BEGIN DRUGS OF PARASYMPATHETIC SYSTEM NICOTINIC AGONISTS
Succinylcholine. This molecule acts like a super‐holding ACh that cannot be degraded. It binds to ACh‐R leading to activation and depolarization (it is the only depolarizing NMJ blocker in clinical use). It initially excites skeletal muscle but then stays on the receptor, preventing ACh from binding. It is used as an adjunct to anesthesia, whereby the endotracheal muscles are paralyzed to allow for endotracheal
intubation. This is not degraded by cholinesterase, but is controlled by the pseudocholinesterase in the
plasma. Therefore, patients with abnormalities in plasma pseudocholinesterase should not be given the drug to avoid prolonged action times (should be 5 minutes, but can be up to hours). A common side effect is malignant hyperthermia, so patients who have it, shouldn’t get it.
MUSCARINIC AGONISTS
Pilocarpine. This is a muscarinic cholinomimetic that is used to treat the dry mouth associated with
cancer radiation and chemotherapy or in the treatment of Sjorgen’s Syndrome. Its major
contraindications are narrow angle glaucoma and asthma. Since its purpose is to increase visceral Ach
effects, it is no surprise that it may result in flushing, sweating, lacrimation, and salivation, though the risk of toxicity is low. There is a risk of cardiac dysrhythmias if coadministered with adrenergic agonists. It has a tertiary amine and therefore crosses the blood brain barrier.
Bethanechol. This is a muscarinic cholinomimetic used to treat Urinary retention in an intact, functional bladder. Postoperative, Postpartum, or Neurogenic atony of the bladder, all conditions where urine is being retained in an unobstructed urinary tract, can be treated with bethanechol. It is a
substitute for ACh, so SLUDGE symptoms can be present. However, given the high degree of selectivity
for muscarinic receptors, the nicotinic symptoms are often absent. It has a quaternary amine and therefore cannot cross the BBB.
Cholinomimetics
Nicotinic Agonists Muscarinic Agonists Anticholinesterase Related
Reversible Irreversible Nictotine Succinylcholine Pilocarpine Bethanecol Physostigmine Neostigmine Edrophonium Pyridiostigmine Echothiophate Sarin Soman VX 2‐PAM
ACETYLCHOLINESTERASE INHIBITORS
Physostigmine. This is a reversible acetylcholinesterase inhibitor used to reverse the effect of
anticholinergic syndrome. Imagine you were treating a patient with ACh antagonists, and you went to far. Give this to bring them back to normal by effectively increasing [ACh] by decreasing its degradation. There are many products that can induce anticholinergic syndrome, which must be identified based on the clinical presentation (too little ACh is the opposite of the common “SLUDGE” associated with ACh overdose). It has a tertiary amine and can therefore easily penetrate the BBB. When treating the patient for too little ACh, physostigmine can cause them to have too much, and push them into a cholinergic crisis (SLUDGE). Give them atropine to cure. This is one of the carbamate drugs.
Neostigmine. This is a reversible and competitive acetylcholinesterase inhibitor which competes for the active site with ACh. The effect is to increase [ACh]. It also has some ACh‐R Agonist activity. It is an Ach‐lookalike. It is used for the chronic management of Myasthenia Gravis and can be used
parenterally for acute MG. It should not be given if there is a mechanical obstruction of the GI tract or urinary tract, as with all drugs that increase [ACh] or have mACh activity. It is poorly absorbed from the GI tract, but is usable in the management of MG.
Edrophonium. Edrophonium is used as a diagnostic test for myasthenia gravis. Caution must be made, however, since the indications for MG (weakness) may mimic the early signs of a cholinergic crisis. Giving the patient with MG this drug will temporarily alleviate their symptoms. Giving this to a patient in cholinergic crisis may result in cardiac standstill or worsen cholinergic crisis. It is super‐short acting but asystole is, well, fatal. It can also be used in the treatment of curare. SLUDGE is a possibility.
Pyridostigmine. Reversible noncompetitive acetylcholinesterase inhibitor. Works just like Soman nerve
gas, binding to the same site, but is not as devastating as Soman. In fact, pretreatment with
pyridostigmine prevents the damage done by Soman by occupying active site. It is also used in the treatment of Myasthenia Gravis but has gained popularity from the US military. Because Soman’s “aging” half‐life is so short, post‐exposure treatment can be ineffective. Essentially, it is a mini‐Soman, decreasing esterase activity thereby effectively increasing [ACh]. Since it sits in the same site as Soman,
Soman is unable to act. However, SLUDGE is still possible.
Echothiophate. This drug irreversibly binds acetylcholinesterase and is therefore a long‐acting
cholinesterase inhibitor. Because it is an irreversible inhibition, caution must be taken in the use of this drug (its mechanism resembles nerve gases). It causes miosis when topically applied to the eye allowing for an efflux of aqueous humor and a reduction in ocular pressure when treating glaucoma. It is a second line drug after Beta‐Blockers have failed. It unfortunately potentiates other cholinesterase inhibitors, so those patients on systemic inhibitors should use caution.
Sarin. A nerve gas that was featured in the movie “The Rock.” This was originally made as a pesticide. It irreversibly inhibits acetylcholinesterase. The process of “aging” is introduced here. When Sarin binds to acetylcholinesterase, its phosphorous binds to and degrades the alkyl group on the esterase. This
effectively permanently inhibits the esterase. An enzyme is considered aged when the alkyl group is removed. The aging time for sarin is about 5 hours, giving those exposed the opportunity to wash, rinse, and administer antidotes. Sarin is a highly volatile liquid and can infect a patient through intact skin, inhalation, or ingestion. It can be dissolved in the water. Atropine and 2‐PAM chloride are antidotes (what Nicholas Cage injects into his heart at the end of the movie). This is what SLUDGE was made for.
Patients exhibiting SLUDGE are more often than not exposed to organophosphate poisonings
(pesticides or terrorist weapons).
Soman. A nerve gas with an aging time of two minutes. This leaves no opportunity for the preventive effects of 2‐PAM, and thus atropine is the only antidote. Prophylaxis with the Pyridiostigmine is the only
thing that will save a patient exposed to Soman. SLUDGE is huge. This is a clear, colorless, tasteless gas
with a camphor odor. It is not as volatile, but far more deadly.
VX. The most dangerous organophosphate in existence. This is a amber (honey‐brown) colored,
tasteless, odorless, oily liquid with low volatility. If you filled the Lincoln’s head on a penny with VX, it would be sufficient to kill you. It has a very long persistence time (5% degradation a month, or a half‐life of approximately 1 year). If exposed, the patient is dead; no amount of atropine nor 2‐PAM will save them.
Pradiloxime / 2‐PAM. This is the antidote for organophosphate poisoning. The oxime group (NOH) on the 2‐PAM interacts with the phosphorous on the organophosphate, preventing the aging step. It is only effective if there has not yet been the alkyl degradation. It will prevent degradation, and thus, if the patient lives, their acetylcholinesterase will be intact after the toxin clears. Used in conjunction with atropine to take up the slack of bunk esterases, it is used to treat patients in terrorist attacks. It is ineffective against carbamates (physostigmine, Neostigmine) because they lack the phosphorous that is the target of 2‐PAM.
REVIEW OF ACETYLCHOLINESTERASE INHIBITORS (THESE INCREASE ACh)
Drug BBB Penetration Treats for / Notes Reversibility
Pyridiostigmine Quaternary Amine = no BBB Myasthenia Gravis and Soman prophylaxis Reversible Neostigmine Quaternary Amine = no BBB Myasthenia Gravis, competitive inhibitor Reversible Physostigmine Tertiary Amine = BBB Cholinergic Toxicity Reversible Edrophonium Quarternary Amine = no BBB Diagnostic for Myasthenia, short half‐life Reversible
Echothiophate Doesn’t Matter Topical Glaucoma Irreversible
Sarin Eventually Crosses Age time 5‐hours Irreversible
Soman Eventually Crosses Age time 2‐minutes Irreversible
VC ? ? Irreversible
MUSCARINIC AGONISTS
Drug BBB Penetration Treats for / Notes
Pilocarpine Tertiary Amine = BBB Sjorgen Syndrome, Xerostomia, etc.
Bethanechol Quarternary Amine = no BBB Unobstructed GI/GU constipation
Name MOA Indications Contraindications Side Effects/ Notes Pilocarpine Muscarinic ACh
agonist
Dry mouth associated with
Sjorgen’s and Cancer treatment
Narrow Angle
Glaucoma and
Asthma
SLUDGE possible, though
toxicity limited.
Well absorbed
3o Amine = Crosses BBB
Bethanecol Muscarinic ACh
agonist
Urinary retention with
functional (patent) GU tract
Asthmaand any
condition where
overactive ACh would
do harm
4o Amine = Does not cross BBB
SLUDGE possible
Succinylcholine Nicotinic ACH
Agonist
Anesthesia Adjunct: paralyze
endotracheal muscles for
intubation Plasma Pseudocholin‐ esterase deficiencies Malignant Hyperthermia
Only depolarizingNMJ blocker
in US.
Causes malignant hyperthermia
Phygostigmine Acetyl‐
Cholinesterase
Inhibitor
(reversible)
Anticholinergic syndrome
associated with a variety of
medications and plant products
NMJ blockade, GI
obstruction, asthma,
others
Cholinergic Crisis (SLUDGE)
treated with atropine
Neostygmine Acetyl‐ Cholinesterase Inhibitor (reversible)
PO: Chronic Myasthenia Gravis
IV/IM Acute Respiratory
Distress with Myasthenia Gravis
Mechanical GI / GU
Obstruction
Competes with ACh active site
on esterase
Has ACh agonist effects as well
Edrophonium Acetyl‐
Cholinesterase
Inhibitor
(reversible)
Diagnostic test for Myasthenia
Gravis.
Mechanical GI/GU Obstrictuction
SLUDGE possible.
Patients in a cholinergic crisis may present with
myasthenia weakness. Administration of Edrophonium
can produce a cholinergic crisis or cardiac standstill. MG
patients improve with administration
Pyridiostigmine Acetyl‐
Cholinesterase
Inhibitor
(reversible)
Pretreatment for Soman Gas
Exposure
Second line Myasthenia Gravis
GI/GU Mechanical
Obstruction
Caution: Asthma
Works just like Soman, except it
has a milder effect. Because
they share the same active site,
it outcompetes Soman. SLUDGE
still possible.
Echothiophate Acetyl‐
Cholinesterase
Inhibitor
(irreversible)
Glaucoma after Beta‐Blockers
have failed. Miosis = efflux of
acqueous humor = reduction in
ocular pressure. Narrow Angle Glaucoma Active uveal inflammation
Forms an irreversible covalent
bond with the ACh binding site,
making it an irreversible, competitive inhibitor. Sarin Organo‐ phosphate Irreversibly binds to acetylcholinesterase and
degrades alkyl group (ages the
esterase) in 5 hours
It’s a pesticide and
terrorist weapon
Treat with 2‐PAM and Atropine
Soman Organo‐
phosphate
Aging time of 2 minutes It’s a pesticide and
terrorist weapon
Treat with Atropine, 2‐PAM
cannot take effect since aging is
so fast
VX Organo‐
phosphate
Stays around for a long time,
small amounts are fatal
Terrorism only Nothing can save you
2‐PAM Acetyl‐
Cholinesterase
Rescuer
Oxime group binds to phos‐
phorous on organophosphate,
preventing the aging step
Ineffective against
Carbamate Poisoning
Atropine. This is the mother of all parasympathetic drugs. You have to know this one, and all the details. Atropine is a competitive muscarinic acetyl choline receptor antagonist that will always be on your crash cart. It has a short half life (about 2 hrs, tops) and effects only muscarinic receptors. Where are those? Well, in particular, they are on the heart above the ventricles (nodal cells), in the sweat glands
(the sympathetic mACh‐R), in the eye (pupil and accommodation), and, even though there is no
systemic acetyl choline, in the vasculature of the skin. Its common indication is systemically as a
pharmacological (and emergent) treatment of bradycardia or asystolic cardiac arrest (not Vtach or
Vfib). It is also commonly used to dilate the pupil in ophthalmologic exams. Since it inhibits mACh‐R
everywhere, common side effects include constipation or difficulty with mictruition. Atropine poisoning
(aka too little ACh activity) results in a clever pneumonic: Mad as a Hatter (crosses the BBB), red as a beat (flushing to the skin), blind as a bat (pupil dilation with vision disturbances), dry as a bone (anhidrosis without sweat glands), hot as hell (from the anhidrosis and the lack of sweating).
Scopolamine. Essentially the exact mechanism of atropine, it just works a little different. It is also a competitive muscarinic acetyl choline receptor antagonist. It is given more for mydriasis (dilation of
the pupil) and cyclopegia, lessening the nausea associated with surgery, and alleviating Parkinson
tremors. It has a longer duration of action than does atropine, with greater CNS penetration (thus its sedative effects). Its side effects are more the CNS depression than the peripheral side effects of Atropine.
Ipratropium. This is a direct, locally applied competitive muscarinic acetyl choline receptor antagonist. Commonly combined with a Beta‐Adrenergic Agonist (like albuterol, together called a “combi‐vent”) this
is an inhaled medication used to treat bronchoconstriction (asthma/copd). Because it is inhaled, it has
no systemic effects, except for what little gets absorbed through the lungs into the lungs (usually not
enough to cause any problems). However, jittery‐ness has been reported.
NONDEPOLARIZING NEUROMUSCULAR JUNCTION RECEPTORS
Tubocurarine. Binds to, but does not activate, nicotinic acetyl choline receptors of the peripheral
musculature. In this sense, it is a nondepolarizing (doesn’t activate like succinylcholine does)
neuromuscular junction blocker. It is useful in induction during surgery for anesthesia.
Cholinolytics Antimuscarinic Nondepolarizing Neuromuscular Blockers Ganglion Blockers Atropine Scopolamine Ipratropium Tubocurarine Botulism Trimethaphan Mecanylamine
Botulism. Ooh! Micro back at yah!. It gets into acetylcholine presynaptic vesicles and prevents the docking of vesicles to the membrane, effectively preventing acetyl choline release (sort of like an uber
bretylium in comparison to Norepi neurons). You get a spastic paralysis when infected by the
clostridium that causes it. Otherwise, you inject it into wrinkled foreheads to paralyze their skin/muscles and have Joan Rivers Skin. Seriously. Its Botox.
GANGLIONIC NICOTINIC RECEPTOR INHIBITOR
Trimethaphan/Mecanylamine. This is a unique one because it is the ganglionic nicotinic receptor inhibitor. Whoa, what does that mean? Well, every ganglionic synapse, be it sympathetic or parasympathetic, uses the nicotinic receptor. Blocking that kills your entire ANS. It is used in the treatment of hypertensive emergencies & dissecting aortic aneurysms by causing massive hypotension. It causes blockade of the everything, giving you cyclopegia/mydriasis, hypotension, tachycardia (intrinsic heart rate is 100 + baroreceptor reflex), decreased contractility, decreased GI motility, problems with mictruition, etc. It must be given by IV infusion and should be reserved for the “ZOMFG!” cases.
Name MOA Indications Notes
Atropine Antimuscarinic Bradycardia, mydriasis (pupil
dilation), resuscitation from
cardiac arrest
Its on your crash cart (for codes and brady), it
has a short duration of action, and is often
used by ophthalmologists for dilation.
Overdose = blind as a bat, mad as a hatter,
red a beat, dry as a bone, hot as hell
(mydriasis, CNS alteration, flush, anhidrosis,
heat intolerance).
Scopolamine Antimuscarinic Mydriasis/Cyclopegia, Parkinson
Tumor, reduction of nausea
post‐surgery
Penetrates CNS better than atropine so gives
CNS depression side effects, rather than
typical atropine symptoms.
Ipratropium Antimuscarinic Asthma/COPD Inhaled, so systemic involvement is low; organ
targeted therapy. Commonly given with Beta‐
Agonists (Albuterol) for bronchodilation
Tubocurarine NMJ Blocker
(nondepolarizing)
Induction of anesthesia prior to
surgery
Binds to, but does not activate, nicotinic ACh and so is a nondepolarizing agent.
Botulsim
(Botox)
NMJ Blocker
(nondepolarizing)
Making wrinkly faces pretty
again!
It is the same toxin you learned about in
micro, preventing vesicle fusion in presynaptic
nACh neurons, causing a flaccid paralysis
Trimethaphan Ganglionic
Blocker
Super severe devastating HTN
(like when there is a dissecting
aortic aneurysm that hasn’t
popped yet)
It inhibits the entire ANS since both symp and
parasymp relies on nACh at the first ganglion.
It causes cataclysmic reduction in BP, CO, HR,
SV, along with all the side effects of Atropine.
Reserve this for severe cases only!
BEGIN DRUGS OF SYMPATHETIC SYSTEM DIRECT ACTING SYMPATHOMIMETICS Noepinephrine. With the trade name “Levophed” prehospital medicine deemed this drug “Leave‐em‐ dead.” Norepinephrine has non‐selective adrenergic activity. However, its alpha effects are greater than its beta effects, with particular lack of selectivity to Beta 2. Beta‐1 stimulation results in a
chronotropic/inotropic response which increases the blood pressure. Alpha‐1 stimulation results in an extreme elevation of peripheral resistance thus increasing blood pressure. This markedly increased blood pressure leads to baroreceptor feedback that inhibits the beta‐1 stimulation. Thus what the patient is left with is an increased blood pressure as a result of increased peripheral vascular resistance. This means that the blood pressure is high but the organ perfusion is low. Its great at maintaining the numbers, but literally strangles the organs to death.
Epinephrine. This is another nonselective adrenergic agonist with preferential selectivity for beta receptors. There are alpha effects, and, as the dosage gets higher, the alpha effects begin to
predominate. Thus, if you overload your patient, you can induce norepinephrine like symptoms. Epi can be given as a constant infusion (as in Norepi), as an IV injection (1:10000), as an IM/SubQ injection (1:1000). It is often given in cardiac arrest, or in anaphylaxis inducing vasoconstriction (alpha effect) and bronchodilation (beta‐2 effect). Now, epi is the adrenal medulla’s extension of the sympathetic nervous
system, so giving a lot can induce tachycardia or tachydisrythmias (Vtach, Vfib, etc). Usually when you
are giving it, epi is indicated as an emergent drug, give it and worry about the dysrhythmias later.
Dopamine. Dopamine is a catecholamine given in as an infusion. It has dose dependent selectivity. At
low does (1‐5ug/kg/min) there is only a dopaminergic effect (improving renal and mesenteric function).
At mid range doses (5‐10ug/kg/min) there are beta effects (chronotropic and inotropic effects on the
heart). At high doses (10‐20ug/kg/min) there are alpha effects (aka, norepinephrine effects, “leave em
dead.”) This is indicated in cardiogenic and septic shock. That is, where the heart may need a little extra boost, or the tank is too large, give dopamine. What do I mean by the tank is too large? In septic shock
Neuron/Synapse Acting Sympathomimetics
Direct Acting (Adrenergic Agonists) Indirect Acting Other Nerve
Terminal Acting Norepinephrine Terbutaline Epinephrine Phenylephrine Dopamine Clonidine Dobutamine Isoproterenol Albuterol Tyramine Ephedrine Amphetamines Cocaine Imipramine Phenelzine Guanethidine* Increase NT release Decrease NT release Reseprine Bretylium Guanethidine* Octopamine Methyl Dopa
the massive inflammatory cytokines cause a severe vasodilation. If you just close up those vessels pharmacologically, wham, you’re fixed.
Isoproterenol. This is a nonselective Beta‐Agonist, effecting both Beta‐1 and Beta‐2 to almost the same extent. It has no alpha activity. When given it is both chronotropic and inotropic to the heart,
increasing cardiac output and assisting the cardiovascular system in maintaining perfusion (Beta‐1 effect). When given it also induces vasodilation of skeletal muscle vasculature leading to a decrease in peripheral vascular resistance, resulting in a decreased diastolic pressure (Beta‐2 effects). Finally, it leads to bronchodilation (other Beta‐2 Effect). It is useful in the management of bradycardia, non severe heart block or cardiogenic shock, until a more definitive treatment can be initiated (such as
transcutaneous pacing). Since it is a beta‐agonist it can lead to tachycardia or any condition associated
with increased myocardial oxygen demand (MI, angina, pulmonary edema, ventricular arrhythmias). It does not enter presynaptic terminals and therefore is not metabolized by MAO, but instead is
metabolized by COMT in most tissues.
Dobutamine. This is like dopamine, but is Beta‐1 selective. Like dopamine, it is given as a constant infusion with a half‐life of 2 minutes. However, it is a safer drug with less alternative side effects than
dopamine. Because it is only Beta‐1 Selective, there is a selective inotropic/chronotropic change
without effects to peripheral vascular resistance. It is used in patients in cardiogenic shock/failure, particularly useful following cardiac arrest. It should cause an increase in blood pressure and heart rate, but often does not induce lethal tachyarrhythmia nor does it have the risk of “Leave‐em‐dead”
reactions.
Albuterol. This is an aerosol Beta‐2 Selective Agonist given for the treatment of obstructive diseases such as asthma and COPD. When combined with Ipratropium, it is called “combi‐vent.” It is a locally administered Beta‐agonist but can go systemic. If it does, and it gets toxic, its beta‐2 selectivity may be lost, and beta‐1 kicks in (tachycardia, seizures, angina, hypetension) etc.
Terbutaline. This is uber albuterol. Same mechanism of action, except this requires a much smaller dose and can be given SubQ. It is used to treat or prevent bronchospasm usually associated with
asthma/copd. It has all the same potential side effects and contraindications, its just a bigger albuterol. Chances are, if albuterol treatments are failing, Terbutaline will not help, but is often the drug ERs turn to next.
Phenylephrine. This is a nonselective alpha agonist. Because it activates both alpha‐1 and alpha‐2, it causes a marked elevation in blood pressure. There is a direct effect (alpha‐1) which causes
vasoconstriction. There is an indirect effect (alpha‐2) which inhibits Norepinephrine’s self‐mediated feedback, causing activation not only by Phenylephrine, but by elevated concentrations of Norepi as well. Thusly, it is used in conditions where profound hypotension has resulted, such as spinal or anesthetic shock. It has hardly any Beta‐ effects. The pressor effects are significantly increased when combined with MAO‐inhibitors.
Clonidine. This is an alpha‐2 selective agonist. If it activates the receptors that normally norepinephrine activates to turn itself off, then Norepi would be turned off without its release. This is used to treat hypertension by limiting the CNS sympathetic outflow. Norepi gets released, causing vasoconstriction (alpha‐1) and also auto‐feedback turning itself off (alpha‐2). Clonidine turns off Norepi without Norepi
ever being released. Overdoses result in profound hypotension fixed by Yohimbine (the alpha‐2
antagonist). INDIRECT ACTING SYMPATHOMIMETICS These drugs do not bind to adrenergic receptors themselves, rather they induce the release of naturally occurring neurotransmitter in vesicles in an indirect manner. Some of these drugs may have no direct agonist activity, others might. What they have in common is the ability to enter the presynaptic nerve terminal and activate vesicle release, resulting in increased sympathetic response.
Tyramine. This drug is the model for indirectly acting sympathomimetics. This is a naturally occurring compound in the plasma, in wine, and in cheese. Its relevance is limited until you interfere with normal
metabolism. It has a structure similar to tyrosine (the decarboxylated form) but has only one hydroxyl
group on its aromatic ring (therefore rendering it not a catecholamine). It enters presynaptic neurons
via the Norepinephrine Transporter (NET) that is normally responsible for the reuptake of NE following
a synapse. This induces the release of norepinephrine by inducing vesicle fusion. When patients are
taking an MAO inhibitor, the mitochondrial enzyme that normally degrades Tyramine (MAO) is inhibits,
and its levels build up, causing a significant increase in the release of Norepi. This leads to malignant hypertension and possibly hypertensive crisis. Thus patients on MAO‐Is should avoid wine and cheese.
Ephedrine. This is a drug that has both direct and indirect activity. You heard about this in the news as “Ephedra” the miracle diet pill. It was used as a diet suppressant and as a bronchodilator that was shown to increase the risk of stroke, MI, and death. It was removed from the market. Tachyphylaxis develops with repeated dosing (the neuron only has so much transmitter loaded into vesicles so that with rapid repeated dosing the reserve transmitter is depleted and subsequent doses cannot induce the release of what’s not there!)
Amphetamines. This is a strong CNS stimulant on schedule 2 as a drug with high abuse potential. It releases monoamines (Norepi, Serotonin/5‐HT, and Dopamine) from their storage sites at nerve terminals, competes with reuptake, and inhibits MAO. It basically takes all the catecholamines you’ve got in your brain, dumps them into the nerve terminal, then keeps them from being reuptaken and
degraded. This is a strong stimulant used for attention‐deficit disorders and narcolepsy. It’s a psych med
so nervousness, insomnia, and weight loss (among other side effects) are possible.
OTHER DRUGS, INCREASE NT RELEASE
Cocaine. This is a drug that you usually snort to get high. It works by blocking monoamine reuptake transport into nerve terminals, and it does so non‐selectively. This effectively increases
channels which is why it causes cardiac arrhythmias and can be used as a local anesthetic. Signs of toxicity include: palpitations, tachycardia, hyperthermia, seizures.
Imipramine. This is a tricyclic antidepressant and probably belongs in the behavioral block. But its here
because it inhibits reuptake of catecholamines (norepinephrine and serotonin). Its mechanism
increases the amount of happy chemicals in the nerve endings in the brain. It does a bunch of other things, too, that lends itself to the side effects: antimuscarinic (dry mouth, dizziness, etc.), Na+ channel blocker, etc. As with MAO‐Is, there is a long period of time (2 weeks) before the therapeutic effects are seen. It should not be given with MAO‐Is as the synergistic increase in catecholamines could lead to a hypertensive crisis. It is meant to target the catecholamines in the brain, but may cause symptoms in the periphery.
Phenelzine. Phenelzine is a monoamine oxidase inhibitor MAO‐I. Whereas Imipramine functioned by preventing reabsorption by blocking the transporter, MAO‐Is inhibit the enzyme that degrades the neurotransmitter. This means that although the transporter is not inhibited, the concentration gradient maintains a large extracellular concentration relative to the stagnant synapse. These drugs take weeks to months to reach peak effect. They target the brain to maintain happy chemicals, but it is possible to
effect the periphery, leading to a hypertensive crisis. These patients are particularly susceptible to foods
containing tyramine which is normally degraded by MAO, increasing their risk for malignant
hypertension (caused by wine, cheese, and smoked meats). Interestingly, pheochromocytoma
(epinephrine secreting tumor), is actually exacerbated by the presence of MAO‐Inhibitors.
OTHER DRUGS, DECREASE NT RELEASE
Reseprine. This is used as an antihypertensive agent. It inhibits vesicular uptake inhibitor (VMAT), thereby reducing the amount of neurotransmitter stored in the vesicle. When an action potential
reaches the axon terminal, the same number of vesicles are released as normal, but the amount of
transmitter per vesicle is reduced. This effectively inhibits adrenergic receptors leading to a decrease in pressure through both decreased cardiac output and decreased peripheral resistance. This drug can penetrate the blood brain barrier and effect dopaminergic neurons there, leading to suicidal tendencies (essentially the opposite of the TCAs or the MAO‐Is).
Bretylium. Bretylium is used as an antihypertensive or as an antiarrythmic. It essentially unlinks the action potential from the Ca2+ dependent vesicle fusion. The amount of neurotransmitter stored in the vesicle is the same, just fewer vesicles are actually released. This results in a decreased adrenergic response, effectively lowering blood pressure. It can also lengthen the effective refractory period in myocytes, making it quite effective at resuscitation of refractory ventricular fibrillation (the American Heart Association does not have Bretylium anywhere in any code algorithms).
Guanethidine. This is a peculiar drug. It is intended to be used as an anti‐hypertensive agent. It is almost never prescribed anymore, but still shows up on the boards and shelf because of its interesting mechanism of action. Guanethidine gets into the neurons through the Norepinephrine Transporter
(NET), then manages to get into the vesicles themselves. In the early phase the accessing of the NET causes an initial and transient increase in catecholamine release (Tyramine effect). In the late phase
(the therapeutic phase) as it replaces normal neurotransmitter, it depletes vesicles (reseprine effect),
and prevents vesicular fusion (bretylium effect). It does not enter the CNS, but can cause some pretty unpleasant side effects (impaired ejaculation, diarrhea, and postural hypotension).
Methyl‐Dopa. This is an anti‐hypertensive medication used when pregnancy contraindicates ACE or
ARBs. Its mechanism of action is not well understood. It is metabolized to alpha‐methylnorepinephrine
which then either acts on alpha‐2 presynaptic receptors or acts as a false neurotransmitter. In any case, arterial pressure is reduced.
Octopamine. This “drug” is a false neurotransmitter that accumulates when MAO is inhibited. It is a
metabolite of Tyramine, a naturally occurring catecholamine‐like compound found in wine and cheese.
When MAO is inhibited, dopamine Beta‐Hydroxylase converts tyramine into Octopamine. This is then
put into vesicles where it is released with Norepinephrine. It competes for Adrenergic Receptors with Norepi, but has a milder effect. This leads to hypotension, bradycardia, and a generalized reduced sympathetic response.
Name MOA Indications/Notes
Norepi Nonselective Adrenergic
Agonist (alpha more than
anything)
Increases BP via alpha‐1, increasing peripheral vascular resistance.
Increase pressure = baroreceptor feedback = bradycardia + increased BP.
Epi Nonselective Adrenergic
Agonist
Increases BP via Beta‐1 (chronotrope/inotrope), ignores baroreceptor
reflex by dilating skeletal muscle vasculature (Beta‐2). High doses are alpha
Dopamine Dose Dependent
Adrenergic Agonist
Low Dose: 1‐5ug/kg/min = dopamine receptor = renal blood flow
Medium Dose: 5‐10ug/kg/min = beta receptor = chrono/inotrope
High Dose: 10‐20ug/kg/min = Norepi = alpha = peripheral resistance
Dobutamine Beta Selective Agonist Dopamine, but Beta‐1 only
Isoproterenol Non selective Beta No alpha activity, chronotrope/inotrope used to treat bradycardia and
cardiogenic shock.
Albuterol Beta‐2 Selective Agonist Inhaled only, targeted therapy for bronchoconstriction (asthma/ COPD)
Terbutaline Beta‐2 Selective Agonist Sub Q, uber version of albuterol
Phenylephrine Nonselective Alpha Agonist Significant vasoconstriction following anesthetic or spinal shock
Clonidine Selective Alpha‐2 Inhibition of Norepi release = hypotension. Complete sympathetic
depression. Treats malignant hypertension.
Tyramine Indirect Agonist Enters through the Norepi Reuptake Transporter (NET), is degraded by
MAO, but first will induce vesicle fusion of Norepi and its release. Found in
wine, cheese, and smoked meats. When on an MAO‐I, toxicity (severe
hypertension) can result
Ephedrine Direct (alpha‐1) and
Indirect
Has tyramine‐like indirect effects while also direct alpha‐1 effects. This was
the diet fad Ephedra that ended up killing people because of lethal
tachyarrhythmias.
Amphetamine Multiple Has a tyramine‐like effect(increase vesicle release), Imipramine like effect (reuptake inhibitor) and Phenelzine like effect (MAO‐I). Schedule 2 drug.
Used to treat attention‐deficit disorder and narcolepsy
Cocaine Reuptake inhibitor, Na+
channel blocker
Get high, feel good (reuptake). High doses = anesthetic and vasoconstrictor
(Na+ channel blocker).
Imipramine Inhibits Reuptake of NT This is a Tricyclic Antidepressant (TCA). Target is the brain. Keep the happy
chemicals in the synapse = feel happy all day. Caution, side effect is what
happens when it gets into the periphery and causes hypertension. Caution
with MAO‐inhibitor synergy = toxic.
Phenelzine MAO‐Inhibitor This is also an antidepressant. Its target is the brain. Keep the happy
chemicals from being degraded = happy all day. Caution, side effect is what
happens when it gets into the periphery and causes hypertension. Caution
with TCAs = toxic. Takes 14 days or more to set in.
Guanethidine Multiple Effects (early and
late)
Early: increase NT release= tyramine + cocaine like effects
Late: decrease NT release = bretylium + reseprine like effects
Reseprine Inhibits VMAT, depletes
vesicles
Inhibiting the enzyme that loads NT into vesicle.
Decreased NT per action potential = decreased sympathetic response.
Target = periphery (hypertension) decreasesing cardiac output and
peripheral resistance. Can get into the brain and deplete happy chemicals,
leading to potential side effect of suicidal thoughts.
Bretylium Inhibits vesicle Fusion Separates action potential from vesicle fusion, decreases number of
vesicles released. Target = periphery (hypertension and tachy heart)
Octopamine Metabolite of Tyramine,
False Transmitter
MAO broken = Tyramine ÆOctopamine. Octopamine gets into vesicles.
Has alpha affinity, less effect. Effectively decreases NT release.
Methyl‐Dopa False transmitter Give as an anti‐hypertensive during pregnancy where ARB and ACE cannot
be applied.
Drug Receptors Effect
Norepinephrine Alpha‐1, Beta‐1 Increased peripheral vascular resistance, reflex bradycardia Epinephrine Alpha‐1, Beta‐1,Beta‐2 Increase pulse pressure, increase HR, decrease TPR Isoproterenol Beta‐1, Beta‐2 Increased pulse pressure, HR, decrease TPR
Dobutamine Beta‐1 Increased pulse pressure, HR.
Phenylephrine Alpha‐1 Increased peripheral vascular resistance, reflex bradycardia Looking at these effects you would think “so many are so similar, what gives?” What gives is the what happens when you BLOCK certain things. For example, if you had Norepi and you blocked alpha‐1, you would get only the Beta‐1 effect (looking like Dobutamine). If you had Phenylephrine and blocked alpha‐ 1, nothing would happen. That is where the questions are going to be at. Each change shown above can be combined together to produce the intended effect. Subtract out what is blocked (from the question) and bam, you’ve got your answer. This you will get in the TBL (why answers are not provided). Alpha‐1, α1 ‐ Total Peripheral Resistance = BP ‐ Reflex Bradycardia (via baroreceptor reflex) ‐ No change in pulse pressure (the distance between systolic and diastolic is the same) ‐ Innervated by Norepi Nerves Beta‐2, β2 ‐ Total Peripheral Resistance = BP via skeletal muscle vasculature dilation ‐ Reflex Tachycardia (via baroreceptor reflex) ‐ No change in pulse pressure (the distance between systolic and diastolic is the same) ‐ No innervation, Circulation Epi only. Beta‐1, β1 ‐ No Change Total Peripheral Resistance ‐ Pulse Pressure = BP (the contractile force is stronger, so systolic pressure is larger) ‐ Little to no Reflex Changes via baroreceptor reflex ‐ in heart rate is from + chronotropic effects ‐ Innervated by Norepi Nerves Alpha‐2, α2 ‐ Looks like Beta‐2 because I used the same image ‐ Alpha‐2s, when blocked, prevent the release of sympathetic discharge, causing a decrease in blood pressure ‐ In here for completeness. ‐ Innervated by Norepi Nerves Wider trace = bradycardia Higher up = Increased BP Narrow trace = tachycardia Lower Down = Decreased BP Same Diastolic trough, higher systolic peak = increased pulse pressure Higher up = Increased BP Narrow trace = tachycardia Lower Down = Decreased BP
ALPHA BLOCKERS
Phenoxybenzamine. Phenoxybenzamine and phentolamine are both nonselective alpha blockers. Since they block both alpha‐1 and alpha‐2, they decrease peripheral vascular resistance (alpha‐1) and
increase Norepi release from nerve terminals (alpha‐2). This causes a lowered blood pressure with reflex tachycardia. Phenoxybenzamine has a long half life and so can be used to manage chronic pheochromocytoma (a rare renal disorder that causes overexpression of circulating epinephrine, elevated to alpha doses).
Phentolamine. Phenoxybenzamine and phentolamine are both nonselective alpha blockers. Since they block both alpha‐1 and alpha‐2, they decrease peripheral vascular resistance (alpha‐1) and increase Norepi release from nerve terminals (alpha‐2). This causes a lowered blood pressure with reflex tachycardia. Because phentolamine has a short half‐life (19 minutes) its uses are a bit more varied. It is
used to treat hypertensive crisis associated with pheochromocytoma (though it doesn’t have to be
pheochromocytoma related), it can be used as a diagnostic test for pheochromocytoma, and it can act
as an antidote for norepinephrine with extravagation or with overdose.
Prazosin and Doxazosin. These are both alpha‐1 selective antagonists. They inhibit only alpha‐1 so cause a decrease in peripheral vascular resistance (alpha‐1) without a reflex tachycardia. These are
prescribed in conjunction with other medications as antihypertensive agents. In reality, they are old
school, though can still be used in the management of hypertension in patients where Beta‐Blockers are
contraindicated (severe asthma or COPD, for example). Doxazosin has a long half life and can be
administered once daily.
Yohimbine. This is a alpha‐2 selective antagonist. It has no clinical use. Theoretically it would increase the release of neurotransmitter at the synaptic terminal to treat some sort of ANS deficiency. In reality,
it is reserved for the treatment of clonidine overdose (an alpha‐2 agonist). Administration of this drug
without reason would result in immediate hypertension, tachycardia, and most likely death.
Symphatholytics
Alpha Blockers Beta Blockers Combined Blockers
Phenoxybenzamine Phentolamine Prazosin Doxazosin Yohimbine Propanolol Pindolol Metoprolol Bisoprolol Boxutamine Labetolol Carvedilol Nevibolol
BETA BLOCKERS.
Beta Blockers have generic names that are easy to spot, ending in –lol. There is no such thing as a Beta‐1
specific blocker, only selective. Since blocking Beta‐2 can lead to bronchoconstriction, most beta blockers are contraindicated in patients with asthma or COPD (obstructive airway diseases). Likewise, all beta blockers slow the heart and decrease conduction velocity, so administration to patients whose heart is already slow (bradycardia), there is already a conduction delay (greater than first degree heart
block), or there is hypotension, is contraindicated as well. The blocking of beta‐1 prevents the
chronotropic and inotropic effects of other sympathomimetics and of the body’s own sympathetic
system. The blocking of beta‐2 prevents vasodilation and induces bronchoconstriction.
Propanolol. This is a nonselective beta blocker used in a variety of treatments. You will have to know the most about this drug for pharmacology. It is primarily indicated in the management of
hypertension. However, it has many other proven uses, such as angina, atrial tachyarrhythmia, prevention of reinfarction after an MI, and migraines. Since it is an inhibitor of beta‐1 and beta‐2, all contraindications stand, as listed above, with the potential for development of any of those conditions.
Pindolol. This is essentially another propanolol, so is a nonselective beta blocker but with beta‐agonist properties. This means that it does what propanolol does, but with less bradycardia. However, since sometimes you want to decrease the workload of the heart by slowing it down (as in with MI and propanolol) pindolol becomes less useful. Therefore, pindolol is only used for the treatment of hypertension where a potential fall in heart rate is dangerous
Metoprolol. This is a beta‐1 selective blocker, though at higher doses (supra‐therapeutic) there is involvement of Beta‐2 as well. It has no intrinsic agonistic activity. It is used for the management of angina, hypertension, and MI. Since it is beta‐1 selective, there is little risk of bronchial involvement,
but bradycardia and heart blocks should be avoided. Following abrupt cessation there has been
documented rebound hypertension and subsequent Myocardial Infarctions.
Bisoprolol. This is Metoprolol that lasts longer (once a day dosing).
COMBO DRUGS
Labetolol. A racemic mixture of both alpha‐1 and nonselective beta‐ antagonists, there is a greater
effect on beta than alpha at therapeutic levels. This is the good stuff because it manages to reduce
hypertension without alterations in heart rate (either up or down), so it is great for the management of chronic hypertension. Beware all the typical beta blocker side effects and contraindications since it is effecting all the systems at once: heart (brady / block), lungs (asthma/copd), periphery (hypotension).
Carvedilol. This is labetolol + antioxidants, making it ideal for heart failure, left ventricular dysfunction following an MI, and hypertension. Like Metoprolol, abrupt cessation resulted in rebound hypertension and subsequent Miss. This is also a racemic mixture like labetolol.
Nevibolol. The most selective Beta‐1 antagonist that also has Nitric Oxide releasing properties. This is also a combination of isomers (a racemic mixture) but has the extra benefit of being nitro + beta blocker all in one. It can rapidly decrease blood pressure for immediate relief (the nitric oxide) and then is
selective for the heart (beta‐1) decreasing workload. Currently, it is prescribed for hypertension but it
can also be used as an emergency drug for MI or hypertension. It is a new drug.
Boxutamine. The Beta‐2 selective antagonist used only in the laboratory to show you what happens when you block beta receptors. It got mention in our drug list, but I don’t know why.
Drug Adrenergic Notes
Alpha‐Blockers Phenoxycarbazine Nonselective
Alpha‐
Long duration of action, management of Pheochromocytoma, induces
reflex tachycardia while decreasing peripheral vascular resistance
Phentolamine Nonselective
Alpha‐
Short duration of action (19 minutes), management of
Pheochromocytoma Hypertensive Crisis, Diagnostic test for
Pheochromocytoma, and as a Norepinephrine antidote for
extravagation and overdose, reflex tachycardia while decreasing
peripheral vascular resistance.
Doxazosin Alpha‐1 Selective Longduration of action (once a day dosing) for Hypertension, no
reflex tachycardia.
Prazosin Alpha‐1 Selective Shortduration of action for Hypertension, no reflex tachycardia
Yohimbine Alpha‐2 Selective Theoretically would inhibit feedback against NE release, causing
increased sympathetic tone. No clinical use, save as an antidote for
clonidine (alpha‐2 agonist)
Beta‐Blockers
Propanolol Nonselective
Beta‐
Used for a lot of stuff: angina, hypertension, MI, migraines, but is
nonselective, so caution must be taken with asthma and copd.
Pindolol Nonselective
Beta‐
Propanolol, plus agonistic propertiesmeaning that the bradycardia is
not as severe.
Metoprolol Beta‐1 Selective Management of Hypertension, Relief from MI with hypertension,
management of chronic angina. Beware rebound hypertension upon
rapid cessation of therapy.
Bisoprolol Beta‐1 Selective Metoprolol with long duration of action(qd PO)
Boxutamine Beta‐2 Selective Used only in the lab, to show what happens
Combos and Special Mention
Labetelol Nonselective
Beta‐ and Alpha‐1
Decrease blood pressure without changing heart rate. Excellent for
management of chronic hypertension. Racemic mixture of isomers
giving wide spectrum of effects.
Carvedilol Nonselective
Beta‐ and Alpha‐1
+ Antioxidants! Is a racemic mixture just like labetolol but the
antioxidant power makes it ideal for the treatment of heart failure,
Left ventricular dysfunction following MI, and hypertension. Rebound
hypertension with abrupt cessation.
Nevibolol Beta‐1 Selective + Nitric Oxide. A new drug, that is the most selective Beta‐1
antagonist on the market. It also releases Nitric Oxide for immediate
relief of hypertension.
Drugs that Treat CHF
Furosamide. This is a loop dieuretic that inhibits the Na/K/2Cl cotransporter in the Loop of Henle in the kidney. It causes an increased sodium delivery to the distal nephron. “Where salt goes, water follows,” thus the increased sodium delivery results in an increased water excretion. This gets rid of extra fluid and is used to treat hypertension, acute pulmonary edema, other edematous conditions, and some toxic cation toxicities. Rapid administration may cause deafness (when bolused IV). Increased sodium
delivery causes an increase in activity of the Na/K exchanger increasing excretion of potassium leading
to hypokalemia. Note that the delivery of Na to the distal nephron is so large that it cannot be overcome by the Na/K exchanger and water is still excreted, despite the overactivity of the Na/K
exchanger losing K as it tries to reabsorb Na. The decreased fluid results in a decreased preload useful
for treating left ventricular heart failure that leads to the pulmonary congestion.
Torsemide. This is furosamide that lasts twice as long. It does the exact same thing but is better for the management of chronic edema / hypertension, requiring dosing only every 4‐6 hrs instead of 2‐3.
Spironolactone. This is a potassium sparing diuretic that is an aldosterone inhibitor. Aldosterone causes increased expression of the Na/K exchanger in the collecting ducts. If there are fewer channels, sodium cannot be reabsorbed (and potassium is not lost) yet water is still excreted with unabsorbed sodium. It is just like furosamide or torsemide, except that when you deplete water and retain potassium you put the patient at risk for hyperkalemia (where the risk with loop diuretics was hypokalemia).
ACE Inhibitors. Captopril and Lisinopril (a prodrug) are examples of ACE inhibitors. They are angiotensin converting enzyme inhibitors, effectively reducing the circulating ANG‐II levels. This means that there is an arterial vasodilation (ANG‐II causes vasoconstriction), there is a dieresis (ANG‐II causes reabsorption
of Na and Potassium in the kidneys, and therefore water), and a further vasodilation (ANG‐II causes
degradation of bradykinin, a vasodilator). This all leads to a decreased preload (venous dilation), decreased afterload (arterial dilation), and general decreased workload on the heart.
Drugs that Treat CHF Diuretics Furosamide Torsemide Spironolactone ACE Inhibitors Adrenergic Agonists Dopamine Dobutamine Vasodilators Nitroglycerin Isosorbide Dinitrate Nitroprusside Nesiritide Hydralazine Others not Discussed here Beta Blockers Calcium Channel Blockers Digoxin
Dopamine and Dobutamine made it into the Drug list in this condition. It isn’t really used to treat CHF per se, just when there is significant cardiogenic shock, left ventricular failure (such as after an MI or cardiac arrest), the heart may need that little extra umph. These both can be +chronotropes + inotropes, with dopamine having a range of effects depending on dosage. See sympathomimetics above.
Nitroglycerin and Isosorbide Dinitrate. This is used in the treatment of both CHF and Angina. Pulmonary edema is caused by blood backing up in the lungs because the left ventricle cannot eject the blood coming in (as a result of left ventricular heart failure). If you reduce the preload, you simultaneously reduce the workload of the heart (treatment of angina) and give the left ventricular the opportunity to clear the fluid from the lungs. Nitro degrades into nitric oxide which directly vasodilates venous vasculature, decreasing preload. Caution in cases of right ventricular failure. In huge dosages it can also act on arteries, but in any real situation of its use, it is intended to be a venous dilator. Isosorbide is given for chronic angina prophylaxis while Nitro is given for acute angina.
Sodium Nitroprusside. This is a general vasodilator used to treat hypertensive emergencies and severe heart failure. It acts on both arteries (decreasing afterload) and veins (decreasing preload). The
combined effect is to drop the blood pressure and decrease the workload on the heart. It is given IV
only and comes with a risk. Accumulation of Cyanide (from nitroprusside metabolism) may develop.
Giving thiosulfate or hydroxycobalamin reduces the toxicity. The mechanisms of action is to directly
stimulate with NO and to activate cGMP which reduces intracellular calcium leading to smooth muscle relaxation.
Hydralazine. This is an arterial vasodilator only decreasing afterload. It is used to treat essential hypertension. It is particularly effective prior to ventricular failure, reducing the resistance and therefore workload the heart must work against. Because it does not affect preload, there is no postural hypotension. Can cause lupus‐like reactions.
Nesiritide. This is a human B‐type Naturetic Peptide that binds to particulate Guanylate Cyclase receptors that increase cGMP leading to decreases in intracellular calcium and smooth muscle
relaxation. This is a critical use drug reserved for in hospital use only and must be delivered IV. This is used in people who have significant heart failure with pulmonary edema at rest.
Drug Mechanism Target Notes
Nitroglycerin Guanylate Cyclase via
Nitric Oxide
Venous Rapid Onset, Emergent Conditions, “Rescue
Inhaler” for CHF or Angina
Isosorbide
Denitate
Guanylate Cyclase via
Nitric Oxide
Venous Same as nitro
Nitroprusside Guanylate Cyclase via
NO or direct stimulation
Venous and
Arterial
Decrease preload, decrease afterload, used for
severe conditions. Prolonged use = cyanide
poisoning (B12 or Thiosulfate rescues toxicity)
Hydralazine Not listed Arterial Prophylaxis for Left Ventricular Failure and
subsequent CHF. Treats essential hypertension
Nesiritide Direct activation of
Guanylate Cyclase
Arterial Sexy new drug, given only IV, given only in most
Normally, some signal causes a rise in calcium, which in turn activates calmodulin. Calmodulin then
phosphorylates (activates) Myosin Light Chain Kinase, which in turn phosphorylates (activates) myosin light chain. Activation of Myosin Light chain results in smooth muscle contraction.
PKA inactivates Myosin Light Chain Kinase. PKG activates a phosphatase that inactivates Myosin Light
Chain. Any time we activate PKA or PKG in a smooth muscle cell, we induce vasodilation, a reduction in afterload or preload, and an alleviation of angina.
Nitric Oxide leads to the activation of PKG. Nitric Oxide comes from Nitroglycerine, Nitroprusside, and Isosorbide, and leads to venous dilation. Nesiritide and Hydralazine work in a similar manner.
Phosphodiesterase Inhibition can maintain either PKA or PKG. Sidenofil (Viagra) inhibits the
phosphodiesterase thereby maintaining cGMP. Theophylline and Imamrinone inhibits the
phosphodiesterase thereby maintaining cAMP.
Diuretic Mechanism Side Effect / Notes Furosamide Loop Diuretic (Na/K/2Cl inhibitor) Hypokalemia
Torsemide Loop Diuretic (Na/K/2Cl inhibitor) Hypokalemia, longer half‐life than furosamide Spironolactone Aldosterone Inhibitor Hyperkalemia
Captopril ACE Inhibitors Causes decreased preload, decreased afterload, slows
or reverses cardiac remodeling of LVF
Lisinopril ACE Inhibitors Same as Captopril, is a prodrug
Anti Anginals Nitroglycerine, Nitroprusside, Isosorbide, Nesiritide, Hydralazine Theophylline, “‐rinones” Sidenofil (Viagra)
Gs Receptors (Beta‐2) Calcium Channel Blockers
(Nefidipine, and to some extent Diltiazem)
Gq Receptors (Me)
HYPERLIPIDEMIA AND CHOLESTEROL
Cholestyramine and Colestipol. These are essentially the same drug. They are both hypolipidemics that are polymeric cation resins that bind bile acids in the intestinal lumen and prevents absorption. Since the bile acids do not reenter the body through the enterohepatic circulation, bile salts, and therefore the cholesterol that made them, is lost. The body determines more bile salts are needed and
synthesizes new bile salts from cholesterol, which are then subsequently lost in the stool. This decreases chylomicrons which depletes the stuff required to make VLDL and therefore LDL. However, the absorption of fats and fat soluble vitamins are dependent on bile salts, so there may be a
decreased fat absorption as well as vitamins A, D, E, and K. I don’t know why, but George said that they increase TG and VLDL as a potential side effect.
Statins. The statins are competitive HMG‐CoA Reductase Inhibitors. They all inhibit the critical step of cholesterol synthesis, whereby HMG‐CoA is converted to mevalonate. This reduces cholesterol synthesis. This sends a signal to the liver that “more cholesterol is needed” so upregulates LDL receptors (the things that grab LDL and degrade them in the liver) thereby reducing LDL. They also decrease oxidative stress and decrease vascular inflammation. The direct goal of statins is to decrease LDL levels. Used in conjunction with Bile‐Acid Binding Resins, Niacin, Both, or Neither, statins are effective. They are automatically indicated following myocardial infarction regardless of lipid levels. In
general, statins should be taken at night (where most of the cholesterol synthesis happens) and have
their absorption increased with food. Statins are potentially hepatotoxic, marked by elevations of amino transferase. The thing people worry about (commercials on TV) is the “muscle weakness” that accompanies rhabdomyolysis which leads to renal failure. They are metabolized by P450, and are contraindicated in pregnancy.
Nicotinic Acid. Also called Niacin, Vitamin B3, this is anti‐everything‐bad drug. It activates niacin receptors in adipose tissue, which decreases hormone sensitive‐lipase in adipose, thereby decreasing lypolysis and free fatty acids. Without fatty acids, new triglycerides in the liver can’t be synthesized. Statin Drug/Prodrug Night/Day With/Without Food
Lovastatin Prodrug Night With
Simvastatin Prodrug Night With
Atorvastatin Drug Day With
Parvastatin Drug Night Without Food
Hypolipidemics
Bile Acid Binding Statins Other
Cholestyramine Colestipol Lovastatin Atorvastatin Parvastatin Gemfibrozil Nicotinic Acid
Statins all share the common features
listed above, except for what is listed
here. It’s easier than remembering each
Without triglycerides in the liver, VLDLs cannot be made. Without VLDLs, there would be no LDLs. Cool, huh? So by decreasing free fatty acids, the net effect is to decrease TG, VLDL, LDL, and cholesterol. In addition, Niacin decreases Apo A1 clearance, increasing HDL longevity. That means all the bad goes
down, all the good goes up. Together with Bile‐Acid‐Binding Resins, it is capable of normalizing LDL.
There is a side effect associated with Nicotinic Acid. There is a harmless cutaneous vasodilation (flushing) along with sensation of warmth with initiation of therapy. This can be blunted by aspirin or NSAIDs. Tachyphylaxis (aka accommodation) to the sensation occurs after repeated doses. Another serious complication could be the development of insulin intolerance, especially in those with borderline diabetes.
Gemfibrozil and Fenofibrate. Fibric Acid Derivatives cause a decrease in VLDL and TG, as well as an increase in HDL, though may decrease LDL. They are ligands for PPAR‐α, a nuclear transcription factor. Activation does two things. (1) It increases the expression of lipoprotein lipase which increases uptake of LDL and TG by tissues, effectively lowering plasma TG and LDL, and (2) it increases Apo A1, which maintains HDL. It is useful in the treatment of hypertriglyceridemia and dysbetalipoproteinemia. It can cause gallstones, myopathy, potentiate hepatic failure, and exacerbates the effects of coumarin and warfarin.
Ezetimibe. This is a luminal cholesterol uptake inhibitor
Drug What it Does Side Effects/ Complications
Cholestyramine
Colestipol
Decrease bile salt reabsorption, increase cholesterol
consumption (to make more bile salts).
– LDL, + HDL, + TG, + LDL‐R,
Constipation, GI discomfort, Vitamin
A,D,E,K deficiency
Statins Inhibit Cholesterol Synthesis.
– LDL, – TG + LDL‐R
Abnormal Liver Function,
Teratogenecity, Myositis Æ
Rhadomylosis Æ Renal Failure
Niacin Decrease Adipose Lipolysis, Decrease HDL catabolism,
Decrease VLDL synthesis
– LDL, – TG, –VLDL, + HDL
Flushing (goes away with repeated
dosing), Gout, Hepatic Toxicity
Gemfibrozil PPAR‐α Agonist,
+ HDL, + LPL, – TG, – VLDL, – LDL
Nausea, liver dysfunction, myositis
Ezetimibe – LDL, – TG, – Cholesterol Absorption Well Tolerated
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