Exam 2 Material Flashcards
Somatic Nervous System vs Autonomic Nervous System
What do the control? Subdivisions?
Somatic: Consciously controlled functions that deal with movement, respiration, and posture
ANS: Largely independent system. Concerned with control and integration of visceral functions necessary for life such as cardiac output, blood flow distribution, and digestion.
1. Sympathetic
2. Parasympathetic
3. Enteric- “gut feeling”
SNS
Fight or Flight
“Fight or flight” or “Ergotrophic” is a sympathetic nervous system response. HR is increased, BP increased, pupillary constriction, up to 75% of blood is shunted to our skeletal muscles. We start to sweat, and our bronchioles dilate. There has to be a continuous stimulus to elicit this response
PNS
Rest and Digest
“Rest-and-digest” or “Trophotropic” Is a parasympathetic nervous system response. It lowers our HR back down to baseline, contricts our bronchioles (bad for asthmatics), shunts blood to systems such as endocrine, GI. Concerned with conserving energy.
SNS
Anatomy, Primary Neurotransmitter
-Arise from the CNS at the level of the T-Spine (T1-L2) or Thoracolumbar spine
-The sympathetic chain is a collection of cells called ganglia that receive information and deliver it to their target organ
-Short preganglionic fibers originate in the chain ganglia at the level of the spine
-Long post-ganglionic fibers that innervate and terminate at their target organ
-Primary neurotransmitter is norepinephrine (adrenergic)
-Adrenal glands will also release epinephrine
ALL PREGANGLIONIC NEURONS RELEASE ACh
PNS
Anatomy, Primary neurotransmitter
-Nerves located in the craniosacral area (Cranial nerves except II)
-Long preganglionic fibers. Leave the CNS through the cranial nerves and sacral spinal roots
-Short postganglionic fibers, terminate on the target organ
-Ganglia are located in visceral organs
-Most important cranial nerve here is X (Vagus)
-> 75% of the PNS output goes through the vagus nerve
-Primary neurotransmitter is ACh (cholinergic)
ALL PREGANGLIONIC NEURONS RELEASE ACh
Sympathomimetics
Direct acting vs indirect. What do these drugs do?
-Drug class that mimics the SNS
-Direct acting drugs: Epinephrine, isoproteronol, albuterol
-Indirect acting drugs: Ephedrine and amphetamines
-> Release stored NE, block reuptake or reverse the NET (transporter)
-Constricts blood vessels, inotropic & chronotropic cardiac effects, decrease bronchiole tone, decrease uterine tone (preterm labor)
Also sympathoplegics
Sympatholytics
what do these drugs do?
-Inhibit the SNS
-Alpha blockers: Phentolamine
-Beta blockers: Propanolol
-non-specific blockers: Labetalol
-Decrease BP, HR
Autonomic Receptors
Adrenergic Receptors
Receptors and Locations
A1: Usually vascular smooth muscle
A2: Presynaptic adrenergic nerve terminals, smooth
B1: Heart, brain
B2: Smooth muscle in lungs, cardiac muscle
D1-D5: Brain
D4: Brain and CV systems
Cholinergic Receptors
Muscarinic vs Nicotinic
Locations. Excitatory or inhibitory?
Muscarinic:
M1- (E) CNS neurons, SNS postganglionic neurons
M2-(I) Myocardium, smooth muscle, CNS
M3- (E) Exocrine glands, vessels, CNS
M4- (I) CNS, vagal nerve endings
M5- (E) Vascular endotheliam (esp. cerebral vessels), CNS
M2, M4: Inhibitory
M1, M3, M5: Excitatory
Nicotinic:
Nn: Neuronal; postganglionic neurons
Nm: Muscular; skeletal muscle
Adrenoreceptors
A1
Receptor pathway, effects on CV system
-Gq Receptor Pathway
Activates phospholipase C–> cleaves PIP2 into IP3 & DAG–> IP3 stimulates release of Ca++ into cytosol–> increased levels of myosin light chain kinase
DAG + Ca++ –> activate protein kinase C–> inhibits myosin light chain phosphatase
-SNS activation: results in muscle contraction of vascular smooth muscle; however, decreases CO due to increased PVR. Can have reflex bradycardia initially
Adrenoreceptors
A2
GI pathway: Inhibits adenlyl cyclase –> less cAMP is formed–> usually means less Ca++ influx into the cell, less K+ out of the cell
Adrenoreceptors
B1 & B2
Receptor Pathway, Effects on CV & Respiratory System
GS Pathway: Stimulates adenylate cyclase–> causing an increase in cAMP (major second messenger in B receptor activation)–> increase in Ca++ influx
-SNS activation in heart: Increases contractility and chronotropy
-SNS activation in skeletal blood vessels (B2): Relax
-In bronchiolar smooth muscle (B2): Relax
Autonomic Feedback Loop, Increase & Decrease in BP
Cardiovascular Feedback Loops
Mean arterial pressure is sensed by the baroreceptors (carotid and aortic arch)
Increase in BP: Brainstem activates PNS –> ACh released to slow down HR and decrease cardiac output
Decrease in BP: Brainstem activates SNS –> NE binds to B1 in the heart –> increasing HR & CO
NE binds to A1 receptors in peripheral vascular system –> constriction, increasing blood return to the heart
Hormonal Feedback Loop
Cardiovascular Feedback Loop
-Renal BP decreases–> renin released–> angiotensinogen converted to angiotensin 2–> causes constriction
Aldosterone released–> Decrease UOP, Increase H20 retention –> increased blood volume, increased venous return, increased CO
Six Types of Neurotransmitters
- Esters; ACh
- Monoamines; NE, serotonin, dopamine
- Amino Acids; GABA, glutamate
- Purines; Adenosine, ATP
- Peptides; Substance P, Endorphins
- Inorganic gases; Nitric Oxide (released by presynaptic cell)
Three of them
Types of Synapses
- Chemical: Release neurotransmitters
- Electrical: Gap junctions between adjacent cells (ions)
- En Passant Synapses: IDK what these do
What happens to them? (4)
Neurotransmitter Fate
- Diffuse away from the synapse
- Degraded by enzymes (ACh-esterase)
- Re-uptake into the presynaptic cell
- Uptake into the surrounding cells
Excitatory vs Inhibitory Pathway
Ion channel opens –> increased PNa+ –> depolarization occurs–> Excitation
Ion channel opens–> increasd PCl- –> hyperpolarization of the cell –> inhibition
Function of 3 Neurotransmitters Dealing w/ Emotion
- NE: Plays a role in fear, anger, distress
- Serotonin: Low levels implicate depression
- Dopamine: Rewarding, pleasurable (addiction)
Formation, Transport, Enzymatic Cleavage of ACh
Synthesized in the cytoplasm of releasing cell from Acetyl-CoA (mitochrondria provide) and choline (from diet)
Acetyl-CoA + Choline + Choline acetyltransferase (ChAT) forms ACh
Transported into vesicles by VAT ( ~50,000 per vesicle)
Acetylcholinesterase breaks down ACh: Binds to the ester, causes tension, breaks down into acetic acid and choline
CHT- Choline transporter back into neuron. Co-transportor of Na+ and choline. Facilitated diffusion
Release of ACh into synapse
Cholingeric Transmission (ACh)
- Action potential generated from axon hillock –> Synaptic bouton
- Triggers P-type Ca++ Channel, Ca++ influx into cell
- Ca++ Destabilizes the VP-2 vesicles
- Fusion of VP-2 vesicles with terminal membrane
- Exocytosis of ACh into synaptic cleft
- ACh binds to nACh-r –> broken down by AChE
Docking Molecules, Fusion molecule
Anchoring ACh Near Synapse
Snare complex is used to anchor VP-2 vesicles near the release site
-Syntaxin, SNAP-25, VAMP are all proteins associated with the Snare complex
-Synaptotagmin: Responds to the Ca++ influx into the cell and facilitates vesicle fusion with the membrane
Presynaptic Receptors
Heteroreceptor vs Autoreceptor
-Receptors on the presynaptic neuron.
-Autoreceptor refers to a receptor that responds to the neurotransmitter being release by that neuron
-Heteroreceptor will respond to a different neurotransmitter
Synthesis,Transport, Storage, Release & Degradation of NE
-Derived from amino acid tyrosine
-Tyrosine is converted into dopamine (tyrosine & tyrosine hydroxylase –> Dopa & dopadecarboxylase –> Dopamine)
-After conversion to dopamine, dopamine is transported into the vesicle VMAT. Dopamine is converted into NE, inside the vesicle, by dopamine-b- hydroxylase & ATP
-Release of NE happens when an action potential opens voltage sensitive Ca++ channels –> increasing intracellular Ca+
-After release, NE diffuses out of the cleft or is transported by NET back into the cytoplasm. If transported back into cytoplasm, it is reused OR degraded by MAO
This mechanism can be blocked by cocaine or certain antidepressants
Effects of Cholinomimetics in Major Organ Systems
Eye, CV, GI, Resp, CNS, NMJ
Eye:
-Muscarinic agonists cause contraction of the pupil
-increase intraocular drainage
CV:
-Reduction in PVR
-Vasodilation, reflex tachycardia. Large doses: bradycardia
Respiratory:
-Bronchiole smooth muscle contracts
-Tracheobronchial secretions increased
GI:
-Increased motility
-Salivary & gastric glands stimulated
-Sphincters relax
CNS:
-Primarily have muscarinic receptors in brain with few nicotinic receptors
-Nicotine crosses the BBB (unlike muscarine) and stimulates release of serotonin, dopamine, GABA, NE
NMJ:
-Immediate depolarization of the end plate
-Increased permeability to Na+ and K+
-Muscle contraction, and if not hydrolyzed immediately, depolariation blockade
Use of Cholinomimetic Agonists
Two categories of them?
These drugs mimic the effects of ACh and are broken down into two categories:
ACh stimulants or cholinesterase inibitors
Examples of them
Directing acting cholinomimetic agents; alkaloids
-Act directly on the nACh-r or mACh-r.
-Considered stimulants
Alkaloids: Plant based
-Muscarine: Activates PNS system
-Nicotine: Stimulates nACh-r
-Pilocarpine, lobelin
Examples of them
Directing acting cholinomimetic agents; Esters of choline
-Act directly on nACh-r or mACh-r
-Not lipid soluble, permanently charged
-ACh: Used primarily for pupil dilation, but we have better drugs
-Methacholine: Dx of asthma
-Succinylcholine: Paralytic
-Carbachol: Decrease intraocular pressure
-Bethanecol: Bladder dysfunction
Examples of them, uses for them, 3 classes of them
Indirect acting cholinomimetic (Cholinesterase Inhibitors)
-Carbamates:
Neostigmine- Post Op ileus, MG
Pyridostigmine- MG
-Alcohols:
Edrophonium: Dx for MG
-Organophosphates:
Echothiopate: Glaucoma, lasts over 100 hours
Difference between Nicotinic and Muscarinic Receptors
Ionotropic vs Metabotropic
Nicotinic: Ligand gated ion channels (ionotropic)
Muscarinic: metabotropic GPCR channels
How does atropine effect this?
Open-Angle & Narrow-Angle Glaucoma
In general, the iris of the eye is flat in comparison to the cornea. This allows aqueuos drainage to pass through the Canal of Schlemm.
In open-angle glaucoma, we can use cholinomimetics to contrict the pupil, widening the angle, allowing for more drainage to pass, and decrease intraocular pressure. Open-angle glaucoma makes up for about 90% of glaucoma cases
In narrow-angle glaucoma, the iris is being pushed forward towards the pupil. The Canal of Schlemm is very narrow because of this. Giving atropine to dilate the pupil, in this situation, would occlude the canal of schlemm and could result in blindness. This is a medical emergency
S/S, Tx
Organophosphate pesticide poisoning & Poisonous mushrooms
-SLUDGE-M
Organophosphates:
-Tx: Vital sign maintenance, decontamination, atropine or pralidoxime (must be given withint the first couple of hours)
Mushrooms:
Atropine
Antimuscarinic Drugs
4 of them we need to know for class
-Atropine (bradycardia)
-Scopalamine (Motion Sickness)
-Tropicamide (eye)
-Ipratropium (COPD)
-MOA: Blocks mACh-r
-Block PNS effects
-Eye indications: Miosis (contraction of pupil), mydriasis (dilation of the pupil), paralysis of cilliary muscle (cycloplegia), accomodation (focus)
S/S, Tx
Nicotine Poisoning
-40mg is fatal dose. Usually happens if children eat cigarettes
-Tremor, vomitting, convulsions, fatal coma, and death
-Need to induce vomitting
Cholinesterase Inhibitors
Organophosphates MOA & Aging
Organophosphates target AChE. The organophosphate binds to the enzyme by hydrolysis and phosphorylation of the active site. A covalent bond is formed with the phosphorylated active site.
After the intial covalent bond is formed, the aging process begins; meaning, the phosphorous-active site bond continues to become stronger and irreversible
Pralidoxime needs to be given immediately, before aging progresses
Antimuscarinic Effects on Major Organ Systems
Eye:
-Dilation, decreased watering (via paralysis of the cilliary muscle)
Heart:
Increased HR
Misc: Decreases salivation, decreases rate at which urine is produced
Atropine Toxicity & Treatment
Belladona plant or deadly nightshade
-Tachycardia, agitation, increased body temperature, dilated pupils, decreased salivation and sweat, dry skin
-These symptoms can be overcome by increasing the amount of ACh in the synapse.
-Physostigmine (dangerous CNS side effects), Neostigmine
Indications & Contraindications for Atropine
Indications: Overproduction of PNS response, parkison’s, poisonous mushroom toxicity
Used to block toxic effects of muscarinic stimulants; use atropine if SLUDGE-M
Contraindicated in narrow-angle glaucoma, BPH
Nicotinic Antagonists: Depolarizing and non-depolarizing muscle relaxants
And ganglion blockers
-Do not use ganglion blockers anymore; their role was to block the release of ACh
-Depolarizing: Succinylcholine; mimics two ACh molecules. Binds to the nACh-r in place of ACh, depolarizes the muscle. Muscle remains depolarized locally at the skeletal muscle end plate
Nondepolarizing: Block ACh from binding. Only need one to bind.
Long acting- pancuronium
Intermediate- Atracurium
Short- Mivacurium
Reversed by neostigmine (increases ACh at the NMJ) or sugammadex (encapsulates the paralytic)
Basic Structure of Catecholamines
-Benzene ring with adjacent hydroxyl groups (cathechol) and an amine group
-Substitution greatly reduces potency
-Cannot be taken PO, inactivated immediately by cOMT in gut
-Catecholamines are degraded by catechol-O-methyltransferase (COMT)
MOA of indirect & direct acting catecholamines
Indirect agonists: Cause the release of the catecholamines
-Ephedrine, Amphetamine
Direct Agonists: Stimulate the adrenoreceptor directly
Epinephrine
-Mixed Adrenergic Agonist
-Binds to A1, A2 (some), B1, B2
-Increases PVR, CO (HR, SV), BP
-B2 vasodilates blood vessels in skeletal muscles, dilation of bronchioles
Phenylephrine/Midodrine
-Pure A1 agonist
-Increases PVR
-Can cause decrease in CO
-Reflex bradycardia immediately after given
-Decongestant if given PO
Midodrine- pure A1 agonist
-Decreases orthostatic HTN, can cause HTN in supine patient
Isoproterenol
-Beta 1 & 2 agonist
-Increases HR, contraction, CO, SV
-Decreases PVR, can cause decrease in BP
Dopamine
-Dose dependent
-Low dose (0.3mcg/ml or less): D1 receptors in kidneys; Induces diuresis
-Intermediate Dose (0.3mcg-0.7mcg): Beta 1
-High dose (>1mg/ml): A1 agonist. Increases the work of the heart, can induce arrythmias
Norepinephrine
-A1, A2, B1 agonist
-Increases both SBP and DBP
-Hardly any B2 activity
Dobutamine
-B1 Selecive Agonist
-Cardiogenic shock, CHF exacerbation
Ephedrine
-Indirect acting; releases stored catecholamines
-Direc acting; acts as epinephrine, crosses BBB
-PO pseudoephedrine
What Questions Should We Ask When Picking a Sympathomimetic?
-Which receptor activation is required?
-Route of administration
-Dosing and monitoring therapeutic dose
Sympathomimetic Toxicity
Adrenergic Agonists
-Effects seen are a direct extension of their receptor effects
-HTN
-Cerebral hemorrhage
-Pulmonary edema
-Angina
-Cardiac tamponade
-MI
CNS toxicity- convulsions
Alpha Blockers
MOA? BP? HR? Drug ex
-Decrease PVR, reducing preload & blood pressure
-Should have no direct effect on HR
-Nonselective uses for alpha blockers: Useful in tx for pheochromocytoma
Phentolamine, Phenoxybenzamine, and then typically end in
“-osin”
If it ends in “-zosin”–> BPH
Phentolamine
Reversible or not?
Competitive antagonist of A1 & A2
-Reduces PVR
-Causes some cardiac stimulation
-Minor agonist of muscarinic and histamine receptors
Adverse Effects:
Cardiac stimulation (M-r in heart, can increase HR)
Abdominal pain, N/V/D
Used for treatment of HTN linked to pheochromocytoma
ED- direct injections
Phenoxybenzamine
Reversible or not?
-Mostly selective for A1
-Forms covalent bonds, non-competitive, insurmountable
-Inhibits NE reuptake, blocks H1, ACh, and Serotonin receptors
-
Beta Blockers
Propranolol, Metoprolol, Atenolol, Esmo, Labeta, and indications
-Propranolol is the prototype:
-Extensive first pass
-Non Selective, B1 and B2
Metoprolol, Atenolol:
Mainly B1 selectivity
Safer in COPD and diabetics
Esmolol:
Ultra short acting
Selective for B1
Safer in critically ill, fast on fast off
Labetalol:
Racemic mixture
S,R isomer is a1 blocker
R,R isomer is a B blocker
Regulators of BP, 3 factors in PVR
Hydraulic equation, PVR, CO, Volume,
-Hydraulic Equation - BP = CP x PVR
Factors that affect BP:
PVR
Vessel elasticity
Blood volume
CO (HR x SV)
PVR is hard to measure. Three factors in PVR
1. Blood vessel diameter
2. Blood Viscosity
3. Total Vessel length
Four anatomic control sites for BP
- Arterioles: Provide resistance
- Venules: Increase return to the heart, contributes to preload
- Heart: CO
- Kidneys: Volume regulation via RAAS
Categories of Anti-HTN Agents
Act on one or more of the anatomic control sites
- Diuretics (Lasix, Bumex, HCTZ): Deplete Na+
- Sympathoplegics (Alpha & Beta blockers): Decrease PVR, reduce CO
- Direct vasodilators: Relax vascular smooth muscle
- Anti- Angiotensins: Block activity or production of
Clonidine & Precedex
Targets, Effects, Indications for use, major side effects
-Targets vasomotor center in CNS
-A2 agonist
-Primary activity is due to inhibition of sympathetic outflow and increased parasympathetic outflow in brainstem
-Crosses BBB, enters rapidly
-Side effect is sedation, used as anesthesia adjunct as well as
Clonidine is primarily used for ADHD, tourettes, w/d symptoms
Methyldopa
Targets, effects, indications, side effects
-Target is vasomotor center in the CNS
-Analog of L-dopa
-Prodrug; works by replacing NE and decreasing NE release
-Does not cross placental barrier
-Does cross BBB
-Primary use for pregnancy- induced HTN
-S/E sedation
Yohimbine
Alpha 2 Antagonist
Does not work
We don’t use it
Vasodilators
MOA
-Relax smooth muscle of arterioles (all vasodilators) and veins (nitroprusside & nitrates)
-Reduces MAP and PVR
-Elicits compensatory responses- RAAS system, so best when given in conjuction with anti-HTN that combat these responses
Vasodilators
Minoxidil
MOA
-Opens K+ channels in smooth muscle, hyperpolarizing membrane potential, less likely to contract
-Dilates arteries and arterioles
-Rogaine
Vasodilators
Hydralazine
MOA, toxicity
Dilates arterioles–> possibly NO production?
-Toxicity includes: HA, N, sweating, flushed. Symptoms are similary to lupus
Vasodilators
Sodium Nitroprusside
MOA, indictions, toxicity
-Relaxes venous and arterial smooth muscle by releasing NO
-Rapidly lowers BP
-Protect from light
-HTN emergencies and heart failure
-Breaks down into cyanide, begins to accumulate >48hours.
Can cause metabolic acidosis, arrythmias, death
Need to give sodium thiosulfate to metabolize CN
Three Classes of CCB & their targets
-Verapamil: Targets the heart
-Diltiazem: Targets heart and peripheral vasc
-Dihydropyridine blockers: end in -dipine, target the peripheral vasc
RAAS System
Low BP detected by kidneys –> Angiotensinogen (an inactive precurse made by the liver) is converted by renin into Angiotensin I–> Angiotensin I is converted into Angiotensin II by ACE which leads to:
1. Vasocontriction in the blood vessels
2. Aldoseterone release causing increased Na+ & water retention
ACE Inhibitors & ARBS
MOA, drug name ending
Ace Inhibitors: By blocking ACE, we stop the conversion from Angiotensin I to Angiotensin II
This also inhibits the breakdown of bradykinins, leading to increased inflammation in the lungs –> dry hacking cough as side effect
Ace inhibitors end in -pril
ARBs block the angiotensin II receptors in the blood vessels and adrenal cortex
Arbs end in -sartan
Pulmonary HTN
- In the lungs, ET-1 binds to both ET-A and ET-B in the presence of things such as AngII, cytokines, thrombin. When bound, ET-A, ET-B both cause vasoconstriction and proliferation of smooth muscle cells
- -Causes: High systemic BP, congenital, COPD, heart failure
-Tx: In the hospital, can use IV prostaglandins to induce pulmonary vessel vasodilation; epoprostanol
At home, can use endothelin receptor antagonists: Bosenten, Tezosentan
HTN Urgency & HTN Crisis
HTN Urgency: >180/110 w/o acute end organ damage. Need to lower BP in hours
HTN Crisis: >180/110 w/ acute end organe damage (stroke, AKI). Need to be treated in the ICU with immediate lowering of BP
Tx for mild, moderate, and emergent HTN
Mild: Decrease Na+ intake, exercise, weight reduction in obese patients. Evaluate whether taking decongestants, NSAIDS, contraceptives, ETOH
Moderate: Meds, will often need a combination
Emergent: IV meds
Differences in arterial, venous, and capillary tone
-Arterial: Consists of arteries and arterioles. Much more forceful than venous tone (16x more forceful in artery)
-Venous tone: Much larger capacitance that arteries. This allows the venous system to function as a reservoir for blood volume and circulate blood volume back to the heart
-Capillary tone: none
Pathophysiology of stable angina, vasospastic angina, unstable angina
-Stable/Angina of Effort: Accumulation of metabolites. O2 requirement increases due to exercise or symapthetic stimulation, and those increased O2 demands are not met because blood flow does not increase proportionally
-Vasospastic/Prinzmetal: O2 delivery decreased due to coronary vasospams
-Unstable angina: Angina at rest; usually due to atherosclerotic plaque
Coronary blood flow is…
Directly related to perfusion pressure (DBP) and the duration of diastole
Coronary vessels are not perfused during systole
Drugs & Interventions to relieve chest pain
Stable Angina: Reduction of aggravating factor/demand. If HTN, CCB & beta blockers. Non-HTN, nitrates. pFox inhibitors
Vasospastic: Potent vasodilators. Nitrates or CCBs
Unstable: Medical emergency. PCI, stent placement, CABG
CCB Vascular tone reduction pathway
-Blocks Ca++ channel–> Ca++ cannot flux into the cell–> this leads to a direct decrease in calmodulin activity –> inhibiting myosin light chain kinase –> preventing contraction
K+ Channel Blockers & Effect on vascular tone
-Causes K+ to leave the cell, hyperpolarizing the cell, making it more difficult to depolarize
Nitrates/ Nitrites
-NO occurs naturally in the body, produced by vascular endothelial cells
-Blood flow against the vascular endothelium cause the release of Ca+ which activates NO synthase
-NO synthase converts L-Arginine into NO
-NO activates the enzyme guanylyl cyclase, found in vascular smooth muscle
-Guanylyl cyclase catalyzes the dephosphorylation of GTP to cGMP–> causes smooth muscle relaxation
1. Inhibits Ca+ entry into cell
2. Increases uptake of Ca+ into endoplasmic reticulum
Increase venous capacitance, decrease ventricular preload, decrease CO output
Can cause reflex tachycardiac, orthostatic hypotension
Methhemoglobin
Drug classes that reduce vascular tone
NO, Nitrates, Nitrites- MOA on other flashcard
Beta-2 Agonists- Increases cAMP in pulmonary vessels –> relaxation here
CCB: Block Ca++ channel, leading to decreased contraction
Sildenafil: PDE inhibitor–> leads to increase in cGMP –> relaxation of vascular smooth muscle
Heart Failure:
Systolic vs Diastolic
Systolic: Thin, floppy ventricles. Causes decreased cardiac output, decreased EJ
Diastolic: Thick, muscular ventricles. Unable to relax to allow to diastolic filling. Decreased CO, normal EJ
Congestive Heart Failure; L vs R
Left heart: Increased left ventricular pressure at the end of diastole. This causes pulmonary congestion.
Right heart: Blood can backup into R IJ, hepatic vein
Normal Cardiac Function; how does Ca++ interact with myocites to allow contraction?
-Ca++ enters the cell through a Ca++ channel. That Ca++ (referred to as the ‘“trigger” Ca++) interacts with the Ca++ release channel on the wall of the sarcoplasmic reticulum –> stored Ca++ is released into the cytoplasm, allowing for actin to interact with myosin –> one heart bear
Four Factors of Cardiac Performance; and how they are altered in heart failure
- Preload: This is our EDP; however, often synonymous with EDV. Decreased in diastolic HF, increased in systolic HF
- Afterload: Resistance in which the heart must pump against. Increases as CO decreases (compensatory)
- Contractility: The force with which the heart contracts. Very poor in systolic HF. Too forceful in diastolic HF
- Heart Rate: Main determinant of CO. First compensatory mechanism to respond to decreased CO. Lowering HR in diastolic HF will allow for more filling time
Frank Starling Law
Strength of contraction increases the more the heart stretches (to a certain point)
What contributes to EDV?
Three things
Passive filling+ atrial contraction + ESV
Strategies and drugs to tx HF-
Correcting Failure of Cardiac Contractility
-Positive Inotropes: Cardiac glycosides; digoxin
-Phospodiesterase Inhibitors: indirectly increase inotropy by inactivating cAMP and cGMP (milrinone)
-Beta adreneric stimulants: Dopamine & Dobutamine
-Ca++ sensitizers: Positive Inotropy & vasodilations
Strategies and drugs to tx HF
Reversing Salt and Water Retention
-Diuretics: Reduce preload, reduce edema, reduce cardiac size, and improve efficiency of cardiac pump
Strategies and drugs to tx HF
Unloading stress on the myocardium
-Reduce compensatory mechanisms in response to HF (RAAS); Ace inhibitors- captopril
-ARBS: Losartan
-Vasodilators: reducing preload and afterload
ADME
Digoxin
MOA & Toxicity, electrolytes, what do we see on EKG?
Inhibits the Na+, K+, ATPase pump on the heart and is a positive inotrope. Increases PR interval, decreases QT interval
Has a narrow therapeutic index. Toxic doses can cause tachycardia, a fib, v fib, and cardiac arrest.
Toxic doses also produce oscillatory after-depolarizations, increasing risk for v-fib and v-tach.
Hyperkalemia: K+ competes with dig
Hypercalcemia & hypomagnesium: Increased risk of arrhythmias
EKG- downward schwoop after QRS
Well absorbed, distributed widely in tissues and CNS
T1/2 36-40hrs
2/3 excreted unchanged in the kidneys
Non-pharmaceutical interventions for HF
-LVAD
-Chronic biventricular resynchronization
-Defibrillatory
-Heart transplant
-End stage: hospice
Intrinsic Conduction System/Pathway
SA node –> enforces a contraction rate of 110bpm –> AV node, located in the junction of the atria and ventricles, slows down the rate of conduction to ~75bpm
Conduction travels from the AV node down the Bundle of His –> down the left and right purkinje fibers
Conduction and how it correlates to a normal EKG
P-Q interval is atrial depolarization
QRS complex is ventricular depolarization
ST segment is ventricular depolarization
Cardiac Action Potential, Phases & Ion Movement
Phase 0: Depolarization of cardiac cells; action potential upstroke. AP is “over-shot” just a litte. Na+ moves in
Phase 1: K+ begins to leave the cell, membrane potential decreases slightly
Phase 2: K+ still leaving; however, Ca++ enters the cell, prolonging the action potential to allow the heart to pump
Phase 3: K+ leaving the cell, repolarization
Phase 4: Vrm
Main Classifications of Arrhythmias; Disturbances in impulse formation
Disturbances in impulse formation:
-SA/AV nodal abnormalities
-Ion changes
-SNS stimulation
- Vagal Discharge: Slows the HR, hyperpolarizes the cell. Reduction in phase 4 slope
- Acceleration of HR caused by beta agonists, fiber stretch, or acidosis.
Will see an increase in phase 4
Main Classifications of Arrhythmias; Disturbances in impulse conduction
Disturbances in impulse conduction:
-1st degree, 2nd degree (Type I & II), 3rd degree block
-Re-entry:
-Block is unidirectional, there must be an obstacle (scar tissue), and conduction time must be long enough to reenter same areas after refractory period
Antiarrhythmic Agents-Four Classes
Class I: Sodium channel blockade
Class II: Sympatholytic (beta blockers)
Class III: Prolong action potential duration, K+ channels
Class IV: CCB
Antiarrhythmic Agents- Class IA, IB, IC
IA: Sodium channel blocker
-Procainimide, Quinidine
-Prolongs action potential duration and increases effective refractory period
IB: Sodium channel blocker
-Lidocaine, Mexiltine
-Shortens APD, decreases ERP
IC
-Flecainide, Propafenone
-Minimal effects on APD, no effect on ERP
All four Vaughn-Williams Class Effects
Antiarrhythmic Agents- Class III
Amiodarone-
i. Na+ channel blockade
ii. Non-competitive alpha & beta inhibition
iii. prolongs cardiac action potential
iv. CCB, dilation in peripheral vasculature
DOC for VT
Toxicity: Bradycardia or heart block, precipitate heart failure, fatal pulmonary fibrosis, concentration in tissues
Antiarrhythmic Agents- Class IV
Verapamil; CCB
-Blocks inactivated and activated Ca++ channels
-Prolongs AV node conduction
-Slows SA node
-Can cause hypotension
Adenosine
Enhances K+ conductance
Inhibits cAMP induced Ca++ influx
T1/2: ~10seconds
