexia, and weight loss
- -Newer long-acting carbamate: Eptastigmine
Characteristics of Reminyl
- -Reversible competitive AChE inhibitor
- -Extract from daffodil (Narcissus pseudonarcissus) bulbs
- -loses effectiveness as disease progresses
- -may be a nicotinic receptor agonist
- inhibitors of p450 enzymes (3A4, 2D6) will increase bioavailability
- -IN liver lots of enzymes metabolize drugs lots are redox reactions.
- Run by cytochrome P450 isosomes. 2 biggest isoforms 3A4 2D6.
- Drug-Drug interaction when one inhibits ex 3A4 so give drug B that usually metabed by 3A4 leads to increase in drug  drug B.
Characteristics of memantine
- N-methyl-d-aspartate receptor antagonist
- -NMDA receptors are activated by glutamate (Primary excitatory N.T. is glutatmate) in the CNS in areas associated with cognition and memory.
- -Neuronal loss in Alzheimer's may be related to increased activity of glutamate.
- MAY SLOW PROGRESSION OF DISEASE.
- -Favorable adverse effect profile .
- *Glutamate receptor antagonist
- -blocks in semisevere method so does not impact function of glutamate.
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