Exam 4 Flashcards
Sympathetic system
Two neurons
Short then long ganglion
Postganglion release NE and E
The sympathetic trunk ganglia innervates what
Thorax, abdomen, head, neck
The prevertebral ganglia innervates what
Organ below diaphragm
What is the percentage release of E and NE in sympathetic system and adrenal medulla
Sympathetic: 80% NE, 20% E
Adrenal Medulla: 20% NE, 80% E
What happens in the adrenal medulla
One neuron system
ACh is released by pregnaglion
Preganglion innervates chromaffin cells in medulla and release NE and E
(NE and E are hormones because they are in the circulation and not released at a synapse)
What are the presynaptic receptors in the sympathetic system and adrenal medulla
Both are nicotinic receptors (Nn)
For the adrenergic presynaptic receptors what do the auto receptors and hetero receptors do in respect to NE release
Auto receptors: inhibit and activate NE release
Hetero receptors: inhibit NE release
What are the two subgroups of the adrenergic receptors
Alpha and Beta
What does a2 receptor do
autoreceptor that inhibits of NE release
What does b2 receptor do
autoreceptor that facilitates of NE release
Heteroreceptors presynaptically
inhibit release of NE (M2, M4)
-DA receptor
-Histamine receptor
-Serotonin receptor
What is a1 receptor
Gq, PLC, increase IP3 DAG and Ca2+
What is a2 receptor
Gi, AC, decrease cAMP
What is b1, b2, and b3 receptor
Gs, AC, increase cAMP
E and NE in a1, a2, b1, b2, b3
a1: E > NE
a2: E = NE
b1: E = NE
b2: E > NE
b3: E < NE
Catecholamines
Involved in chemical transmission in the CNS and PNS
Dopamine (mesocortical neuron) -> NE (sympathetic postganglionic neurons) -> E (adrenal medulla)
Synthesis of catecholamines
hydroxylation -> decarboxylation -> hydroxylation -> methylation
Enzyme locations of catecholamines
DBM in secretory vesicles
Enzymes and primary product of dopaminergic neurons
Product: Dopamine
Little or no DBM and PNMT
Enzymes and primary product of adrenergic neurons
product: NE
Less PNMT than DBM
Enzymes and primary product of adrenal medulla
E (80%) NE (20%)
DBM and PNMT present
What drugs inhibit CA synthesis
alpha-methyltyrosine (inhibit tyrosine hydroxylase, treat pheochromocytoma)
carbidopa (increases DOPA, treatment of parkinsonism)
What drugs inhibit CA storage
reserpine (inhibit VMAT, antihypertensive drug)
tetrabenazine (inhibit VMAT, hyperkinetic disorders)
Inhibitor effects of VMAT mechanism
decrease NE storage -> decrease NE release
depletion of CA at synapse
NE accumulated in cytoplasm is degraded
Diffusion of CA (catecholamine action) at synapse
Dilution of CA at synapse
Uptake at extraneuronal sites by non-neuronal transporters
Reuptake of CA (catecholamine action) at synapse
(85% of CA)
Into nerve terminals by neuronal transporters
CA can be stored in vesicles and/or metabolized
Metabolism of CA (catecholamine action) at synapse
Following uptake and reuptake, CA undergoes enzymatic catabolism
Reuptake of CA: Neuronal and Non-Neuronal transporters
Neuronal:
-Norepinephrine transporter (NET) –neurons, adrenal medulla, liver, placenta
-Dopamine transporter (DAT) –neurons, kidney, stomach, pancreas
Non-neuronal:
-OCT1, OCT2, ENT –liver, kidney, intestine
NET affinity and DAT affinity
NET: NE > E and DA
DAT: DA > NE and E
DAT and NET transporters
block antidepressants and substance of abuse
increase NT levels at synapse
NET - Cocaine, Desipramine
DAT - Cocaine, Mazindol
NET transporter movement of molecules
Co-transporter (symport) Na+, Cl-, NE
Na+ and energy dependent, Na/K ATPase creates Na+ gradient
Binding of K+ returns the transporter to outward position
What are MAO (monoamine oxidase)
MAO-A
-Periphery: placenta and liver
-Brain: region containing catecholamines
-NE, E, DA, serotonin
MAO-B
-Periphery: platelets, lymphocytes, liver
-Brain
-DA, amines
What are COMT (catechol-O-methyl-transferase)
Largely cytoplasmic enzyme
Exception in adrenal medulla is membrane bound
Less COMT than MAO in sympathetic neurons
Catabolism of NE and E: MAO mechanism
MAO forms aldehyde (DOPGAL) then turns into an alcohol (DOPEG)
Catabolism of NE and E: COMT mechanism
COMT methylates DOPEG to form MOPEG converted to VMA
What is the final end product of DA metabolism
HVA (homovanillic acid)
What is another route to form VMA other than COMT main pathway
minor pathway in neurons
methylation of NE and E by COMT then deamination by MAO, MOPGAL formed then VMA
Classification of adrenergic agonists
Adrenergic agonists:
Directing acting -> Selective and nonselective: act directly on one or more of the adrenergic receptors
Mixed-acting: indirectly release NE and activate receptors
Indirect acting -> Releasing agents, uptake inhibitor, MOA inhibitor, COMT inhibitors: increase NE or E levels to stimulate adrenergic receptors
Adrenergic Effects in the eye
Dilation of pupils (mydriasis)
Far vision: muscle relaxation, increase ligament tension, flat lens
Adrenergic receptors: Iris dilator
radial muscle only sympathetic innervation
pupil dilation
Adrenergic receptors: Ciliary muscle
also parasympathetic innervation M3R
far vision (flat lens)
a1 adrenergic receptors in the eye
Gq
increase Ca2+
Muscle contraction
B2 receptors in the eye
Gs
Increase cAMP
myosin light chain kinase-P (inactive)
Muscle relaxation
Difference between radial muscle and circular muscle
radial muscle: pull out, dilation
circular muscle: muscle relaxation, decrease pupil size
Adrenergic effects on the respiratory tract
Bronchodilation: relax bronchial smooth muscle, decrease airway resistance
Decrease bronchial secretion
What kind of receptors do bronchi have
B2 receptors -> E has a better effect than NE
Short-acting beta 2 adrenergic agonists
Albuterol (salbutamol)
Levalbuterol (xopenex)
sulfation metabolism
Systemic SABA beta 2 adrenergic agonists
Terbutaline (brethine)
Epinephrine
sulfation metabolism
Long Acting beta 2 adrenergic agonists
Formoterol (foradil)
Salmeterol (serevent)
COMT and MAO metabolism
Very long acting beta 2 adrenergic agonists
Indacaterol (arcapta neohaler)
Arformoterol (brovana)
Olodaterol (striverdi, resoimat)
Vilanterol only in combination inhalers
Glucuronidation and O-demethylation
Mechanism of action of smooth muscle contraction
Increase intracellular Ca2+
bind to calmodulin (CaM)
activates myosin light chain kinase (MLCK)
Increase myosin ATPase activity
cross bridges slide along actin and create muscle tension
Combination inhalors
Contain long-acting inhaled B2 agonist & corticosteroid
Advair: Salmeterol and fluticasone
Symbicort: Formoterol and budesonide
Dulera: Formoterol and nometasone
Brea Ellipta: Vilanterol and fluticasone
Adverse effect die to excessive activation of B2 receptors
Muscle tremor (skeletal muscle)
Tachycardia: due to reflex effect, vasodilation, stimulation of heart
Hypokalemia
Metabolic effects
Adrenergic effects in the heart
Increase heart rate (chronotropy)
Increase rate of conduction (dromotropy)
Increase force of contraction (inotropy)
Disturb cardiac rhythm and cause arrhythmias
What does the AV and SA node do
AV increase conduction velocity
SA increase heart rate
Cardiac therapeutic uses of beta agonists
Rapid on set short duration
E: cardiac arrest
Dobutamine: increase contractility -> used for cardiac surgery, heart failure, acute myocardial infarction
Blood vessels are only activated by what system
Sympathetic (increase system, increases vasoconstriction)
What are the receptors in the sympathetic vessels and what do they do
Alpha 1: contraction caused by baroreceptors
Beta 2: relaxation, increases blood flow
Alpha 1 adrenergic agonist drugs to treat hypotension
Metadaminol
Midodrine (prodrug)
Side effects are urine retention, goose bumps, bradycardia
Condone alpha 2 adrenergic agonist
Treats hypertension and opiate withdrawal
Diagnose hypertension and pheochromocytoma
Postsynaptic a2 agonist Brimonidine
Treat glaucoma (reduce eye pressure)
Side effects: drowsiness, eye itching
Treat eye redness
Decrease fluid pressure and construction
Difference between direct and indirect effect on glands
Direct: increase secretion (Refresh-eye, Glaucon-eye)
Indirect: decrease secretion (decongestant, afrain)
Sympathetic effects in the urinary tract
Detrusor muscle - B2 activation, muscle relaxation
Urethral Sphincter - a1 activation, contract sphincter
Urinary retention
Adrenergic effects in the GI tract
Decrease motility and GI tone
Constrict sphincters
Decrease movement
B2 receptors in smooth muscle
a1 in sphincter
Adrenergic effects on uterine contraction
uterine relaxation B2
uterine contraction a1
Ritodrine and Terbutaline receptor selectivity (uterine contraction)
Beta 2
E in emergency treatment for anaphylaxis
Release histamine
a1 - increase vasoconstriction, increase BP, decrease mucosal edema
B2 - increase bronchodilation, decrease mediator release
NE effects
Increase contractility and heart rate and vasoconstriction
Used for maintain BL in cardiogenic and septic shock
Adverse reaction: arrhythmia, anxiety, headache
Adrenergic agonists releasing agents and uptake inhibitors
releasing: amphetamine, tyramine
uptake: cocaine
(increase E and NE to stimulate adrenergic receptors)
What are indirect adrenergic agonists drugs that decrease and increase NE and E
Drugs that decrease NE and E re-uptake
-Cocaine
-Desipramine
Drugs that increase NE and E release
-Amphetamine
-Ephedrine
-Tyramine
Does indirect adrenergic agonists have the same mechanism as NT release
no
Mechanism of action of indirect agonists
-Amphetamine is transported into nerve terminal by NET -> competitively inhibit reuptake
-Drug taken in by VMAT -> exchange drug for NE
-NE increase in cytosol
Amphetamine effects in CNS stimulant
wakefulness
good mood
increased motor
physical improvement
need to keep increasing dosage
Amphetamine effects in peripheral alpha and beta actions
Increase BP
Increase HR -> cardiac arrhythmias
Pupil Dilation
Urinary incontinence
Ephedrine effects
Mixed-acting sympathomimetic
-a and B receptors
-Increase release of NE from sympathetic neurons
Effects
-Increase HR
-Increase peripheral resistance
-Broncodilation
-Urinary retention
-CNS stimulant
Tyramine effects (not a drug)
Product of tyrosine metabolism
Produced in high concentration in rich-protein foods by decarboxylation of tyrosine during fermentation
Indirect sympathomimetic action (caused by catecholamines)
Tyramine increase NE release causing severe hypertensive response. If patient is taking MAO inhibitors, patient should avoid eating what
Cured meats, pickled food, cheese, wine
Inhibitors of NE uptake: Cocaine
causes tachycardia and increase BP
CNS causes euphoria and excitement
Inhibitors of NE uptake: Desipramine
Tricyclic antidepressent
Inhibitors of NE uptake: Atomxetine
selective inhibitor with clonidine-like effect in CNS
What do adrenergic antagonist do
Block the effects of NE, E and other sympathomimetic drugs by preventing their binding to adrenergic receptors
alpha 1 receptor antagonists
block contraction of arterial and venous smooth muscle -> vasodilation -> decrease BP
(block contraction of visceral smooth muscle
alpha 2 receptor antagonists
block regulation of sympathetic output
beta 1 receptor antagonists
block cardiac receptors
Non-selective alpha 1 antagonists
reversible antagonist -> Phentolamine
irreversible antagonist -> Phenoxibenzamine
selective alpha 1 antagonists
“-osin” ending drugs
Phentolamine
can dissociate from receptor
competitive inhibitor -> can be reversed with sufficiently high concentration of agonists
used in short-term control of hypertension
decreases BP
Phenoxybenzamine
blocks alpha 1 and alpha receptors
alkylating agent
persistent effects
anti-hypertensive
decreases vasoconstriction produced by NE and E
decreases BP
What do prazosin, terazosin, and doxazosin do (alpha 1 adrenergic antagonists)
used for hypertension
What do tamsulosin, silodosin do (alpha 1 adrenergic antagonists)
selective for alpha 1 A
mainly for benign phosphate hyperthrophy
Effects of alpha 1-antagonists
Block alpha 1 receptors in blood vessels
Block vasoconstriction produced by endogenous CA
Decrease venous return
Decrease BP
How do alpha 1 antagonists completely reverse effects of phenylephrine but only partially reverse the effects of NE
NE has an extra methyl group
Therapeutic uses of alpha 1 adrenergic antagonists
-Treatment of essential hypertension
-Benign prostatic hyperplasia - Tamsulosin and Silodosin
—Enlargement of prostate increased smooth muscle mass and tone in prostate
—Decrease flow of urine
Adverse effects of alpha 1 antagonists
Orthostatic hypotenstion
Dizziness and headache
Syncope
Tachycardia
Miosis
Nasal stuffiness
alpha 2 receptor antagonists
Block CNS receptors
Increase NE release
Increase HR and BP
(Yohimbine, Indoramin)
Beta adrenergic antagonists
Antagonize effects of catecholamines
Treatment of hypertension, heart failure
Traditional beta blockers: nonselective and selective
nonselective: block beta 1 and 2, propanolol
selective: block beta 1, esmolol, metoprolol
Third generation beta blockers: nonselective and selective
nonselective: carvededilol, vasodilation (alpha 1)
selective: betaxolol, vasodilation
Beta blockers with ISA activity
B1 > B2
selective
not used because of partial agonist activity
Effects of beta antagonists in the heart
Decrease HR, rate of conduction, force of contraction, cardiac output
Therapeutic uses of beta blockers
Hypertension
Angina
Cardiac arrhythmias
Glaucoma
Adverse effects of Beta 1 adrenergic antagonists
hypotension
bradycardia
dizziness
fatigue
heart block
Histamine
biologically active amine that functions as a NT
-mediator for allergic rxns
Histamine metabolism
rapidly inactivated
excreted in urine
N-methyltransferase in most tissues (MAO)
Histamine release: Immunologic
Allergic reactions
Degranulation of sensitized mast cells or basophils
(needs Ca2+)
Histamine release: Chemical release
Caused by therapeutic agents
released from mast cells directly and without sensitization
Allergin-induced histamine release
evokes IgE production
cell sensitization
allergen (antigen) binds to IgE
degranulation of sensitized cells
Localized responses of histamine
Allergic Rhinitis (hay fever)
-rxn in conjunctivae and nasal mucosa
Asthma
-rxn in mucous membranes of bronchi
Food Allergy
-rxn in upper or lower GI can induce smooth muscle contraction and vasodilation -> vomiting and diarrhea
Systemic Type 1 responses
Systemic Anaphylaxis (shock-like reaction)
-onset w/in minutes of type I reaction
-decreased BP, urination, defecation
Wide range of antigens
E used to counteract effects of mediators
H1 Histamine Receptors
Gq
Phospholipase C
IP3, DAG
In Smooth muscles, heart, CNS
Increases vascular permeability at sites of inflammation
Allergies
H2 Histamine receptors
Gs
Adenylyl cyclase
Increase cAMP
In gastric parietal cells, cardiac muscle, mast cells, CNS
Increase gastric acids release, cardiac stiimulation
Acid reflex
Histamine effects in cardiac system
Increase HR, AV conduction, force and rate of contraction
Histamine effects in vascular system
vasodilation -> smooth muscle relaxation
-decreases BP
Edema
In blood vessels
Histamine effects at H1 receptors
Higher affinity for histamine
activation at low histamine concentration
vasodilation is mediated by NO production
rapid onset short duration
Histamine effects at H2 receptors
Produces vasodilation
mediated by cAMP and PKA pathway
Slow onset long duration
Histamine effects on capillaries
Dilation of blood vessels
increased capillary permeability in small vessels -> activation of H2 receptors
Induction of endothelial cell contraction -> capillaries become leaky
Fluid and proteins move into ECM tissue -> edema formation
Histamine effects on bronchial smooth muscle
Bronchoconstriction
Increased broncho secretion
(important for asthma patients)
Histamine effects on exocrine glands
Increase lacrimation, mucus secretion, salivation
Effect of histamine on GI tract
H1 receptors: contraction of intestinal smooth muscle, increase motility and GI tone, increase GI movement
H2 receptors: activation of parietal cells, increase gastric acid secretion
Flush, flare and wheal
Flush: red line or spot due to capillary dilation
Flare: red zone redness in the surrounding area due to arteriolar dilation
Wheals: localized edema due to education of fluid from capillaries and venules
Clinical uses of histamine
Bronchial hyper-reactivity in asthmatics
Allergy skin testing
Histamine toxicity
Hypotension
Headache
Tachycardia
Bronchoconstriction
Upset GI
Histamine effects
Increase secretion from glands, mucus secretion, heart rate, HCl secretion, motility of GI, bronco constriction
Histamine release inhibitors mechanism of action
Reduce or inhibit degranulation of mast cells -> mast cell stabilizers
Prophylactic Drugs (nasalcrone, opticrome, gastrocom, nedocromil sodium)
Poor absorption though GI
Therapeutic uses of histamine release
Decrease histamine effects
Asthma - reduce level of bronchial reactivity
Allergic reactions - rhinoconjunctivatis
Histamine receptor antagonist
H1 receptor antagonist
Antihistamines
H2 receptor antagonists
Treatment of gastric acid secretion
First generation H1 blockers
Sedating drugs
Not for children
Second gen H1 blockers
Reduce distributions into the CNS -> no sedating effect
First gen H1 antagonist drugs
Diphenhydramine
Pyrilamine
Chlorpheniramine
Cyclizine
Well absorbed
Muscarinjc cholinergic responses
Second gen H1 antagonists drugs
Cetirizine
Fexofenadine
Loratadine
Non sedating
Anti inflammatory effects
Main effects of H1 antagonists
Decrease secretion of glands, broncoconstriction, mucus secretion, hypotension, edema, vasodilation
H1 antagonist effects on nerve endings
Suppress the action of histamine on nerve endings
Suppress itching, pain, flare
H1 antagonist effects in the CNS
Depression:
Slow alertness, reaction times, and somnolence
Don’t use at bedtime
Stimulation:
Uncommon
Restlessness, nervous, unable to sleep
Adverse effects of H1 antagonists
Sedation
Dry mouth
Loss of appetite
Allergic response
H1 antagonist drug interactions
Antibiotics
Grapefruit juice
Additive effects with CNS depression drugs
Clinical uses of H1 antagonists
Allergic reactions
Motion sickness (vertigo)
Local anesthesia
Organization of components for gastric acid secretion
Parietal cells secrete H+ and Cl- separately into the gastric lumen of the stomach
HCl is formed in the gastric lumen
Acid secretion of parietal cells
H+ from H2CO3
Exchanged for K+
Cl- into cells for HCO3
Excess K+ removed
Regulation of gastric acid secretion
ACh
Histamine
Gastrin
They activate specific receptors on the parietal cells
Direct regulation of gastric acid
Bind ACh, gastrin, and histamine to receptors in surface of parietal cells
Increase cAMP and Ca2+ activate PKA
PKA phosphorylates and activates H+, K+ ATP-ase producing gastric acid
Indirect regulation of gastric acid secretion
ECL cells produce and release histamine
Histamine activates H2 receptors on parietal cells producing gastric acid
Defense mechanism of gastric acid
Esophageal sphincter: prevent reflex of Garrick content into esophageal
Stomach: traps bicarbonate at cell surface increase pH
Mucus production: PGs stimulate this by decreasing acid secretions, NSAIDs inhibit PG synthesis -> decreasing production
antacids react with hydrochloric acid to form what two things
salt
water
Therapeutic uses of antiacids
intermittent heartburn
dyspepsia
What are the 4 gastric acid drugs
alka seltzer
gaviscon
maalox
tums
H2 antagonists
inhibit gastric acid secretion from parietal cells
H2 antagonist drugs
cimetidine
famotidine
nizatidine
H2 antagonists: mechanism of action
-reduce gastric acid secretion
-competitively inhibit histamine by binding to H2R
-inhibit acid secretion stimulated by gastrin and ACh through activation of ECL cells
PPIs
-most potent inhibitors of gastric acid secretion
-new pump molecules need to be synthesized to resume secretion
What are the 4 proton pump inhibitors
Omeprazole
Zegrid
Esomeprazole
Lansoprazole
