Afferent- from Periphery to CNS

Efferent-from CNS to periphery

Sympathetic or Parasym

a) not essential

b) dec heart rate

c) dec GI motility

d) functions as individual systems

e) postgang. neurons branched

a) not essential-S

b) dec heart rate-P

c) dec GI motility-S

d) functions as individual systems-P

e) postgang. neurons branched-S

Sympath/Parasymp

a) Dilates pupils

b) Secretion of renin

c) copious water secretion of saliva

d) stimulates tears

e)stimulates sweating

f) Trachea and bronchioles constrict

a) Dilates pupils-S

b) Secretion of renin-S

c) copious water secretion of saliva-P

d) stimulates tears-P

e)stimulates sweating-S

f) Trachea and bronchioles constrict-P

Cholinergic Receptors

a) what are the receptor subtypes

b) What is the ligand

a) Nicotinic and Muscarinic

b) Acetylcholine

Adrenergic Receptors

a) what are the receptor subtypes

b) What is the ligand

a) alpha and beta adrenergic receptors

b) Epi and NE

What kind of receptors are cholinergic receptors?

Which are muscarinic and nicotinic

Ligand-gated ion channels and GPCRs

Muscarinic-GPCR

Nicotinic-LGIC

How do the cholinergic muscarinic GPCR work?(hint start with Ach binding)

Be specific abt subtypes

Ach bindin-->conformational change-->couples to Gproteins-->biochemical signal

M1,3,5 activate Gq-->PLC--> inc Ca--inc contractio

M2,4 activate Gi-->AC -->dec Ca, inc K efflux, dec contraction/BP

Where are Nicotinic Ach receptors?

Where are Muscarinic Ach receptors?

N: CNS, PNS ganglia, PNS adrenal medulla, NMJ

M: CNS, PNS effector organs

What happens when cholinergic muscarinic(M3) receptors are activated?

What organs are do Muscarinic receptors affect?

a) M3 activates Gq-->PLC-->DAG & IP3-->Ca-->muscle contraction and inc secretion

b) bladder, GI smooth muscle, secretory organs

What happens when cholinergic muscarinic(M2) receptors are activated?

What organs are do Muscarinic receptors affect?

a) M2 activates Gi--> inhibit Adenyl Cyclase-->cAMP reduced-->dec PKA-->dec phos of Ca-->dec Ca & dec contraction

b) Cardiac smooth muscle

Ach

a) medicinal chemistry (membrane penetration)?

b) synthesis and degredation

c) half-life

d) target MOA

e) tissue MOA

a) quarternary amine, charged and can't penetrate membranes

b) synthesized(Achtransferase) and degraded locally(Achesterase)

c) short half-life

d) ion channels (nicotinic) GPCR (muscarinic)

e) CNS, PNS(sym and para) Somatic

Bethanechol

a)Pharmacological Class

b) Rx

c)Med Chem

d)half-life

e) selectvity

a) Direct Muscarinic Agonist

b) Urinary retention

c) quarternary amine, cannot penetrate CNS

d) longer than Ach, not metabolized by Achesterase

e) more selective to muscarinic receptor

Bethanechol

a) Therapeutic effects (sym or para)

b) Undesirable effects (sym or para)

c) Where are its targets? ( ganglia?)

a) Stimulate bladder and GI smooth muscle-inc urination & inc intestinal motility (para)

b) stimulation in multiple organs- inc sweating (sym), dec BP (para), nausea, abdominal pain, diarrhea (para) salivation (para)

What interactions may be caused by generalized cholinergic stimulation?

Atropine

a)Pharmacological Class

b) Rx

c)Med Chem

d)half-life

e) selectvity

a) Direct acting, muscarinic antagonist

b) antispasmodic, antisecretory, induce pupol dilation

c) tertiary amine, uncharged, penetrates CNS, plant alkaloid

d) longer than Ach, not hydrolyzed by Achesterase

e) selective for muscarinic

Atropine

a) Therapeutic effects (sym or para)

b) Undesirable effects (sym or para)

c) Where are its targets? ( ganglia?)

a) blockade of bladder, GI, bronchial, optical smooth muscle(para)

b)  @ M2 inc heart rate, dec salivation (para), dec sweating(symp)

What are some drugs with generalized cholinergic inhibition?

What are the common undesirable effects?

Anti-histamines, antidepressants

dry mouth, urinary retention, blurred vision

Choline is actively transported across the membrane with Na (rate limiting step)

Choline and Acetyl CoA from the mitochondria are put together by choline acetyl transferase

Voltage gated Na channels (Depolarization) cause Ca channels to open, inc in intracellular Ca causes exocytosis of the vesicle

Ach is  released into the synapse

What happens during Ach degredation and signal termination?

Ach is hydrolyzed by Achesterase into choline and acetate

signal is terminated within msec due to hydrolisis, Ach receptors are subject to downregulation and desensitization for hrs-days

Synthesis of Ach, Uptake into storage vesicles, Ach release, degradation and recycling of choline

They affect transporters or release of enzymes

Physostigmine

a)Pharmacological Class

b) Rx

c)Med Chem

d)half-life

e) selectvity

a) natural plant, parasympathomimetic, indirect acting cholinergic agonist, reversible Achesterase inhibitor (substrate analog)

b) atony, enhance bladder and GI motility, glaucoma, overdose of anticholinergics

c) substrate analog for Achesterare, enters CNS

d) gives Ach a longer half lfie

e) prolongs Ach binding to nicotinic and muscarinic (symp and para)

Physostigmine

a) Tissue MOA

b) AE

a) inc bladder and GI motility, contracts pupils, lower pressure

b) reduce heart rate (autonomic), paralysis if excess Ach at nicotinic NMJ (somatic), convulsions if excess Ach in CNS

Hemicholinium, Vesamicol and Botulinum toxin are all what class of drugs? (specific)

How does each affect Ach?

Indirect acting cholinergic antagonists (parasympatholytics)

Hemi: Inhibits Choline transport/reuptake into neuron

Vesam: inhibits Ach transport into synaptic vesicles

Bot:Inhibits exocytotic release of Ach from synaptic vesicles

Indirect choline antagonist (parasympatholytic)

Dry mouth, dec sweating, Inc heart rate, urinary retention

CNS, PNS-ANS-Sympathetic

NOT in the somatic or parasympathetic systems!!!

What affect does activation of a2 receptors have  on NE?

Pre or Post synaptic?

It dec the amount of NE

a2 stimulates Gi which ends up inhibiting Ca needed for vesicle fusion. (feedback inhibition)

Presynaptic

What are the effects of stimulating β adrenergic receptors?

specicfy 1 2 &3

What is a vasopressor?

What is an ionotriope?

V: increase vasoconstriction (inc BP)

I: increase contractility (inc Cardiac Output)

Which adrenoreceptor?

a) bronchodilation

b) increase release of renin

c) Inc glucagon release

d) vasodilation

e) vasoconstriction

f) Inhibition of insulin release

g) Inc peripheral resistance

a) bronchodilation- B2

b) increase release of renin-B1

c) Inc glucagon release-B2

d) vasodilation-B2

e) vasoconstriction-a1

f) Inhibition of insulin release-a2

g) Inc peripheral resistance-a1

Epinephrine

a) Rx

b) Pharmacologic Class

c) Med Chem

a) acute asthma, anaphylactic shock, cardiac arrest,used with anesthetics

b) direct acting adrenergic agonist, catecholamine, sympathomimetic, + inotrope, +chronotrope

c) metabolized by COMT and MAO, short DOA

Epinephrine

greater affinity for a or B

It stimulates B₂ which increases glucagon release (more glucose)

It also stimulates a₂ which inhibits the release of insulin(more glucose)

Norepinephrine

a) Rx

b) Pharmacologic Class

c) Med Chem

d) greater affinity fore alpha or beta?

a) shock

b) direct adrenergic agonist, sympathomimetic, catecholamine

c) metabolized by COMT and MAO

d) alpha

very little activity on Beta receptors

Effects seen on alpa1 (vasoconstriction, Inc BP and dec HR due to feedback)

Phenylephrine

a) Therapeutic Class

b) Pharmacologic Class

c) Med Chem

a) Rx nasal congestion, raise BP
b) direct, selective alpa-1 adrenergic agonist, sympathomimetic, vasopressor

c) not metabolized by COMT-longer DOA, acts primarily on alpha adrenergic receptors

Clonidine

a) sympatholytic or sympathomimetic

b) can it penetrate the CNS

c) What is its tissue MOA

d) side effects

a) sympatholytic

b) yes, nonpolar

c) reduces overall sympathetic tone

d) insomnia, hyperactivity

Dobutamine

a) Rx

b) how does it affect Cardiac Output

c) sympatholytic or mimetic

d) does it penetrate the CNS

e) DOA

f) affects which receptors

a) CHF

b) Inc CO

c) sympathomimetic

d) no, it is a catechol derivative and polar

e) short, administered IV

f) Beta-1>Beta2

Albuterol

a) Rx

b) Pharmacologic Class

c) sympatho___

d) CNS penetration?

e)DOA

a) asthma

b) direct acting Beta2 adrenergic agonist

c) sympathomimetic

d) No, polar

e) not a catechol derivative, not metabolized by COMT, longer DOA

Prazosin

a) Rx

b) sympatho___

c) pharm. class

d) how does it affect HR, why?

a) HTN

b) sympatholytics

c) direct acting, selective alpa-1 adrenergic antagonist

d) dec HR because it lowers BP  causing a baroreceptor reflex to Inc HR

Prazosin

a) affect on Peripheral Resistance and Cardiac Output

b) Therapeutic uses

c) AE

a) lowers PR, minimal changes in CO

b) HTN, BPH

c) first dose syncope, dizziness, nasal congestion, sexual dysfunction

What effect will pretreatment with an alpa-1 blocker have on cardiac contractility?

peripheral vasoconstriction?

a)No effect

b) decrease in constriction

Yohimbine

a) Rx

b) Pharm class

c) sympatho____

d) CNS penetration?

e) side effects

a) sexual dysfunction

b) direct alpha-2 adrenergic antagonist

c) sympathomimetic

d) yes even though its polar

e) HTN, dizziness, inc HR, sleeplessness

Metoprolol

a) Rx

b) Pharm class

c) sympatho____

a) HTN

b) direct acting Beta-1 antagonist

c) sympatholytic

B/c metoprolol is a Beta-1 blocker which affects heart contractility (neg inotrope)

It does not have a great effect on Beta-2 (bronchoconstriction) or alpha-1(peripheral vasodilation)

Which are catecholamines?

NE, Epi, Serotonin, Histamine Dopamine

What is the precursor for each

Cat: Dopamine, Epi, NE (tyrosine)

Serotonin (tryptophan)

Histamine(histidine)

T/F

MAO cannot oxidize serotonin

FALSE

 it can because it is a monoamine

What is the rate limiting step for adrenergic agonists?

What is the primary mechanism to terminate NE action?

Agonist: Tyrosine hydroxlated to form DOPA

Antagonist

NE axn: reuptake into neuron

1) Tyrosine is brought in by ATP dependent Na co-transport

2) Tyrosine is hydroxylated into DOPA*

3) DOPA-->Dopamine-->transported into vesicle by ATP dependent H antitransport

4) Dopamine is hydroxylated to form NE

Which biogenic amines are stored in the vesicles of presynaptic neurons?

Which are stored in chromaffin cells of the adrenal medulla?

Vesicles: NE and Dopamine

AM: Epi and NE

T/F

reuptake of NE is an energy dependent process

TRUE

Na/K ATPase

Indirect Agonist or Antagonist

a) inhibit reuptake of NE into presynaptic neuron

b) Inhibit NE metabolism by MAO

c) Inhibit tyrosine hydroxylase

d) Inhibit DOPA decarboxylase

e) disrupt NE storage in synaptic vesicles

a) inhibit reuptake of NE into presynaptic neuron-Agonist

b) Inhibit NE metabolism by MAO-agonist

c) Inhibit tyrosine hydroxylase-antagonist

d) Inhibit DOPA decarboxylase-antagonist

e) disrupt NE storage in synaptic vesicles-antagonist

Which has a more potent antagonist effect?

AMPT-inhibit tyrosine hydroxylase

Carbidopa-Inhibit DOPA decarboxylase