1. Skeletal muscle

2. CNS

3. Presynaptic ganglion (ANS)

1. Pre-synaptic membrane

2. Synaptic cleft

3. Post-synaptic membrane

1. Acetate

2. Choline

There are 15 to 40 million ACh receptor

There are 60 ACh vesicles

Each vesicle contains 10,000 ACh

1. Pharmacologic drugs

2. Disease

3. Toxins

1. Episodic exercise intolerance

2. Weakness - stilted gait, varies in severity, usually more prominent in hind limbs vs. thoracic limbs (b/c longer pathway for neurotransmission)

3. +/- tremors

4. Normal muscle tone, flaccidity

5. Normal postural reactions

6. Normal, decrease to absent spinal reflexes

7. +/- cranial nerve signs (megaesophagus)

8. Normal sensation

Muscle weakness

It is a postsynaptic disease

Congenital

Acquired - Immune

1. Jack Russell terrier

2. Dachshund

3. Springer spaniel

1. Golden retriever

2. German shepherd

3. Labrador retriever

4. Newfoundland

5. Pure bred cats

1. Ab-mediated ACh receptor destruction

2. Complement mediated damage to endplate

1. Focal

2. Generalized

3. Acute Fulminating

1. Double vision/blurry vision

2. Dilated esophagus - megaesophagus

3. Cranial nerve signs

4. Pharyngeal/laryngeal weakness

26-43% of MG cases present this way

1. Appendicular muscle weakness, predominately pelvic limb weakness, some involve thoracic limb

2. Megaesophagus - in 75% of cases

1. Patients are showing flaccid weakness

2. Can't support limbs

3. Lose ability to breathe

4. Severe appendicular muscle weakness

5. Cranial nerve involvement

6. Respiratory distress

7. Acute onset and rapid progression

B/c patients come in w/acute respiratory distress it can be mistaken for toxicity

1. Skeletal muscle weakness

2. Pharyngeal muscle weakness

3. Megaesophagus

4. Aspiration pneumonia

1. Thymoma (5% in dogs, 25% in cats)

2. Paraneoplastic disease

3. Hypothyroidism

Measure serum ACh receptor antibodies

Radioimmunoassay (>0.6 nmol/L in dogs; >0.3 nmol/L in cats)

DUMBELS

Diarrhea

Urination

Miosis

Bronchospasm

Emesis

Lacrimation

Salivation

Cholinesterase inhibitors

1. Pyridostigmine (PO)

2. Neostigmine (IM)

1. Immunomodulation

2. Thymectomy

Need to make sure that you have supportive care

0.25 mg/kg/day

They are sensitive to anticholinesterase agents

True - start with a low starting dose and dose to effect.  Want to see a reduction of clinical signs with the fewest unacceptable side effects.

Also monitor for overdose and side effects

Muscarinic - Cholinergic crisis (DUMBELS)

Nicotinic - paradoxical muscle weakness (depolarizing neuromuscular junction blockade)

Myasthenic crisis - reduce dosage

Cholinergic crisis - reduce dosage and reduce frequency

You want to SLOWLY titrate to immunosuppression

1. initiated 0.25 to 0.5 mg/kg q 24 hr (SID)

2. increase to 2.0 mg/kg SID/BID for immunosuppressive effects

3. After remission slow taper every 2 to 4 weeks to alternate day therapy

1. Iatrogenic Cushings

2. Muscle weakness

3. Wasting

4. PU/PD

5. Polyphagia

6. Personality Changes

1. Azathioprine

2. Mycophenolate

3. Cyclosporine

4. Plasmapharesis

Antibiotics - penicillin, aminoglycosides, fluoroquinolones, tetracyclines, quinolones, and beta-blockers

Antiarrhythmics

Phenothiazines

Guarded in early stages

If there is a poor response to therapy w/in 2 weeks - 50% mortality

1 - year mortality 40%

Inhibits action of acetylcholinesterase (irreversible inhibition, "aging")

Depolarizing neuromuscular junction blockade

Muscarinic signs - hypersalivation, lacrimation, urination, diarrhea, miosis, bronchoconstriction, increased GI motility, cyanosis and incontinence

Nicotinic signs - muscle weakness (usually generalized) - depolarizing NMJ blockage

1. Symptomatic therapy

2. Enzyme reactivators

Atropine (muscarinic cholinergic blocker)

Diphenhydramine (nicotinic cholinergic blocker)

2-PAM, pralidoxime chloride is used.

It acts specifically on the organophosphate-enzyme complex and freeing the enzyme from the organophosphate compound.  Should not be used in carbamate toxicity.

1. Dermacentor andersoni

2. Ambylomma americanum

3. Dermacentor variabilis

Diagnosis - diagnosed by rapid improvement after tick removal

Treatment - removal of ticks making sure to remove the head as the toxin is secreted from the salivary gland; should also be treated with an ectoparasiticide therapy

Prognosis is good

Causative agent - Clostridium botulinum

Botulinum toxin C and D

Toxin is absorbed from the GI tract

Clinical signs show up w/in 12 hours to 6 days

Progressive, symmetric, generalized lower motor neuron disease.

Severity varies w/amount of toxin ingested - range from mild generalized weakness to tetraplegia w/respiratory failure.

Cranial and Spinal nerves are affected

1. Facial nerve paralysis

2. Megaesophagus

3. Decreased gag reflex

4. Decreased jaw tone

1. Heart rate variation

2. Mydriasis

3. Urinary retention

Mainly supportive care - make sure to prevent aspiration pneumonia; monitor bladder

Antitoxin for Type C1 is made, but hard to obtain and is only effective if given before binding to NMJ which is not usually possible

Antibiotics are usually contraindicated

1. Tick paralysis

2. Botulism

The drug is a mydriatics/cycloplegics drug

Don't want to put in your own eyes! (wash hands after using)

Dispensed in uveitis

1. Cranial nerve III - oculomotor nerve

2. Cranial nerve VII - facial nerve

1. Iris sphincter muscle contracts --> miosis (this opens the ciliary cleft which reduces IOP)

2. Ciliary muscle --> accomodation

3. Uveal vascular smooth muscle --> vasodilation

Preganglionic fibers - T1-T3(or T4) to sympathetic trunk

Autonomic ganglion - cranial cervical ganglion

Postganglionic fibers - distributed to orbital structures via branches of CN V

Iris dilator muscle constricts --> mydriasis

Trabecular meshwork and the ciliary body epithelium help to reduce IOP

Uveal vascular smooth muscle --> vasoconstriction

Direct acting - reversible, competitive muscarinic antagonists

Atropine

Tropicamide

1. Treat uveitis

2. Diagnostic mydriasis

Block muscarinic receptors on post-synaptic terminal of neuroeffector junction

Causes mydriasis and cycloplegia

Paralysis of the ciliary muscle in the eye; paralysis in accomodation

Usually accompanied by dilation of the pupil

1. Eliminates ciliary spasm and decreases pain

2. Dilates pupil and prevents synechia (pupil getting stuck where we don't want it to get stuck)

3. Stabilizes blood aqueous barrier (anti-inflammatory effect)

1. Ocular hypertension/glaucoma

2. Decreased tear production

Direct-acting parasympathomimetics - pilocarpine, carbachol, and acetylcholine

Indirect-acting parasympathomimetics - organophosphates (echothiophate), carbamates (demecarium bromide)

1. Induce miosis

2. Increase aqueous outflow

3. Stimulate lacrimation

4. Enhance uveitis

1. Epinephrine

2. Dipivefrin

1. Phenylephrine (mixed alpha receptor agonist)

2. Apraclonidine (alpha-2 agonist)

3. Brimonidine (alpha-2 agonist)

1. Vasoconstriction (want to constrict pupil to open up the drain and reduce IOP)

2. Hemostasis

3. Reduce IOP

4. Mydriasis w/o cycloplegia (iris dilator muscle not ciliary muscle is affected)

5. Diagnosis and treatment of autonomic disorders

1. Ptosis - Muller's muscle (droopy upper eyelid)

2. Miosis - Iris dilator muscle

3. Enopthalmos - Orbitalis muscle

4. Elevation of the third eyelid - Passive, due to enophthalmos

1. Muller's muscle (eyelid)

2. Iris dilator muscle

3. Trabecular meshwork

4. Ciliary epithelium

5. Uveal vascular smooth muscle

In the post ganglionic neuron if something is wrong with it, what happens is that the iris is wanting epinephrine so it upregulates the number of receptors looking for epinephrine.  If you give it enough time to upregulate (think it's about 10 days) and you expose it to epinephrine or a similar drug it is going to respond quicker than the other eye.

Resolution of clinical signs if post-ganglionic lesion

Denervation hypersensitivity

Take dilute phenylephrine (0.1 - 1%) which is an adrenergic agonist

It's diluted to the [] that has no effect on normal eye

Give one drop to each eye so that what you give is equal amounts

Check every five minutes

W/in 15-20 minutes if it is a post-ganglionic lesion - affected eye will be widely dilated and third eyelid will be down

Beta-blockers!

Beta-1 & beta-2 non-selective:  timolol, metipranolol, carteolol, levobunolol

Beta-1 selective:  betaxolol

1. Conventional route - iridocorneal angle

2. Unconventional route - uveoscleral outflow

1. Ciliary body epithelium

2. Posterior chamber

3. Anterior chamber

4. Iridocorneal angle

5. Uveal trabeculae meshwork

6. Angular aqueous plexus

7. Out the Scleral venous plexus

TRUE!

Cats - 3%

Dogs - 15%

Horses - >15%

1. Aqueous humor percolates thru the ciliary muscle

2. To suprachoroidal space, through sclera

3. To extraorbital tissue/fat

4. To orbital lymphatics

1. Decrease production of aqueous humor

2. Increase outflow of aqueous humor

1. Autonomic agents

2. Non-autonomic agents

1. Cholinergic agonists

2. Adrenergic agonists

3. Adrenergic antagonists

1. Pilocarpine

2. Demecarium

3. Echothiopate

1. Dipivefrin

2. Apraclonidine

3. Brimonidine

1. Osmotic diuretics

2. Carbonic anhydrase inhibitors

3. Prostaglandins

1. Mannitol

2. Glycerin

1. Methazolamide

2. Dorzolamide

1. Osmotics

2. CAIs

3. Beta-blockers

4. Adrenergic agonists

1. Cholinergic agonists

2. Prostaglandins

3. Adrenergic agonists

Cause miosis

Increase aqueous outflow by conventional outflow

Decrease aqueous production

Increase aqueous outflow by conventional outflow

1. Active secretion (70%)

2. Ultrafiltration

3. Diffusion

1. Adrenergic agonists - vasoconstriction

2. Osmotic agents

1. Alpha-2 agonists

2. Beta-blockers

3. Carbonic anhydrase inhibitors

1. Mannitol - intravenous

2. Glycerin - oral

1. Short term use for emergency reduction of intraocular pressure

2. Causes rapid increase in serum osmolarity, dehydration of vitreous, and decreases aqueous humor production

1. May induce nausea and vomiting

2. Metabolized to sugars --> hyperglycemia and glucosuria

1. Diabetes mellitus

2. Cardiac disease - can precipitate pulmonary edema

3. Severe renal disease

4. Dehydration

1. Must be warmed to dissolve crystals

2. Filter in IV line

3. NPO for 4 hours

Not metabolized, excreted in urine

Can be administered to diabetics

1. Cardiac disease

2. Severe renal disease

3. Dehydration

Topical - Dorzolamide

Oral - Methazolamide, Acetozolamide

An enzyme that is made in non-pigmented ciliary body epithelium

Enzyme catalyzes this reaction:  CO₂ + H₂O --> HCO₃^- + H⁺

Aids in the formation of aqueous humor

Oral medication:

CA is present in other places other than eye like:

Renal PCT epithelium - diuresis, hypokalemia, metabolic acidosis, compensatory respiratory alkalosis

GI - anorexia, vomiting, diarrhea

Higher prevalence of side effects w/acetozolamide than methazolamide

Topical medication:

Rare

(dorzolamide)

Latanaprost

A PGF2alpha analogue

Increases unconventional (uveoscleral) outflow of aqueous humor

Think there may also be an effect on conventional as well

Also causes intense miosis in the dog and cat

Latanaprost!

Says it is essentially replacing mannitol

And now is in a generic form so it isn't as expensive

TEARS!!!!!!!

not aqueous humor (very important to not mix these up)

1. Lipid - Meibomian glands

2. Aqueous - Lacrimal glands (Gland of 3rd eyelid, Lacrimal gland)

3. Mucin - Conjunctival goblet cells

1. Lacrostimulants (trying to make more tears)

2. Lacrimomimetics (tear substitutes)

1. Cholinergic agents

2. Immunosuppressive agents like cyclosporine A

1. Aqueous replacement

2. Mucinomimetics

3. Lipid replacement

1. Parasympathetic innervation to the lacrimal glands

Topical solution is given orally

2. See a systemic increase in parasympathetic activity - know we've given too much and have to back down a dose when the dog starts vomiting

A drug given to transplant patients - noticed that it made women who were on it didn't have dry eyes

ONE OF THE FEW DRUGS APPROVED FOR USE IN VET MED BEFORE GOING TO PHYSICIANS

Inhibits T cell activation, thereby decreasing inflammation w/in the lacrimal gland - decreases IL-2 release and IL-2 receptor expression

Stimulates tear production

Non-inhibitory to corneal healing so can use w/ulcer

Vacillates btwn commercially available and not available - usually compound it if it is available

1. Define therapeutic goals

2. Select appropriate drug

3. Monitor progress towards goal

4. Know potential adverse effects

Abnormal electrical activity in the brain (on EEG) with one or more of the following:

1. Loss or deranged consciousness

2. Altered tone & movement

3. Autonomic disturbances

4. Abormal behavior (sensation)

1. Altered resting membrane potential

2. Altered balance of excitation and inhibition

1. Enhance inhibition thru the GABA-chloride ion channel complex

2. Pre-synaptic mechanism

3. Topiramate

4. Decrease action potential generation thru the sodium channels

1. Pregabalin (Lyrica)

2. Bromide

3. Benzodiazepines

4. Barbiturates

Displaces chloride and diffuses thru channel more readily.  Thus more inhibition per channel opening

Used as a potassium salt orally

Affect GABA binding and channel kinetics

1. Diazepam used primarily in status epilepticus

2. Clonzepam or clorazepate occasionally used as short-term anticonvulsant

Affect channel kinetics

1. Phenobarbital used intravenously to treat status epilepticus and used orally as maintenance anticonvulsant

2. Pentobarbital occasionally used intravenously for treating status epilepticus

3. Primidone - metabolized to phenobarbital but more hepatotoxic, only drug approved for use in epilepsy in dogs

1. Levetiracetam (Keppra) - newer anticonvulsant available as a generic

Very low toxicity

2. Mechanism not clear but appears to alter neurotransmission thru an effect on presynaptic vesicle binding

May decrease excitation thru excitatory AA neurotransmitters and calcium channels

1. Type of mechanism of action of anticonvulsant drugs

Short serum terminal half-life but may have longer brain levels

2. Multiple mechanisms - sodium channel inactivation, GABA prolongation, Glutamate antagonism (AMPA receptor)

1. Phenytoin & carbamazepine (also valproate) - limits high frequency opening of sodium channels at axon hillock by enhancing channel inactivation, commonly used in ppl but half-life is too short in dogs

2. Zonisamide - new drug that is seeing increased use in dogs, reduces calcium currents and increases sodium channel inactivation

1. Anti-anxiety

2. Anticonvulsant

3. Muscle relaxant

4. Appetite stimulant

1. Route of administration

2. Delivery to target tissue

3. Half-life

4. Core principles of therapy

1. Oral - easy to give, but slower to action.  Bioavailability may be a concern for some drugs

2. Intravenous - rapid action, but difficult to give, more likely to have side effects

3. Per rectum (intranasal, transdermal) - can get rapid blood levels w/o having to give IV if highly lipid soluble

1. Important in maintaining therapeutic levels

2. Influences time needed to reach steady state blood levels - loading dose can achieve rapid levels, but more risk of side effect

1. The BBB:  tight junctions and lack of fenestration in endothelial cells inhibit diffusion of most substances into brain.  High lipid solubility necessary to adequately cross

2. Blood supply:  brain receives a relatively high proportion of total blood flow due to its high metabolic demand

3. Intravenous bolus will lead to high blood levels initially

4. Highly lipid soluble drugs given IV will reach high brain concentrations due to the high blood levels, high blood flow and large lipid pool (the brain).  However, they cross back into the bloodstream just as quickly and will then get redistributed into the body fat.  Thus the effective half-life following an IV bolus is much shorter than the elimination half-life.  With repeated doses body fat gets saturated and equilibrium established

1. High lipid solubility - very rapid action, but short effective half-life due to redistribution; can be given per rectum if necessary

2. Good safety margin - sedation (rare paradoxical excitation/aggression); hypotension; propylene glycol/alcohol base can cause arrhythmia

3. High efficacy

IV phenobarbital or pentobarbital

1. shower to equilibrate across BBB

2. Narrow margin of safety; may end up having to intubate and support

3. Longer half-life

1. Reduce frequency of seizures by at least 50%

2. Reduce severity of seizures

3. Prevent cluster seizures

4. Reduce postictal behavior changes

5. Ensure client compliance

6. Minimize side effects

1. For some drugs, the metabolite is more active than the parent compound.

2. Some can have different metabolism in different species

3. Lipid solubility = non-polar = hepatic metabolism necessary for excretion for many drugs

4. If hepatic problems exists, need a drug that is not metabolized by the liver or toxic to it

1. Tolerance (benzodiazepines for chronic epilespy in dogs)

2. Enzyme induction - (phenobarbital)

3. Liver failure

4. Cimetidine inhibits P450 enzymes

1. Phenobarbital - Dr. O'Brien's drug of choice b/c inexpensive, effective in 70% of epileptics, side effects not too bad

2. Bromide - add on if phenobarbital is ineffective.  Can use as sole anticonvulsant esp. if hepatic disease is present

3. Diazepam used per rectum in cases which tend to have clusters of seizures.  Not used much for chronic maintainence since develop tolerance

1. CNS effects

2. Hepatoxicity

3. Possible pancreatitis w/bromide

4. Allergic reactions

1. Sedation, ataxia

2. Rarelly excitability, irritability (disinhibition)

3. Usually develop tolerance to these after a few days unles levels are too high

4. Polyphagia, polydipsia (secondary polyuria)

5. Most are addictive and sudden withdrawal can precipitate seizures in normal animals

6. The side effects are usually dose dependent

Reticular activating system - pons, midbrain & diencephalon

Oversimplification of action - projects to cortex & regulates consciousness

Catecholamines:

Norepinephrine

Dopamine

Serotonin (5-HT)

1. Abolish or enhance specific behaviors

2. Tranquilization w/o excess lethargy

3. Sedation w/o side effects

4. +/- analgesia

5. +/- amnesia

1. Major tranzuilizers

2. Act by blocking catecholamine receptors (antagonists)

1. Block multiple receptor types

2. Acepromazine, chlorpromazine, azaparone

1. More selective for dopamine receptors

2. Droperidol, haloperidol

1. Hypotension and other cardiovascular effects

2. Hypothermia

3. May lower seizure threshold.  (want to avoid this w/epileptics)

4. Extrapyrimidal signs - tremors & weakness (rare)

Xylazine

Dexmedetomidine

1. Often induces emesis

2. In addition to tranquilizer, also has analgesic properties

3. Cardiovascular side effects

4. Is reversible by alpha-2 antagonists

1. Benzodiazepines

2. Buspirone

1. Slight risk of irritability & aggression (release from inhibition)

2. Rare acute hepatic necrosis reported in cats following diazepam

1. Benzodiazepines - very potent in cats

2. Cyproheptadine - histamine and serotonin antagonist

1. Should always be used in conjunction w/behavior modification

2. Few are approved for use in animals

3. Most recommendations based on anecdotal reports; very little hard science

4. Effects could be unpredictable

5. Need to consider liability if human is injured

1. Tricyclics

2. Fluoxetine (prozac)

1. Block catecholamine reuptake

2. Cardiovascular side effects

3. Clomipramine now approved for use in separation anxiety in dogs - needs to be combined w/behavior modification

1. Selective serotonin re-uptake inhibitor

2. Approved for use in dogs

3. Aggression and urine marking

1. L-deprenyl (selegiline)

2. Inhibits monoamine oxidase B, thus increasing catecholamines

1. Used especially in cats to prevent hepatic lipidosis

2. Diazepam - worry about precipitating acute hepatic necrosis (rare)

Cyproheptadine - antihistamine and serotonin antagonist

1. Regulation of water and inorganic-ion balance

2. Removal of metabolic waste products from the blood (urea, uric acid, and creatinine)

3. Removal of foreign chemicals from the blood and their excretion in the urine

4. Gluconeogenesis (during prolonged fasting)

5. Secretion of hormones - erythropoietin (controls erythrocyte production); renin (enzyme) (controls formation of angiotensin, which influences blood pressure and sodium balance); 1,25-Dihydroxyvitamin D3 (influences calcium balance)

Those in bold are affected by diuretics - number 1 is most important

1. Macula densa:  specialized cells sense Na+ load

2. Juxtaglomerular cells:  secrete renin (modulated by sympathetic nervous system)

Inulin or creatinine

~ GFR

Completely reabsorbed like many nutrients

Specifically glucose

Filtered and secreted to the extent that all of it passes thru the kidney to the urine

Ex:  PAH ~ renal blood flow

1. Reabsorption of Na+ is by diffusion and/or mediated transport

2. Water reabsorption is by diffusion - dependent on Na+ reabsorption (in general)

3. Reabsorption of water and ions is regulated. (nutrient reabsorption is not regulated)

4. Reabsorption of Na+ is an active process occurring in all tubular segments except descending limb of loop of Henle

Increase the volume of urine (also can change composition of urine)

Predominant effect:  Na+ and H2O reabsorption

1. Active Na+ transport (major site for it)

2. Major site for solute secretion (EXCEPT for K+)

1. Carbonic acid is formed by enzyme, carbonic anhydrase

2. Bicarbonate is reabsorbed

3. H+ is secreted into tubular lumen in exchange for Na+

4. Electrogenic Na+/K+ ATPase maintains low intracellular Na+

Creates a hyperosmotic interstial fluid:  countercurrent multiplier system

Have a hyperosmotic medullary interstitium

Highly permeable to H2O (diffuses out - down the conc. gradient)

NO NA+ REABSORPTION

Increased solute conc. in lumen

IMPERMEABLE TO H2O!

Na+ diffuses out - down the conc. gradient

IMPERMEABLE TO H20 & UREA

Active Na+ transport (Na+K+/2Cl- symport) - reabsorbs 25% filtered Na+

Lumenal fluid - becomes dilute

K+ secretion & hormonal regulation

Active Na+ reabsorption in exchange for K+

Aldosterone promotes Na+, K+ exchange

K+ gets into the urine and you lose K+

1. Sense decreased Na+ load

2. Makes JG cells secrete renin

Also controlled by K+

Increased K+ in extracellular fluid of adrenal cortex leads to

Increased aldosterone secretion

Causes:

Increased K+ excretion by kidney instead of saving Na+

Major site for hormonal control of Na+ and H2O reabsorption

Vasopression (ADH) is required for H2O reabsorption

Some H+ excretion - carbonic anhydrase dependent

1. Freely filtered

2. Limited reabsorption

3. Pharmacologically inert

4. Resistant to metabolism

1. Proximal tubule and loop of Henle:  osmotic effect - hold water in tubular lumen

2. Reduced Na+ reabsorption - reduced medullary tonicity - reduced water reabsorption along loop of Henle

1. Initial expansion of intravascular fluid volume, increased renal blood flow - sometimes a good thing, but not usually

2. Increased excretion of urinary electrolytes - isosmotic water loss due to disturbance w/countercurrent balance

3. Maintain diuretic effect during hypovolemia or shock - trauma

Mannitol!!!

How should you give mannitol and what are the indications and contraindications of mannitol?

1. Poor GIT absorption - give parenterally

2. Indications - cerebral edema, glaucoma, prophylaxis of acute renal failure (questionable value if given after renal damage), promote excretion of certain toxins

3. Contraindications - congestive heart failure (especially w/pulmonary edema); anuric renal failure that does not respond to a test dose

Primarily proximal tubule (inhibits carbonic anhydrase - duh!)

Decrease H+ secretion, decreases Na+ and HCO3- reabsorption

Minor effects at collecting duct - more Na+ in lumenal fluid, more Na+ exchanged for K+ - increased K+ secretion

1. Increased excretion of HCO3-, Na+, K+ and water (transient)

2. Metabolic acidosis and decreased excretion of ammonia

3. Decreased production of aqueous humor (b/c dependent on CA)

1. Major use if for treatment of glaucoma (to lower IOP)

2. Can be used to produce alkaline urine (transient effect)

3. Also have been used for udder edema in cattle (extralabel use)

1. Allergy to sulfonamides (these are related compounds)

2. History of renal or urinary calculi that form in alkaline urine

3. Presence of Na+ or K+ depletion

4. Presence of metabolic or respiratory acidosis

1. Thick ascending limb of loop of Henle

2. Inhibit Na+/K+/2Cl- symport (why used so much in vet med)

3. Inhibit paracellular diffusion of Na+, K+, Mg++, Ca++ (decreased electrical gradient)

4. Minor effect - some inhibition of Na+ and Cl- reabsorption in proximal and distal tubules

1. Highly protein bound in plasma, but actively secreted by proximal tubule

2. Profound diuresis - most effective for edematous conditions - where the name "high ceiling diuretic" comes from

1. Profound increase in Na+ excretion (up to 25% of filtered load) - also increase excretion of Cl-, H2O, K+, H+, Ca++, and Mg++ (most profound effects on Na+ and Ca++ excretion)

2. Mild systemic venodilator (acutely increase renal blood flow)

3. Bronchodilator in humans, horses and guinea pigs

4. Increased renin secretion (due to decreased plasma Na+)

5. Metabolic alkalosis - rarely clinically significant

FUROSEMIDE

Onset of action - IV = 5 min; oral = 1 hr

Peak effect:  IV = 30 min; oral = 1-2 hrs

Duration: IV ~ 2-3 hrs; oral 4-6 hrs

Oral absorption may be decreased in right heart failure

1. Congestive heart failure:  ascited, pleural effusion, & pulmonary edema (i.e. non-inflammatory edema)

2. Hypercalcemia

3. Prophylaxis for epistaxis (exercise induced pulmonary hemorrhage, EIPH) in the equine

4. Udder edema (food animal withdrawal time = 48 hrs)

5. Cerebral edema (if haven't had significant blood loss; if you do have that use mannitol)

6. Only diuretic w/significant effect in patients w/impaired renal function

1. Anuria/progressive renal disease

2. Hypokalemia (b/c causes K loss)

3. Allergy to sulfonamides

4. Possible ototoxicity (ear loss) w/rapid IV administration (rare)

5. Ca++ wasting in cows may precipitate milk fever

6. Beware of profound dehydration (esp. if stops drinking - duh)

7. NSAIDS attenuate natriuretic effects of furosemide (might have to increase dose)

1. Early distal tubule (BEFORE Na+/K+ exchange)

2. Inhibit Na+/Cl- symport

3. Also minor inhibition of CA in proximal tubule

1. Secreted into proximal tubule

2. Decreased Na+ reabsorption and increased K+ secretion

(increased Na+ load in tubular fluid, promotes Na+/K+ exchange)

1. Moderate diuresis - rarely used as first line diuretic

2. Increased excretion of Na+, Cl-, and K+

3. Decreased excretion of Ca++

HYDROCHLOROTHIAZIDE (HydroDiuril)

Onset of action (oral): 2 hrs for hydrochorothiazide

Peak effect at 4 hrs

Duration ~ 12 hrs

1. Not first-line for mono-therapy

2. Refractory heart failure (resistance to furosemide) - rescue w/thiazide - canine (diuretic effect on own + restores diuresis to furosemide)

3. Ascites due to liver disease

4. Diabetes insipidus (paradoxically decreases urine flow)

5. Udder edema (extra-label use)

1. Hypokalemia

2. Diabetes mellitus (due to diabetogenic effect)

3. Use w/caution in CHF (high aldosterone levels) - may already have K+ loss

4. If using as "rescue", decrease dose of furosemide by 50% (may need K+ replacement)

Site:  late distal tubule and collecting duct

1. Antagonize aldosterone (spironolactone) - blocks active Na+/K+ exchange

2. Block sodium channels (triamterine) in tubular cells of the late distal tubule and collecting duct

1. Increased excretion of NaCl

2. Decreased excretion of K+, H+, Ca++ and Mg++

1. Protein bound, but actively secreted by renal tubules

2. Gradual onset and offset of action:  peak effect 2-3 days after therapy is started

1. Used in small animals - mainly cats & dogs

2. Refractory heart failure - used mainly in combination w/other diuretic agents (primarily furosemdie - small additional diuretic effect & decreases K+ excretion); spironolactone + ACE inhibitor - be aware of risk of hyperkalemia (both are K+ sparing) unless furosemide is also given

3. Ascites caused by RHF, hepatic disease, or nephrotic syndrome

1. Hyperkalemia

2. Use caution administering w/other drugs that increase blood K+ (ACE inhibitors & NSAIDS)

3. Not advisable to combine w/ACE inhibitor, unless also giving furosemide

4. Induces hepatic microsomal enzymes (watch for drug interactions)

1. Stable w/o preservatives

2. Compatible w/existing equipment

3. Non-flammable

4. Easily vaporized under ambient conditions

5. Non-irritating to airways

6. Low blood solubility to allow rapid changes of anesthetic depth

7. Very potent

8. No cardiovascular depression

9. Compatible w/catecholamines and other vasoactive drugs

10. Produces good skeletal muscle relaxation

11. Resists degradation in the body

12. Inexpensive

13. Non-toxic

Gas = an agent that exists in its gaseous form at room temperature and sea level pressure

Vapor = the gaseous state of a substance that at room temperature and sea level pressure is a liquid

1. Desflurane

2. Important b/c a special vaporizer is needed in order to use it and it is very expensive

The partition coefficient is the ratio of the concentration of anesthetics in 2 phases, such as blood and gas.  It describes the affinity of an anesthetic for one solvent over another after equilibrium has been reached.

This is clinically important b/c this determines the solubility of an anesthetic

Which anesthetic is the most metabolized?

1. Halothane

2. Methoxyflurane

3. Sevoflurane

4. Isoflurane

Which of the following anesthetics is metabolized the least?

1. Halothane

2. Methoxyflurane

3. Sevoflurane

4. Isoflurane

1. Lidocaine

2. Bupivicaine - longest

3. Procaine - shortest

Which of the following is most cardiotoxic?

1. Lidocaine

2. Bupivicaine

3. Procaine

Acetylcholinesterase inhibitors are used including edrophonium, neostigmine, pyridostigmine.

They act by inhibiting the enzyme that breaks down ACh in nicotinic ACh receptor synapses, so that ACh stays around in the synapse longer.  They are usually administered along w/atropine or glycopyrollate to prevent bradycardia, lacrimation, etc. b/c of activation of muscarinic receptors.

4-Aminopyridine can also be used as a reversal, which acts by increasing the release of ACh at the NMJ

1. Xylazine

2. Ketamine

3. Thiopental

1. Inhibits steroidogenesis --> rise in cortisol blunted; stress response can be beneficial in helping animal heal

2. Can cause myoclonus, vocalizations, and pain on injection

3. Contains propylene glycol, so can cause hemolysis

Propofol is a phenol, thiopental is a Schedule III drug

Beware of stuff growing in propofol

Propfol metabolizes faster and does not have cumulative effects like thiopental can

Mu1/Mu2 = morphine, endorphins, endomorphins

Kappa = dynorphins, ketocyclazine

Delta = enkephalins

Sigma = SKF-10, 047

N/OFQ = buprenorphine

Fentanyl is an example

Act at the receptor to have an effect

Determines magnitude of effect and potency (also depends on receptor density, efficiency, affinity and efficacy)

Butorphanol is an example

Effect is less than what it would be if it was a full agonist

Has a ceiling effect (affords some safety from overdose)

Effects most at mu receptors

Morphine-Butorphanol is an example

Partial agonist partially reverses effect of agonist

Morphine + Naloxone is an example --> decreases amount of analgesia (doesn't completely turn off agonist)

Act as antagonist at some receptors and agonist at others

Shifts curve to the right

Central effects on supraspinal and spinal = can be given in CSF, alter ascending nocioceptive transmission, alter descending pain control circuits via midbrain to spinal cord dorsal horn

Sedation (dysphoria or excitement can also occur)

Vomiting = vomiting at low doses, inhibition at high doses

Increased sphincter tone

Atropine