BPS 401 EXAM 3 AUTONOMICS

What are the direct-acting parasympathomimetic drugs?

methacholine

pilocarpine

What are the indirect-acting parasympathomimetic drugs?

Carbamates: physostigmine, neostigmine

What are the CNS parasympathomimetic drugs?

Donepezil (Aricept)

rivastigmine (Exelon)

What are the muscarinic receptor antagonists?

Homatropine Hydrobromide (Homatropine)

Tropicamide (Mydriacyl)

Scopolamine (Transderm Scop)

Atropine

Terodine tartrate (Detrol)

Fesoterodine fumarate (Toviaz)

What are the endogenous sympathomimetics?

Epinephrine

Norepinephrine

Dopamine

What are the other (non-endogenous) symapthomimetics?

Isoproterenol

Albuterol (Ventolin)

Salmeterol (Serevent)

What are the alpha1-selective agonists?

Oxymetazoline (Afrin)

Phenylephrine

What are the alpha2-selective agonists?

Clonidine

Dexmedetomidine (Precedex)

What are the non-specific alpha-adrenoreceptor blockers?

phenoxybenzamine (dibenzyline)

phentolamine (regitine)

What are the alpha1-selective blockers?

Prazosin (minipress)

Doxazosin (cardura)

Tamsulosin (Flomax)

What are the non-selective beta blockers?

Propanol (Inderal)

Timolol (blocadren)

Pindolol (Visken)

Labetalol (Normodyne)

Carvedilol (Coreg)

What are the selective beta blockers?

Metoprolol (lopressor)

Atenolol (Tenormin)

Esmolol (Brevibloc)

Nebivolol

What is the autonomic nervous system (ANS)?

The part of the nervous system that regulates visceral functions without conscious control

Where do the sympathetic fibers originate from?

Thoracic and lumbar spinal cord

Where do the parasympathetic fibers originate from?

Midbrain, medulla oblongata, and sacral spinal cord

What are autonomic ganglia?

Structures that reside outside of the spinal cord that contain axodendritic synapses between pre- and postganglionic neurons

Why aren’t there any drugs that act on the ganglia?

There is no receptor specificity

Where do preganglionic parasympathetic and preganglionic sympathetic fibers originate?

Cerebrum, brain stem, and spinal cord

Where does the sympathetic nervous system originate from?

Thoracic and lumbar spinal cord

What types of fibers are located in SNS

Short preganglionic

Long postganglionic

What neurotransmitter has no reuptake?

Acetylcholine (Ach)

What are the 2 major neurotransmitters?

Acetylcholine (Ach)
Norepinephrine (NE)

What is the NT present in all autonomic ganglia?

Ach

Where is Ach located in the autonomic ganglia?

Neuro-effector junction

How is Ach synthesized?

In the neurons from acetyl COA + choline via choline acetyltransferase

How is Ach broken down?

In the ganglionic junction OR neuro-effector junction by acetylcholine esterase

What ANS division does norepinephrine (NE) participate in?

Sympathetic. NT @ neuro-effector junction of sympathetic division

What group of endogenous chemicals does NE belong to? What other chemicals belong in this group?

Catecholamines

• Dopamine

• Epinephrine

How is NE synthesized?

L-tyrosine → L-DOPA → Dopamine → NE

Removal of amino acid from L-tyr, removal of COOH from L-DOPA, addition of oxygen to dopamine

Where does NE reuptake happen? How is it mediated?

Reuptake by pre-synaptic fiber. Mediated by pre-synaptic alpha2 receptors.

What does stimulation of the alpha2 receptor do to NE?

Slows down NE production

Where are muscarinic (M) receptors located?

The end/target organs (heart, lungs, etc.)

Where are the nicotinic (N) receptors located?

Ganglia

Where are M receptors present?

Neuro-effector junction of parasympathetic division

Where are N receptors present?

Autonomic ganglia of sympathetic and parasympathetic ANS. Located in NMJ

What are the differences between a muscarinic receptor and a nicotinic receptor?

Muscarinic are G-protein linked. 5 primary subtypes

Nicotinic receptors have 2 major subtypes (neuronal and skeletal muscle). Skeletal muscle found on NMJ. Receptors are ionotropic / ion channels

Where are alpha2 receptors found?

The pre-ganglia, also found in CNS

What happens during activation of alpha 1 receptors?

Vasoconstriction

What happens during activation of alpha 2 receptors?

Decreased sympathetic flow from CNS

Where are B1 receptors found?

Heart and kidney

Where are B2 receptors found?

Smooth muscles of blood vessels and bronchi

What happens when B1 receptors are activated?

Increased HR, increased force of contraction, release of renin from kidneys

What happens when B2 receptors are activated?

Vasodilation, bronchodilation.

Stimulates breakdown of glycogen to glucose

What is the difference between norepinephrine and epinephrine?

Additional methyl group on NE

How does NE affect b2 receptors?

Limited to no activity

Will NE or EPI have more activity on an a1 receptor?

NE/EPI will have aprox. the same amount of activity

Will NE or EPI have more activity on an a2 receptor?

NE

Will NE or EPI have more activity on b1 receptors?

NE will have activity equal to or less than EPI; NE still has decent b1 activity

NE ≤ EPI

Will NE or EPI have more activity on b2 receptors?

EPI.

NE has very little b2 activity; will not dilate bronchioles

What does the term adrenergic refer to?

The sympathetic nervous system

What does the term cholinergic refer to?

The parasympathetic nervous system

What do parasympathomimetics do?

Mimic effects of parasympathetic nerve stimulation

Why can Ach not be used in direct-acting parasympathomimetics

It’s hydrolyzed rapidly

Direct-acting parasympathomimetics mechanism of action

M receptors at the neuro-effector junction are stimulated with little to no N receptor stimulation

What type of agonist is a parasympathomimetic?

Muscarinic receptor agonist

What are the therapeutic uses for parasympathomimetics?

GI disorders

Urinary bladder disorders

Xerostomia (dry-mouth)

Ophthalmological

Indirect-acting parasympathomimetics mechanism of action

Prolong the duration of action of endogenous Ach by inhibiting Ach esterase. Don’t stimulate M receptors

What are the therapeutic uses of indirect-acting parasympathomimetics?

Glaucoma

Paralytic ileus

Myasthenia gravis

What is the mechanism of action for parasympatholytics (muscarinic receptor antagonists)? 

Competitive blocking of muscarinic receptors at the neuro-effector sites on smooth muscle, cardiac muscle, gland cells, in the CNS with little blockade of the effects of acetylcholinesterase at nicotinic receptor sites.

How do muscarinic receptor antagonists effect the cardiovascular system?

Heart: Increase HR by blocking vagal nerve effect on M2 receptors

Blood vessels: Do not affect vascular smooth muscle contractability. No parasympathetic control.

How do parasympatholytics / muscarinic receptor antagonists effect the respiratory tract?

Induce bronchodilation, inhibit secretions of the nose, pharnyx, and bronchi. Dry out the mucous membrane of the respiratory tract

How do parasympatholytics / muscarinic receptor antagonists effect the GI tract?

Inhibit motility and secretions, inhibit gastric acid secretion induced by parasympathetic nerve stimulation

How do parasympatholytics / muscarinic receptor antagonists effect the urinary tract?

Decrease contractions of the ureter and bladder

How do muscarinic receptor antagonists effect the sweat glands

Inhibit sweating

How do muscarinic receptor antagonists effect the CNS?

At high doses: restlessness, hallucinations, delirium (central excitation). This is then followed by drowsiness, amnesia, and fatigue (CNS depression)

How do muscarinic receptor antagonists effect the eye?

Mydriasis (dilation) and cycloplegia (loss of accommodation)

What are the effects of atropine in relation to dose?

Low dose (0.5-1mg)

• Dry mouth

  • Lack of sweat

Low/mid dose (2mg)

• Cardiac acceleration

  • Rapid HR

    • Also dilated pupils

Mid/high dose (5mg)

• Bladder control issues

  • Inhibits parasympathetic control of urinary bladder

    • Plus GI tract, gastric secretions, gastric motility

High dose (10mg+)

• Severe CNS impact

  • Restlessness, excitement, hallucination, delirium, coma

How are muscarinic receptor antagonists used?

COPD, eye exams, salivary hyperexcretion, overactive bladder

What are the side effects of muscarinic receptor antagonists?

• Dryness of mouth

• Urinary retention

• Anhidrosis (inhibition of acid secretion in the stomach)

• Tachycardia

• Constipation

Mechanism of action for sympathomimetic agents

Direct stimulation of adrenergic receptors (a1, a2, b1, b2), leading to non-specific pharmacological effects

What happens to HR when BP decreases?

HR speeds up

What happens to BP when HR decreases?

BP rises

Why is epinephrine inactive when given orally?

Rapidly metabolized by enzymes

Why is epinephrine effective in treating cardiac arrest (heart stops beating)?

Stimulates beta 1 and beta 2 receptors

• Beta 1 = increase HR, increase contractility

• Beta 2 = vasodilation, decreases peripheral resistance

Why is norepinephrine not useful as a bronchodilator?

It has weak affinity for beta-2 receptors

• B2 responsible for bronchodilation 

What does isoproterenol (isuprel) do? What type of agonist is it?

Used to stimulate HR because of increased cardiac output. Non-specific B agonist

What type of selective agonist would be ideal for asthma treatment?

B2

What does oxymetazoline (afrin) do? What type of agonist is it?

Used as a nasal decongestant; constricts blood vessels in nasal tissue and decreases fluid accumulation in nasal tissues. a1-selective agonist 

What does phenylephrine do? What type of agonist is it?

Used as a nasal decongestant; constricts blood vessels in nasal tissue and decreases fluid accumulation in nasal tissues. Also used to increase BP in shock. a1-selective agonist

What is clonidine used for? what type of agonist is it?

Decrease in central sympathetic outflow; decreases BP (used for hypertension). It is an a2-selective agonist

What is Dexmedetomidine (Precedex) used for? What type of agonist is it?

Used for anesthesia or sedation. a2-selective agonist

What is prazosin (minipress)? What type of medication is it?

Decreases peripheral resistance by blocking a1 receptors in vascular smooth muscle. a1-selective blocker/antagonist

What is doxazosin (cardura)? What type of medication is it?

Decreases peripheral resistance by blocking a1 receptors in vascular smooth muscle. a1-selective blocker/antagonist

What is tamsulosin (flomax)? What type of medication is it?

Decreases peripheral resistance by blocking a1 receptors in vascular smooth muscle. a1-selective blocker/antagonist

What are the adverse effects of alpha 1-selective blockers?

1. First-dose phenomenon

   • Postural hypotension + syncope 60-90 minutes after first dose

2. Can promote water retention due to vasodilating effects

What are the therapeutic applications of alpha 1-selective blockers?

Treatment of primary systemic hypertension

How do beta-adrenergic receptor blockers effect the heart?

Blocking beta 1 receptors will slow HR and decrease myocardial contractility

How do beta-adrenergic receptor blockers effect the pulmonary system?

Little effect on normal individuals. In asthma/COPD, life threatening bronchoconstriction can occur 

How do beta-adrenergic receptor blockers effect peripheral vascular resistance?

Blocking B2 receptors in arteriolar smooth muscle could increase vascular resistance

Long-term effect of B1 blocker in hypertensive patients w high circulating renin = decrease in peripheral vascular resistance

How are beta-blockers used for glaucoma?

Reduce pressure in eye by lowering aqueous humor production.

Stimulated beta receptors = increase in aqueous humor production

Describe activity of labetalol (normodyne) and carvedilol (coreg)

Nonselective B-blockers that also have alpha 1 blocking activity.

• a1 blocking activity leads to decrease in peripheral resistance. Helps treat hypertension

What are the therapeutic applications of beta blockers?

• hypertension

• congestive heart failure

• angina and myocardial infarction

• cardiac arrythmias

• glaucoma

What are some adverse effects of beta blockers?

• In patients with AV conduction defects, B1 blockers can cause life-threatening bradycardia

• Sudden discontinuation of long-term B1 use in angina can increase risk of sudden heart attack + make angina worse

• B2 receptor blockage can worse bronchoconstriction in asthma

How would you treat a beta blocker overdose? Why?

• Give glucagon

  • Activates adenylate cyclase by stimulates G protein in B receptor complex

What do alpha 1 receptors do

Contract

• Vasoconstriction

• Increase peripheral resistance (increase blood flow)

• Increase blood pressure

• Close bladder sphincters

What do alpha 2 receptors do

Decrease transmitter release

• Inhibit norepinephrine

• Inhibit acetylcholine

Relax bodily systems

• Vascular smooth muscles

• GI system

• Skin

• Mucosa

What do beta-1 receptors do?

Excite

• Increase heart rate

• Increase myocardial contractility

• Increase renin release

What do beta-2 receptors do?

Relax smooth muscle

• Vasodilation

• Decrease peripheral resistance

• Bronchodilation

• Relax uterine smooth muscle

Also

• Increase glycogenolysis

• Releases glucagon

What do muscarinic receptors do?

Bind acetylcholine to regulate processes in parasympathetic nervous system

My pet dog, Ine, always played

Methacholine, pilocarpine

Indirect acting parasympathomimetic