MCMP407 Test 2

Central Nervous System and Peripheral Nervous System

Autonomic and Somatic Nervous Systems

Sympathetic and Parasympathetic

The Brain and Spinal Cord

Automatic functions (ex respiration, digestion, cardiac)

Controls things under conscious control.

Gets ready for fight or flight.

Rest and relaxation works in opposition to the sympathetic.

Acetylcholine, muscarine, nicotine

Norepinephrine (noradrenaline) and Epinephrine (Adrenaline)

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.

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)

• 1) Long
• 2)Synapse with postganglionic neurons at or near organ
• 3)Release ACH to activate nicotinic receptors on postganglionic neurons

• 1) Short
• 2) Synapse on the target organ
• 3) Release ACH to activate muscarinic receptors on the target organ

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

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

• 1)Short
• 2)Synapse with postganglionic neurons near spinal cord
• 3) Release ACH to activate nicotinic receptors on postganglionic neurons

• 1) Long
• 2) Synapse on Target Organ
• 3) Release Norepinpethrine to activate adrenergic receptors on target organs

Norepinephrine

• 1) Sweat Glands
• 2) Kidneys
• 3) Adrenal 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)

Sweat glands

1) Post ganglionic neurons to the smooth muscle of the renal vascular bed release dopamine (cause vasodilation)

• 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)

Norepinephrine

• 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

• 1) Nicotinic
• 2) Muscarinic

• 1) Ganglionic
• 2) Skeletal muscle
• 3) Neuronal CNS

• 1) Under somatic control
• 2) This uniqueness allows drug delivery to be localized

M1-5

Found in glands and smooth muscle

M2 is found in the hear MOST IMPORTANT

Ligand Gated Channels

G-protein receptors

7 Transmembrane domain, G protein coupled receptors

Use signal transduction pathway known as Gq

• 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)

• 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

a(alpha) 1, 2 , B

1a, 1b, 1d

A2a A2b A2C

B1, 2, 3

Smooth muscle, particularly vasculature and arterioles

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.

in the heart

In the smooth muscle and some in the heart classified based on drug response but have started looking at genes.structure of each receptor.

Gq follow same signal transduction as M1, 3 , 5

Gi same pathway as m2,4 (coupled to Gi inhibitory)

Gs (coupled to Gs stimulatory) stimulate/activate adenylate cyclase.

• B1 Receptor - Rate of Contraction Increases (Chronotropic)
• B1 Receptor- Force of Contraction Increases (inotropic)

• M2 Receptor- Rate of Contraction Decreases (More pronounced effect on rate of contraction)
• M2 Receptor- Force of Contraction Decreases

a1- vasocontriction

No direct activation (very little control)

a2- vasoconstriction

No direct activation

B2- Vasodilation

• M3- Release EDRF (Endothelial derived releasing factor)
• NO vasodilation but no direct effect

B2- Bronchodilation (this is why asmatics use B2-agonists for brochodilation)

M3- Bronchoconstriction

• 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

B2 agonist

• M3- Bladder wall Contraction
• -Ureter relaxation
• - Spincter (bladder) Relaxation
• - Uterus (pregnant) variable
• - Penis/ vas deferens Erection

• a1- Salivary glands Increase Secretion
• a1- smooth muscle sphincter contract
• a2,B2- Smooth Muscle Walls Relax
• NO effect on GI secretion

• M3- Increase in Salivary Secretion
• - Increase in Smooth Muscle Wall contraction
• - Smooth muscle sphincter relaxation
• - Increase in GI traction Secretion

• 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

Sweat Glands Thermoregulation Increase in secretion

Salivary Glands Both lead to increase in secretion

NO response

• Iris
• -a1-Radial Muscle contraction
• - NO response on circular muscle
• Ciliary muscle
• -B2- Ciliary muscle relaxation
• Ciliary Epithelium
• -B2 Increase in secretion of aqueous humor

• M3
• -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

inside eye shape of lens control deals with accomodation (ability to see up close)

?

hole (like drain) cycles humor out if gets blocked increases interocular pressure

fibrous

B2- Aqueous Humor production

connect muscle to lens

Under radial/circular muscle control

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.

• Liver
• -Glycogenolysis (a1,B2)
• -Gluconeogensis
• Fat Cells
• -Lipolysis (B1,B3)
• Kidney
• -Increase in renin secretion (B1)
• Pancreas
• -Decrease insulin release (a2)

Important because renin and angiotensin system control increase cardiac system. Hypertension patients have problem with this system.

• 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)

• 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)

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.

• 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)

The Cis Conformation

• Dibasic
• Nicotinic receptors less stereoselective

• 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)

• Receptor: M,N
• Cholinesterase sens: Yes
• Clinical Use: Intraocular use for miosis during surgery (eye drop)

• Receptor: (M,N)
• Cholinesterase sens: No
• Clinical Use: Intraocular use for miosis during surgery. (carbomoyl group makes less sensitive),Glaucoma

• Receptor: M
• Cholinesterase: No
• Clinical Use: Gluacoma

• 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.

Because will clock cilliary muscle contraction preventing the opening of the canal of schlemm draining so cannot decrease intraocular pressure.

• Acetylcholinesterase
• -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

• 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

• 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)

• 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.

• -Tetraalkylammounium (multialkyl)
• -Simplest structures
• -Bind to anionic site and block ACh binding
• -Reversible
• -Non-covalent

• 1)CH3 1.0
• 2)C2H5 5.0
• 3)C3H7 100
• 4)C4H9 50

• -Quaternary ammonium alcohol
• -Simplest structures
• -Bind to anionic site and block ACh binding
• -Reversible
• -Noncovalent

• *diagnostic agent in myasthenia gravis (neuromuscular/degenerative disease)
• Skeletal CHolinergic break down.
• If Build up Ach levels can help bring function back.

• Neostigmine, Pyridostigmine, physostigmine
• -carbamates
• -Quaternary or tertiary ammonium groups
• -Reversible
• -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

• 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.

• -Isofluorophosphate; DFP, Echothiophate
• -Organophosphate (very strong electrophile; when serine activated becomes nucleophile want to get together. Draws phosphate to serine.
• -Irreversible
• -Covalent modification to AChE
• -Longer acting
• Used in the treatment of Glaucoma

• -Sarin, Soman
• -Organophosphate
• -Nerve Gases (chemical warfare)
• -Irreversible
• -Covalent modification to AChE
• -Very lipophilic
• -absorbed through the skin
• -distribute across body.

• -Malathion, Diazinon
• -Organophosphates
• -Insecticides (in insects actually activates compounds)
• -Irreversible
• -Covalent modification to AChE
• -Rapidly inactivated in mammals

• Malathion --> (cyt p450 insects) --> malaoxon Oxidize sulfur--> Active substance
• -Ex of prodrug
• -Activated by p450 --> more active version

-Malathion --> (carboxyesterase mammals, birds) Inactive

• -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.

• -Partial hydrolysis so organophosphates strengthens bond.
• -Slows future hydrolysis makes treating hard.

• -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)

• REV
• Diagnostic for Myasthenia Gravis

• REV
• 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.

• REV
• Glaucoma, Alzheimer's disease, antidote to anticholinergic overdose

REV Alzheimer's Disease

• REV
• Alzheimer's disease

• IRREV
• Glaucoma eye drops contract cilliary muscle

• IRREV
• Glaucoma

• -Asthma
• -COPD
• -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

• SLUD: Salivation, Lacrimation, urination, defecation
• Also:
• -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

• -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)

• -Tacrine
• -Rivastigmine
• -Reminyl
• -Memantine

• -Bind to anionic site and black ACh binding
• -reversible
• -non-covalent
• -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)

• -Alzheimer's
• -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

• -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.

• 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.