Pharmacology Test 2

Tyrosine from diet is converted to Dopa by tyrosine hydroxylase (rate limiting step)
Dopa to Dopamine by dopamine decarboxylase
Dopamine to nEpi by dopamine b-hydroxylase
nEpi to Epi by phenylethanolamine-N-methyl transferase

Oculomotor Nerve
eye lens: causes accommodation by relaxing suspensory ligaments
eye pupil: causes sphincter muscle to contract to constrict pupil

Facial Nerve
Lacrimal gland: causes tearing
Sublingual and submandibular gland: causes salivation

Hypoglassopharyngeal Nerve
Parotid Gland: causes salivation

Vagus Nerve
Heart: slow HB
Lungs: constrict to decrease airflow
Stomach: increase motility & gastric acid secretion
Liver: increase glucose storage
Gall bladder: increase bile secretion
Small inestines & proximal colon: increase peristalsis

Penis: erection
Rectum & Bladder: defication, urination by causing internal sphincter to relax & muscular wall contracts

adrenal medulla
kidney
pilomotor muscles
sweat glands
spleen
BP mainly controlled by SNS

ciliary muscles of the eye
lacrimal gland
gastric secretions

All are cholinergic, Ach has same affinity for all
Muscarinic (m1-m5) vs Nicotinic (Nn & Nm)

Hexamethonium
Trimethaphan
Mecamylamine

Tubocurarine
Vecuronium
Atracurium

(a1)2B1ED
Na+ and K+ channels

(a3)\\2(B4)3
found at autonomic ganglia, adrenal medulla
Na+ and K+ channels

(a4)2(B4)3
CNS Pre & post junctional
Na+ and K+ channels

(a7)5
CNS pre and post synaptic
Ca2+ channels

Coupled to Gq
activates PLCb, IP3 & DAG
IP3 interacts with ER to release Ca2+
PKC increased
increase MAP kinases

Coupled to Gi
decreases cAMP
decreases adenylyl cyclase
decrease v-gated Ca2+ channels
increases K+
increases MAP kinases

Cerebral cortex, hippocampus (alzheimer's dopaminergic cells are dying) & striatum (nuclie in basal ganglia important for motor activity)
Autonomic Ganglia
Glands (gastric & salivary): increases secretions
Lacrimal gland has mostly M1 and some M3 (facial nerve pSNS)
Parietal Cells: increase secretions (vagus nerve, pSNS)

Coupled to Gi
CNS, heart, smooth muscle, autonomic nerve terminals
SA/AV node: inward rectifying K+ channels, decrease HR
Atrium: refractory period contraction
Smooth muscle: contraction

glandular secretions
smooth muscle cells: ciliary muscles, M3 dominates, but M2 also present
vasculare endothelium: synthesis of NO to dilated BV

activate Gp
increase PLCB
PIP2 --> DAG + IP3
IP3 releases Ca2+ from ER
DAG works with Ca2+ to activate PKC
PKC phosphorylates different proteins

M1, M3, M5 Cascade

Gi is activated
BD subunit activated K+ channels to increase K+ conductance, hypoerpolarization
Alpha subunit inhibits adenylyl cyclase which causes a decrease in cAMP & Ca2+

Ach made from choline that is taken up through a Na+ cotransport channel, Choline and Na+ in
Choline + Acetyl-CoA from mitochondria made into Ach by choline acetyl transferase
Ach is pumped into vesicles by a channel that pumps H+ out and Ach in

AP depolarizes membrane, v-gated Ca2+ channels to open, Ca2+ flows in
Ca2+ binds to VAMPS on the vesicle causing it to bind with SNAPS at the synaptic terminal causing vesicle to fuse
Ach travels across cleft to bind with muscarinic or adrenergic receptors (presynaptic & postsynaptic)
ACHE present in cleft to hydrolyze Ach back to Choline & acetate, has 2 active centers (anionic site & histidine serine esteratic site) that Ach binds to
Choline recycled with Na+ cotransport mechanism

null

Hemicholinium (HC-3): blocks choline uptake, blocks Na+/Choline cotransport
Vesamicol: blocks Ach uptake into vesicles
Botulinum toxin: prevents vesicle fusing
Latrotoxin: spider venom, enhances vesicle fusing
Physostigmine & Neostigmine: blocks AchE

1.AChE - Acetylcholinesterase
True cholinesterase
Found in cholinergic neurons, cholinergic synapse, RBC [not in plasma], and NMJ)
Hydrolyzes ACh rapidly, main reason why Ach doesn't last long in cleft
Both nerves and muscles synthesize AChE

2.BuChE -Butyrylcholinesterase (pseudo-cholinesterase)
Obtained via splicing
Present at NMJ, plasma, liver
Hydrolyzes ACh slowly

Succinylcholine: agonists of Nm receptors, causes relaxation transientyl
Procaine: is a local anesthetic, similar to proparacaine, imp in GLC

Cardiovascular: Blood vessels do not receive pSNS but endothelium possess M3; leading to vasodilation NO release
Heart – SA – decrease HR
GI – Increased tone, peristaltic activity, secretions from parietal cells (M1)

Urinary tract – Contraction of the detrusor muscle(M3) and relaxation of trigone and sphincter (urination)
Eye – miosis (constriction) and contraction of ciliary muscle (accomm) decrease IOP (ciliary muscles connect to trab mesh); increase lacrimal secretion (M3)

Ateriole endothelial cells have smooth muscle bundle underneath
Endothelial cells have M3 receptors which mobilize Ca2+
Ca2+ activates nitric oxide synthase NOS which cleaves arginine into citrulline giving off NO which diffuses into the smooth muscle & latches onto guanylate cyclase converting GTP to cGMP (cGMP causes relaxation)

have and integral ion channel
located at plasma membrane
permeable to cations, not anions
5 subunits each with 4 TM domains

Tyrosine from diet is brought into the varicosity of an adrenergic fiber by a Na+ dependent transporter, converted to Dopa by tyrosine hydroxylase (rate limiting). Dopa changed to dopamine by dopamine decarboxylase. Dopamine taken up into vesicles

Dopamine then becomes nEpi by dopamine hydroxylase. NEPI is stored in vesicles until an AP activates Ca2+ channels causing SNAPs and VAMPs to interact and the vesicle fuzes, dumping its contents. nEpi travels a longer distance to receptors than Ach

Both degrade nEpi
MAO on surface of mito of neurons & periph organs, rich in liver/kidney, more specific for Epi
COMT in cyto of postsynaptic cells/peripheral organs, NOT found in adrenergic neurons, rich in liver/kidney, more specific for dopamine

Uptake I: major mode of clearance, back into the original neuron that released it
Uptake II: uses different transporter and occurs in the postsynaptic neuron
after uptake nEpi is broken down by MAO and COMT, inactive byproducts are released into urine

Reserpine: blocks dopamine from entering vesicles
Guanethedine: slowly replaces nEpi in the vesicles so that when an AP comes no nEpi is released
Bretylium: causes the adrenergic fiber to hyperpolarize thus preventing fusing

alpha-2 adrenergic receptor on presynaptic membrane, nEpi binds so if too much, the feedback mechanism opposes exocytosis by reducing cAMP thus Ca2+ influx, esp imp in brain
Too much nEpi causes euphoria then anxiety
Too little nEpi causes depression

In the SNS, neuropeptide Y (NPY) and ATP are also in the vesicles with nEpi so when nEpi is released, these are released with it.
Outside of the cell, ATP can act as a NT with a variety of responses
NPY is not true NT, may have some paracrine functions

Vanilymandelic acid (VMA): is a metabolite dumped into the urine and there will be elevated levels in those with pheochromocytoma, a form of CA in the adrenal gland where the cells are making catecholamines (Epi, nEpi, dopamine) uncontrollably

Monoamine oxidase
MAO A: Anywhere & everywhere
MAO B: only in Brain

Cocaine/imipramine: blocks uptake I mech, nEpi accumulates causing euphoria then anxiety, imipramine is tricyclic antidepressant
Glucocorticoids: Uptake II inhib
Metyrosine: tyrosine hydroxylase (TOH) inhibitor
Carbidopa: dopa decarboxlase inhib

Disulfiram: dopamine hydroxylase inhib
Reserpine: prevents NE storage
Tranylcypromine/Selgiline: MAO inhib
Entacapone: inhibit COMT (treat severe depression)

2 families: alpha & beta adrenergic receptors
Classified based on affinity for nEpi, Epi, & Isoproterenol (Iso)
Isoproterenol mimics the effects of adrenergic postganglionic fibers of SNS (sympathomimetic)

highest affinity for Epi then nEpi, almost none for Iso
found in smooth muscle cells like iris & vasculature

Affinity for Iso, then Epi then nEpi
nEpi can't activate B2, only B1 (esp in heart)

B2 largely activated by epi from adrenal medulla
Found in cardiac muscles (B1 & B2 but B1 dominates)
Iso interacts with B2 only

3 subtypes, B1, B2, B3

A1: post-synaptic receptors like smooth muscle cells
A2: usually pre-synaptic receptors, aka auto-receptors

B cells of pancreas that release insulin in response to glucose
Ciliary epithelial cells that secrete aqueous when activated, can use A2 receptors to treat GLC
Platelets, A2 receptors are useful in preventing platelet aggregation

Coupled to Gq g-protein, like M1, M3, M5
activate Gp
increase PLCB
PIP2 --> DAG + IP3
IP3 releases Ca2+ from ER
DAG works with Ca2+ to activate PKC
PKC phosphorylates different proteins

coupled to Gi g-protien, just like M2 & M4
Gi is activated
BD subunit activated K+ channels to increase K+ conductance, hyperpolarization
Alpha subunit inhibits adenylyl cyclase which causes a decrease in cAMP & Ca2+

B1, B2, B3

Affinity: Iso > Epi > nEpi

B1 affinity nEpi=Epi

B2 epi >>nEpi, almost none from nEpi

Iso interacts with B2 only

Found in cardiac muscles (B1 & B2 but B1 dominates)

Coupled to Gs (exact opposit of Gi) exact oppisite of M2, M4, a2

Gs activated

increases adenylyl cyclase

increases cAMP

increase cAMP-dependent protein kinase (PKA)

increase Ca2+ & phosphorylation of proteins

a1--Epi>nEpi--Gq--IP3/Ca2+;DAG

a2--nEpi>Epi--Gi-- less cAMP

B1--nEpi=Epi--Gs-- more cAMP

B2--Epi>nEpi--Gs-- more cAMP

Vasoconstriction: skin & abdominal viscera

SNS controls BP b/c BV has a1 R that can incr PVR thus incr BP, pSNS controls HR

Mydriasis: iris radial musc Ca2+ induced contracts(dilation)

Prevent urination: internal sphincter of bladder contracts

(-)feedback nEpi: prevent nEpi release from presyn. fiber

Inhibit Insulin release from pancreatic B cells

Reduce aqueous secretion

tachycardia: B1 on SA node opposes M2, inc cAMP, inc Ca2+

inc myocardial contract: B1 on heart wall inc cAMP, inc PKA, phosphrylate L-type Ca2+ ch. so inc Ca2+

inc cond vel: B1 on AV node/Purkinje (dec delay time in AV node, inc cond vel of purk)

Chronotropic: affects in HR

Inotropic: affecting the force of muscle contraction

Dromotropic: affecting conductivity of a nerve fiber

vasodilation in skeletal vascular beds: BVof skel musc B2>a1 R

Brochodilation: M3 & B2

Inc glycogenolysis: epi activates musc/liver to rel glucose from glycogen

Inc release of glucagon: a cells from panc have B2 R, to inc glu on plasma

Relaxation of uterine smooth muscle: useful to fix premature labor

B2(Gs, inc cAMP vasodil)

a1/M3 R (Gq, inc Ca2+ via IP3 constrict)

INC cAMP=vasodilate (constriction in heart)

INC Ca2+ = vasoconstrict

increased lipolysis, B3 found on adipocytes