Pronouned hypotension during anesthesia is often associated with what two things

Volume Depletion and Cardiac insufficiency

With autonomic pharmacological interventions, what can be used to increase heart rate?

anticholinergics

With autonomic pharmacological interventions, what effects does a sympathomimetic cause?

Increase heart rate, cardiac contractility, and vasoconstriction

What signs of adequate anesthesia are lost during NMJ blockade?

Reflexes, muscle tone, respiratory rate, and depth of anesthesia

With NMJ blocks, what parameters can be looked at to asses adequate anesthesia?

Blood Pressure, Heart rate, and temperature (Influenced by autonomic drugs)

Describe the critical condition of shock.

Poor delivery of oxygen and nutrients to vital organs resulting in a hypotensive state

What are the three types of shock?

Hypovolemic, Distributive, Cardiogenic

Describe Hypovolemic Shock

Intravascular volume deficit

Describe Distributive Shock

Peripheral vasodilation (Examples: Septic, anaphylactic, and neurogenic)

You make the swimming pool bigger without adding any more water!

Describe Cardiogenic Shock

Myocardial pump failure

What are three key responses to a hypotensive system?

Reflex resonse to restore BP and preserve organ perfusion, activation of renin-angiotensin system, and increase in sympathetic flow

An increase in sympathetic outflow causes what?

Increase in heart rate,contractility, CO, TPR, and BP and vasoconstriction

MAP=?

MAP = CO x TPR

T or F: If you have increased Sympathetic Outflow, you need to address the underlying cause regardless of compensation

TRUE

Inadequate sympathetic compensation is achieved through what?

Autonomic drugs (sympathetics), Increased cardiac output (B1 stim), and increased peripheral resistance (alpha1)

What Is an inadequate, short-term solution to sympathetic compensation?

Autonomic drugs

Shock associated vasoconstriction causes what?

Increased TPR, maldistribution of blood flow, tissue ischemia/infarction, aliguria/anuria

What is enhanced by sympathomimetics?

Beta 1 or alpha 1 stimulation

What do sympathomimetics cause?

Increased BP, CO, and TPR

What are two autonomic innervations?

Maintain BP and Perfuse vital organs

List the sympathetic agonists that are given IV

Dopamine, Norepinephrine, epinephrine, and phenylephrine

Describe the low dose (1-10μg/kg) effects of Dopamine

1- stimulates vascular D1 dopamine receptors, 2-increased renal blood flow and sodium excretion, 3-stimulates cardiac Beta 1 receptors, 4-positive inotropic effect

Describe the high dose (>10μg/kg) effects of Dopamine

1-Stimulate vascular Alpha1 receptors, 2-Vasoconstriction

Norepinephrine (NE) and Epinephrine (EPI) potency on Beta1

EPI~NE

Norepinephrine (NE) and Epinephrine (EPI) potency on Beta2

EPI>>>>>>>>>>>>>NE

Norepinephrine (NE) and Epinephrine (EPI) potency on apha

EPI>NE

EPI excessively stimulates what receptor?

Beta1!!!!!

NE vs EPI: what is prefered for maintaining blood pressure during shock associated with vasodilation

Norepinephrine

What is the primary therapy for Anaplylactic Shock?

Epinephrine

What key effects are caused by epinephrine?

Cardiovascular support, bronchodilation, inhibits mast cell degranulation

What drug is a prototypical selective alpha1 adrenergic agonist?

Phenylephrine

Dobutamine had complex agonist activity on what receptors?

Beta1>Beta2 and alpha1

What are the cardiovascular effects of Dobutamine?

1-Increased cardiac contractility, 2-minimal vascular-dependent changes in BP, 3 - Increased CO and BP

What treatment is appropriate when you have a mix of mypcardial insufficiency and vasodilation

Moderate infusion of dopamine

What influences your choice/dose of drug?

1-rational decision based on pharmacology, 2-what worked in the past, 3-what is working now

What is the goal in treating shock?

To establish and maintain perfusion

What is an autonomic agent you could use during shock that causes minimal vasoconstriction?

Dobutamine or low dose dopamine

What is an autonomic agent you could use during shock that causes maximal vasoconstriction?

Norepinephrine

What is the definition of Glaucoma?

Disease in which the pressure in the eye is too high (leads to increased intraocular pressure and vision loss)

What is the difference between primary and secondary glaucoma?

Primary shows increased intraocular pressure in the absence of signs of concurrent ocular disease while secondary is associated with concurrent ocular disease.

What is a key concurrent ocular disease in secondary glaucoma?

Uveitis

What kind of angle is present in Primary glaucoma?

Narrow angle (EXCEPTION - Beagles have an open angle)

What are the goals of autonomic drugs given topically for Glaucoma?

1-manage primary glaucoma, 2-adjunct to surgical treatment, 3-lower intraocular pressure

What is a beta agonist used for Glaucoma treatment and what are its effects?

Timolol = 1-decrease aqueaous humor production, 2-systemic effects

What are the effects of alpha 2 agaonists when used for glaucoma?

1-decrease aqueous humor production, 2-limits CNS effects, 3-ionized a physiological pH

What is a cholinergic agonist used for Glaucoma treatment and what are its effects?

Pilocarpine = 1-miotic agents that increase aqueous outflow, 2-open the closed angle, 3-used with timolol

The heart contracts in which two manners?

sequentially and synchronized

What is current?

The flow of electric charge

Cardiac electrical activity originates where?

Sinoatrial (SA) node

Cardiac electrical activity spreads rapidly throughout the ventricles via what?

The His-Purkinje System

Electrical current spreads from one cell to another via what?

Gap Junctions

Where does cardiac electrical activty come from?

It arises from diverse populations of ion channels throughout the heart

At rest, what is the charge of the interior of the cell in respect to the exterior?

The interior of the cell is negative (-90mV) with respect to the exterior

What are three major ions for membrane potential?

sodium, calcium, potassium

Each ion will naturally drive the cell membrane potential towards what if it is allowed to move freely in or out of the cell?

Its own reversal potential

At rest the cell is permeable to which ion?

Potassium

What happens when sodium channels open?

Depolarizes

What is activated by depolarization?

voltage-gated sodium channels

Ion channels generally have what 3 basic functional states?

1-Closed (pore is shut/no current), 2-open (pore is open/current), 3-inactivated (pore is open but blocked/no current)

What is the threshold for activation of voltage-gated sodium channels?

-60 mV

Describe calcium channels

1-selectively permeable to Calcium, 2-open slowly, 3-inactivate slowly, 4-recover from inactivation only by repolarizing

What is the threshold for activation of voltage-dependent calcium channels?

-40 mV

What is a key result of calcium channels inactivating slowly?

It allows for substantial calcium influx to trigger contraction

Describe potassium channels

1-selectively permeable to potassium, 2-many types of potassium channels, 3-set resting membrane potential, 4-contribute to the plateau, 5-repolarize the cell to terminate the action potential

Are there slow or fast opening voltage-gated calcium channels in phase 0 depolarization?

ONLY SLOW!!

What phase is the NO plateau phase?

2

What occurs during phase 3?

Potassium channel repolarization

Phase 4 results from activation of what current?

The "FUNNY" current, haha! (Slowly depolarizing inward current activated by hyperpolarization)

What does the "FUNNY" channel cause?

Causes slow gradual depolarization during phase 4 in pacemaker (SA nodal) cells

What are methods for calcium influx?

1-triggers calcium release from internal stores (Junctional sarcoplasmic reticulum), 2-stimulates the opening of intracellular calcium channels (ryanodine receptors), 3-calcium induced calcium release

How is calcium removed?

1-pumped back into the SR by Calcium ATPase, 2-Shunted out of the cell by a Na/Ca exchanger

If cardiac potential generation and propogation becomed unordered, unpredictable, and uncoordinated, what occurs?

arrhythmias

Proper depolarization resulst in an increase in what?

Calcium

Increased calcium leads to what?

Coordinated contraction?

Arrhythmias result from disorders of what?

Impulse formation, coduction or both

What are the four potential pacemaker sites in the heart?

SA node atrial foci, AV node, ventricular foci

When do new pacemaker sites become dominant

Slowing of SA firing, abnormal acceleration of an ecotopic site

Bradycardia occurs from what type of block?

AV nodal block

Tachycardia occurs from what kind of circuit?

Reentrant circuit

Descibe an AV Block?

See no QRST wave on EKG, Signal is not making it from the atria to the ventricle. Stopped at AV node

Describe Atrial Fibrillation

Too much depolarization going through the AV node to the ventricles

What kind of pathway results from a reentrant arrhythmia

accessory pathway (Electrical flow does not eliminate itself

Main goal of antiarrhythmic drugs?

Restore cardiac electrial activity, minimize cardiac pump dysfunction, prevent serious arrhythmias from becoming more serious

What does the class 1 antiarrhythmic drugs block?

Sodium channels

There are three groups of class 1 drugs how do they differ

In how much they slow conduction in sodium channel inhibition ad how they change the refractory period

Describe how much each group (1A, 1B, 1C) class 1 drug slows down the Na channel

Class 1A- Moderate, Class 1B- little, Class 1C-profound

Example of Class 1A Na channel blocker

Procainamide

Example of Class 1B Na channel blocker

Lidocaine

Example of Class 1C Na channel blocker

Flecainide

Descibe the how class (1A, 1B, 1C) change the refractory period of Na channel

1A- prolongs, 1B- shortens, 1C- little change

Which class 1 blocks the sodium channel

Class 1A (procainamide)

What class 1 inactivates the sodium channel

Lidocaine

Describe Lidocaine effects

Class 1B Na blocker-

keeps Na channels in the inactivate state

effect is increased in depolarized tissue, decreased automaticity in depolarized cells

What are class 2 antiarrhythmic drugs are used for

Beta blockers

name a B1 selective competitive antagonists

Atenolol

What are class 3 antiarrhythmic drugs used for?

Prolong AP (Action Potential) by blocking K channels

Do class 3 antiarrhythmics affect Na channels?

No- therefore conduction velocity is not decreased

Name a class 3 antiarrhythmic

Amiodarone

What are the side effects for amidoarone

Because of AP prolongation can cause arrhythmias----THAT’S STUPID

What are class 4 antiarrthymics block?

Inhibit calcium channels

Example of calcium channel blockers?

Diltiazem, verapamil

What are calcium chanel blockers primary effect on the heart (what node)

Slow AV nodal conduction

When do we use calcium channel blockers?

Decrease ventricular response to atrial fibrillation (Stop vent fib not atrial fibrillation)

Which calcium blocker (diltiazem or verapamil decrease cardiac contractility?

Verapamil- can be a problem in heart failure

What antiarrhythmic does digoxin act like?

Calcium channel blocker

What does digoxin do?

Decrease AV nodal conduction

What does adenosine do?

Antiarrhythic and blocks AV nodal conduction

3 Ways to increase cardiac performance

1. Increase B1 adrenergic (sympathetic) Stimulation

2. Increase cardiac myocyte intracellular calcium

3. Enhance the contractile process directly

Adrenergic (sympathetic) stimulation

B1 rector stimulation- increased cardiac myocyte calcium. Happens automatically when cardiac output (and BP) drops during heart failure through the baroreceptor

What are some B1 adrenergic stimulation drugs

Epinephrine, Norepinephrine, Dopamine, Dobutamine

Which two drugs are not that useful

Epinephrine and Norepinephrine bc too much vasoconstriction via the Alpha 1 receptor stimulation in the vasculature

Dopamine

Stimulate cardiac B1 receptors to increase cardiac output (heart rate and contractility) (more of a B1 effect than an A1 affect) Short term use

Dobutamine

Stimulate cardiac B1 receptors to increase cardiac output (heart rate and contractility) (more of a B1 effect than an A1 affect) Short term use

Do Dopamine and Dobutamine have a ceiling effect?

Yes. Both are often a last ditch effort to keep patient alive (not really true in CCU medicine if you know what your doing)

Can you use dopamine or dobutamine with a patient taking a B blocker

NO!!!

What mechanism do we use to increase cardiac myocyte intracellular Ca

Calcium induced calcium release- causes contraction

2 ways to increase intracellular calcium

increase calcium influx, decrease calcium efflux

What Does PDE type 3 degrade

cAMP

What does PDE type 3 work

increased PKA activity- increased calcium channel activity- increased ca - increased contraction

What is a PDE type 3 inhibitor

milrinone

Does a PDE type 3 inhibitory mimic the effect of a B1 stimulation

Yes. Mimicks dopamine or dobutamine

2nd way to increase intracellular calcium

decrease calcium efflux

How do we decrease calcium efflux

inhibition of the Na/Ca exchanger (indirectly by digoxin)

Digoxin

Inhibit the Na/K ATPase- Increases intracellular sodium - Na/Ca exchanger is regulated SOLEY by the concentration of sodium and Ca. Increase sodium in the cell will decrease calcium efflux through the exchanger Digoxin can lead to a AV block

What are problems associated with increased adrenergic (sympathetic) stimulation and and Increase in cardiac myocyte calcium influx?

Increase cardiac oxygen demand and an increase in the chance of arrhythmias

What process avoids the increase in cardiac oxygen demand and increase in the chance of arrhythmias?

Enhancing the contractile process directly

What drug enhances the contractile process directly

pimobendan

(pimo is the shit!)

Pimobendan

increase cardiac contraction by sensitizing the contractile machinery to calcium (related to an increased affinity of troponin C) this effect requires only a small increase in energy (oxygen) consumption

PIMO IS THE SHIT!

Is pimobendan associated with arrhythmias?

NO

What is Excitation-contraction coupling?

translation of smooth muscle cell electrical stimulation into contraction

What do vasodilators do?

Disrupt excitation-contractoin coupling in vascular smooth muscle

Do Vasodilators decrease cardiac oxygen demand

Yes, due to the decreased afterload and or decreased preload

What do vasodilators do to the workload of the heart?

Decrease it

What affect does the renin-angiotensin-aldosterone system have on Blood V?

It increases it through aldosterone/adh

Angiotensin 2 has what affects

increased blood volume and vasoCONSTRICTION

Enalapril

Conpetitive antagonist of Angiotensin Converting Enzyme (ACE inhibitor) prevents conversion of Ang 1 to Ang 2

Losartan

A competitive Angiotensin receptor Type 1.

Effects of Ang 2 inhibition

decrease in sympathetic NS activity, decrease vasoconstriction, decrease tubular sodium and water retention, decrease collecting duct water absorption

What adernergic receptor do we block to get dialation

A1

Prazosin

competitive antagoinsit at A1 receptor AKA alpha blockers

Will an Alpha adrenergic antagoinist cause a possible increase in CO?

Yes, due to vasodialation in the vasculature. USUALLY TEMPORARY

What is a calcium channel antagonist?

inhibits arterial smooth muscle calcium channels- decreases vasoconstriction (promotes vasodilation)

What is a calcium channel antagonistic drug?

Amlodipine

Amlodipine

decrease calcium channel activity, DECREASE TOTAL PERIPHERAL RESISTANCE

What does Nothin but a G thang have to do with

NO goes to GC goes to cGMP goes to PKG which promotes smooth muscle relaxation

Nitroglycerine- Exogenous NO donors

Venous dialation at low levels arterial dilation only at high doses, Decreases preload, tolerance develops over time

Sodium nitroprusside

Arterial and venous dilation- decreases preload and decreases afterload. Light sensitive producing cyanide. Freshly prepared soln is slightly brown.

Sildenafil

a phosphodiesterase type 5 inhibitor- inhibition results in increased levels of cGMP- which end result is vasodialation

(BONER PILLS!! increase blood flow)

PDE5 inhibitors (Sildenafil)

increased cGMP causes smooth muscle relaxation resultion in vasodilation. PDE5 inhibitors prevent the breakdown of cGMP, thereby prolonging its actions

Used to treat pulmonary hypertension in Vet Med.

What does hyperpolarization do to the opening of the calcium channel?

Decreases it thus decreases calcium entry and contraction

How would we hyperpolarize smooth mm

Increase potassium conductance (open potassium channels)

Minoxidil

Potassium channel activators

What is a diuretic?

An agent which produces diuresis

What does diuresis mean?

Increased urine flow rate

Describe how urine is formed? Three steps

1)Filtered at the glomerulus

2)Selective secretion

3)selective tubular reabsorption

What are the major osmolytes being reabsorbed?

NaCL, Bicarbonate, Calcium

Which is greater filtration rate or urine flow rate?

Filtration rate

Urine volume is determined by?

Rate of tubular reabsorption of solutes and water

What are the major osmolytes being secreted?

Hydrogen, potassium

Major NaCL and H20 reabsorption occurs where?

Proximal tubule

What are some reasons you would use a diuretic?

Need to reduce extracellular fluid volume (pulmonary congestion, ascites), oliguric renal failure, hypertension (EIPH) in racehorses, promote urinary excretion of selected agents like hypercalcemia

Name the 5 classes of diuretics

Osmotic diuretics

carbonic anhydrase inhibitors

loop diuretics

thiazide diuretics

K+ sparing diuretics

What is the main mechanism for osmotic diuretics?

Amount filtered exceeds tubular transport

(Draw water into urine by osmosis)

Name an osmotic diuretic

Mannitol

What is Mannitol used to treat

Oliguric renal failure, cerebral edema, acute glaucoma

What condition does too much glucose in filtrate lead to?

Diabetes mellitus- Water trys to dilute all the glucose in the urine leading to a dilute urine and dehydration

another way to think about it: glucose pulls H2O into the urine

What is the mechanism of carbonic anhydrase (CA) inhibitors?

Increase loss of bicarb and increase of urine pH

Name a carbonic anhydrase (CA) inhibitors

Acetazolamide

What is carbonic anhydrase inhibitors used to tx?

Metabolic alkalosis and glaucoma

What are some negativve effects of CA

Alkalinizing effect on urine may cause systemic acidosis, may cause HYPOKALEMIA (due to increase H+/K+ exchange

What is the main mechanism for loop diuretics?

Inhibit NaCL reabsorption in the thick ascending limb of the loop of Henle (Most effective and most comonly used)

Name a Loop Diuretic?

Furosemide (Lasix, Salix)

What are some negative effects of Furosemide (Loop diuretic)

May cause HYPOKALEMIA, may increase urinary loss of Ca

What are Loop diuretics used to tx

Oliguric renal failure, acute pulmonary hypertension

Explain EIPH (Bleeders) in horses?

Give racehorses furosemide to decrease body fluid, Bronchodilator, and increase urine to mask the presence of other drugs. Known as Bleeders because is can cause nosebleeds in severe cases

What is the mechanism for Thiazides

Blocks Na and Cl symport which makes it so that H20 doesn't follow Na back into the cell thus making a dilute urine. Also increases Ca reabsorption into the interstital space

Name a Thiazide and is it used in vet med often

Chlorothiazide and no commonly for human hypertension

When Cholorothiazide is used in vet med what does it tx?

Nephrogenic diabetes insidpidus, udder edema in cattle, Ca containing uroliths (because of the Ca reabsorption effects)

What are the two classes of K+ (Potassium) Sparing Diuretics?

Competitive Aldosterone Antagonists

Principal cell Na Channel Blockers

What K+ Sparing diuretic blocks Aldosterone?

Spironolactone

Is spironolactone most often used alone or in combo?

In combo because it causes mild diuresis with reduced K loss

What are two K+ Sparing Diuretics that block Prinicpal cell Na channels

Amiloride and triamterene

Do we use Amiloride alone or in combo

In combo because it’s a mild diuretic effect

Lecture 12

Introduction to Autonomic Pharmacology

T or F: Organs are innervated by either the sypmathetic NS or the parasympathetic NS

False: Organs are innervated by BOTH the Sympathetic and Parasympathetic

What organ is an exception to the dual ANS innervation?

Blood Vessels

Parasympathetic target organs have _______________ cholinergic receptors

Muscarinic

Preganglionic neurons (symp and parasymp) release what?

ACh

Parasympathetic post ganglionic neurons release what?

ACh

Sympathetic post ganglionic neurons release what?

Norepinephrine

Sympathetic target organs have _______________ cholinergic receptors

adrenergic

Adrenergic rece3ptors have what two families

alpha and beta

What cells release epinephrine?

chromaffin cells

What are four ways to terminate a signal

re-uptake (presynaptic)

diffusion

degradation

uptake (post synaptic)

What are catecholamines?

epinephrine

norepinephrine

dopamine

What degrades Ach?

acetylcholinesterase

Is Ach a catecholamine?

NO

Can a catecholamine be degraded?

NO

What is the primary route of inactivation of Catecholamines?

re-uptake

What does cholinergic mean?

nerves that are stimulated by Ach

How does a nicotinic receptor work?

Ach binds to the receptor which opens the receptor and allows for the sodium influx

What are the types of muscarinic cholinergic receptors?

M1 through M5

What are the types of adrenergic alpha receptors?

Alpha1 and Alpha 2

What are the types of Adrenergic beta receptors?

Beta 1 and Beta 2(and beta 3)

Muscarinic cholinergic, adrenergic alpha and adrenergic beta are all what kind of receptors

G protein

Which adrenergic receptor increases heart rate, conduction, and contraction of the heart?

Beta 1

Which cholinergic receptor decreases heart rate, conduction and contraction in heart?

M2

What do sypmathetic innervation do to blood vessels

directs blood flow to skeletal m. Constriction

Lecture 13 

Cholinergic Pharmacology

Cholinergic Agonists. AKA- parasympathomimetics

Mimic/ enhance the effects of endogenously released ACh.

Major Effects of Cholinergic Agonists

Heart (M2): decreased CO via bradycardia by decreased SA nodal automaticity, decreased conduction via AV node, decreased contractility.

Vasculature (M3): vasodilation via increased NO.

Lungs (M3 and M2): bronchoconstriction, increased secretions.

GI (M3 predomiately, M2): increased motility, increased secretions (salivation).

Urinary (M3): promotes micturition.

Eye (M3 and M2): lacrimation, miosis, loss of accommodation to far vision.

Cholinergic Agonists- Excess Signs

SLUDGE- Salivation, Lacrimation, Urination, Defecation, GI Signs, Emesis;

DUMBELS- Diarrhea and diaphoresis, Urination, Miosis, Bronchorrhea/ Brochospasm/ bradycardia, Emesis, Lacrimation, Salivation.

Direct Acting Cholinergic Agonist

R- mACh

Ex-endogenous Ach

Indirect Acting Cholinergic Agonist

R- mACh

Ex-AChE (Acetylcholinesterase) inhibitors (prevent the breakdown of Ach)

Acetylcholine

Direct Acting Cholinergic Agonist.

R- mACh and nACh.

Rarely used clincially except in Ophthamic.

Rapid degradation by AChE and in plasma= VERY SHORT HALF LIFE

Alkoloids- def

naturally occuring chemical compounds containing basic nitrogen atoms

Direct Acting Cholinergic Agonists

Cholinomimetic Alkoloids

Muscarine

Pilocarpine

Direct Acting Cholinergic Agonists

Synthetic Choline esters

Bethanechol, methacholine, carbachol

Bethanechol

Direct Acting Cholinergic Agonist.

R- some M3 selectivity (GI and Uriniary Bladder).

Promotes voiding by contraction of the destusor and relexation of the trigone and sphincter,

**contraindicated in uretheral obstruction**

Muscarine

Direct Acting Cholinergic Agonist.

R- muscarinic (allowed for the discovery of the mACh receptor.

Found in mushrooms.

Mushroom Toxicosis

Multiple toxins present- Muscarine.

Signs- DUMBELS and SLUDGE

Pilocarpine

Direct Acting Cholinergic Agonist.

R- mACh.

Use- topical ophthalmic (to induse miosis, and decrease IOP) rarely used to systemically promote salivation.

Acetylcholinesterase Inhibitors

Indirect Acting Cholinergic Agonist.

Prevent hydrolysis of Ach. Leads to accululation of Ach at site of release (autonomic effector organs and ganglia, skeletal mm, cholinergic synapses in CNS.

Pharamacological Effects of AChE Inhibitors

Stimulation of autonomic effector organs via mACh.

Simulation then depression of autonomic ganglia and skeletal mm via nACh.

Stimulation then depression of cholinergic receptors in the CNS.

Categories of AChE Inhibitors

Non-Covalent- completely reversibble interaction, competitive antagonists.

Reversiable Covalent.

Irreversiable Covalent

Edrophonium (not that important)

Non-Covalent inhibitor (competitive antagonists) quaternary compound (No CNS effects)

Used to Dx myasthenia gravis (Ach receptor deficiency).

Rapid renal elimination (short duration of action)

Reversiable covalent AChE Inhibitors

Physostigmine and Neostigmine.

Uses- smooth mm atony (GI and Urinary), Glaucoma (topical decrease IOP), reversal of competitive non-depolarizing NMJ blocking agents, Tx- myasthenia gravis, counter CNS symptoms of anticholinergic intoxication (physostigmine).

*Physostigmine not quaternary and crosses blood brain barrier.*

Irreversiable Covalent AChE Inhibitors

Organophosphates

Insecticides (ie- malathion)

nerve gases (ie- sarin).

Organophosphate Toxicity

Signs- SLUDGE, colic, shock, hypotension.

Tx- possible if early w/ cholinesterase reactivators (pralidoxime, 2-PAM); symptomatically w/ anticholinergics (will affect both mACh and nACh)

Cholinergic Antagonists

AKA- parasympatholytics or Anticholinergics

Block the effects of endogenous ACh @ mACh (little effect at nACh)

General classification: direct acting competive antagonists (reversiably block the stimulation of mACh by Ach)

Groups of Anticholinergics

Natural anticholinergic alkaloids (ie- atropine, scopolamine)

Semi-synthetic and synthetic alkaloids (ie- tropicamide, ipratropium, glycopyrrolate, propantheline.)

Effects of Anticholinergics

Heart: increased CO (via tachycardia- increased SA nodal automaticity and increased conduction via the AV node.)

Vasculature: little to no effect (no innervation by parasypathetic NS).

Lungs: bronchodilation, decreased secretions.

GI: decreased motility, decreased secretion (dry mouth).

Urinary: decreased contraction (decreased micturition).

Eye: decreased lacrimation, mydriasis, cyclopegia (paralysis of the ciliary m. resulting in loss of accommodation.)

Signs of Anticholinergic Drugs

Anti-SLUDGE/ Anti-DUMBELS

**NOTE- some sites are more sensitive than others, anticholinergic effects also depends on the degree of parasympathetic tone

(remember its balance b/w sympathetic and parasympathetic tone)

Atropine

Anticholinergic.

Competitively inhibits the binding and stimulation of mACh by ACh. Enters the CNS (non-quaternary) possible toxicity (excitation then depression).

Concerns- tachyarrhythmia, GI stasis (esp. in horses), urine retention.

Use- during general anestheisa (decrease respirtory secretions, increase HR), tx of AChE inhibitor poisoning. [increased salivation possible if topical sol. for eye drains into mouth b/c its very bitter (stimulates salivation)]

Scopolamine

Cholinergic antagonist

similar effects as atropine

Enters the CNS: low dose: slight sedation; high dose: excitement; antiemetic (not generally the drug of choice).

Glycopyrrolate

Cholinergic antagonist

Similar to atropine but quaternary= little CNS effects.

Uses: Anesthesia- decrease salivary and airway secretions, prevent vagally-mediated bradycardia

Tropicamide

Cholinergic antagonist

Uses: ophthalmic exam topically to produce

mydriasis and cycloplegia (loss of ability

to maintain focus on an object as it draws

near the eye)

shorter duration of action

Ipratropium

Cholinergic antagonist

decreased bronchoconstriction and airway secretions

Use: asthma (cats), chronic bronchitis (dogs), horses with recurrent airway inflammation

Propantheline

Cholinergic antagonist

decreases detrusor contraction, incresases trigone and sphincter contraction

***promotes urine retention***

Uses: treat incontinence due to detrusor instability

LECTURE 14

Neuromuscular Junction Blockers

General Uses of NMJ Blockers

adjunct during general

anesthesia to: relax skeletal muscle (no sedative effects). NO ANALGESIA!!!! :(

Causes profound relaxation

Can be used to facilitate: tracheal intubation, orthopedic manipulations, balanced anesthesia, any time that skeletal muscle paralysis is

desired. 

Is the nACh receptor at the NMJ different from other nACh receptors and why would we care?

YES it is some what different. 

We care b/c this differnce allows for differential pharmacology

Allows for selectivity (gangilonic vs NMJ blockers)

T/F

For muscle contraction not all nicotinic receptors need to be activiated by ACh.

TRUE

B/c of spare receptors

Provides a saftey factor at the NMJ (think about the diaphragm)

In general with NMJ blockers: need to block more receptors than expected, absence of clinical blockade with drug present (sub-threshold), reversal of clinical blockade with drug still present

Competitive NMJ blockers

AKA non-depolarizing NMJ blockers

No motor end plate depolarization

Initial muscle weakness followed by

flaccid paralysis

Examples: pancuronium (long acting), Atracurium (intermediate), Mivacurium (short acting)

Pancuronium

Competitive NMJ blocker

long duration of action (2-3 hours) (renal elim- so even longer if renal dz)

Other: little ganglionic blockade, no histamine release, blocks muscarinic receptors (tachycardia) 

Atracurium

Competitive NMJ blocker

intermediate duration (0.5 -1 h)

spontaneous degradation (temp and pH dependent) + hydrolysis by

plasma esterases + renal elimination (1/2 life not effected by renal dz)

little/no ganglionic blockade and promotes histamine release

Mivacurium

Competitive NMJ blocker

short duration of action (15 min)

rapid hydrolysis by plasma esterases (1/2 life not effected by renal dz)

little/no ganglionic blockade and promotes histamine release

T/F

Action of competive NMJ blockers is pharmacologically reversible

with acetylcholinesterase inhibitors

TRUE

physostigmine and neostigmine act by increasing ACh via esterase inhibition allows

for ACh to out-compete the competitive

antagonists

Depolarizing NMJ blockers

AKA non-competitive NMJ blockers

Cause prolonged motor end plate

depolarization by stimulation of NMJ

nicotinic receptors

Initial muscle fasciculations (uncoordinated

contractions) followed by relaxation

Succinylcholine

Depolarizing NMJ blocker

resistant to acetylcholinesterase and not pharmacologically reversible

rapid onset (1 min) and Ultra short acting (5 mins)

useful for rapid and short lived NMJ

blockade (e.g. facilitate tracheal

intubation)

Other considerations: some histamine release and can cause hyperkalemia from release of intracellular

potassium from skeletal muscles 

Phases of Depolarizing NMJ blockers

Early (phase I): depolarization

– fasciculations to flaccid paralysis

Late (phase II): repolarization

– flaccid paralysis

– resembles receptor desensitization

Potential problem with NMJ block

Monitoring depth of anesthesia

Many signs of anesthesic depth (palpebral, toe pinch, corneal, jaw tone) are lost during

neuromuscular blockade

Must look at other parameters: BP, HR, temp, and ECG to asses depth.  

The principal source of distress in

anesthetized patients is often respiratory so even closer observation of sPO2, ETCO2, and RR. 

General NMJ blockade toxicity

Respiratory paralysis

Ganglionic blockade- diaphragm stops contracting

histamine release (leading to vasodilation, hypotention, bronchospasm, ↑ resp. secretions and saliva)

consider pre-tx w/ diphenhydramine

NMJB toxicity interventions

Vagal (parasympathetic) reflex

often procedure (not drug) induced (e.g. visceral manipulation)

Can cause and/ or compound signs of histamine release (bradycardia, bronchospasm, hypotension,

bronchial and salivary secretion)

General NMJ blockade toxicity

Malignant hyperthermia

life-threatening; excessive contracture and heat production from skeletal muscle; initiated by the release of calcium from the sarcoplasmic reticulum of skeletal muscle

usually a combination of halogenated

anesthetics (e.g. halothane) and

succinylcholine

prevalent in pigs, also reported in dogs

(especially Greyhounds), cats, and horses.

Tx- dantrolene (drug that limits SR

calcium release) plus supportive measures (rapid cooling, oxygen…)

Lec 15 & 16

Adrenergic Pharmacology

Adrenergic agonists

AKA-Sympathomimetics

Mimic the effect of endogenous

sympathetic catecholamine (EPI and NorEPI)

neurotransmitters

General classification of agonists

Direct acting agonists

– endogenous catecholamines

Indirect acting agonists

– amphetamine

Mixed acting agonists

– Phenylpropanolamine (PPA)

Epinephrine

Direct acting adrenergic agonist (alpha and Beta)

Effects: ↑ HR, automaticity, conduction velocity, contraction (B1) Result: ↑ CO. Ateries constrict (A1) Skeletal ateries dilate (B2). Bronchodilator (B2)

Low dose: ↓ BP via B2 dominance (vasodilation in skel. mm)

High dose: ↑ BP via A1 (also ↑ CO)

Uses: cardiac arrest, anaphylaxis

Norepinephrine

direct A and B receptor agonist

A1: EPI = NE

– B2: EPI >>>>> NE

– B1: EPI > NE

Effects: sames as EPI except no B2 stim. (no bronchodilation) and more intense vasoconstriction = ↑ BP which causes vagal reflex= slow HR.

Uses: maintain BP

Dopamine

Endogenous catecholamine

Short half life (must be given via CRI)

low dose (1-10 μg/kg): stimulates vascular D1 dopamine receptors, ↑ renal blood flow and sodium

excretion, + inotropic effect (↑ CO)

Higher dose (>10 μg/kg): stimulate vascular A1 receptors, vasoconstriction, ↓ renal blood flow.

Uses: Renal Failure, low dose for CHF with compromised renal function

Dobutamine

Non-selective B adrenergic agonist

Mostly B1 little B2

↑ cardiac contractility (B1 agonist)

with minimal changes in HR

Use: as + inotrope during CHF

Selective B2 adrenergic agonists

B2 agonist = bronchodilator

Minimal Cardio effects esp. when aeroslized

prolonged duration of action

Drugs: Albuterol (Bronchospasm in K-9, fel, EQ)

Clenbuterol (used for allergic bronchitis, recurrent airway

obstruction (“heaves”), and bronchoconstriction

in EQ)

Prolonged use can cause B receptor down regulation w/ chronic admin and over-useage. Minimize with proper dosing and dosing schedule.

Selective A1 adrenergic agonists

Phenylephrine

A1 agonist = vasoconstrictor

Primary effect of A1 stimulation is

constriction of vascular smooth muscle

causes: ↑ TPR, ↑ BP (pressor agent), nasal decongestant.

Phenylephrine:  topical, oral and parenteral decongenstant/ vasopressor

Selective A2 adrenergic agonists

(dex)medetomidine (and xylazine)

Effect primarily central (CNS) and presynaptic

inhibition of sympathetic neurons

Causes: sedation, analgesia, ↓ sympathetic outflow from brain

(dex)medetomidine (and xylazine): widely used as adjunct for sedation, anesthesia, and analgesia in veterinary medicine; allows for a lower dose of other

anesthetic/analgesic agents with lower

safety profiles

Adrenergic antagonists

AKA Sympatholytics

Block the effect of endogenous sympathetic catecholamines

effects dependent on sympathetic activity (tone)

Classes:

-Direct acting competitive antagonists (reversiable)

-Direct acting non-competitive antagonists (irreversiable)

Phenoxybenzamine

Direct acting non-competitive antagonist

irreversibly blocks A1 and A2 receptors

Causes: reduced urethral sphincter tone

Used to manage urethral blockage

phentolamine