1 - PNS Part II Flashcards
There are three categories of anticholinergic drugs:
Muscarinic antagonists
ganglionic blocking agents
neuromuscular blocking agents
muscarinic antagonists block Ach at:
muscarinic receptors
Ganglionic blocking agents block Ach at:
NicotinicN receptors (at ganglions)
Neuromuscular blocking agents block Ach at:
NicotinicM receptors (NMJ)
Why are Muscarinic agonists referred to as parasympatholytic drugs?
Most Muscarinic receptors are located on structures innervated by the ParaSNS
What are alternative names for muscarinic antagonists?
Parasympatholytics
Antimuscarinics
Muscarinic blockers
Anticholinergic drugs
When you think “anticholinergic” think ______
Muscarinic antagonist
What is the prototype anticholinergic?
Atropine
How does atropine produce its effects?
prevents receptor activation by binding competitively at muscarinic receptors
At therapeutic doses its selective for muscarinic cholinergic receptors
At high doses, it can effect nicotinic receptors
Muscarinic agonists primarily exert their effects on which organs?
Heart (increases heart rate)
Exocrine Glands (decreases salivation/sweat/gastric glad function)
Smooth Mm (relaxation of bronchi, decreased urinary tone, decreased GI tone and motility)
Eyes (mydriasis - pupil dilation, focusing the lens for far vision)
Why is atropine given before procedures?
Procedures that stimulate baroreceptors of the carotids can initiate reflex slowing of the heart, so pretreating with atropine prevents the body from being able to mount a response (drop the heartrate)
Prevents excessive secretions
If atropine is a bronchodilator, why isn’t it often used in asthmatics?
It causes drying and thickening of bronchial secretions, making them even more tenacious
Plus, better drugs are available that don’t come with all the other antimuscarinic side effects (dry mouth, urinary retention, etc.)
Why would atropine help provide short term relief of biliary colic from a gallstone?
It causes decreased GI tone, including the sphincter of Oddi
What drug would you expect to be given to someone admitted with an organophosphate poisoning?
Atropine
What are the adverse effects of muscarinic antagonists?
Xerostomia
Blurred Vision and Photophobia
Elevation of IntraOcular Pressure (IOP)
Urinary Retention
Constipation
Anhidrosis (inability to sweat)
Tachycardia
Asthma (by worsening tenacity of secretions)
How does scopolamine differ from atropine?
It produces sedation rather than excitation/irritability
Suppresses emesis and motion sickness
One of the biggest uses of anticholinergics is:
Overactive Bladder (OAB)
Why do anticholinergics help with OAB?
OAB is caused by overactivity of the detrusor muscle, which anticholinergics block
How can side effects be limited in an OAB patient placed on anticholinergics?
- Use long-acting formulations
- Use drugs that are selective for muscarinic receptors in the bladder
- use drugs that don’t cross the BBB
Which Muscarinic receptor subtype is responsible for bladder innervation?
M3
Which anticholinergic is highly selective for M3?
Darifenacin (Enablex)
Which anticholinergic is primarily selective for M3?
Oxybutynin
What are symptoms of antimuscarinic poisoning?
Dry Mouth
Blurred Vision
Photophobia
Hyperthermia
CNS (hallucinations, delirium)
Skin: hot, dry, flushed
What is the treatment for antimuscarinic poisoning?
- Minimizing intestinal absorption (charcoal)
- Giving Physostigmine (allows Ach to congregate, competing more heavily for receptor binding sites)
What is a mnemonic for Anticholinergic Poisoning?
Hot as a hare
Dry as a bone
Red as a beet
Blind as a bat
Mad as a hatter
Adrenergic agonists are often referred to as _____
Why?
sympathomimetics
Adrenergic agonists activate adrenergic receptors, through which the sympathetic nervous system acts
Responses to adrenergic agonists are very similar to stimulation of the SNS
Drugs can activate adrenergic receptors in four ways:
- Direct Receptor Binding
- Promotion of NE release (indirect)
- Blockade of NE reuptake (indirect)
- Inhibition of NE inactivation (indirect)
What mechanism do almost all adrenergic agonists use to produce adrenergic stimulation?
Direct binding to receptors
What are some examples of drugs that block NE reuptake?
Cocaine, Tricyclic Antidepressants
What are some examples of drugs that promote NE release?
Ephedrine, Amphetamines
What are some drugs that inhibit NE inactivation?
MAOIs
Structurally, how do catecholamines differ from noncatecholamines?
Contain a catechol group and an amine group
What is a catechol group?
A benzene ring with hydroxyl groups on two adjacent carbons
Because of their chemistry, all catecholamines have three properties in common:
- cannot be used orally
- have a brief DOA
- cannot cross the BBB
Why do catecholamines have short half lives?
MAO and COMT
Both are located in the liver and intestinal walls and account for almost 100% clearance of first pass effect
Even IM and SubQ injections are broken down too rapidly by these bad boys to be useful
It has to be circulating in the plasma (IV) to be useful. Once it hits the liver it’s over.
Name three adrenergic agonists that are noncatecholamines
Ephedrine
Albuterol
Phenylephrine
Why aren’t noncatecholamines broken down as quickly?
The lack of a catechol group means COMT doesn’t break them down, and MAO does so slowly
Which is more polar: catecholamines or non?
Catecholamines, which is why they can’t cross the BBB
BUT
Noncatecholamines CAN and do cross the BBB
The ability of a drug o selectively activate certain receptors exclusively depends on:
the dose
At low doses, selectivity is maximal
As the dose increases, selectivity decreases
Activation of Alpha 1 receptors elicits two responses that can be therapeutic:
Vasoconstriction
Mydriasis
Alpha 1 agonists are usually used for (5):
- Hemostasis through vasoconstriction
- Nasal Decongestion
- Adjunct to local anesthesia (keeps blood away from area, prolonging action)
- Elevating BP
- Mydriasis (dilating pupils)
What are adverse effects of alpha 1 activation?
HTN
Necrosis
Bradycardia (Alpha mediated vasoconstriction elevates BP, which triggers a baroreceptor reflex)
Alpha 2 activation causes:
inhibition of NE release PRESYNAPTICALLY
More important in the CNS than the PNS
By activating CNS alpha 2 receptors, what happens?
- Reduction of sympathetic outflow to the heart and blood vessels
- Relief of severe pain
All of the clinically relevant responses to Beta 1 activation result from activating Beta 1 receptors in which organ?
The heart
Action of renal beta 1 receptors is not associated with any effects whatsoever (good or bad)
What are therapeutic uses of beta 1 receptor activation?
Inotropy (shock, heart failure)
Increased AV conduction (AV heart block)
Initiating contraction during cardiac arrest
What are adverse effects of Beta 1 activation?
Dysrhythmias
Angina (increases myocardial oxygen demand)
Applications of Beta 2 activation are limited to which two organs?
The lungs
the uterus
What are therapeutic applications of Beta 2 activation?
Asthma (usually inhalation)
Delay of preterm labor
What are adverse effects of Beta 2 activation
Hyperglycemia (activate B2 receptors in the liver and skeletal muscles, which promotes breakdown of glycogen into glucose)
Tremor (activation of B2 receptors in muscles enhances contraction)
EPINEPHRINE
Receptor specificity
Chemical Classification
Onset
Metabolism
Half Life
Elimination
Receptor: Alpha 1, Alpha 2, Beta 1, Beta 2
Classification: Catecholamine
Onset: Immediate
Metabolism: MAO and COMT
Half Life: <5 min
Elimination: Urine
NOREPINEPHRINE
Receptor specificity
Chemical Classification
Onset
Metabolism
Half Life
Elimination
Receptors: Alpha 1, Alpha 2, Beta 1
Class: Catecholamine
Onset: Immediate
Metabolism: MAO and COMT
Duration: 1-2 min
Elimination; Urine
ISOPROTERENOL
Receptor specificity
Chemical Classification
Onset
Metabolism
Half Life
Elimination
Receptor: Beta 1 and Beta 2
Class: Catecholamine
Onset: Immediate
Metabolism: COMT
Half life: 2.5-5 min
Elimination: Urine
DOPAMINE
Receptor specificity
Chemical Classification
Onset
Metabolism
Half Life
Elimination
Receptors: DOSE DEPENDENT
Dopamine, beta 1, alpha 1 (at high doses)
Class: Catecholamine
Onset <5 min
Metabolism MAO and COMT
Half Life 2 min
Elim Urine
DOBUTAMINE
Receptor specificity
Chemical Classification
Onset
Metabolism
Half Life
Elimination
Receptor: Beta 1
Class: Catecholamine
Onset: 1-2 min
Metabolism COMT
Half Life 2 min
Elimination Urine
PHENYLEPHRINE
Receptor specificity
Chemical Classification
Onset
Metabolism
Half Life
Elimination
Receptor: Alpha 1
Class: noncatecholamine
Onset: Immediate
Metabolism: Hepatic (Deamination)
Half LIfe 5 min
Elimination Urine
Adrenergic Agonists interact with what drugs?
MAOIs
Tricyclics (can intensify and prolong epinephrine’s effects)
General anesthetics (render the myocardium hypersensitive to B1 activation)
Adrenergic antagonists cause:
direct blockade of adrenergic receptors
Adrenergic Antagonists can be divided into two groups:
Alpha blockers
Beta Blockers
What are some therapeutic applications for alpha blockade (5)?
Primarily alpha 1. There are no recognized therapeutic applications for alpha 2 blockade
- Essential HTN
- Alpha 1 agonist overdose (using phentolamine injections around an area where epi has extravasated)
- BPH (reduced contraction of the trigone and sphincter)
- Pheochromocytoma (suppressing HTN effect of exogenous catecholamines)
- Raynaud’s Disease (suppress alpha mediated vasoconstriction in response to cold)
What are adverse effects of alpha 1 blockade?
- Orthostatic Hypotension
- Reflex Tachycardia (from widespread vasodilation and baroreceptor activation)
- Nasal congestion
- Inhibition of ejaculation
- Sodium retention and fluid overload (because they decrease BP, the kidneys retain sodium and water. This is why alpha agents are often used with diuretics.)
Adverse effects of alpha 2 blockade include:
potentiation of the reflex tachycardia that can occur in response to the blockade of alpha 1 receptors
Alpha 2 receptors naturally inhibit the release of NE presynaptically. If they are no longer inhibited, more NE is released, which makes the reflex tachycardia even worse
PRAZOSIN
Actions and Uses
Adverse Effects
Selective blockade of ALPHA 1
Dilation of arterioles and veins
Relaxation of smooth mm in the bladder neck and prostate capsule
Orthostatic HypoTN, reflex tachy, nasal congestion
First dose effect: about 1% of people pass out after the first dose, and they should be told not to drive etc for 24 hours after taking for the first time (take right before bed)
TERAZOSIN
Actions and Uses
Adverse Effects
ALPHA 1 ANTAGONIST
HTN and BPH
Same AE as usual, but high incidence of headaches
When you se “-osin” think:
Alpha antagonist
There is only one non-competitive Alpha Antagonist:
Phenoxybenzamine
Blocks alpha 1 and alpha 2 irreversibly. A single dose persists for several days.
Only approved for use for patients with pheochromocytoma
Beta 1 blockade results in:
- Reduced Heart Rate
- Reduced Inotropy
- Reduced velocity through AV node
Beta blockers are especially helpful in treating dysrhythmias that:
involve excessive electrical activity in the SA node and atria
Prevents the ventricles from being driven by the excess atrial activity
What are the parameters for giving Beta blockers to high-risk patients having noncardiac surgery?
pretreatment with small doses that begin several days to weeks before surgery
Low dose initially then titrated up
Treatment should continue for 1 month after surgery
Only three beta blockers have been show effective in heart failure:
Carvedilol
Bisoprolol
Metoprolol
Why are beta blockers prescribed for hyperthyroidism?
Hyperthyroidism makes the heart exquisitely sensitive to catecholamines. Even normal SNS activation can result in tachydysrhythmias and angina.
Blockade of Beta 1 receptors suppresses these response
Why are beta blockers prescribed for migraines?
They work as prophylaxis only, won’t stop an active headache. No one is totally sure why.
What are adverse effects of Beta 1 blockade?
- Bradycardia
- Reduced Cardiac Output
- Heart Failure
- AV Block
- Rebound cardiac excitation
Adverse effects of beta 2 blockade
- Bronchoconstriction (usually insignificant, but in patients with asthma any increase in airway resistance can be life threatening)
- Hypoglycemia from inhibition of glycogenolysis (this is really only a concern in diabetic patients, who are dependent on beta 2 mediated glycogenolysis as a way of overcoming insulin-induced hypoglycemia. Diabetic patients should get Beta 1 blockers if possible)
There are three groups of beta blockers:
- First Generation (nonselective) - block Beta 1 and Beta 2
- Second Generation (cardioselective) - block Beta 1 receptors
- Third Generation (vasodilating) - act on blood vessels to cause dilation, but may produce nonselective or cardioselective Beta blockade
PROPANOLOL
Generation
Receptors
First Generation
Beta 1 and Beta 2
Which kind of beta blocker do you not want to give a patient with asthma?
Beta 2
You want a selective Beta 1 blockade, like metoprolol
Why are beta blockers doubly dangerous for diabetics?
Not only do they predispose to hypoglycemia, they mask the effects of hypoglycemia until it’s severe
Which two beta blockers also have alpha blocking capabilities?
Carvedilol and labetalol
Abrupt discontinuation of any beta blocker can cause:
Rebound cardiac excitation
How does a centrally acting alpha 2 agonist effect peripheral sympathetic neurons?
In the CNS, Alpha 2 receptors are located on presynaptic nerve terminals.
As NE accumulates in the synapse, it activates Alpha 2 receptors to stop the synthesis of NE.
A central alpha 2 agonist will decreased production of NE at sympathetic nerve fibers, which will result in decreased sympathetic activation
This results in decreased BP, pain, and ADHD
The prototypical central alpha 2 agonist is:
Clonidine
What is the action of Clonidine?
Alpha 2 agonist that causes selective activation of alpha 2 receptors in the CNS (esp. areas in the brainstem associated with autonomic regulation of the CV system)
Reduces sympathetic outflow to blood vessels and the heart
Why doesn’t clonidine cause orthostatic hypotension?
It’s effects are not posture dependent
What are adverse effects of clonidine?
Drowsiness
Xerostomia
Rebound Hypertension (from stopping abruptly)
CANNOT BE USED IN PREGNANCY
Lots of people abuse it (as an adjunct to other drugs or by itself)
Two side effects of methyldopa can be severe:
hemolytic anemia and hepatic necrosis
What is the prime difference between clonidine and methyldopa?
It’s a prodrug
It has to be converted in the brainstem to methylnorepinephrine
The only indication for methyldopa is”
Hypertension (particularly during pregnancy)
Approximately 10-20% of patients who take methyldopa chronically will have:
a positive coombs test (detects the presence of antibodies directed against the patient’s own red cells)
Can a patient with a positive Coombs test keep taking methyldopa?
Yes, unless/until hemolytic anemia develops If it does develop, it usually resolves after cessation of drug
