Pharm Exam 2

blood vessels

organ system NOT innervated by both the sympathetic and parasympathetic nervous system

ACh

chief NT of the parasympathetic nervous system

• Contraction of smooth mm, dilation of blood vessels, increase secretions, decrease HR

Degradation by AChE

metabolism of ACh

Catecholamines

Major NT for SYMPATHETIC nervous system

• Dopamine, Epinephrine, Norepinephrine

• Produced by adrenal glands

re-uptake mainly, some diffusion & uptake

metabolism of catecholamines

cholinergic

receptors that receive ACh

adrenergic

receptors that recieve Epi/NE

parasympathomimetics

cholinergic agonists

SLUDGE

visible signs of excessive cholinergic stimulation

effects of cholinergic agonists on the heart

DECREASED CO

bradycardia ( decreased SA nodal automaticity), decreased conduction (eg AV node), decreased cardiac contractility

vasodilation

effects of cholinergic agonists on the vasculature

effects of cholinergic agonists on the lungs

bronchoconstriction, increased secretions

effect of cholinergic agonists on the GI system

increased motility, increased secretion

contraction

effect of cholinergic agonists on the urinary bladder

effect of cholinergic agonists on the eye

lacrimation, miosis, loss of accommodation to far vision

Used to empty the urinary bladder

bethanacol

used to induce miosis in the eye

pilocarpine

used to reverse NMJ blockade

AChE inhibitors

used to stimulate visceral smooth mm

neostigmine

used to counter anticholinergic toxicity

physostigmine

Acetylcholine

DIRECT, ENDOGENOUS

Rarely used clinically (exception: ophthalmic)

• Muscarinic AND nicotinic stimulation (wide activity)

• Rapid degradation by AChE and plasma butyrylcholinesterase

Muscarine

DIRECT (alkaloid)

Stimulates muscarinic receptors

Not used clinically

Found in certain mushrooms (contributes to some cases of mushroom poisoning)

Pilocarpine

DIRECT (alkaloid)

Muscarinic stimulation

Topical ophthalmic used to induce pupil constriction and decrease intraocular pressure during glaucoma

Rarely used systemically to promote salivation (sialogogue)

Bethanechol

DIRECT (synthetic choline ester)

Muscarinic stimulation, some GI/urinary bladder selectivity (some M3 selectivity)

Promotes voiding by contraction of the detrusor and relaxation of the trigone and sphincter

Used to treat urinary retention when obstruction is absent

• Can cause more straining if there is obstruction (poss. bladder rupture)

• Don’t use on overly toned bladder (don’t use on blocked toms!)

Physostigmine

INDIRECT,  "IRREVERSIBLE" AChE INHIBITOR

Counter CNS symptoms of anticholinergic intoxication

Note that it is NOT a quaternary compound and crosses the BBB

Neostigmine

INDIRECT,  "IRREVERSIBLE" AChE INHIBITOR

Stimulate visceral smooth mm

Clinical uses of AChE Inhibitors

Smooth mm atony (GI tract and urinary bladder)

Glaucoma (topical)

Reversal of competitive non-depolarizing neuromuscular blocking agents (more later)

Myasthenia gravis (Ach receptor deficiency)

Counter CNS symptoms of anticholinergic intoxication (physostigmine)

parasympatholytics

Cholinergic Antagonists

effect of cholinergic antagonists on the heart

Increased CO

tachycardia (increased SA nodal automaticity), increased conduction (eg AV node)

effects of cholinergic antagonists on the vasculature

little effect, no innervation

effects of cholinergic antagonists on lungs

bronchodilation, decreased secretions

effects of cholinergic antagonists on GI system

decreased motility, decreased secretions (dry mouth)

effects of cholinergic antagonists on the urinary bladder

decreased contractions

effects of cholinergic antagonists on the eye

decreased lacrimation, mydriasis, cycloplegia

used to decrease secretions and prevent bradycardia

atropine, glycopyrrolate

cholinergic antagonist used to promote bronchodilation

ipratropium

used to induce mydriasis & cycloplegia

tropicamide

used to promote urine retention

propantheline

Atropine

(natural alkaloid)

Competitively inhibits the binding and stimulation of muscarinic receptors by ACH and other muscarinic agonists

Prototypical anticholinergic isolated from Atropa belladonna (deadly nightshade)

Enters the CNS

• Non-quaternary

• Possible toxicity

• Excitation followed by depression

Primary concerns: tachyarrhythmia, prolonged GI stasis, urine retention

Used as adjunct during general anesthesia

• Decrease salivary and airway secretions

Ipratropium

Decreased bronchoconstriction and airway secretions

• Good for pt w excessive airway constriction during anesthesia, asthma, etc

Quaternary: restricted distribution

• Administer via inhalation, limit systemic effects

Uses:

• Asthma (cats) and chronic bronchitis (dogs)

• Horses w recurrent airway inflammation

Glycopyrrolate

(synthetic)

Similar to atropine but

• Quaternary

• Does not cross BBB: little CNS effects

More esspensive

Used as adjunct to general anesthesia

• Decrease salivary and airway secretions

• Prevent vagally-mediated bradycardia

Tropicamide

(synthetic)

Used topically in the eye to produce mydriasis and cycloplegia (loss of ability to maintain focus on an object as it draws near the eye)

• Ophthalmic exam

• Shorter duration of action than atropine

Propantheline

Decrease detrusor contraction

Increase trigone and sphincter contraction

Promotes urine retention

Uses:

• Treat incontinence due to detrusor instability

Sympathomimetics

Adrenergic agonist

Epi, albuterol, clenbuterol

adrenergic agonists used for bronchodilation

Epi, NE, dopamine, dobutamine

adrenergic agonists used to increase Hr and contractile force

adrenergic agonist used for presynaptic inhibition & sedation

medetomidine

Epi, NE, phenlyephrine

adrenergic agonists used for vasoconstriction

prejunctional actions of adrenergic agonists

↓ NT release

↓ sympathetic outflow; CNS depression

POTENT α and β agonist

(direct acting)

(α1, β1, β2; endogenous)

epinephrine

Direct acting

 (D1, β1, (α1); endogenous)

Dopamine

complex agonist activity on β1, β2 and α1 receptors

(β1 > β2 and α1)

Dobutamine

Selective β2 agonists

(AKA salbutamol)

Albuterol

Selective β2 agonists

Clenbuterol

SELECTIVE α1 adrenergic agonists

Phenylephrine

SELECTIVE α2 adrenergic agonists

(Dex)Medetomidine

cardiac effects of epi

(β1)

↑ contractility (positive inotrope)

↑ HR (positive chronotrope)

↑ O2 consumption

general result: ↑ CARDIAC OUTPUT

vascular effects of epi

↓ cutaneous, visceral, renal blood flow via vasoconstriction (α1)

↑ skeletal muscle blood flow via dilation (β2)

Vascular effects are dose dependent

respiratory effects of epi

powerful bronchodilator (β2)

especially if bronchioles pre-constricted

• e.g. anaphylaxis or asthma

small decrease in bronchial secretions

route of epi

Can be given IV, IM or SQ (NOT orally active)

therapeutic uses of epi

Rapid relief of hypersensitivity rxns (e.g. anaphylaxis and asthma) 

Restoring cardiac rhythm

Topical hemostatic agent

Adjunct w local anesthetics (lidocaine)

vascular effect of NE

intense vasoconstriction and increase in blood pressure

• initiates baroreceptor reflex (negative feedback mechanism) which slows heart rate

• Baroreceptor reflex: ↑ pressure

bronchodilation

dont use NE for ______

therapeutic use of NE

Limited use

cardiovascular support (maintain BP) during shock via α1 (vasculature) and β1 (heart) effects

Sometimes used during cardiac resuscitation

low dose effects of dopamine

stimulates vascular D1 receptors

coupled to Gαs = ↑ cAMP = vasodilation

INCREASED renal blood flow and sodium excretion during an anesthetic event

• Beneficial for cats & other animals w kidney disease

stimulates cardiac β1 receptors

positive inotropic effect

higher dose effects of dopamine

stimulate vascular α1 receptors

vasoconstriction, ↓ renal blood flow, etc.

• No longer protecting kidneys

clinical considerations of dopamine

Given IV (infusion)

• short half-life

Use low dose IV infusion for congestive heart failure w compromised renal fxn

• short term only

Often used to treat hypotension during anesthesia

cardiovascular effects of dobutamine

increased cardiac contractility (β1 agonist) w minimal changes in HR

• To perfuse better/pump more efficiently w/o making heart race

• Esp useful under anesthesia

minimal change in BP as α1 and β2 agonist activities are weaker and counterbalance        

use as positive inotrope during heart failure (IV only, short term)

possible adverse effects of dobutamine

unwanted and/or excess β stimulation

e.g. ↑ HR (β1) when used as bronchodilator (β2)

bronchospasm in dogs, cats, horses

therapeutic use of albuterol

allergic bronchitis, recurrent airway obstruction (“heaves”), and broncho-constriction in horses

therapeutic use of clenbuterol

General adverse effects/toxicity of selective β2 agonists

unwanted and/or excess β stimulation

tremor, restlessness, cardiac excitation (β1)

how to minimize adverse effects of selective β2 agonists

inhalation

• Works best when given directly where it needs to work

• Minimizes other effects

phenylephrine

prototypical α1 agonist → constriction of vascular smooth mm

• increased total peripheral resistance

• increased BP (pressor agents)

• limited use in hypotension and shock

• nasal decongestant (systemic & topical)

therapeutic use of phenylephrine

decongestant, vasopressor (vasoconstriction)

adverse effect of phenylephrine

excess α1 activity (hypertension)

(Dex) Medetomidine

α2 agonists  = CNS depression

widely used as adjunct for sedation, anesthesia, and analgesia in vet med

pre-anesthetic, light anesthesia by itself

relatively high safety profile (i.e. TI)

allows for a lower dose of other anesthetic/analgesic agents w lower safety profiles

OVERALL effect is a decrease in BP (and sedation/analgesia)

• stimulation of pre-synaptic α2 receptors

• Decrease in BP may be profound.

Transient increase in BP (immediately after administration)

• stimulation of post-synaptic α2 receptors on arterial smooth mm cells

sympatholytics

adrenergic antagonists

 decrease heart rate

general use of β1 adrenergic antagonists

bronchoconstriction

general use of β2 adrenergic antagonists

Non-selective α antagonist (α1, α2; NON-COMPETITIVE)

Phenoxybenzamine

Non-selective α antagonist (α1, α2; COMPETITIVE)

Phentolamine

Phenoxybenzamine & Phentolamine

reduces urethral sphincter tone to manage urethral blockage

SELECTIVE α1 adrenergic antagonists

Prazosin

Prazosin

major effect is to relax arterial and venous smooth muscle = vasodilation

• decrease in total peripheral resistance (after-load)

• decrease in venous return (pre-load)

• produce less reflex tachycardia than other vasodilation agents

Allows for relaxation of the urethral sphincter for passage of stones or urine

therapeutic use of prazosin

used as antihypertensive and in congestive heart failure (reduced pre-and after-load)

most commonly used to treat urethral spasm in cats and dogs

selective α2 antagonists (competitive)

Atipamezole

Atipamezole

Rapid reversal of sedation (minutes) w minimal risk for relapse into sedation

• Specific to reversal as opposed to α2 activation

primarily relieving central (CNS) and pre-synaptic inhibition

• less sedation, analgesia

• increased sympathetic outflow from brain

• increased NE release

• ↑ sympathetic activity (↓ CNS inhibition)

Atipamezole consideration

do not use in patients w cardiac and respiratory dz or other conditions where excessive sympathetic stimulation is contraindicated

NON-SELECTIVE β adrenergic antagonists

Propranolol & Timolol

Propranolol

prototypical β antagonist w EQUAL affinity for β1 and β2 receptors

decreases cardiac output (β1 blockade)

antiarrhythmic action from decreased sympathetic stimulation and non-adrenergic effects (e.g. “membrane stabilization”)

clinical considerations of Propranolol

limited use bc of β2 blockade and availability relatively selective β1 inhibitors

• increased bronchoconstriction is NOT generally a desirable effect

more pronounced during exercise (increased sympathetic tone)

Timolol

decrease aqueous humor production (ocular use during glaucoma)

SELECTIVE β1 adrenergic antagonists

Atenolol

Atenolol effects

decreased heart rate

counteract anticholinergic tachycardia

• anticholinergic toxicity (e.g. atropine)

• e.g. during pancuronium NMJ block

therapeutic uses of atenolol

potentially useful in feline hypertrophic cardiomyopathy (↓ HR, oxygen demand, etc.)

Long term cardiac therapy not rescue drug

pronounced hypotension during anesthesia is associated w:

hypovolemia & cardiac insufficiency

autonomic pharmacological intervention for hypotension during anesthesia (general idea)

increase HR (thus cardiac output) w an ANTICHOLINERGIC

Increase HR, cardiac contractility, and vasoconstriction w a SYMPATHOMIMETIC

autonomic pharmacological intervention for hypotension during anesthesia (specific drugs)

treat bradycardia => ATROPINE, GLYCOPYRROLATE

α1 = vasoconstriction (EPI, NE, phenylephrine)

β1 = ↑ HR and contractile force (EPI, NE, dopamine, dobutamine)

hypotension during anesthesia

V common during general anesthesia

• induced by anesthetics (IV and inhalational)

  • cardiovascular and central sympathetic depression

• Parasympathetic reflexes

• Neuromuscular junction (NMJ) blocker: histamine release