Pharm Lecture # 11: Cholinergic And Adrenergic Receptors

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Types of cholinergic drugs

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1. Cholinergic agonists (Cholinergic Stimulants or Cholinoneumetics--bc they mimic ACh)
a) direct acting--ACh itself
-Bind directly to the cholinergic receptor and activate it
-One will bind to muscarinic and one to nicotinic receptor--those binding to muscarinic are generally more useful

b) Indirect acting--drugs that break down acetylcholinesterase--if this is inhibited their is more ACh around to bind to receptors bc this enzyme breaks down ACh

2. Cholinergic Antagonists
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Why is specificity helpful for muscarinic receptors

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Want to affect the periphery more and the muscarinic receptors tend to be in the periphery

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Slide 5?

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Duvoid can increase GI motility and are specific for muscarinic receptors in the area

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Side effects in other places that indirect acting cholinergic drugs occur--bc not fully selective

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-Decrease intestinal peristalsis
-If there is bladder distension

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End result is to decrease the pressure

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Autoimmune response causes MG--so long term immune suppressants may be used to treat the pt

By using the cholinesterase inhibitors you can get a more immediate effect--may be important bc diaphragm may be affected in these pts short term

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Overdose is d/t relative non-specificity of the drug affecting the CNS--explains certain side effects

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sdf

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Anti-nicotinic arent used much at all

Ganglion blockers can be used during hypertension--not often

Anti-muscarinic are used much more often

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1. Hypertension--only in emergency bc these drugs are very powerful and have lots of strong side effects

2. Neuromuscular Blocker

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18) Dec tract stimulation may be necessary to decrease secretion during peptic ulcers or overactive bowels

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asd

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All these seem like SNS responses--occurring bc there is too much of a decrease in PNS

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?

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Schedule pt after they void or after their medication when there not likely to void again

For both you want to avoid the peak affect of the drug

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Increase the SNS activity

Sympatholytics--antagonists (breaking down the sympathetic response)

Sympathomimetics: mimicing sympathetic responses

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a1 response: vasoconstriction if smooth muscle is stimulated

Inhibiting interneurons & sympathetic signals inhibits the AMN

B1 response-- increased HR and contractility in the Heart with SNS response

B1 antagonists would be beta blockers

B2 response-- bronchodilation

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B2 blockers were used to decrease urine contraction but not anymore bc too many side effects

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Indirect agonists are not used often--often used more in mixed agonists

2 Mixed Agonists:
1. Ephedrine-- works on both a & B receptors--also works as an indirect agonist---used for severe or emergent hypotension or as a bronchodilator
2. Epinephrine-- endogenous
--Direct agonist to all 4 receptors--why its known as mixed agonist

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Reflex bradycardia--drug induces increased HR and then the baroreceptor wants to decrease cardiac output so it causes bradycardia

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Dobutrex is given to increase the work of the heart?

B2's are commonly used with pts needing bronchodilation in conjunction with pt that has a heart problem

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27 note

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Any agonist--even if selective--if at high enough concentrations will affect any of the alpha or beta subtypes

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Beta blockers names tend to end in "olol"

Given for decreasing HR or contractility

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Phentolamine--used when their is a specific type of tumor

Propanolol--oral or IV

Asmatic or COPD pts with pulmonary pts causing them to already be bronchoconstricted should not take B antagonist--should take B1 antagonist

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Give the 3 main locations of cholinergic synapses

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1. ANS
2. NMJ
3. Specific areas of the brain
-Anticholinergics to treat motion sickness and parkinsons dz

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Locations of muscarinic cholinergic receptors

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Effector Organs in PNS
1. GI tract
2. Bladder
3. Heart
4. Eye

Also found in the CNS

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Locations of nicotinic cholinergic receptors

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1. Autonomic ganglia
2. NMJ

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Fxn of cholinergic stimulants

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Increase activity at ACh synapses

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What are the 2 categories of Cholinergic stimulants

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1. Direct-Acting--exert their effects by binding directly with the cholinergic receptor

2. Indirect-Acting-- increase synaptic activity by inhibiting the acetylcholinesterase enzyme located at the cholinergic synapse

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Why is ACh not administered exogenously

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Bc it is degraded rapidly & extensively by acteylcholinesterase which is found all over the body

Direct cholinergic stimulants act just like the ACh molecule on receptors

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Which type of cholinergic receptors are most beneficially stimulated with direct-acting cholinergic stimulants

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Muscarinic Receptors

They primarily affect the peripheral tissues while exerting a minimal effect on the cholinergic receptors in the autonomic ganglia and NMJ

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List some of the major Direct Acting Cholinergic Stimulants

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1. Bethanechol (Duvoid): preferentially stimulates muscarinic receptors on the GI and bladder tissues
-Used to increase GI and bladder contractions

Carboachol & Pinocarpine are used for Glaucoma

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Give a major difference between Direct & Indirect acting cholinergic stimulants

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Direct-acting stimulants are much more specific to the tissue they affect--peripheral tissues only

Indirect Acting stimulants are not very specific so they will effect peripheral and more central acetylcholinesterase at the NMJ, autonomic ganglia, and CNS resulting in some adverse side effects

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What are the 2 most common Indirect Cholinergic Stimulants

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Neostigmine

Pyridostigmine

Both help treat Myasthenia Gravis--Neostigmine does other things too

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Main clinical uses of Direct-Acting Stimulants

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Decrease in smooth muscle tone in the GI tract and bladder--after abdominal sx

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Main clinical uses of Indirect acting stimulants

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1. Glaucoma
2. MG
3. Alzheimers
4. Reverse the side effects from overdose of neuromuscular blocking agents and anticholinergics

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How do indirect cholinergic stimulants help treat Alzheimers Dz

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Akzheimers Dz involves neuronal degeneration of cholinergic neurons that are critical in cognitive functioning

Tacrine and Donepezil help decrease some of the cognitive symptoms in the early stages of the Dz by prolonging the effects of ACh at the synapse

However, these drugs lose effectiveness later in the Dz process as cortical neurons degenerate extensively and cannot use ACh anymore--nor is ACh being synthesized in the brain

Better QOL in early stages

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How are cholinergic stimulants used to treat GI and Urinary atony (lack of tone)

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A direct acting (Bethanechol) and an indirect acting (neostigmine) are normally used to treat this condition

Assist with stimulation of smooth muscle contraction to initiate peristalsis

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What is glaucoma

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An increase in intraocular pressure brought on by accumulation of aqueous humor within the eye.

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How can cholinergic stimulants help txt Glaucoma

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Direct and Indirect acting stimulants can be used to increase the outflow of aqueous humor from the eye preventing excessive accumulation

By placing medications topically right in the eye side effects are decreased

These agents are not typically the 1st drugs used to treat glaucoma

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How can indirect cholinergic stimulants be used to treat MG

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In MG the # of functional cholinergic receptors located postsynaptically at the NMJ is diminished

Indirect acting cholinesterase inhibitors help alleviate the muscular fatigue associated with the dz by allowing the endogenous ACh released from the presynaptic terminal to remain at the junctions longer

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How do indirect cholingeric stimulants reverse neuromuscular blockage

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Drugs that block transmission at the NMJ are often used during anesthesia--maintain muscle paralysis

By making more ACh available at the junction for a longer period of time--bc cholinesterase is not breaking down the NT--binding to the receptors can occur (even though their are less available)--thus overcoming the neuromuscular blockade

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How can indirect acting stimulants reverse anticholinergic OD causing liver toxicity

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An overdose of anticholinergic can result in CNS effects including hallucinations, delirium, & coma

By inhibiting cholinesterase, the indirect-acting stimulants enables endogenous ACh to overcome anticholinergic drug effects--similar mechanism to NM blockage treatment

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Describe adverse effects of cholinergic stimulants

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Caused by the relative nonspecificity of these drugs--especially indirect-acting

Generally adverse effects are the same seen in exaggerated parasympathetic response (since cholinergic receptors occur at the effector tissues in the PNS)

1. GI distress (nausea, vomiting, diarrhea, cramping)
2. Inc salivation
3. Bronchoconstriction
4. Bradycardia
5. Difficulty in visual accomodation

Increased sweating and vasodilation occur bc of an effect on the respective tissues supplied by special sympathetic post ganglionic neurons that release ACh

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Summarize anticholinergic drugs

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Competitive antagonist binding of postsynaptic cholinergic receptors--bind reversibly to the cholinergic receptors but do not activate it

Blocks the receptors from receiving endogenous ACh--diminishing cellular response

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What are the two antinicotinic anticholinergic drugs

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1. Mecamylamine
2. Trimethaphan
-Nn subtype--used to txt extremely high BP

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Mechanism of Antimuscarinic anticholinergic drugs

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Atropine if the main drug

Although they all work by blocking the post-synaptic cholinergic receptor--certain antimuscarinic agents preferentially antagonize some tissues more than others
-GI vs CNS cholinergic receptors
-Suggests some specificity in these drugs are their are 5 different muscarinic receptor subtypes and perhaps specific drugs affect specific ones
-How ever the specificity is not complete and all drugs antagonize a number of tissues

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Give the main clinical applications of anti-muscarinic drugs

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1. Decrease GI overactivity
-Peptic Ulcer
-IBS
2. Parkinsons Dz
-Works bc deficiency of Dopamine in parkinsons causes overactivity of central cholinergic synapses

3. CV System
-Blocks effects of Vagus N which slows HR and cardiac output--can txt bradycardia associated occurring after MI

4. Motion Sickness


Less common uses include Preoperative before surgery (decrease respiratory secretions), to alleviate urinary frequency and incontinence secondary to hypertonicity of the bladder, bronchodilation of respiratory tract, & dilation of the pupil

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What are the categories of adrenergic receptors

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Alpha- 1 & 2

Beta- 1-3

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Give examples of adrenergic drugs with differing selectivity

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Phenylephrine: alpha-1 agonist that specifically binds alpha-1 subtypes

Propranolol: nonselective Beta antagonist that blocks beta-1 and beta-2 receptors but doesnt affect alpha receptors

Epinephrine: Nonspecifically affects alpha and beta receptors equally

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Describe the relationship between selectivity and dose

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The relative degree of receptor selectivity decreases as higher doses are administered of the drug

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3 Main indications for Alpha-1 Agonists

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Mainly located on vascular smooth muscle

1. Increase BP via vasoconstriction increasing peripheral vascular resistance

2. Nasal Congestion: Preferentially constrict the vasculature in the nasal and upper respiratory mucosa thus decreasing congestion and mucousal discharge

3. Decrease HR during tachycardia by increasing peripheral vascular resistance which will cause a cardiac baroreceptor reflex to decrease HR

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What is the major Alpha-1 agonist

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Phenylephrine (Neo-Synephrine)

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Give the adverse effects of Alpha-1 agonists

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1. HTN
2. HA
3. Bradycardia (from baroreceptor reflex)

Less common include difficulty breathing, chest pain, and nervousness

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Main indications for alpha-2 agonists

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1. HTN: Stimulate receptors located in the brain/brainstem exerting an inhibitory effect on the sympathetic discharge from the vasomotor center of the brain decreasing BP

2. Spasticity: Alpha-2 receptors also occur in SC interneurons--stimulation of these receptors causes interneuron inhibition and a decrease in excitability of motor neurons supplied by the interneurons normalizing neuronal activity

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What are the 2 main Alpha-2 agonists

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1. Clonidine (Duraclon) : HTN (but centrally acting)
2. Tizanidine (Zanaflex): spasticity

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Adverse effects of Alpha-2 agonists

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Drowsiness, dry mouth, dizziness

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Indications of Beta-1 agonists

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Receptor is located on the myocardium

Indicated for increasing HR and force of myocardial contraction--thus increasing cardiac output

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What is the major Beta-1 agonist drug

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Dobutamine (Dobutrex)

Adm for short term use with IV

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Adverse effects of Beta-1 agonists

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Chest pain, Cardiac Arrythmias

Also difficulty breathing & SOB

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Indications for Beta-2 receptors

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1. Located on bronchiole smooth muscle--mediates the relaxation of the bronchioles during asthma, bronchitis, and emphysema

2. Stimulate Beta-2 receptors on the uterine muscle causing inhibition and relaxation of the uterine muscle--inhibit premature uterine contractions during pregnancy preventing premature labor and delivery

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Main Beta-2 drug

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1. Albuterol (Proventil): Bronchodilator

2. Ritodrine (Yutopar) : inhibit premature labor

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Adverse effects of Beta-2 agonists

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Nervousness, trembling, and restlessness

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Describe the differences bt epinephrine, norepinephrine, & ephedrine (metaraminol)

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Epinephrine: stimulates all four adrenergic receptor subtypes

Norephinephrine: binds to all four receptors subtypes but Beta-1 to a lesser extend and has little or no affinity for beta-2 receptors

Ephedrine: indirect adrenergic agonist acts nonselectively by increasing the release of norepinephrine from presynaptic storage

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Indications of Mixed alpha & beta agonists

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1. ADD
2. Narcolepsy
3. Hypotension
4. Asthma (inhalers)
5. Anaphylactic shock
6. Anesthesia

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Mixed alpha & beta drugs

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1. Amphetamines
2. Epinephrine
3. Norepinephrine
4. Ephedrine
5. Metaraminol
6. Phenylpropanolamine

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Adverse effects of Mixed alpha & beta agonists

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1. Excess CNS excitation (nervousness, restlessness, & anxiety)
2. Excess stimulation of CV system (hypertension, arrythmias, cardiac arrest)

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What are catecholamines

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Epinephrine and Noriepinephrine

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What is the major use for alpha adrenergic antagonists

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Decreasing vascular tone and causing vasodilation for decreasing BP during HTN

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Adverse effects of Alpha antagonists(nonselective)

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Reflex tachycardia & OH

Phentolamine (Regitine) is the major alpha antagonist--best for short term use against HTN

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Give the adverse effects of Alpha-1 selective antagonists

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Same as alpha antagonists

Prazosin (Minipress) is the major a1 antagonist--used for long term management of HTN

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Give main indications for Beta antagonists (nonselective)

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"Beta Blockers" :Blocking the beta-1 receptors on the myocardium to decrease cardiac workload via decrease HR and cardiac contraction

Used during HTN and angina pectoris or after MI to help reduce the workload of the damaged heart

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What is the major Beta Antagonist

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Propanolol (Inderal) : adm orally for the long term mgmt of HTN, arrythmias, angina pectoris, & prevention of MI

Major Beta-1 selective antagonist is metoprolol (Lopressor)

B1 antagonists are considered "Cardioselective" bc of their preferential effects on the myocardium

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Adverse effects of Beta nonselective antagonists

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1. Bronchoconstriction & increased airway resistance

2. Excess depression of cardiac fxn

#2 is the only side effect in B1 selective antagonists