PHARMACOLOGY

TOPIC #9: ANS - ADRENERGIC AND CHOLINERGIC DRUGS

Dr. K. Balmilero • December 2, 2020• 1St Semester (Finals)

 Understand adrenergic and cholinergic pharmacology

LEGEND LEGEND

LEGEND
Black:PPT•Blue:BOOK•Red:Audio  Able to identify drugs involve in autonomic nervous
system, MOA, uses, side effects and adverse reactions
OUTLINE
I. AUTONOMIC NERVOUS SYSTEM
A. SYMPATHETIC NERVOUS SYSTEM
B. PARASYMPATHETIC NERVOUS SYSTEM
II. ADRENERGIC PHARMACOLOGY
A. DRUGS THAT ACT ON ADRENORECEPTORS
1. Non-selective catecholamine Sympathomimetic Agents
a. Epinephrine
b. Norepinephrine
c. Dopamine
2. Non-selective Non-Catecholamine sympathomimetic
Agents
a. Ephedrine
3. Selective Alpha Agonists
a. Phenylephrine I. AUTONOMIC NERVOUS SYSTEM
b. Clonidine
c. Methyldopa  Regulates the everyday requirements of vital bodily
d. Apraclonitidine functions without the conscious participation of the
4. Selective Beta Agonists
a. Isoproterenol
mind.
b. Dobutamine  Aka Visceral, Vegetative, or Involuntary Nervous
5. Selective Dopamine Agonists System.
a. Fenoldopam  Essential for survival and responsible for the body’s
6. Selective Alpha Blockers
involuntary activities such as cardiovascular,
a. Phenoxybenzamine
b. Phentolamine gastrointestinal, and thermoregulatory homeostasis
c. Prazosin  “AUTONOMIC”, meaning self-sufficient, self-governing,
d. Other alpha blockers automatic.
7. Selective Beta Blockers
a. Beta-nonselective agonists
b. Selective beta 1 blockers
III. CHOLINERGIC PHARMACOLOGY
A. DIRECT ACTING CHOLINOMIMETICS
a. Acetylcholine
b. Betanechol/Methacholine
c. Pilocarpine/Cevimeline
d. Nicotine/Varenicline
B. INDIRECT ACTING CHOLINOMIMETICS
a. Edrophonium
b. Neostigmine
c. Rivastigmine
C. CHOLINORECEPTOR BLOCKERS
a. Atropine
b. Benztropine
c. Ipratropium
d. Scopolamine
e. Dicyclonine
f. Pralidoxime
D. GANGLION BLOCKERS
a. Hexamethonium
E. NEUROMUSCULAR BLOCKERS

IV. REFERENCES
V. APPENDIX

OBJECTIVES
 Able to define autonomic nervous system and its
division
 Able to differentiate sympathetic and parasympathetic
nervous system based on neurotransmitters and
receptors

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PHARMACOLOGY: ANS - ADRENERGIC AND CHOLIGERNIC

A. SYMPATHETIC NERVOUS SYSTEM

 The preganglionic fibers (always be SHORT)
originate from the thoracolumbar region (T1 to L2 or
L3) of the spinal cord
 Cell bodies of these neurons lie in the spinal gray
matter
 Nerve fibers: paired ganglia
 Preganglionic sympathetic fibers not only synapse
at the ganglion of the level of their origin in the
spinal cord but can also course up and down the
paired ganglia
 Postganglionic – LONG
 Neurotransmitters:
o Preganglionic sympathetic neuron –
Acetylcholine
o All Angels (Ach) are in heaven (preganglionic)
 all applicable to Somatic, Sympa and
Parasympa
Figure 1. Schematic distribution of the craniosacral o Postganglionic sympathetic neuron –
(parasympathetic) and thoracolumbar (sympathetic) nervous Norepinephrine
systems. Parasympathetic preganglionic fibers
 Receptors (adrenergic/sympathetic):
 Pass directly to the organ that is innervated. Their o Alpha, beta, dopamine
postganglionic cell bodies are situated near or within o Different subscript for Adrenergic: 1 (INC,
the innervated viscera. This limited distribution of STIMULATION CONSTRICTION) and 2 (DEC,
parasympathetic postganglionic fibers is consistent INHIBITION, DILATION)
with the discrete and limited effect of parasympathetic
B. PARASYMPATHETIC NERVOUS SYSTEM
function. The postganglionic sympathetic neurons
 Arises from cranial nerves III, VII, IX, and X as well
originate in either the paired sympathetic ganglia or
as from sacral segments S1-S4
one of the unpaired collateral plexuses. One
 Acetylcholine is release at preganglionic (always
preganglionic fiber influences many postganglionic
LONG - to have more time to process the stimuli)
neurons. Activation of the SNS produces a more
and postganglionic (SHORT) nerve terminals
diffuse physiologic response rather than a discrete,
 Receptors(cholinergic):
localized effect. GI, gastrointestinal.
o Muscarinic (more relax mood of the body)
o Nicotinic (more on contraction or stimulation
part of the body)

SNS PNS

“Fight and flight” “Rest and digest”

Catabolic Anabolic

Wide spread and diffused

effect (epinephrine and
norepinephrine are being
excreted directly into the Localized effect (branching is
bloodstream by adrenal limited except vagus nerve)
medulla), divergence and
branching preganglionic
fibers

Longer lasting duration

Short-lived duration (enzymatic
(epinephrine reuptake
destruction
takes longer (a minute)
(Acetylcholinesterase) of
than enzymatic
acetylcholine is faster (30secs)
destruction)

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PHARMACOLOGY: ANS - ADRENERGIC AND CHOLIGERNIC

 Alpha1 – majority is in vascular smooth muscles,

iris, CNS neurons
 Alpha2 – majority is in presynaptic terminals, ciliary
epithelium, CNS, smooth muscles
 Beta1 – myocardium/heart, juxtaglomerular cells
(kidneys)
 Beta2 – lungs (bronchial smooth muscles), uterus

 Homeostatic balance between SNS and PNS

 Diagramatic picture of adrenergic receptors: alpha2-
presynaptic, alpha1 & beta1&2- postsynaptic
 Receptors appear to be protein macromolecules on
cell membranes, which when activated by an
agonist (ACh or norepinephrine) lead to a response
by an effector cell. An antagonist is a substance that
attaches to the receptor (prevents access of an
agonist) but does not elicit a response by the
effector cell.
 In contrast to PNS, all cholinergic receptors are
located post-synaptically
 Cholinergic receptors are subdivided into muscarinic  M2- found in the heart
(postganglionic nerve endings) and nicotinic  M3- GIT, bronchial trees
(autonomic ganglia, neuromuscular junction)  M1,4,5- found centrally
receptors. ACh is the neurotransmitter at cholinergic  M2,3- found peripherally
receptors. Atropine is a specific antagonist at  READ: Appendix, Figure 1 for the Responses
muscarinic receptors Elicited in Effector Organs by Stimulation.

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PHARMACOLOGY: ANS - ADRENERGIC AND CHOLIGERNIC
II. ADRENERGIC PHARMACOLOGY  STEP 3 – RELEASE
 Entry of calcium triggers interaction among SNARE
proteins (VAMPs and SNAPs)
o Inhibited by GUANETHIDINE
o Promoted by METHAMPETHAMINES and
TYRAMINE
 STEP 4 – TERMINATION
 Diffusion and reuptake via NET and DAT in synaptic
cleft
o Inhibited by COCAINE and TCA
 Metabolized by MAO and COMT into metanephrine
and VMA
o Inhibited by MAOI and COMTI
ADRENERGIC
STEPS
INHIBITORS
Synthesis Metyrosine
Storage Reserpine
Release Guanethidine
Termination
Metabolism MAOIs and COMTIs
 See Appendix, Fig 2 (Adrenergic Transmission) and Reuptake Cocaine and TCA
Fig 3 (Synthesis, Storage Release and Termination
Diagram). A. DRUGS THAT ACT ON THE ADRENORECEPTORS
 Classification of medications
 STEP 1 – SYNTHESIS  Sympathomimetic Agents (It mimics the effects of
 Tyrosine is hydroxylated by Tyrosine hydroxylase to the sympathetic)
DOPA (inhibited by METYROSINE)  Non-selective Catecholamine
 DOPA is decarboxylated to dopamine Sympathomimetic Agents
 Dopamine is hydroxylated to Norepinephrine  Non-selective Non-Catecholamine
 STEP 2 – STORAGE Sympathomimetic Agents
 Norepinephrine and dopamine are transported into  Selective alpha and beta agonists
vesicles  Adrenergic Blockers
o Inactivated by Monoamine oxidase in the  Selective alpha and beta antagonists
cytoplasm
 If drugs are more on catecholamine, it has the
 MAOIs increase stores of NE and dopamine
benzene ring same in the EPI and NE produced by
 Vesicular transport inhibited by RESERPINE
the body (same structure).
I. SYMPATHOMIMETIC AGENTS

A. CATECHOLAMINES, NON-SELECTIVE

DRUG MOA INDICATION SIDE EFFECTS CLINICAL REMARKS

Epinephrine  Non-selective, direct  Cardiac arrest  Hypertension  DOSE
(aka Adrenaline) acting - INC the aortic  Tachycardia o B2: 1 - 2 ug/min (low dose)
 Activates α and β pressure-alpha1:  Ischemia o B1 + B2: 2-10 ug/min
adrenergic receptors vasoconstriction (INC  Hyperglycemia o α1: >10 ug/min, 0.5-1 mg bolus
- α1: vasoconstriction, SVR=INC aortic  Palpitations, o AHA guideline: 1 mg every 3
increases BP pressure), arrhythmia minutes during ACLS (during
- β1: increases HR,  Anaphylaxis  severe resuscitations)
conduction and bronchoconstriction in  Inactive per orem, do not enter CNS
(all Catecholamines)
contractility response to allergen (DOC) significantly
β2: bronchodilation  Beta2 effect:  Short duration of action (metabolized
BronchoDilation by COMT and MAO)
 Asthma, COPD, Hemostasis  Can cross placenta – may cause fetal
- Remember: Coronary anoxia
perfusion depends on
the aortic pressure
(higher aortic
pressure=higher
perfusion)
- Remember: Heart is
not already beating
(asystole). Beta1 is
located in the SA

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PHARMACOLOGY: ANS - ADRENERGIC AND CHOLIGERNIC
node. Cardiac
compression during
cardiac arrest will act
on Beta1 (pumping the
heart for that person).
Norepinephrine  Non-selective, direct  Septic shock  severe  Extreme vasospasm  DOSE
acting vasodilation  Tissue necrosis o 4-12 ug/min (α1, B1 >> B2)
(Levophed®)  Activates α and β  Neurogenic shock  Excessive blood o Can start as low as 0.01 mcg/kg
adrenergic receptors  Cardiogenic shock to INC pressure increase o 2019 Sepsis Guidelines:
 Primarily alpha 1 SVR  Arrythmias 12mcg/kg/min for sepsis
agonists  Infarction  Compensatory vagal reflexes tend to
 α1: vasoconstriction,  Reflex bradycardia overcome the direct positive
increases BP  BP = ↑SVR/TPR, vasoconstrictive effects (alpha>beta
 β1: increases HR, ↓HR (vagal activity)
conduction and reflexes)  Inactive per orem
contractility  Do not cross CNS significantly
 β2: bronchodilation  Short duration of action

Dopamine  Non-selective, direct  Renal failure (increase  Cardiovascular  Dopamine Dose- Dependent
acting blood flow) associated with disturbance Action (Please read Appendix,
 Activates α, β, and D1 shock  HTN, palpitations Figure 4 – Dopamine Dose-
adrenergic receptors  Cardiogenic Shock  Arrhythmias Dependent Action)
- α1: vasoconstriction,  Heart failure - Dopamine is - All the three doses will have
increases BP  Severe Bradycardia arrythmogenic, renal perfusion.
- β1: increases HR, very High in high - If you start at medium dose add
conduction and doses) with B1 receptors together with
contractility D1 receptor stimulation (Inc HR,
- D1: vasodilation in cardiac contractility and cardiac
splanchnic and output but more on chronotropic
renal blood effect of Dopamine)
vessels - If you start with high doses add
o (D2,3, 4, 5 are
with alpha1 receptor stimulation
more involved
(VasoConstriction)
in
- Max dose of DA: 20 mcg/kg/min
antipsychotic
medication,  Inactive per orem, do not enter CNS
centrally significantly
located)  Short duration of action
 Dose dependent action
 Rapidly metabolized by MAO and
COMT

B. NON-CATECHOLAMINES, NON-SELECTIVE

DRUG MOA INDICATION SIDE EFFECTS CLINICAL REMARKS

Ephedrine  Non-selective, direct  Hypotension in the setting  Hypertension  Inactive per orem (IV form), do not
acting of anesthesia  Tachycardia enter CNS significantly
 Alkaloid from  Activates α1 and β1  Urinary incontinence,  Arrhythmias  Short duration of action
ma huang adrenergic receptors bronchospasm, nasal  Dizziness  Tachyphylaxis to the indirect effects
(Ephedra - α1: vasoconstriction, congestion, narcolepsy  Nausea of ephedrine (repetitive doses) may
sinica). increases BP develop as norepinephrine stores are
 Vomiting
- β1: increases HR,  Palpitations, depleted. Once depleted it will not
conduction and elicit any response already after
insomnia
contractility ephedrine is given
 May cause fetal acidosis (crosses
placenta)

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PHARMACOLOGY: ANS - ADRENERGIC AND CHOLIGERNIC

C. SELECTIVE ALPHA AGONIST

DRUG MOA INDICATION SIDE EFFECTS CLINICAL REMARKS

Phenylephrine  Alpha 1 agonists,  Nasal decongestant  Rebound nasal  Ocular administration causes
selective  Mydriatic congestion mydriasis WITHOUT cyclopegia
(Dimetapp®)  Selectively activates  Drug induced hypotension  Supine hypertension (alpha1 in the iris)
α1 adrenergic  Ortostatic hypotension  Stroke  Local vasoconstriction for nasal
receptors  Spinal shock  Myocardial infarction decongestant (intranasal)
- α1:  Piloerection  Avoid pseudoephedrine during 1st
vasoconstriction,  Urinary retention trimester – associated with possible
increases BP  REFLEX risk of gastroschisis (teratogenic)
bradycardia  Oxymetazoline – no available data
(Bainbridge reflex)
to inform drug associated major birth
defects
 Phenylephrine – DOC as
vasopressor during 3rd trimester (do
not cause fetal acidosis)
 Other Alpha 1 Agonists:
- Pseudoephedreine (Sudafed ®,
nasal decongestant)
- Oxymetazoline (Alpha 1 & 2
agonist, mostly a1)
- Tetrahydroxyline
- Midodrine
- Naphazoline
- Xylometazoline

Clonidine  Alpha 2 agonists,  Hypertension  Sedation  Taper use prior discontinuation to

selective - BP lowering from  Withdrawal induced avoid rebound hypertension (reason
(Catapres®)  Selectively activates reduction of CO due to rebound why they seldom give Clonidine as a
α2 adrenergic decrease HR and hypertension maintenance medication)
receptors relaxation of capacitance  Dry mouth  Rebound hypertension – administer
- α2: decreases vessels, as well as Phentolamine
central sympathetic reduction in peripheral
outflow vascular resistance
 Cancer pain
 Opioid withdrawal
Methyldopa  Alpha 2 agonists,  Preeclapmsia and  Sedation  Similar Drugs with Methyldopa
selective Gestational  Hemolytic anemia o Guanfacine
 (Aldomet®)  Selectively activates hypertension beyond 20 (positive Coomb’s o Guanabenz
 Prodrug α2 adrenergic weeks of pregnancy) test) o Dexmedetomidine
 Active: a- receptors  Sedative o Tizanidine
methyldopami - α2: decreases (Dexmedetomidine is also  Lowers BP chiefly by reducing
ne & a- central sympathetic classified as Total peripheral vascular resistance, with a
methylNE outflow Intravenous Anesthesia and variable reduction in heart rate and
has Analgesic property cardiac output.
same with Clonidine)
 Muscle relaxant
(Tizanidine)
Apraclonidine  Alpha 2 agonists,  Glaucoma  Blurring of vision  Similar drugs with Apraclonidine:
selective (Topical- eye drops)   Dry mouth o Brimonidine - for treatment of
 Selectively activates DECs secretion of aqueous  Hyperemia glaucoma (eye drops)
α2 adrenergic humor = DEC ocular  Pruritus eye
receptors pressure discomfort
- α2: decreases
secretion of
aqueous humor
D. SELECTIVE BETA AGONIST

DRUG MOA INDICATION SIDE EFFECTS CLINICAL REMARKS

Isoproterenol  Beta-selective  Bronchial asthma  Cardiovascular  Not readily taken up into nerve
 Nonselectively Present: not patronized in disturbance endings
activates β adrenergic the clinics and hospitals  Arrythmias  Synthetic Cathecolamine
receptors because of B1 stimulation   HTN, palpitations
- β1: increases HR, more on chronotropy, severe
conduction and tachycardia effect
contractility
- β2: bronchodilation

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PHARMACOLOGY: ANS - ADRENERGIC AND CHOLIGERNIC
Dobutamine  Beta-1 selective  Acute heart failure  Tachycardia  DOSE - 1-20 mcg/kg/min
(Dobutrex®)  Selectively activates  Cardiogenic shock  Arrythmias  May also be used in cardiac stress
β1 adrenergic  Tachyphylaxis testing (To determine a silent MI
receptors  Hypertension during cardiac stressed state push
- β1: increases HR,  Eosinophilic the heart to contract more to identify
conduction and  Myocarditis ischemic portion of the heart while the
contractility px is attached to the ECG
 Premature
- Dobutamine is more  Inotropy (contraction) is more affected
ventricular beats
on inotropy than chronotropy (heart rate)
 Angina
(contraction)  Synthetic Cathecolamine
 Dyspnea fever,
headache, nausea,
palpitations

Albuterol/  Beta-2 selective  Acute asthma attack (DOC)  Tachycardia  May precipitate arrythmias in patient
Salbutamol  Selectively activates  Tocolysis (decrease uterine  Tremors with concurrent COPD and heart
β2 adrenergic contraction) for preterm labor  Nervousness disease
receptors (terbutaline  used in  Restlessness  Rapid development of tolerance
- β2: bronchodilation asthma after the exhaustion  Arrythmias when  Isoxuprine may also be used as a
(smooth muscle of salbutamol/albuterol), used excessively vasodilator in Reynaud.s
relaxation) ritodrine, isoxuprine) phenomenon
 Tolerance, loss of
 Isoxuprine may cause maternal
responsiveness
pulmonary edema (in high doses)
 Palpitations  Other Beta 2 Agonist:
 Stimulates b1 at
- Terbutaline
high doses (loss of
- Ritodrine
selectivity)
- Isoxuprine

D. SELECTIVE DOPAMINE AGONIST CLINICAL APPLICATIONS OF SYMPATHOMIMETICS

DRUG DESCRIPTION Desired Sympathomimetic of

Clinical Condition
Parameters Choice
Fenoldopam  A selective D1 agonist and potent vasodilator Acute heart failure Increase cardiac B1 and D1 agonists
that enhances renal blood flow and diuresis Prob: myocardium output 1st choice: Dobutamine
 Fenoldopam is an alternative to sodium (want to INC then Dopamine
nitroprusside with fewer side effects contractility)
 Because of mixed results in clinical trials,
fenoldopam is no longer used for treatment of
chronic hypertension or CHF Septic shock Increase cardiac Α1, B1, D1 agonists
 Faced out in the market several mixed output, Increase DOC: NE then Epi
results in clinical trial BP, followed by Dobutamine
vasoconstriction before Dopamine it is
always
ARRYTHMOGENIC
1Hemostasis, Vasoconstriction, A1 agonists
2Decongestion temporary 1 Epi, Phenylephrine
3Spinal shock maintenance of BP 2 Phenylephrine,
Oxymetazoline
3 NE, Phenylephrine
Bronchospasm Bronchodilation, B2 agonists
2premature labor uterine smooth Salbutamol
muscle relaxation 2 Isoxuprine

1Hypertension, Decrease BP A2 agonists

2glaucoma, 1Clonidine
3sedation 2 Apraclonidine
3 Dexmetedomidine

II. ADRENERGIC BLOCKERS

A. SELECTIVE ALPHA BLOCKERS

DRUG MOA INDICATION SIDE EFFECTS CLINICAL REMARKS

Phenoxybenza  Adrenergic antagonists (Alpha  HTN due to  Orthostatic hypotension  Forms covalent bond with
mine non-selective antagonists) Pheochromocytoma,  Reflex tachycardia (once a receptor (effect last
 IRREVERSIBLY blocks alpha tumor of adrenal medulla dec svr  dec hr) several days)
adrenergic receptors (a1>a2) leading to overproduction  Gastrointestinal irritation
and release of  Myocardial ischemia
epinephrine and NE (pre-
surgical)

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PHARMACOLOGY: ANS - ADRENERGIC AND CHOLIGERNIC
Phentolamine  Adrenergic antagonists (Alpha  Pheochromocytoma -  Orthostatic hypotension
non-selective antagonists) associated HTN (pre-  Reflex tachycardia
 REVERSIBLY blocks alpha surgical),  Gastrointestinal irritation
adrenergic receptors (a1>a2)  Antidote for a1 agonist
overdose,
 Rebound hypertension

Prazosin  Adrenergic antagonists (Alpha  Benign prostatic (bladder  1st dose causes  Tamsulosin is most
selective antagonists) relaxation, prevents orthostatic hypotension selective for prostatic
 Selectively blocks a1 urinary retention) (because blocked a1) -> smooth muscle
adrenergic receptors  Hyperplasia first dose syncope  Doxasozin, Tamsulosin,
 Hypertension  Reflex tachycardia (less Silodosin and Alfuzosin
ENote: pronounced) are not indicated for use in
Alpha-1 blockers usually end in "-  Dizziness, drowsiness, female for the treatment of
zosin". headache, weakness, hypertension
asthenia, nausea, edema

OTHER ALPHA 1 ANTAGONISTS  Doxazosin, Terazosin, Tamsulosin, Silodosin, Alfuzosin

B. SELECTIVE BETA BLOCKERS

ENote: Beta-blockers usually end in "-olol".

CLASS MOA INDICATION SIDE EFFECTS CLINICAL REMARKS

Beta  Blocks B1 and B2 receptors,  Angina prophylaxis  Bronchospasm  Relative contraindicated
NON- blocks sympathetic effects on  Hypertension  Bronchoconstricti with asthmatic patients
SELECTIVE heart and BP. Reduces renin  Arrhythmias on -> C/I in and diabetic patients
Antagonists release  Migraine prophylaxis asthmatic pxs) ** Isoproterenol – is a beta
 Adrenergic  Drugs:  Performance anxiety -> panic  AV blocks AGONIST, non – selective
antagonists - Propanolol, Pindolol, attacks  Heart failure
(beta non- Timolol, Labetalol,  Hyperthyroidism  CNS sedation
selective Carvedilol, Nadolol,  Glaucoma (Timolol, Nadolol ->  Erectile
antagonists) Levobunolol, decrease aqueous humor dysfunction
Metipranolol, Pindolol, production)
Carteolol, Bipondolol,
Oxprenolol, Celiprolol,
Penbutolol, Timolol
SELECTIVE  Selectively blocks B1  Angina prophylaxis  Bronchospasm  Drugs:
BETA 1 receptors, blocks sympathetic  Hypertension (less chance) - Atenolol
Blockers effects on heart and BP  Supraventricular tachycardia  AV blocks - Betaxolol
 Adrenergic (Esmolol only)  Heart failure - Esmolol
antagonist - An example of  CNS sedation - Acebutolol
(beta 1 tachyarrythmias, an  Erectile - Metoprolol
selective arrhythmia on the dysfunction - Alprenolol
antagonists) tachycardic site. - Nebivolol
- Based on AHA, DOC for ENotes:
stable SVT’s is Adenosine. “BE A MAAN b1”
But for the Phil Heart Assoc
if you don’t have Adenosine
you can give verapamil or
esmolol

CLINICAL IMPORTANCE OF BETA BLOCKERS  Intrinsic Sympathomimetic Activity

 Beta blockers for Angina prophylaxis - Partial agonist activity
- All cardiac patients on the tachycardic side, - Lowers BP with modest reduction of HR
remember perfusion happens during diastole. So - Advantage of treating patients with asthma
once tachycardia, there is less perfusion. You because these drugs are less likely to cause
could have chest pain or angina, also coronary bronchospasm
steal or the vasospasm of the coronary arteries - Eg. Labetalol Acebutolol, Pindolol, Carteolol,,
due to decreased perfusion Bopindolol Oxprenolol, Celiprolol, Penbutolol
 Beta Blockers in Diabetic Patients Carvedilol
- Mask premonitory symptoms of hypoglycemia  Local Anesthetic Activity
from insulin overdose (tachycardia, tremor, - Membrane stabilizing activity
anxiety) - Disadvantage when beta blockers are used
- Once you see a patient using a beta blocker topically in the eye
always remember the first sign that the patient is o Decreases protective reflexes (such as
already hypoglycemic is hypertension without blinking)
tachycardia, tremor and anxiety, you’ll only see o Increases the risk of corneal ulcerations
hypertension) - Absent with TIMOLOL and BETAXOLOL –
- Impaired hepatic mobilization of glucose making them useful in glaucoma
(pushing the patient further to hypoglycemia)  Propanolol

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PHARMACOLOGY: ANS - ADRENERGIC AND CHOLIGERNIC
- given to thyrotoxicosis to lessen tachycardia and  STEP 4: TERMINATION
inhibits coversion of thyroxine to active form T3  Degradation of ACh into choline and acetate by
the periphery (DOC for thyroid patients) acetylcholinesterase
- IUGR, small placenta and congenital o Inhibited by Indirect Acting Cholinomimetics
abnormalities noted such as: Carbamates and
 Nadolol Organophosphates
- Longest half-life [ENotes: “naolol sa sobrang
haba”; Naolol – Nadolol]
 Esmolol
- Hydrolyzed by blood borne esterases
- Shortest half-life [ENotes: “esmol”]
- Treatment of SVT’s
 Atenolol
- Has been shown to lower birthweights and impair
fetal growth during pregnancy
 Carvedilol and Labetalol
- With ISA and may be used in
Pheochromocytoma
 Metipranolol
- Used as an ophthalmic drop for glaucoma
- Similar with Timolol and Metaxonol

III. CHOLINERGIC PHARMACOLOGY

CHOLINERGIC
STEPS
INHIBITORS
Synthesis Hemocholinium
Storage Vesamicol

Release Botulinum
Termination
Metabolism Neostigimine
Reuptake -

 CLASSIFICATION OF MEDICATIONS
A. Direct-Acting Cholinomimetics
B. Indirect-Acting Cholinomimetics
C. Cholinoreceptor Blockers

 STEP 1: SYNTHESIS
 ACh is synthesized from acetyl CoA and choline by
the enzyme choline acetyltransferase (ChAT)
o Choline transport is inhibited by
HEMICHOLINIUM
 STEP 2: STORAGE
 ACh is actively transported into presynaptic
vesicles for storage by vesicle-associated
transporter (VAT)
o Inhibited by vesamicol
 STEP 3: RELEASE
 Entry of calcium triggers interaction among SNARE
proteins (VAMPs and SNAPs)
o Botulinum toxin alter synap to brevins to
prevent release of Ach

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 PHARMACOLOGY
TOPIC #9: ANS - ADRENERGIC AND CHOLINERGIC DRUGS
Dr. K. Balmilero • December 2, 2020• 1St Semester (Finals)

I. CHOLINOMIMETICS

A. DIRECT ACTING CHOLINOMIMETICS

DRUG MOA INDICATION SIDE EFFECTS CLINICAL REMARKS

Acetylcholine  Act on both M  Mitotic during ocular surgery  CNS stimulation  Main action: Decrease in heart rate
(muscarinic) and N (topical ACh used in ocular  Miosis and cardiac output and Decrease in
(nicotinic) receptors, surgery, it is not available in IV  Bronchoconstricti blood pressure
activates M1 and M3 form since it is very fatal) on  Results to increased secretion,
receptors in all  Excessive GI and smooth muscle contraction (except
peripheral tissues GU smooth in vascular smooth muscles where it
muscle causes relaxation) and changes in
contraction heart rate
 Increase  Very short-lived duration of action
secretory activity (5-30sec)
of sweat glands o Rapidly hydrolyzed by AChE
 Vasodilation
Betanechol /  Betanechol: activates  Betanechol: bladder and bowel  Cyclospasm  Results in smooth muscle
Methacholine muscarinic (M1-M3), atony (post-surgery or spinal  Diarrhea contraction except in vascular
Oral form receptors, and acts on cord injury)  Urinary urgency smooth muscles where it causes
M receptors only. (M3  Carbachol: glaucoma  Vasodilation relaxation
more on GIT)  Reflex  Resistant to AChE, orally active
 Increases intestinal tachycardia
motility and tone.  Sweating
 Stimulates the detrusor (because of the
muscle of the bladder, activity of the
whereas the trigone and muscarinic
sphincter muscles are receptors)
relaxed. These effects
produce urination.
 Metacholine: act on
both M and N receptors
Pilocarpine /  Activates muscarinic  Glaucoma (drug of choice for  Miosis  Good lipid solubility
Cevimeline (M3) receptors in ciliary emergency lowering of  blurring of vision
Cholinomimetic muscle (increasing intraocular pressure of both (due to
(direct-acting, aqueous humor outflow) open-angle and angle-closure cyclospasm)
muscarinic) and salivary glands glaucoma)  increased
 Available as (increasing salivation)  Sjogren syndrome (Dry mouth salivation
ophthalmic  Produces rapid miosis and dry eye syndrome)
drops and contraction of the  Sicca syndrome (Sjorgren
ciliary muscle. syndrome with RA)
Nicotine /  Activates Nicotinic ACh  Smoking cessation (available  Generalized  Overdose leads to convulsions,
Varenicline receptors (Nn and Nm) as a patch) ganglionic paralysis, and coma
Cholinomimetic stimulation  Activates autonomic post ganglionic
(direct-acting, (hypertension, neurons (both PNS and SNS) and
nicotinic) tachycardia, skeletal muscle nueromuscular end
nausea and plates (initial effect is convulsions
vomiting, because of the stimulation of NM
diarrhea) end plates)
 Able to enter CNS and activates Nn
receptors
 Duration: 1-6hours only
 Varenicline: selective partial
agonists at nicotinic receptors,
duraion is 12-24hours

MUSCARINIC TOXCITY
NICOTINIC TOXCITY
 CNS stimulation
 Ganglionicstimulation
 EYE: miosis, spasm of accommodation
 Blockade of neuromuscular end plate depolarization
 LUNGS: bronchoconstriction
 Leading to fasciculation followed by paralysis
 GIT/GUT: excessive GI and GU smooth muscle activity
 CNS toxicity: stimulation (convulsions) followed by CNS depression
 Increased secretory activity (sweat glands, airway GIT, lacrimal
glands)
 Vasodilation

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PHARMACOLOGY: ANS - ADRENERGIC AND CHOLIGERNIC

B. INDIRECT ACTING CHOLINOMIMETICS

MECHANISM OF ACTION
 Bind to Cholinesterase and undergo prompt hydrolysis
 Alcohol portion released
 Acidic portion retained and released slowly
General o prevents the binding and hydrolysis of endogenous acetylcholine
o amplify acetylcholine effects wherever ACh is released
 No significant actions at uninnervated sites where ACh is not normally released
 aka Cholineterase inhibiting drugs

DRUG MOA INDICATION SIDE EFFECTS CLINICAL REMARKS

Edrophonium  Inhibits  Myasthenia gravis (diagnosis -  Miosis  IV, short lived duration of action: 5-25
Cholinomimetic acetylcholinesterase tensilon test)  Salivation min
(indirect-acting), (short acting)  Differentiation of cholinergic  Nausea  In MG: improves muscle strength in
Cholinesterase  Amplifies crisis vs. myasthenic crisis  Vomiting myasthenic crisis, weakens muscle
inhibiting drugs endogenously  Diarrhea strength in cholinergic crisis
released acetylcholine  Bradycardia
 Excess drug
may provoke a
cholinergic
crisis (Antidote:
Atropine)
Neostigmine  Inhibits  Myasthenia gravis (treatment)  Miosis  Muscarinic effects are blocked by
Cholinomimetic acetylcholinesterase  Reversal of nondepolarizing  Salivation ATROPINE is administered to block
(indirect-acting), (similar with neuromuscular blockade (used  Nausea effects such as salivation
Cholinesterase edrophonium but during surgery)  Vomiting  Neostigmine: poor lipid solubility,
inhibiting drugs longer duration of  Glaucoma (physostigmine,  Diarrhea DOA: 30min- 2hr (IV form)
action) echothiophate, demecarium)  Bradycardia  Pyridostigmine: poor lipid solubility,
 Amplifies  Stimulates bladder and GI tract oral, DOA: 4-8hr
endogenously  Duration of Action: 30min-2  Physosdigmine: good lipid solibility,
released acetylcholine hours able to enter the CNS, DOA: 4-8hr
 Echothiophate: moderate lipid
solubility, DOA: 2-7days (only
available as optic drops)
 Similar Drugs with Neostigmine:
o Pyridostigmine
o Physostigmine
o Ambenonium
o Demecarium (Carbamates)
o Echothiophate
(Organophosphate)
Rivastigmine  Inhibits  Alzheimer’s disease  Miosis  Rivastigmine is available as
Cholinomimetic acetylcholinesterase  Salivation transdermal patch
(indirect-acting), (possible remedy for  Nausea  Donepezil is combined with
Cholinesterase loss of cognitive  Vomiting Memantine (NMDA antagonists) for
inhibiting drugs function)  Diarrhea Alzheimer's dementia
 Amplifies  Bradycardia  Similar Drugs with Rivastigmine:
endogenously  Hepatoxicity o Galantamine
released acetylcholine o Donepezil
o Tacrine

 Myasthenia Gravis
 Autoimmune destruction of Nicotinic ACh receptors characterized as:
o fluctuating muscle weakness (PM)
o ocular symptoms (ptosis)
o bulbar symptoms (dysphagia, dysphonia)
o proximal muscle weakness
Myasthenic Crisis Cholinergic Crisis
CLINICAL CORRELATIONS OF INDIRECT
ACTING CHOLINOMIMETIC  weakens with Edrophonium
 improves with Edrophonium
 excessive activation of
 acute worsening of
cholinoreceptors (skeletal
symptoms due to infection,
muscle weakness and
stress of UNDER medication
parasympathetic signs) due to
OVER medication

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PHARMACOLOGY: ANS - ADRENERGIC AND CHOLIGERNIC

II. BLOCKERS

C. CHOLINORECEPTOR BLOCKERS (ANTICHOLINERGIC DRUGS)

DRUG MOA INDICATION SIDE EFFECTS CLINICAL REMARKS

Atropine  Competitively blocks  Mydriatic  Tachycardia  Similar drugs (all available as optic
Belladona ALL muscarinic  Cycloplegic  Mydriasis drops)
Alkaloid receptors  Antidote for organophosphate  Cyclopedia o Homatropine
Cholinergic  Acts centrally and poisoning (first choice, because  skin flushing o Cyclopentolate
antagonist peripherally organophosphates acts  delirium o Tropicamide
(muscarinic) Neostigmine it prolongs Ach  hallucinations
activity)
 Bradycardia (first line if patient is
hemodynamically unstable,
meaning hypotensive, but if the
patient is normotensive don’t
give atropine)
 Hypersalivation
 Cycloplegic, Antispasmodic,
Antisecretory and treats
bradycardia
Benztropine  Competitively blocks  Parkinson’s disease  Blurring of  Similar drugs:
Cholinergic ALL muscarinic vision o Biperiden
antagonist receptors  Dry eyes o Trihexyphenidyl
(muscarinic)  Restores  Constipation  Reduces tremors more than
neurotransmitter  Dry mouth bradykinesia or rigidity
balance in basal ganglia  Urinary
retention
Ipratropium  Given together with  Asthma  Dry mouth  Similar drugs:
Cholinergic short acting beta  COPD (Don’t give SABAS only,  Cough o Tiotropium (longer duration of
antagonist agonist (SABAS) rather give SABAS and  Nasal dryness action)
(muscarinic)  Blocks muscarinic Ipatropium  DOC for COPD  Advantage: It is
receptors in bronchial exacerbation) administered once daily
smooth  Bronchodilators via Inhalation while Ipratropium is 4x
daily.
 Not as effective as SABAs but less
tachycardia and arrhythmia
 Few muscarinic effects outside the
lungs
Scopolamine  Competitively blocks  Motion sickness  Drowsiness  Applied as transdermal patch (3 day
Cholinergic ALL muscarinic  decrease acid secretion in GIT  blurring of effect)
antagonist receptors  nausea and vomiting (post op) vision, dry eyes  Not available in the Philippines
(muscarinic)  Antagonizes histamine  constipation
and serotonin  dry mouth
 Similar to Atropine:  urinary retention
produces peripheral
effects.
 Greater action on the
CNS (unlike atropine)
 Longer duration of
action than Atropine
Dicyclomine  Competitively blocks M3  IBS, diarrhea, decrease acid  Tachycardia,  Similar drugs: Hyoscyamine
Cholinergic receptors secretion in GIT confusion, (Buscopan), glycopyrolate
antagonist urinary  Available PO and IV forms, relatively
(muscarinic) retention, short t1/2 life (6 hours)
increase IOP
Oxybuntin  Slightly blocks M3  Urge incontinence (avoiding  Tachycardia  Similar drugs:
Cholinergic receptors severe detrusor spasms)  Constipation  Darifenacin
antagonist  Reduces detrusor  Post-operative spasms  Xerostomia  Solifenacin
(muscarinic) muscle tone  Increased IOP  Tolteradine
 Trospium
 Available as patch (may cause
pruritus)

Pralidoxime  Binds phosphorus of  Antidote for early stage  Muscle  Must be administered before 6-8
Cholinergic organophosphate cholinesterase inhibitor weakness hours of organophosphate bond with
regenerator  Breaks poisoning (organophosphate cholinesterase occurs (beyond 6-8
organophosphate bond poisoning and nerve gas hours not indicated)
with cholinesterase poisoning), can relieve skeletal  Has oxime group group which has
(regenerates active muscle and endplate block high affinty for phosphorus
acetylcholinesterase)

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PHARMACOLOGY: ANS - ADRENERGIC AND CHOLIGERNIC
CLINICAL CORRELATIONS OF ANTICHOLINERGIC o Sarin, Tabun, Soman: Nerve Gases
DRUGS -
Treatment: Atropine, Pralidoxime (only within 6-8
 Atropine Toxicity hours beyond that stick to atropine)
- Atropine fever (hyperthermia) - Signs and Symptoms: DUMBBELLSS
- Atropine flush (Cutaneous vasodilation) o D - diarrhea
- Decreased secretions o U - urination
- Tachycardia o M - miosis
- Arrhythmias (Intraventrucal conduction block) o B - bronchospasm
- Constipation o B - bradycardia
- Blurred vision o E - emesis, excitation (skeletal muscle and
- CNS toxicity (hallucinations, delirium) CNS)
 HOT as a hare o L - lacrimation
 DRY as a bone o L - lethargy
 RED as a beet o S - sweating
 BLIND as a bat o S - salivation
 MAD as a hatter CONTRAINDICATIONS TO MUSCARINIC BLOCKERS
 Organophosphate Poisoning  Cautious use in infants
- Malathion (Scabicide) and Parathion (Insecticide)  Acute angle-closure glaucoma (we want to
o high lipid solubility prevent midriasis)
o DOA: 7-30 days  Benign prostatic hyperplasia
D. GANGLION BLOCKERS

Competitive pharmacologic antagonists at nicotinic acetylcholine receptors
Definition 
First successful agents for treatment of hypertension but were abandoned
o Adverse effects of ganglion blockade in hypertension are severe
SIDE
DRUG MOA INDICATION CLINICAL REMARKS
EFFECTS
Hexamethoni  Competitively  Hypertension (obsolete)  Postural  Similar drugs: (not already
um blocks Nn  hypertensive hypotension available in the market)
Cholinergic nicotinic ACh emergencies  dry mouth o Trimethaphan
antagonist receptors  blurred o Mecamylamine
(nicotinic) vision
 constipation
 sexual
dysfunction

D. NEUROMUSCULAR BLOCKERS
 Important for producing complete skeletal muscle relaxation in surgery
 Competitively blocks Nicotinic receptors in neuromuscular endplate
 Classification:
Definition - Nondepolarizing (Tubocurarine, pancuronium, atracurium, cisatracurium, vecuronium,
rocuronium)
- Depolarizing (Succinylcholine)

IV. REFERENCES
1. Katzung, B. G., Masters, S. B., & Trevor, A. J. (2012). Basic & clinical pharmacology. New York: McGraw-Hill
Medical.
2. Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincott illustrated reviews: Pharmacology (6th ed.).
Philadelphia, PA: Wolters Kluwer

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 PHARMACOLOGY
TOPIC #9: ANS - ADRENERGIC AND CHOLINERGIC DRUGS
Dr. K. Balmilero • December 2, 2020• 1St Semester (Finals)

V. APPENDIX

Figure 1: Responses Elicited in Effector Organs by Stimulation

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PHARMACOLOGY: ANS - ADRENERGIC AND CHOLIGERNIC

Figure 2: Adrenergic Transmission

Figure 3: Synthesis, Storage, Release and Termination of NE

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PHARMACOLOGY: ANS - ADRENERGIC AND CHOLIGERNIC

Figure 4: Dopamine
Dose-Dependent Action

AVENGER’S APPENDIX

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PHARMACOLOGY: ANS - ADRENERGIC AND CHOLIGERNIC

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