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63 Cards in this Set

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Which branch of the ANS utilizes thoracolumbar outflow?
Sympathetic (fight or flight)
Which branch of the ANS utilizes craniosacral outflow?
Parasymp (conservation of energy, rest and digest)
Sympathetic NS:
NTs involved
Result of Stimulation
Receptors Involved
Pregang: ACh to activate Nicotinic receptors

Postgang: NE released except in adrenal medulla (Epi: 80%)

Target Cell receptors: adrenoreceptors: alpha-1, alpha-1, beta1, beta2, beta3
NE:
Synthesis
Storage
Termination of Effect
-Synthesized from DA (which is synthesized via Tyrosine and Tyrosine Hydroxylase) in preganglionic nerve terminal
-Must be stored in vesicles
or would be metabolized by monoamine oxidase (MAO)

-Termination via:
1) Removal from synaptic cleft: reuptake via NET
2) Negative feedback via presynaptic alpha-2 receptors
3)Co-transmitters (modulators)
Reserpine:
Mechanism
Blocks uptake of NE into vesicles
Gunethidine:
Mechanism
Blocks release of NE into synaptic cleft
Effect of cocaine and trycyclic antidepressants on NE.
Cocains inhibits NET and inhibits reuptake of NE
Describe the mechanisms of sympathetic signal transduction for alpha-1, alpha-2, beta-1, and beta-2 receptors.
All autonomic receptors are coupled to GTP-binding proteins with second-messenger systems!!

Alpha-1: activate phospholipase C, inc IP3 and intracell Ca2+

Alpha-2: Inhibit adenylyl cyclase, decrease cAMP

Beta-1/Beta-2: stimulate adenylyl cycalse, inc cAMP
What are the relative receptor potencies of NE and Epi for alpha and beta receptors?
Alpha-1/2: EPI>NE
Beta-1: EPI = NE
Beta-2: EPI>>>NE (BIG DIFFERENCE)
What are the physiologic effects of stimulation of beta-1 receptors?
Mostly heart, little bit of kidney

SA node: inc'd heart rate
AV node: inc'd conduction velocity
HIS-purkinje cells: Inc'd conduction velocity and automaticity
Cardiac muscle: inc'd contractility

Kidney juxtaglomerular cells: inc'd renin
What are the physiologic effects of stimulation of beta-2 receptors?
Smooth muscle:
Arteriolar, bronchiolar, intestinal, uterine relaxation

Other:
Ciliary muscle (eye) relaxation, skeletal muscle: inc'd K+ uptake

Liver: inc'd glycogenolysis

Panc Isleta beta cells: inc'd insulin secretion
What are the physiologic effects of stimulation of alpha-1 receptors?
Smooth Muscle
Arteriolar, venous, genitourinary CONTRACTION

Intestinal RELAXATION

Eye:
Radial muscle contraction
Lacrimal gland secretion

Liver: inc'd glycogenolysis

Kidney Juxtaglomerular cells: dec'd renin secretion
What are the physioloic effects of stimulation of alpha-2 receptors?
Pancreatic Isleta (beta cells): dec'd insulin secretion

Presynaptic receptors: dec'd release of NE
A 30 year old patient is diagnosed with pheochromocytoma generated by a benign tumor in her right adrenal gland causing excessive release of epinephrine and norepinephrine.

What signs and symptoms would you expect in this patient?

If you were designsin a drug to treat the signs and symptoms, what would be it mechanism of action?
Syx: HTN (alpha-1 receptors), tachycardia

Drug: alpha then beta block
Parasympathetic Nervous System:
Neurotansmitters Involved
Result of Stimulation
Receptors Involved
PNS:
Pre-gang neurons: ACh which activates Nicotinic receptors
Postgang: Release ACh, which binds MUSCARINIC receptors of TARGET CELLS
Acetylcholine:
Synthesis
Storage
Choline uptake, combined with acetylCoA
Choline Acetyltransferase combines to two into ACh
Storage into vesicles
Release through exocytosis
Vesamicol:
Mechanism
Reduced uptake of ACh into vesicles
Botulinum Toxin:
Mechanism
Blocks release of Ach via inhibition of exocytosis
Hemicholinium:
Mechanism
Reduces choline uptake (reduced synthesis of Ach)
Acetylcholine:
Termination
Acetylcholinesterase degrades ACh in synaptic cleft (reuptake is relatively small)
Describe the second messenger signal transduction of muscarinic receptors.
G-protein coupled but slower response than nicotinic receptors

M1/3/5: increase release of intracell Ca2+ and protein phosphorylation

M2/4: inc K+ permeability, dec cAMP

M2: inc'd K+ perm (inhibitory), dec'd adenylyl cyclase activity (dec'd cAMP), dec'd Ca2+ perm; located in heart; effect: SLOWS CONDUCTION

M3: Smooth muscle contraction, relaxation of sphincters, dilation of vessels through NO production, inc'd secretion of glands
What is the general effect of stimulation of muscarinic receptors?
SA Node: dec'd heart rate
AV: dec'd conduction velocity
Muscle: dec'd contractility

Vasc SM: relaxation if endothelium intact, contraction if endothelium removed

Other SM: GI, bronchiolar contraction

Eye: sphincter/ciliary muscle: contraction

Glands: inc'd secretion (salivary, lacrimal, nasopharyngeal, bronchiola, GI, panc, skin sweat glands)

Sphincters: Urinary/GI: relaxation
What nerve is responsible for the decreased contractility of the heart?
VAGUS
Which of the following statements is correct regarding the parasympathetic nervous system?

Acetylcholine is synthesized in the postganglionic neuron and is released passively into the synaptic cleft.

Activation of presynaptic M4 receptors decreases release of acetylcholine into the synaptic cleft.

Removal of acetylcholine from the synaptic cleft is primarily through reuptake and the process is inhibited by cocaine.

Stimulation of M3 receptors in the heart result in decreased calcium permeability and slowing of heart rate and AV nodal conduction.
Activation of presynaptic M4 receptors decreases release of ACh into the synaptic cleft.
List 3 catecholamines.

Can be they delivered orally? Why or why not?
Epi, NE, DA

Cannot be given orraly because rapidly inactivated by COMT and MAO in liver
I.V. Epinephrine:
Receptors acted on
Effects
Agonist of a-1, b-1, b-2

a-1: BP incrcrease at higher doses

b-1: inc in chronotropic (inc SA firing), dromotropic (inc AV conduction), inotropic (inc contractility) of heart

b-2: bronchodilation
I.V. Norepinephrine:
Receptoprs acted on
Effects
POTENT Agonist of a-1, moderate agonism of b-1

No beta-2 to counteract, so get significant inc in BP and sig inc in inotropy
Dopamine:
Receptors acted on
Effects
Precursor of NE but direct agonist for b-1 and a-1, in addition to D-1 (mesenteric, renal, coronary vasodilation)

Dose-related effect!

Low dose (1-2 mcg/kg/min): renal/mesenteric vasodilation

Medium (5-10 mcg/kg/min): inc'd heart rate, inotropy

High (10-20 mcg/kg/min): inc'd vasoconstricion, HR, inotropy

(low dose: improves renal fn, high dose: vascular effects dominate)
Isoproterenol:
Drug Class
Receptors Affected
Uses
Sympathomimetic
Beta-1, Beta-2

IV: inc in contractility (treat cardiogenic shock), inc heart rate

Inhaled: asthma patients (but cardiac effects)
Dobutamine:
Drug Class
Receptors Affected
Uses
Sympathomimetic
a-1,b-1,b-2

IV: inc contractility (treat cardiogenic shock)

DOBUTAMINE LESS LIKELY TO CAUSE REFLEX TACHYCARDIA
Pseudophedrine:
Drug Class
Receptors Affected
Uses
Sympathomimetic
A-1, b-1, b-2

Nasal decongestant, precursor for methamphetamine

Can significantly raise BP increasing risk of stroke due to potent a-1 stimulation
Terbutaline:
Drug Class
Receptors Affected
Uses
Sympathomimetic
beta-2

Inhalation: bronchodilator to tx asthma, COPD
Albuterol:
Drug Class
Receptors Affected
Uses
Sympathomimetic
beta-2

Inhalation: bronchodilator to tx asthma, COPD
Salmeterol:
Drug Class
Receptors Affected
Uses
Sympathomimetic
beta-2

Inhalation: bronchodilator to tx asthma, COPD

NOTE: SALMETEROL CANNOT BE USED FOR ACUTE MANAGEMENT OF ASTHMA BECAUSE OF ITS SLOW ONSET
What sympathomimetic cannot be used for acute management of asthma because of its slow onset?
Salmeterol
Sympathomimetics:
Adverse Events
Due to beta-1 over simulation: tachycardia, arrythmia, cardiac damage, inc'd myocardial O2 demand

Use beta-1 agonists in short term management of heart failure, not chronically

Beta-2 over-stimulation: skeletal muscle tremors, tachycardia, arrhythmia, hypokalemia (less common with inhaled drugs, but possible)

alpha-1 stimulation: severely elevated BP, inc'd myocardial O2 demand, predisposing to stroke and cardiac damage
Prazosin:
Drug Class
Receptors Affected
Uses
Sympatholytic

Alpha-1 receptor antagonist:
Dec vascular resistance in HTN, improves urinary flow in BPH

MAY CAUSE ORTHOSTATIC HYPOTN, SYNCOPE
Terazosin:
Drug Class
Receptors Affected
Uses
Sympatholytic

Alpha-1 receptor antagonist:
Dec vascular resistance in HTN, improves urinary flow in BPH

MAY CAUSE ORTHOSTATIC HYPOTN, SYNCOPE
Doxazosin:
Drug Class
Receptors Affected
Uses
Sympatholytic

Alpha-1 receptor antagonist:
Dec vascular resistance in HTN, improves urinary flow in BPH

MAY CAUSE ORTHOSTATIC HYPOTN, SYNCOPE
Tamsulosin is an Alpha-1 selective blocking agent. It is very effective for the treatment of benign prostatic hyperplasia but is not effective as an antihypertensive agent. Why is this true?
(Block alpha receptors-->relax urinary muscle tone)

For prostate, alpha-1a is receptor
In vessels have alpha-1a and alpha-1b

tamsulosin affects alpha-1a so has less of an effect on BVs
Phentolamine:
Drug Class
Receptors Affected
Uses
Adverse Effects
Alpha sympatholytic

Blocks alpha-1 and alpha-2

Use: pherohromocytoma

AE: significant hypotn causing reflex stimulation of heart resulting in tachycardia, arryhtmias and myocardial ischemia
Phenoxybenzamine:
Drug Class
Receptors Affected
Uses
Adverse Effects
Alpha sympatholytic

Blocks alpha-1 and alpha-2

Use: pherohromocytoma

AE: significant hypotn causing reflex stimulation of heart resulting in tachycardia, arryhtmias and myocardial ischemia
What properties are considered when selecting beta-blockers?
Blocks only beta-1 receptors (selectivity)
Can act as beta-agonist (intrinsic sympathomimetic activity)
Can cause alpha-1 blockade
Can cross into CNS (lipophilicity)
Why would selectivity be an important factor in choosing a beta-blocker?
When you want to avoid bronchoconstriction (when act beyond beta-1, and block beta-2); selectivity is dose-related (max dose = low selectivity)
Why would intrinsic sympathomimetic activity be an important factor in choosing a beta-blocker?
Can act as beta-agonist at times of low sympathetic tone (while sleeping)

Can be advantageous in pts with HTN on beta-blockers that have excessively low heart rates at night

Not useful in pts w/ischemic heart dz
Propranolol:
Drug Class
Receptors Affected
Uses
Beta-blocker
beta-1, beta-2 block
Metoprolol:
Drug Class
Receptors Affected
Uses
Beta-blocker
beta-1 blockade
Carvedilol:
Drug Class
Receptors Affected
Uses
Beta-blocker
beta-1, beta-2, alpha-1 blockade
Labetalol:
Drug Class
Receptors Affected
Uses
Beta-blocker
beta-1, beta-2, alpha-1 blockade
HAS BETA-2 AGONIST INTRINSIC ACTIVITY
Beta-1 blockade:
Uses
HTN (reduces cardiac output)

Ischemic Heart Dz:
reduces cardiac workload (dec syx)
Acute Coronary sndromes (decreases workload, ischemia)

Systolic heart failure (blocks effects of NE)--doses must be titrated slowly to avoid exacerbation of heart failure symptoms

Arrythmias (blocks effects of symp NS)

Glaucoma (decreases intraocular pressure), Thyroid Storm, Performance Anx, Migraine Prophylaxis
What drug class must be titrated slowly in treating patients with heart failure in order to avoid an exacerbation of heart failure symptoms?
beta-1 blockers
Beta-blockers:
Adverse effects
AEs may be dependent/modified by characteristics of beta-blocker, e.g., selectivity

Direct cardiac effects

Bronchoconstriction (avoid in pts with asthma)

Dyslipiedmias (dec'd HDL)

Signs of hypoglycemia in DM may be harder to recognize (esp insulin-dependent)
Why shouldn't patients abruptly discontinue beta-blockers?
Increased rick of ischemia due to up-regulation of beta-receptors during chronic therapy (severe hypertension, inc'd Q)
Parasympathomimetics:
Direct vs Indirect Mechanisms of action
Increase effect of parasymp NS by:

Direct mech: stimulation of muscarinig receptors

Indirect mech: inhibition of Acetylcholinesterase
SLIDE 62, 40:52
xxx
What are the two kinds of direct acting muscarinic agonists? Provide examples of each.

Uses?

AE's?
Choline Esters:
Carbachol
Bethanechol
Methacholine
Acetylcholine (can't be used clinically)

Alkaloids:
Pilocarpine

Uses:
Glaucoma (reduce intraoc pressure through inc outflow of aq. humor)

Xerostomia (inc salivary secretion)

Gastric atony/urinary retention (in patients without obstruction)

AE:
Bradycardia, Hypotn

Bronchoconstriction, glandular hypersecretion

GI distress, inc'd acid secretion
What are examples of indirect acting parasympathomimetics?

Uses?

AE's?
Edrophonium...

Physostigmine, neostigmine, pyridostigmine (-stigmine)--medium strenth binding

-Organophosphates (insecticides, topical treatments, nerve gases)---STRONG binding

Used for dry mouth, glaucoma

Myasthenia gravis (for increase at NMJ')

Prophylaxis against nerve gas poisoning

AE:
Bradycardia, Hypotn

Bronchoconstriction, glandular hypersecretion

GI distress, inc'd acid secretion
Organophosphate insecticide poisoning:
Signs
Management
CV: hypotn, bradycardia, arrythmia
Pulm: resp distress, failure
GI: nausea, vomiting, cramps, diarrhea, incont
Eyes: miosis, reduced vision, ocular pain
CNS: confusion, seizures, coma

Management:
Decontamination--atropine for muscarinic side effects, Pralidoxime (cholinesterase reactivator)
Respiratory support
Anti-Muscarinic Drugs:
Actions
Effects
Block exog/endog muscarinic agonists

Effects:
Inc'd heart rate, conduction velocity, block of reflex bradycardia

Bronchodilation, reduced bronchial secretions

Inhibit GU/GI tone, inhibit gastric acid secretion

Mydriasis (open eyes for eye exam)
Atropine:
Drug Class
Effects
Uses
Antimuscarinic (Alkaloid)

opposite of muscarinic f/x

Little CNS effects; used IV for significant bradycardia

Effects are dose-related
Scopolamine:
Drug Class
Effects
Uses
Antimuscarinic (Alkaloid)

OPP of muscarinic

More BBB penetration than atropine so used for motion sickness
An 85 year old man with Alzheimer's Disease is given donepezil. Which of the following should you anticipate as an adverse effect of the drug?

Constipation
Urinary incontinence
Dry eyes
Sinus tachycardia
Donepezil inhibits Acetylcholinesterase, so get increased cholinergic effects

URINARY INCONTINENCE
Malathion poisoning:

A 6 year old child comes home from school with a note from the school nurse indicating that she has head lice. Her mother receives a prescription buys a bottle of malathion, an organophosphate. She mistakenly gives her child the malathion orally instead of using it as a topical application.

What symptoms who you expect this child to exhibit and why?
Worry about excess cholinergic and nicotinic activity (excess skeletal muscle activity?)