PHARMA ● PHARMA-THERAPEUTICS SHIFT

AUTONOMIC PHARMACOLOGY 01
Maria Minerva P. Calimag, MD, MSCE, PhD, FPBA, FPSECP (08/23/22)

LECTURE OUTLINE ● Contains neurons and signals from the tendons, joints, skin, skeletal
muscles, eyes, nose and many other organs
1. The Nervous System 1 ● Signals are conveyed to the cranial and spinal nerves
1.1. Central Nervous System
1.2. Peripheral Nervous System 1.2.2. AUTONOMIC NERVOUS SYSTEM
2. The Autonomic Nervous System 1 ● Releases Acetylcholine (Ach)
2.1. Sympathetic Nervous System ● Functional Considerations:
2.2. Parasympathetic Nervous System ○ Mediates control of vegetative or involuntary functions
2.3. Autonomic Nervous System Drugs ○ Innervation of cardiac muscle, vascular and nonvascular smooth muscle
2.4. Homeostasis and exocrine glands
2.5. Autonomic Nervous System Responses ○ Functions in these systems often occur without control
3. ANS Neurotransmitters 3 ● Anatomical Considerations:
3.1. Acetylcholine ○ In contrast to somatic efferents, it consists of 2 sequential neurons:
3.2. Norepinephrine preganglionic and postganglionic neurons that synapse in autonomic
4. Autonomic Nervous System Receptors 3 ganglia
4.1. Muscarinic Receptors
2. THE AUTONOMIC NERVOUS SYSTEM
4.2. Nicotinic Receptors
4.3. Alpha Receptors 2.1. SYMPATHETIC NERVOUS SYSTEM
4.4. Beta Receptors
● Adrenal medulla is considered to be a modified sympathetic ganglion
4.5. Potential Ways to Affect Autonomic Transmission
○ Embryologically and anatomically homologous to the sympathetic ganglia
5. Classification of Autonomic Nervous System Drugs 4
● Catabolic
(Sympathetic)
● Consists of one short preganglionic fiber synapsing with several long
5.1. Adrenergic Agonists (Sympathomimetic)
postganglionic fibers in sympathetic ganglia
5.2. Adrenergic Antagonists (Sympatholytics)
● Preganglionic neurons exit the spinal cord at the thoraco-lumbar level to
6. Classification of Autonomic Nervous System Drugs 7
synapse with postganglionic nerves at the paravertebral ganglia
(Parasympathetic)
● All the paravertebral ganglia provide sympathetic innervation to blood
6.1. Cholinergic Agonists (Parasympathomimetic)
vessels in muscle and skin, arrector pili muscles and sweat glands
6.2. Cholinergic Antagonists (Parasympatholytic)
● Sympathetic trunk (22 pairs on each side of the spinal cord)
7. Cholinergic Agonists / Parasympathomimetic Drugs 7
○ Cervical (3)
7.1. Direct-Acting Cholinergic Drugs
■ Superior Sympathetic Ganglion - innervates viscera of the head
7.2. Indirect Acting Cholinomimetic Drugs
■ Middle Cervical Ganglion and Stellate Ganglion (Cervicothoracic
7.3. Toxicity
Ganglion) - innervate viscera of the neck, thorax and upper limbs
8. Cholinergic Antagonists 8
○ Thoracic (10 or 11)
8.1. Muscarinic Antagonists
■ Innervate the trunk region
8.2. Nicotinic Antagonists
○ Lumbar (4)
9. APA References 9
○ Sacral (4)
10. Review Questions 9
■ Lumbar and sacral innervate the pelvic floor and the lower limbs
11. Rationalization 9
○ Coccygeal (Ganglion Impar)
12. Freedom Wall 9
■ Unpaired

📕Book 📝 Previous Trans ● Greater ramification of sympathetic fibers compared to parasympathetic

○ Ratio of pre- to postganglionic fibers = 1:20
● Diffusion action: fight or flight response
1. THE NERVOUS SYSTEM ○ Not essential for life
● The nervous system has several properties in common with endocrine ● Normally active with the degree of activity varying from moment to moment
system: and organ to organ
○ High-level integration in the brain ● Adjust to changing environment, especially during rage or fright
○ Has the ability to influence processes in distant regions of the body ● Synapse of preganglionic neurons uses Acetylcholine as a
through the use of chemicals for the transmission of information neurotransmitter
○ Makes extensive use of negative feedback ○ All preganglionic nerves are cholinergic
■ By using drugs that mimic or block the action of chemical transmitters, ● Synapse of postganglionic neurons with the target organ uses
we can selectively modify many autonomic functions Norepinephrine
○ Except sympathetic postganglionic neuron that terminates on the sweat
glands (uses acetylcholine)
1.1. CENTRAL NERVOUS SYSTEM (CNS)
● Typical Response:
● Brain ○ Increase HR (tachycardia)
○ Receives and processes sensory information, initiates responses, stores ○ Shift blood flow to muscle
memories and generates thoughts and emotions ○ Increase in blood glucose level
● Spinal Cord ○ Dilation of pupil
○ Conducts signals to and from the brain and controls reflex activities ■ Mydriasis (Pupil Dilation) happens during fight or flight to be able to let
more light enter your eyes so you can see the threat even from a
1.2. PERIPHERAL NERVOUS SYSTEM (PNS) distance
● Somatic Nervous System ● Sweating, blushing, Goosebumps or Horripilation are stress responses
○ Regulates activities under conscious control ● “Adrenaline Rush”
○ Acetylcholine is the neurotransmitter released at the neuromuscular ○ Emergency, Exercise, Excitement, Embarrassment
junction ○ ANS response to fear, anger, stress
● Longitudinal muscles are relaxed while sphincters are constricted
1.2.1. SENSORY DIVISION
● Afferent division

PHARMA (TWG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q. SAMSON (TEG) CLEDERA, CONVENTO, MANGUSSAD, ROLLOM, ROMUALDO, ROQUE 1
2.2. PARASYMPATHETIC NERVOUS SYSTEM 2.3.1. SAME PHARMACOLOGICAL EFFECTS
● Anabolic ● Sympathomimetic & Parasympatholytic
● Preganglionic neurons originate in cranial nerves and sacral portion of ○ Both can cause tachycardia only in different mechanisms
spinal cord ○ Both stimulate different receptors
● Long preganglionic fiber; Short postganglionic fibers ○ Examples:
● More circumscribed than sympathetic system (1:1 ratio although but not ■ Sympathomimetic = NE
always true) ■ Parasympatholytic = Atropine (anticholinergic, antimuscarinic)
● Preganglionic neurons synapse with postganglionic neurons in preaortic ● Sympatholytic & Parasympathomimetic
ganglia very close or in the organs innervated
○ Discrete action 2.3.2. PHARMACOLOGICAl ANTAGONISM
● Essential for life
● Cell bodies of the parasympathetic nervous system are located in the spinal ● A type of antagonism between two drugs wherein one serves as an agonist
cord (sacral region) and in the medulla at a particular receptor site and the other serves as an antagonist at the
● In the medulla, CN III, VII, IX and X form the preganglionic parasympathetic same receptor site
fibers ○ Examples
○ Projects close to target organ and make a synapse ■ Sympathomimetic ANTAGONIST and Parasympathetic ANTAGONIST
● Preganglionic synapses and postganglionic synapses use Acetylcholine
(cholinergic) 2.3.3. PHYSIOLOGICAL ANTAGONISM
● Preaortic or Prevertebral Ganglion lies on the anterior surface of the aorta ● Sympathetic and parasympathetic usually do not function independently
which retain a pattern of innervation that originates in the embryo ○ They are physiological antagonists (causes opposite effects)
○ Celiac Ganglion ● Often when one system INHIBITS a process, the other system will
■ Innervates structures from embryonic foregut including stomach, liver, AUGMENT the level of activity so that the total response depends on the
pancreas, duodenum and first part of the small intestine influence of BOTH SYSTEMS but this is not always the case.
○ Superior Mesenteric Ganglia ● Integration of systems regulates function below the level of consciousness
■ Innervates small intestine (from embryonic midgut)

[BATCH 2023] INFORMATION

● LOCATION OF GANGLIA
○ Parasympathetic NS Ganglia (Craniosacral Division)
■ Found closer to the organs
■ Effects are more discrete for the specific organ
○ Sympathetic NS Ganglia (Thoracolumbar Division)
■ Paravertebral (closer to vertebral column and further from organ)
■ Effect is usually all or none and usually all the organs are recruited in
one quick response in order to respond to the stressful situation

● Key Points
○ Peripheral Nervous System (PNS) transmits signals between CNS and
the rest of the body.
■ Motor Neurons - carry signals from the CNS that control the activities
of muscles and glands
■ Sensory Neurons - carry signals to the CNS from the sensory signals
○ Under Motor Neurons:
■ Somatic Nervous System - controls voluntary movements by activating
skeletal muscles
■ Autonomic Nervous System - controls involuntary responses by Figure 1. PNS and SNS Ganglia
influencing organs, glands and smooth muscles 2024 Trans (originally from Biological Science, 2nd Edition)
○ Under Autonomic Nervous System:
■ Sympathetic Division - fight or flight
● Adrenergic Receptors
■ Parasympathetic Division - rest and relaxation
● Cholinergic Receptors

2.3. AUTONOMIC NERVOUS SYSTEM DRUGS

● Drugs acting on the ANS can be divided into four groups:
○ Adrenergomimetic or Sympathomimetic
○ Cholinomimetic or Parasympathomimetic
○ Adrenergolytic or Sympatholytic
○ Cholinolytic or Parasympatholytic

Table 1. Four Groups of Drugs Acting on the ANS

SYMPATHETIC PARASYMPATHETIC
(Adrenorgo-) (Cholino-)
AGONIST Adrenergomimetic or Cholinomimetic or Figure 2. PNS and SNS Ganglia
(-mimetic) Sympathomimetic Parasympathomimetic Plenary Lecture
Stimulates Sympathetic NS Stimulates
Parasympathetic NS
ANTAGONIST Adrenergolytic or Cholinolytic or
(-lytic) Sympatholytic Parasympatholytic

Antagonize/Against Antagonize/Against
Sympathetic NS Parasympathetic NS
Source: 📝 2024 Trans

PHARMA (TWG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q. SAMSON (TEG) CLEDERA, CONVENTO, MANGUSSAD, ROLLOM, ROMUALDO, ROQUE 2
2.4. HOMEOSTASIS 3.1.6. NICOTINIC RECEPTORS
● Homeostasis is the dynamic balance between the autonomic branches ● Neuromuscular junction of skeletal muscle
(PNS and SNS). ○ Effects blocked with non-depolarizing neuromuscular blockers (e.g.
curare, pancuronium, atracurium, vecuronium)

3.2. NOREPINEPHRINE

Homeostasis
Plenary Lecture

2.5. AUTONOMIC NERVOUS SYSTEM RESPONSES

Table 2. PNS & SNS Responses

SYMPATHETIC PARASYMPATHETIC
EYES Mydriasis Miosis
GLANDS Inhibit Secretion Enhance Secretion
SMOOTH MUSCLES Relax Contrat
BV IN MUSCLES Dilate Constrict
BV IN SKIN Constrict Dilate
(EXCEPT for blush
areas of face and neck) Figure 3. Synthesis of Norepinephrine
Plenary Lecture
HOLLOW ORGANS Retention Evacuation
● Longitudinal muscles: relax ● Longitudinal: contract 3.2.1. NOREPINEPHRINE CHEMISTRY
● Sphincters: constrict ● Sphincters: relax

Source: Plenary Lecture & 📝 2024 Trans

● Norepinephrine is ultimately synthesized from tyrosine using the enzyme
tyrosine hydroxylase, which converts tyrosine to DOPA
● Aromatic L-amino acid decarboxylase converts DOPA to dopamine
3. ANS NEUROTRANSMITTERS ● Dopamine b-hydroxylase converts dopamine to norepinephrine

3.1. ACETYLCHOLINE

3.1.1. ACETYLCHOLINE (ACH/CHOLINERGIC) SYNAPSES

● All preganglionic fibers outside the CNS (sympathetic and parasympathetic)
● All parasympathetic postganglionic nerve endings (Ach is the transmitter)
● Somatic motor neurons innervating the skeletal muscles

3.1.2. NORADRENERGIC (NE) SYNAPSES

● All postganglionic sympathetic fibers
○ Exception: sympathetic postganglionic nerve endings of sweat glands
(release ACh).
● Adrenal medulla (norepinephrine and epinephrine)

3.1.3. ACETYLCHOLINE CHOLINERGIC) RECEPTORS

● Muscarinic
○ Glands Figure 4. Synthesis of Norepinephrine
○ Heart Plenary Lecture
● Nicotinic
○ Muscles
○ Ganglia 4. AUTONOMIC NERVOUS SYSTEM RECEPTORS

3.1.4. ACETYLCHOLINE AND MUSCARINIC RECEPTORS 4.1. MUSCARINIC RECEPTORS

● Postganglionic parasympathetic fibers innervating the heart, smooth ● Autonomic ganglia
muscles and exocrine glands M1 ● Central nervous system
○ Exception: postganglionic sympathetic fibers innervating the sweat glands ● Common in secretory glands (with M3)
● Blocked by antimuscarinic agents (e.g. atropine) Excitatory
● Smooth muscles
3.1.5. ACETYLCHOLINE AND NICOTINIC RECEPTORS M3 ● Glands
● Endothelium of blood vessels
● Classically a biphasic response is observed with stimulation at low doses
and inhibition at high doses ● Heart
Inhibitory M2
● Sympathetic and parasympathetic autonomic ganglia and adrenal medulla ● Supraventricular muscles
● Effects blocked with ganglionic

PHARMA (TWG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q. SAMSON (TEG) CLEDERA, CONVENTO, MANGUSSAD, ROLLOM, ROMUALDO, ROQUE 3
4.2. NICOTINIC RECEPTORS 5. CLASSIFICATION OF AUTONOMIC NERVOUS SYSTEM DRUGS
(SYMPATHETIC DRUGS)
N1
(nicotinic muscle) DISCLAIMER. See Appendix for complete list of ANS drugs.
Excitatory Neuromuscular junction
N1
(nicotinic neuronal) 5.1. ADRENERGIC AGONISTS (SYMPATHOMIMETIC)
● Postganglionic neuron
Inhibitory N2 5.1.1. CLASSIFICATION OF ADRENERGIC AGONISTS
● Activation produces EPSPs
● Direct-acting
4.3. ALPHA RECEPTORS ○ Mixed alpha and beta (Norepinephrine, Epinephrine)
○ Alpha-2 selective (Clonidine)
Excitatory ● Alpha 1 ○ Beta-2 selective (Terbutaline, Isoproterenol)
○ Smooth muscles ● Indirect acting (Amphetamine, Cocaine)
○ glands ● Dual-acting (Ephedrine)
Inhibitory ● Alpha 2
5.1.2. MEDICINAL CHEMISTRY OF ADRENERGIC DRUGS
○ Feedback inhibition of Norepinephrine release
● Beta-phenylethylamine may be considered the parent compound from
which adrenergic/sympathomimetic drugs are derived and consists of a
4.4. BETA RECEPTORS
benzene ring with ethyl amine side chain
Excitatory ● Beta 1
○ Heart (tachycardia)
● Beta 3
○ Fat cells (degradation of fat cells into fatty acids
Inhibitory ● Beta 2
○ Smooth muscles and glands

REMEMBER.
● Subscript 1 is EXCITATORY
○ Contraction of muscles
○ Constriction of blood vessels
○ Enhanced secretion of glands
● Subscript 2 is INHIBITORY
○ Relaxation of muscles
○ Dilatation of vessels and bronchi
○ Inhibited secretion of glands

4.5. POTENTIAL WAYS TO AFFECT AUTONOMIC TRANSMISSION

Remember the mnemonic: SSRRBB
● Synthesis
○ Availability of precursors for the neurotransmitters Figure 5. Structure of Beta-phenylethylamine and its substituents.
■ Ex: for the sympathetic nervous system, precursor is Tyrosine Plenary Lecture
consisting of benzene ring, acetyl side chain and amine side
○ Availability of synthesis enzymes Addition of hydroxyl substituent at beta carbon of
■ Ex: Acetylcholine requires availability of Acetyl-CoA and Choline Norepinephrine
dopamine
acetylase
● Storage (vesicles) Addition of a methyl substituent to the amine side of
Epinephrine
○ Protects the neurotransmitters from degradation norepinephrine
○ Provides for the quantal release of neurotransmitters Addition of another methyl substituent (yielding to 2
● Release Isoproterenol
substituents) to the amine side of norepinephrine
○ Ca2+-dependent exocytosis
○ Agents could interfere with or enhance the release of neurotransmitters Transfer the hydroxyl substituent of carbon 4 to carbon 5
Terbutaline
● Reuptake of isoproterenol
○ Agents could interfere with the reuptake of neurotransmitters
Has a 3,4-hydroxy substituent having a long chain on the
○ If reuptake is inhibited, then there are more neurotransmitter in the end Dobutamine
amine side. It has 2 benzene rings
organ
● Binding IMPORTANT. Highest beta-2 effect is exhibited by terbutaline, followed by
○ Agonist - high affinity, high intrinsic activity Isoproterenol, followed by epinephrine.
■ Affinity with efficacy
○ Antagonist - high affinity, no intrinsic activity 5.1.3. EFFECT OF SUBSTITUTION ON ADRENERGIC DRUGS
■ Affinity no efficacy
● Breakdown ● Substitution on the Benzene Ring
○ Acetylcholine - metabolized and broken down in synaptic cleft via ○ Hydroxyl (-OH) groups at 3- and 4-positions of the ring converts benzene
acetylcholine esterase to catechol with maximal alpha and beta effects
■ Due to this, it is very short acting ○ Absence of one/other substituent at 3 position causes marked diminution
○ Norepinephrine - reuptake into presynaptic neuron in potency:
■ It is being recycled and serves as a precursor for epinephrine ■ Alpha effect is decreased by 100-fold
■ Beta effect becomes negligible
○ Catecholamines are subject to inactivation by catechol-O-
methyltransferase (COMT)
○ Hydroxyl (-OH) groups at 3- and 5-positions of the ring imparts Beta-2
selectivity (i.e. Terbutaline)

PHARMA (TWG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q. SAMSON (TEG) CLEDERA, CONVENTO, MANGUSSAD, ROLLOM, ROMUALDO, ROQUE 4
● Unsubstituted Benzene Ring
○ Removal of all substituents from benzene rings = non-catecholamines 5.2.3. ALPHA-BLOCKING DRUGS
(aka sympathomimetic amines)
○ Loss of either of the two hydroxyl (-OH) groups enhances oral [KATZUNG] ADRENORECEPTOR BLOCKERS (pp. 85)
effectiveness and duration of action because the drug is no longer
● Subdivisions of the α blockers are based on selective affinity for α1 versus
metabolized by COMT.
α2 receptors or a lack thereof.
○ Increased CNS effect and may produce anorexia
● Other features used to classify the α-blocking drugs are their reversibility
○ Amphetamines and phentermine resins are examples
and duration of action.
○ Noncatecholamines are primarily metabolized by monoamine oxidase
(MAO) Alpha-Blocking Drugs
● Substitution at the Alpha Carbon
○ Alpha carbon is the one attached to the amine side Selective Alpha-1 Antagonist
○ Noncatecholamines that have a substituted alpha carbon have a longer
● Leaves alpha-2 receptor unblocked Prazosin
duration of action because they are NOT metabolized by either COMT
hence norepinephrine release is
or MAO
inhibited
○ Alpha-methyl compounds are also called phenylisopropylamine
● Less stimulation of beta-1 and
● Substitution at the Beta Carbon
beta-2
○ Beta carbon is the one attached to the benzene ring
○ NO reflex tachycardia (beta-1)
○ Typical of direct acting agonists
○ NO postural hypotension
○ Important for storage of sympathomimetic amines in neural vesicles
(beta-2)
○ Example: Beta-hydroxylation of dopamine to norepinephrine
● Substitution at the Amine Side Chain
○ Increased beta-2 selectivity
○ Decreased affinity for alpha receptors Selective Alpha-2 Antagonist
○ Protects against the metabolism by COMT
● Drugs that block the presynaptic Yohimbine
■ Epinephrine - 1 methyl substituent
alpha-2 receptors Rauwolscine
■ Isoproterenol - 2 methyl substituents
N/A ● Inhibits release of norepinephrine (research)
■ Terbutaline - 3 methyl substituents
(noradrenaline) in form of negative
feedback
5.2. ADRENERGIC ANTAGONISTS (SYMPATHOLYTICS)
Non-Selective Alpha-1 Antagonist
5.2.1. CLASSIFICATION OF ADRENERGIC ANTAGONISTS
● There is no feedback inhibition on Phenoxybenz
● Alpha blockers the release of norepinephrine so amine
○ Nonselective (Phenoxybenzamine, Phentolamine) they can produce: Phentolamine
○ Alpha-1 selective (Prazosin) ○ Reflex tachycardia (beta-1
● Beta blockers stimulating effect)
○ Nonselective (Propranolol) ○ Postural hypotension (beta-2
○ Beta-1 selective (Metoprolol) stimulating effect)

[KATZUNG] ADRENORECEPTOR BLOCKERS (pp. 85)

[KATZUNG] CLASSIFICATION, PHARMACOKINETICS, & EFFECTS OF

ALPHA-BLOCKING DRUGS (pp. 85-86)
● Prazosin
○ Highly selective, reversible pharmacologic a1 blocker
○ Similar drugs: Doxazosin, Terazosin, and Tasmsulosin
● Prazosin and the other α1-selective blockers act for 8–24 h.
● Because prazosin and its analogs block vascular α1 receptors much more
effectively than the α2-modulatory receptors associated with cardiac
sympathetic nerve endings, these drugs reduce blood pressure with much
less reflex tachycardia than the nonselective α blockers. These drugs also
● Alpha- and beta-adrenoceptor-blocking agents are divided into primary have useful relaxing effects on smooth muscle in the prostate
subgroups on the basis of their receptor selectivity
● All of these agents are pharmacologic antagonists or partial agonists and [KATZUNG] CLASSIFICATION & PHARMACOKINETICS OF
most are reversible and competitive in action. ALPHA-BLOCKING DRUGS (pp. 85)
● α and β blockers differ markedly in their effects and clinical applications. ● Alpha-blocking drugs are all active by the oral as well as the parenteral
route, although phentolamine is rarely given orally.
5.2.2. RECEPTOR ACTIONS AND EFFECTS OF ADRENERGIC ● Phenoxybenzamine
ANTAGONISTS ○ Is the prototypical long-acting α blocker;
○ It differs from other adrenoceptor blockers in being irreversible in action.
● Alpha-1, Beta-1 and Beta-2 are postsynaptic
○ It is nonselective but also slightly α1 selective.
● Alpha-2 receptor is presynaptic
○ Half-life: short elimination half-life
○ Stimulation causes feedback inhibition on the release of norepinephrine
○ Duration of action:
○ Clonidine, an alpha-2 agonist drug, has an anti-hypertensive effect
■ Long—about 48 hrs—because it binds covalently to its receptor.
● Phentolamine
○ Is a competitive, reversible blocking agent
○ Does not distinguish between α1 and α2 receptors
○ Duration of action:
■ 2–4 hrs when used orally
■ 20–40 mins when given parenterally.

Figure 6. Receptors at the synaptic cleft

Plenary Lecture

PHARMA (TWG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q. SAMSON (TEG) CLEDERA, CONVENTO, MANGUSSAD, ROLLOM, ROMUALDO, ROQUE 5
[KATZUNG] EFFECTS OF NONSELECTIVE ALPHA BLOCKERS (pp. 86) 5.2.4. BETA-BLOCKING DRUGS
● These agents cause a predictable blockade of α-mediated responses to ● All clinical β-blockers are competitive pharmacologic antagonists
sympathetic nervous system discharge and exogenous sympathomimetics
● The most important effects of nonselective α blockers are those on the Beta-Blocking Drugs
cardiovascular system: a reduction in vascular tone with a reduction of
both arterial and venous pressures. Non-Selective Beta Antagonist
○ There are no significant direct cardiac effects. ● Bradycardia (Beta-1 blocking effect) Propranolol
○ However, the nonselective α blockers do cause baroreceptor ● Blocks both beta 1 and beta 2 Nadolol
reflex-mediated tachycardia as a result of the drop in mean arterial ● Bronchoconstriction (Beta-2 blocking) Timolol
pressure
○ This tachycardia may be exaggerated because the α2 receptors on
adrenergic nerve terminals in the heart, which normally reduce the net
release of norepinephrine, are also blocked (see Figure 6–3).
● Epinephrine reversal
○ A predictable effect in a patient who has received an α blocker.
○ The term refers to a reversal of the blood pressure effect of large
doses of epinephrine, from a pressor response (mediated by α Selective Beta-1 Antagonist
receptors) to a depressor response (mediated by β2 receptors).
○ The effect is not observed with phenylephrine or norepinephrine ● Bradycardia (Beta-1 blocking effect) Metoprolol
because these drugs lack sufficient β2 effects. ● Leaves Beta-2 receptor unblocked Acebutolol
○ Epinephrine reversal, manifested as orthostatic hypotension, is ○ Norepinephrine stimulates beta-2 Atenolol
occasionally seen as an unexpected (but predictable) effect of drugs for ○ NO bronchoconstriction Esmolol
which α blockade is an adverse effect (eg, some phenothiazine
antipsychotic agents, antihistamines).

[KATZUNG] CLINICAL USES OF NONSELECTIVE ALPHA BLOCKERS

(pp. 86)
● Nonselective α blockers have limited clinical applications.
● The best-documented application is in the presurgical management of [KATZUNG] RECEPTOR SELECTIVITY OF BETA-BLOCKING DRUGS (pp.
pheochromocytoma. 86)
○ Such patients may have severe hypertension and reduced blood ● B1 receptor selectivity may be an advantage when treating patients with
volume, which should be corrected before subjecting the patient to the asthma because functioning β2 receptors are important in preventing
stress of surgery. bronchospasm in such patients.
○ Phenoxybenzamine is usually used during this preparatory phase; ● Except for β blockers that start with the letter “c,” blockers with names
phentolamine is sometimes used during surgery. starting with letters “a” through “m” are β1 selective
○ Phenoxybenzamine also has serotonin receptor-blocking effects, which
justify its occasional use in carcinoid tumor, as well as H1 antihistaminic [KATZUNG] EFFECTS AND CLINICAL USE OF BETA-BLOCKING DRUGS
effects, which lead to its use in mastocytosis. (pp. 86)
● Accidental local infiltration of potent α agonists such as norepinephrine
may lead to severe tissue ischemia and necrosis if not promptly reversed; ● Most of the organ-level effects of β blockers are predictable from blockade
infiltration of the ischemic area with phentolamine is sometimes used to of the β-receptor–mediated effects of sympathetic discharge.
prevent tissue damage.
● Overdose with drugs of abuse such as amphetamine, cocaine, or ● Open angle glaucoma treatment
phenylpropanolamine may lead to severe hypertension because of their ○ Involves the use of several groups of autonomic drugs as well as other
indirect sympathomimetic actions. agents.
○ This hypertension usually responds well to α blockers. ● The cardiovascular applications of β blockers—especially in
● Sudden cessation of clonidine therapy leads to rebound hypertension hypertension, angina, and arrhythmias—are extremely important.
(Chapter 11); this phenomenon is often treated with phentolamine. ○ Treatment of chronic (not acute) heart failure has become an important
● Raynaud’s phenomenon sometimes responds to α blockers, but their application of β blockers.
efficacy in this condition is not well documented. ○ Several large clinical trials have shown that some, but not all, β blockers
● Phentolamine or yohimbine has been used by direct injection to cause can reduce morbidity and mortality when used properly in heart failure.
penile erection in men with erectile dysfunction, but phosphodiesterase ● COPD treatment
inhibitors are more popular. ○ A similar paradoxical benefit of β blocker therapy has been observed in
some patients with chronic obstructive pulmonary disease (COPD).
[KATZUNG] TOXICITY OF ALPHA-BLOCKING DRUGS (pp. 85) Labetalol, carvedilol, and metoprolol have documented benefits in this
application.
● The most important toxicities of the α blockers are simple extensions of ● Pheochromocytoma
their α-blocking effects. ○ Sometimes treated with combined α- and β-blocking agents (eg,
● The main manifestations are: labetalol), especially if the tumor is producing large amounts of
○ Orthostatic hypotension epinephrine as well as norepinephrine.
○ Reflex tachycardia (in nonselective agents) ● Infantile hemangiomas
● Tachycardia is less common and less severe with α1-selective blockers. ○ A novel and unexplained beneficial reduction in the size of infantile
● Phentolamine also has some non-alpha-mediated vasodilating effects. hemangiomas has been reported for propranolol.
● In patients with coronary disease, angina may be precipitated by the
tachycardia. [KATZUNG] TOXICITY OF BETA-BLOCKING DRUGS (pp. 86)
● Oral administration of some of these drugs can cause nausea and
vomiting. ● Cardiovascular adverse effects (extensions of the β blockade)
● α1-selective agents: associated with exaggerated orthostatic hypotensive ○ Bradycardia
response to the first dose in some patients. ○ Atrioventricular blockade
○ First dose is usually small and taken just before going to bed. ○ Heart failure
● Respiratory adverse effects
○ Patients with asthmatic airway disease may suffer severe asthma
attacks although some patients with COPD may benefit from careful use
of β1-selective agents.
● Endocrine adverse effects
○ Beta blockers have been shown experimentally to reduce insulin
secretion, but this does not appear to be a clinically important effect.

PHARMA (TWG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q. SAMSON (TEG) CLEDERA, CONVENTO, MANGUSSAD, ROLLOM, ROMUALDO, ROQUE 6
 ○ Premonitory symptoms of hypoglycemia from insulin overdosage ● 2 molecules of acetylcholine back to back
(tachycardia, tremor, and anxiety) may be masked by β blockers, and ● Stimulates nicotinic receptor to the point of fatigue
mobilization of glucose from the liver and sequestration of K+ in skeletal
muscle may be impaired. 6.2. CHOLINERGIC ANTAGONISTS (PARASYMPATHOLYTIC)
● CNS adverse effects
● Antimuscarinic
○ Sedation
○ Belladona alkaloids (treatment for organophosphate poisoning)
○ Fatigue
■ To know if it is working, monitor pupillary dilation and heart
○ Sleep alterations.
● Antinicotinic
○ Atenolol, nadolol, and several other less lipid-soluble β blockers are
○ Nondepolarizing NMB (prevents ACh to stimulate, no twitching)
claimed to have less marked CNS action because they do not enter the
○ Ganglionic blockers
CNS as readily as other members of this group.
● Sexual dysfunction has been reported for most of the β blockers in some
patients. 7. CHOLINERGIC AGONISTS / PARASYMPATHOMIMETIC DRUGS
● Drugs with acetylcholine-like effects
5.2.5. POTENTIAL WAYS TO AFFECT AUTONOMIC TRANSMISSION - ● Have 2 major subgroups based on their mode of action:
SYMPATHETIC DRUGS ○ Direct-acting drugs
■ Act directly at the acetylcholine receptors
Table 4. Sympathetic Drugs (SSRRBB) ○ Indirect-acting drugs
■ Act indirectly through inhibition of acetylcholinesterase
SSRRBB DRUGS ■ Excess acetylcholine stimulates the cholinoreceptors
Synthesis Reserpine and Alpha Methyl-DOPA ● Act where acetylcholine is physiologically released
● Amplifiers of endogenous acetylcholine
Storage Reserpine
Release Clonidine (alpha-2 agonist) 7.1. DIRECT-ACTING CHOLINERGIC DRUGS
Reuptake Duloxetine (Serotonin-Norepinephrine reuptake inhibitor) ● Direct acting drugs can be further subdivided based on:
○ Spectrum of action
Binding Agonist (Epi and NEpi) ■ Whether they act on muscarinic, nicotinic, or both receptors
Antagonists (alpha and beta blockers) ○ Chemical structure
Breakdown MAO inhibitors ■ Choline ester (ACh)
■ Alkaloids (Muscarine and Nicotine)
Source: Plenary Lecture
Table 5. Effects of Direct-Acting Cholinergic Drugs
[KATZUNG] CLINICAL APPLICATION (p. 228)
Organ Response
Horner syndrome is a condition—usually unilateral—that results from
interruption of the sympathetic nerves to the face. The syndrome can be Eye Sphincter Contraction (miosis)
caused by either a preganglionic or a postganglionic lesion, and knowledge muscle of iris
of the location of the lesion (preganglionic or postganglionic) helps determine Ciliary muscle Contraction of near vision (accommodation)
the optimal therapy.
Heart Sinoatrial node ↓ Rate (negative chronotropy)
If the lesion is postganglionic, indirectly acting sympathomimetics (eg, Atria ↓ Contractile strength (negative inotropy)
cocaine, hydroxyamphetamine) will not dilate the ↓ Refractory period
abnormally constricted pupil because catecholamines have been lost from Atrioventricular node ↓ Conduction velocity (negative dromotropy)
the nerve endings in the iris. In contrast, the pupil dilates in response to ↑ Refractory period
phenylephrine, which acts directly on the α receptors on the smooth muscle
of the iris. Ventricles Small decrease in contractile strength
Blood Arteries Dilation (via EDRF)
A patient with a preganglionic lesion, on the other hand, vessels Constriction (high-dose direct effect)
shows a normal response to both drugs, since the postganglionic fibers and Veins
their catecholamine stores remain intact in this situation.
Lung Bronchial muscle Contraction (bronchoconstriction)
Bronchial glands Secretion
6. CLASSIFICATION OF AUTONOMIC NERVOUS SYSTEM DRUGS
(PARASYMPATHETIC DRUGS) GI Tract Motility Increase
Sphincters Relaxation
6.1. CHOLINERGIC AGONISTS (PARASYMPATHOMIMETIC)
Secretion Stimulation
● Direct-acting muscarinic
○ Naturally occurring alkaloids Urinary Detrusor Contraction
■ Muscarine bladder Trigone Relaxation
■ Arecoline
■ Pilocarpine (constricts pupils; treatment for glaucoma) Sphincter Relaxation
○ Synthetic alkaloids (contracts urinary bladder, sphincter muscles relax to Glands Sweat Secretion
pass urine)
Salivary
■ Carbachol
■ Bethanechol Lacrimal
● Indirect-acting muscarinic (AChE Inhibitors) (Increased parasympathetic Nasopharyngeal
ACh due to inhibiting ACh Enzymes)
○ Short acting Source: 📕Katzung’s Basic Clinical Pharmacology, p. 112
■ Edrophonium (used to check for myasthenia gravis) 7.2. INDIRECT ACTING CHOLINOMIMETIC DRUGS
○ Medium acting
■ Neostigmine ● Three chemical groups of Cholinesterase inhibitors
■ Physostigmine (excess induces secretion) ○ Simple alcohols bearing a quaternary ammonium group (eg.
○ Long acting edrophonium);
■ Organophosphates (Increased secretions) (organophosphate ○ Carbamic acid esters of alcohols having quaternary or tertiary
poisoning ex. Wet miosis; Treatment is antimuscarinic) ammonium groups (carbamates, eg. neostigmine);
● Organophosphate poisoning can be from insecticides ○ Organic derivatives of phosphoric acid (organophosphates,
● Direct-acting nicotinic eg. echothiophate)
○ Depolarizing NMB (Neuromuscular Blockers) ● Effects are similar, but not always identical, to the effects of direct acting
■ Fasciculation (twitches) happens cholinomimetic agonists.
■ Exemplified by succinylcholine

PHARMA (TWG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q. SAMSON (TEG) CLEDERA, CONVENTO, MANGUSSAD, ROLLOM, ROMUALDO, ROQUE 7
 Table 6. Effects of Indirect-Acting Cholinoreceptor Stimulants ○ However, some inhibitors could develop a permanent bond with
cholinesterase, known as aging
Organ Response ■ Here, oximes like Pralidoxime can’t reverse the bond
● Low Concentrations: subjective alerting response
CNS ● High Concentrations: Generalized convulsions → 8. CHOLINERGIC ANTAGONISTS / PARASYMPATHOLYTIC DRUGS
coma → respiratory arrest
8.0.1 TERTIARY AMINE
Eye
GI Tract
● Similar with direct-acting cholinomimetics
● 📑
📕 Lipid soluble, can easily penetrate the brain
Respiratory Tract
Urinary Tract
●
● 📕 Well absorbed from the gut and conjunctival membranes
Naturally occurring alkaloids
○ Atropine
● Bradycardia ○ Darifenacin
● Decrease in atrial contractility ○ Dicyclomine
● Reduction in ventricular contractility ○ Oxybutynin
● Fall in cardiac output ○ Scopolamine
● Increased vascular resistance → rise in blood ○ Solifenacin
Cardiovascular
pressure ○ Tolterodine
System
● Synthetic Esters
High/Toxic Doses: ○ Dicylomine
● Marked bradycardia
● Significant decrease in cardiac output
8.0.2 QUATERNARY AMINE
● Hypotension
Low Therapeutic Concentrations
● 📑 Water-soluble and does not penetrate the CNA well
○ Anisotropine
● Contraction
○ Clinidium
Neuromuscular ○ Mepenzolate
Higher Concentrations
Junction ○ Ipratropium
● Fibrillation of muscle fibers depolarizing
○ Propantheline
neuromuscular blockade followed by
○ Glycopyrrolate
nondepolarizing blockade
Source: 📝 2024 Trans 8.1. MUSCARINIC ANTAGONISTS

DISCLAIMER. See Appendix for complete list of muscarinic antagonist

7.3. TOXICITY
● Block the effects of parasympathetic autonomic discharge
Agent of Toxicity Description ● Effect in the organs:

Direct-Acting Muscarinic ● Predictable signs of muscarinic excess when Table 7. Effects of Muscarinic blocking drugs.
(Pilocarpine, Choline) given in overdose ORGAN EFFECT MECHANISM
○ Effects nausea and vomiting, diarrhea,
urinary urgency, salivation, sweating, CNS Sedation, anti-motion sickness Block of muscarinic
cutaneous vasodilation, and bronchial action, antiparkinson action, receptors, several
constriction. amnesia, delirium subtypes
● Effects are all blocked competitively by
Eye Cycloplegia, mydriasis Block of M3 receptors
atropine and its congeners
Bronchi Bronchodilation, especially if Block of M3 receptors
Direct-Acting Nicotinic ● Acute Toxicity
constricted
○ Convulsions → coma → respiratory arrest
○ Skeletal muscle end-plate depolarization→ GI Tract Relaxation, slowed peristalsis, Block of M1, M3
depolarization blockade and respiratory reduced salivation receptors
paralysis
○ Hypertension and cardiac arrhythmias Heart Initial bradycardia, especially at Tachycardia from
● Chronic Toxicity low doses, then tachycardia block of M2 receptors
○ Increased risk for cardiovascular disease in the sinoatrial node
○ High incidence of ulcer recurrences Blood vessels Block of muscarinic vasodilation; Block of M3 receptors
Organophosphate ● Inhibits the enzyme that breaks down not manifest unless a muscarinic on endothelium of
acetylcholinesterase; therefore, it is an agonist is present vessels
acetylcholinesterase inhibitor Glands Marked reduction of salivation; Block of M1, M3
● Increased acetylcholine → PNS stimulation moderate reduction of receptors
● Result: lacrimation, sweating; less
○ Increased bronchial gland secretion reduction of gastric secretion
○ Increased salivary gland secretion
○ Bradycardia Skeletal muscle None None
○ Difficulty of breathing
○ Miosis
Source: 📕Katzung’s Basic Clinical Pharmacology, p. 119-120
○ Vomiting and diarrhea
○ Cognitive disturbances, convulsions, coma 8.1.1. ATROPINE TOXICITY
○ Depolarizing neuromuscular blockade ●
●
📕
📑 “Dry as a bonne, blind as a bat, red as a beet, mad as a hatter”
“Blind as a bat, mad as a hatter, red as a beet, hot as Hades, dry as a
7.3.1. TREATMENT
bone, the bowel and bladder lose their tone, and the heart runs alone”
● Antimuscarinic drugs
● Atropine ● Sweating, salivation, and lacrimation are
a Dry as a bone
○ Cholinergic antagonist, specifically a muscarinic antagonist reduced or stopped
● Pralidoxime b Blind as a bat ● Mydriasis or dilation of pupils and cycloplegia
○ It attaches to where cholinesterase inhibitor attaches → attaches to the
inhibitor → remove organophosphate from cholinesterase → ● Dilation of cutaneous vessels of the arms,
c Red as a beet
acetylcholinesterase works again head, neck, and trunk → “atropine flush”
○ This is known as “regenerating” or “reactivating” acetylcholinesterase ● CNS toxicity: sedation, amnesia, delirium,
d Mad as a hatter
hallucinations, and convulsions may occur

PHARMA (TWG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q. SAMSON (TEG) CLEDERA, CONVENTO, MANGUSSAD, ROLLOM, ROMUALDO, ROQUE 8
 ● Blockage of thermoregulatory sweating → 10. REVIEW QUESTIONS
hyperthermia
e Hot as Hades No. QUESTION
● Most dangerous effect of antimuscarinic drugs
in children 1 A child has swallowed the contents of 2 bottles of a nasal
Bowel and bladder ● Relaxation of bladder wall, urinary retention decongestant , the primary ingredient of which is an alpha
f adrenoceptor agonist drug. This signs of alpha activation that
lose their tone
may occur in this patient include:
g Heart runs alone ● Tachycardia a. Bronchodilation
b. Tachycardia
c. Pupillary dilatation
8.1.2. TREATMENT
d. Vasodilation
● Physostigmine
○ Should be used cautiously especially when there’s severe tachycardia 2 K.L., a 40 year old school teacher lives in a Manila condominium.
● Cooling blankets One day the condominium management announced a scheduled
○ To combat hyperthermia fumigation and when she arrived home late in the afternoon she
experienced difficulty breathing and coughing with increased
bronchial gland secretions. K.L. is most likely suffering from:
8.2. NICOTINIC ANTAGONISTS a. Acute muscarinic intoxication
● Block the action of acetylcholine and similar agonists at neuronal nicotinic b. Acute organophosphate toxicity
receptors of both parasympathetic and sympathetic autonomic ganglia c. Myasthenia gravis
● Classified as a nondepolarizing competitive antagonists d. Autonomic hyperreflexia
● Drugs of interest are synthetic amines
● Effects in the organs: 3 Which of the following is a direct-acting cholinomimetic that is
lipid-soluble and is used to facilitate smoking cessation?
Table 8. Effects of Nicotinic Blocking Drugs a. Physostigmine
b. Varenicline
ORGAN EFFECT
c. Acetylcholine
CNS Antinicotinic action may include reduction of nicotine d. Bethanechol
craving and amelioration of Tourette syndrome e. Neostigmine
(mecamylamine only)
4 What are the potential ways to affect autonomic transmission?
Eye Moderate mydriasis and cycloplegia
5 If one or all hydroxyl substituent/s us/are removed from the
Bronchi Little effect; ashmatic patients may note some benzene ring or the substance, it is no longer a catecholamine.
bronchodilation Instead it is called a?
GI Tract Relaxation, slowed peristalsis, reduced salivation
11. RATIONALIZATION
Heart Marked reduction of motility, constipation may be severe
Blood vessels Reduction in arteriolar and venous tone, dose-dependent No. ANSWER
reduction in blood pressure; orthostatic hypotension
1 Pupillary dilatation
usually marked
2 Acute organophosphate toxicity
Glands Reductions in salivation, lacrimation, sweating, and
gastric secretion 3 Neostigmine
Skeletal muscle No significant effect 4 SSRRBB
Source: 📕Katzung’s Basic Clinical Pharmacology, p. 112-115 5 Sympathomimetic amine

Table 9. Parasympathetic Drugs (SSRRBB)

12. FREEDOM WALL
SSRRBB DRUGS
Synthesis Muscarine, Arecoline, Pilocarpine
Storage Muscarine
Release Ganglionic blockers (Trimethaphan, Hexamethonium)
Reuptake Agonists (Carbachol, Betachenol @ muscarinic
receptor) and (Succinylcholine @ nicotinic receptor)
Binding
Antagonists (Atropine @ muscarinic receptor) and
(nondepolarizing neuromuscular blockers @ nicotinic
receptors, e.g. curare, pancuronium, atracurium)
Breakdown Acetylcholinesterase inhibitors (edrophonium,
neostigmine, organophosphates)
Source: Plenary Lecture

9. APA REFERENCES
Calimag, M.M. (2022). Lecture on Autonomic Pharmacology. Manila:
University of Santo Tomas Faculty of Medicine and Surgery
Katzung, B.G., Vanderah, T.W., (2021). Basic and Clinical Pharmacology. 15th
ed. McGraw Hill
Batch 2024 Trans, Autonomic Pharmacology

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ANNEX A: ADRENERGIC AGONISTS: MECHANISM OF ACTION, CLINICAL APPLICATION, AND FEATURES

DRUG MECHANISM OF ACTION CLINICAL APPLICATION FEATURES

Used in asthma and other allergic diseases
Decrease in total peripheral resistance
Acts directly on both alpha and beta (relaxes airway and reduces swelling)
Epinephrine (TPR) which explains the fall in diastolic
receptors (direct-acting)
pressure in some cases
Potent vasoconstrictor and cardiac stimulant
Used as treatment for rhinitis NTK: Restricted drug due to it being a
Causes release of norepinephrine
Pseudoephedrine precursor in the manufacture of
(indirect-acting)
Used as decongestant for colds methamphetamine (shabu)
Used as decongestant in rhinitis and colds
Selective alpha-1 agonist
Phenylephrine Not inactivated by COMT
Acts directly on ɑ-receptors (direct-acting) Used as vasopressor (increases BP through
vasoconstriction)
No longer used clinically EXCEPT for treatment for
Causes accumulation of noradrenaline at No substituents at the benzene ring →
Amphetamines narcolepsy and attention deficiency
the synapses increased CNS activity
hyperkinesis
Acts directly on both alpha and beta Used as a bronchodilator in asthma
Ephedrine receptors, causing release of endogenous
catecholamines (indirect-acting) Tocolytic agent in premature labor (relaxes uterus)
Used as a bronchodilator in asthma
Terbutaline Selective beta-2 agonist May increase maternal morbidity
Tocolytic agent in premature labor (relaxes uterus)
Though being an agonist, but because it
is found presynaptically, it inhibits the
Selective alpha-2 agonist (affects
Clonidine Used for treatment of hypertension release of norepinephrine
R-release in SSRRBB)
Inhibits adenylyl cyclase

ANNEX B: ADRENERGIC ANTAGONISTS: MECHANISM OF ACTION, CLINICAL APPLICATION, AND FEATURES

DRUG MECHANISM OF ACTION CLINICAL APPLICATION FEATURES

Used in management of some types of
Blocks synthesis and storage of hypertension
Reserpine
norepinephrine
Sedation is a side effect
Cannot be reversed by increasing the dose
of agonist (norepinephrine/epinephrine)
Phenoxybenzamine Noncompetitive alpha blocker
May cause tachycardia and myocardial
Used in the management of malignant ischemia
hypertension secondary to pheochromocytoma
Can be reversed by increasing dose of
agonist (norepinephrine/epinephrine)
Phentolamine Competitive alpha blocker
Half-life: ~45 minutes after IV injection
No reflex tachycardia and postural
hypertension because only alpha-1
Used in management of some types of
Prazosin Selective alpha-1 blocker receptors are blocked (leaving alpha-2
hypertension
receptors unblocked → controlled release
of norepinephrine)
Worsens asthma (since it’s a non-selective
Used in hypertension, angina pectoris, migraine,
Propranolol Nonselective beta blocker beta blocker, it can also block beta-2
headaches, and mitral valve prolapse
receptors causing bronchoconstriction)
Used in hypertension, angina pectoris, arrhythmia, Safer to prescribe in hypertensive patients
Metoprolol Selective beta-1 blocker
glaucoma with asthma

PHARMA (TWG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q. SAMSON (TEG) CLEDERA, CONVENTO, MANGUSSAD, ROLLOM, ROMUALDO, ROQUE 10
ANNEX C: DIRECT-ACTING CHOLINERGIC AGONISTS: MECHANISM OF ACTION, CLINICAL APPLICATION, AND FEATURES

DIRECT-ACTING CHOLINERGIC AGONISTS

DRUG MECHANISM OF ACTION CLINICAL APPLICATION FEATURES
AT MUSCARINIC SITES
Used as eye drops in ophthalmology to constrict
the pupil of the eye, relax the iris
Hydrolyzed by cholinesterase (ChE)
Cholinergic → Miosis
Acetylcholine Acts directly on muscarinic receptors Duration of action: 5-2
Relaxes the radial muscles of the iris
Poor lipid solubility
Contraction of the sphincter muscles
Synthetic alkaloid
Treatment of GI and bladder atony
Bethanechol Acts directly on muscarinic receptors Resistant to ChE
Note: PNS is for contraction of urinary bladder and GI muscles

Longer duration of action: 30 mins → 2 hrs

Eye drops in ophthalmology to constrict the pupil
Good lipid solubility
of the eye, relax the iris
Pilocarpine Acts directly on muscarinic receptors
Duration of action: 30 mins → 2 hrs
Treats acute angle-closure glaucoma
AT NICOTINIC SITES
Acts directly on nicotinic NMJ receptors, Depolarizing NMJ blocker Highly polar
Succinylcholine and causes noncompetitive inhibition on
nicotinic NMJ receptors Fasciculations followed by paralysis is a hallmark Duration: 5-10 mins
OTHERS
Nonselective, muscarinic, and nicotinic
Carbachol Topically almost exclusively for glaucoma Synthetic alkaloid
agonist
Medical use in smoking cessation High lipid solubility
Nicotine Acts directly on nicotinic and muscarinic
Nonmedical use in smoking and insecticides Duration of action: 1-6 hrs
Low lipid solubility
Muscarine Same as bethanechol Mushroom poisoning of fast-onset type
Readily absorbed in the gut
High lipid solubility
Varenicline Partial agonist as N receptors Smoking cessation
Duration: ~12 hrs

ANNEX D: INDIRECT-ACTING CHOLINERGIC AGONISTS/CHOLINESTERASE INHIBITORS: MECHANISM OF ACTION, CLINICAL

APPLICATION, AND FEATURES

DRUG MECHANISM OF ACTION CLINICAL APPLICATION FEATURES

Short-acting reversible Alcohol

Acts on muscarinic and nicotinic Quaternary amine

Diagnostic and acute treatment for myasthenia
Edrophonium
gravis
Alcohol, binds briefly to active site of Poor lipid solubility
acetylcholinesterase (AChE) and
prevents access of acetylcholine (ACh Duration of action: 5-15 minutes
Intermediate-acting reversible
Carbamate
Reverse nondepolarizing NMJ blockers
Acts on muscarinic and nicotinic
Quaternary amine
Used in myasthenia gravis
Neostigmine Forms covalent bond with AChE, but
hydrolyzed and released Poor lipid solubility
Postoperative and neurogenic ileus and urinary
retention
It also has modest direct action to Duration: 30 mins - 4 hrs
neuromuscular nicotinic cholinoreceptors
Carbamate

Tertiary amine
Same with neostigmine BUT it is natural
Physostigmine Reverse nondepolarizing NMJ blockers
alkaloid tertiary amine and enters CNS
Good lipid solubility

Duration of action: 30 mins - 2 hrs

Same with Neostigmine
Pyridostigmine Same with Neostigmine BUT longer actin Used in myasthenia gravis

PHARMA (TWG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q. SAMSON (TEG) CLEDERA, CONVENTO, MANGUSSAD, ROLLOM, ROMUALDO, ROQUE 11
 Duration of action: 4-6 hours
Organophosphate (thiocholine der.)

Moderate lipid solubility

Same with Neostigmine BUT longer
Echothiophate Obsolete - was used in glaucoma
acting + released more slowly
Duration of action: 100 hours

More stable in aqueous solution

Organophosphate (thiophosphate der.)

Long-acting; High lipid solubility

Parathion Acts on both muscarinic and nicotinic Insecticide - agricultural use
receptors Duration of action: 7-30 days

Used as insecticide
Organophosphate (thiophosphate der.)

Sarin Used in warfare and terrorism Very high lipid solubility

Nerve gas
Organophosphate (thiophosphate der.)

Malathion Long acting Medical use as ectoparasiticide High lipid solubility

Duration: day
Used as insecticides
Organophosphate Long acting, irreversible
Poisoning with organophosphates is treated with
anticholinergic drugs

ANNEX E: ANTIMUSCARINIC-NONSELECTIVE: MECHANISM OF ACTION, CLINICAL APPLICATION, AND FEATURES

DRUG MECHANISM OF ACTION CLINICAL APPLICATION FEATURES

Tertiary: Naturally-occurring alkaloids
Mydriatic, cycloplegic
Lipid soluble
Atropine Competitive antagonist
Antidote for cholinesterase inhibitor toxicity
Duration: 5-6 days (effects on iris and
ciliary muscle last ≥72 hours)
Tertiary: Naturally occurring alkaloid

Scopolamine Unknown mechanism in CNS Anti-motion sickness via transdermal patch IM injection for postoperative use

Duration: 3-7 days

Benztropine Competitive antagonist Antiparkinsonian
Shorter duration of action that atropine:
Homatropine Topically to produce mydriasis, cycloplegia
12-24 hours
Quaternary
Ipratropium
Prevention/relief of acute bronchospasm
Aclidinium Aerosol canister
Competitive antagonist
Tiotropium
Bronchodilation in asthma, COPD
Umeclidinium Aclidinium, tiotropium, and
umeclidinium: longer duration
Acts directly as competitive
Propantheline Antispasmodic by decreasing gastric motility Quaternary
antagonist at muscarinic receptors
Preoperative medication to reduce salivation
Glycopyrrolate Quaternary
and maintain heart rate during surgery

ANNEX F: ANTIMUSCARINIC-SELECTIVE: MECHANISM OF ACTION, CLINICAL APPLICATION, AND FEATURES

DRUG MECHANISM OF ACTION CLINICAL APPLICATION FEATURES

Darifenacin
Urinary urgency Tertiary amines
Fesoterodine Like atropine, BUT modest selectivity for
Solifenacin M3 receptor
Incontinence Duration: 12-24 hours
Tolterodine
Tertiary: synthetic ester
Used for irritable bowel syndrome
Dicyclomine Competitive antagonism at M3 receptors
Short half-life
Minor diarrhea

PHARMA (TWG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q. SAMSON (TEG) CLEDERA, CONVENTO, MANGUSSAD, ROLLOM, ROMUALDO, ROQUE 12
 Duration of action: 6 hours
Urinary urgency
Oxybutynin Slightly blocks M3 receptors
Incontinence
Pirenzepine
Significant M1 selectivity Peptic disease Taken orally
Telenzepine

ANNEX G: ANTINICOTINIC GANGLION BLOCKERS: MECHANISM OF ACTION, CLINICAL APPLICATION, AND FEATURES

DRUG MECHANISM OF ACTION CLINICAL APPLICATION FEATURES

Hexamethonium Selectively blocks 𝑁𝑛 receptors Obsolete – used for hypertension Oral, parenteral
IV only
Trimethaphan Selective antagonist Hypertension and controlled hypotension
Not anymore available for clinical use
Oral
Mecamylamine Non-competitive agonist Smoking cessation
Enters CNS

ANNEX H: NONDEPOLARIZING NEUROMUSCULAR JUNCTION BLOCKERS: MECHANISM OF ACTION, CLINICAL APPLICATION, AND
FEATURES

DRUG MECHANISM OF ACTION CLINICAL APPLICATION FEATURES

Gallamin
Pancuronium
Competitively inhibits Ach at nicotinic NMJ Block can be reversed by increasing the
Atracurium Causes nondepolarizing block of the NMJ
sites amount of Ach at the NMJ
Vecuronium
Rocuronium
Botulinum toxin Spastic conditions and cometic purpose

ANNEX I: ACETYLCHOLINESTERASE REGENERATOR: MECHANISM OF ACTION, CLINICAL APPLICATION, AND FEATURES

DRUG MECHANISM OF ACTION CLINICAL APPLICATION FEATURES

Relieve skeletal muscle end plate block
Very high affinity for phosphorus atom
Pralidoxime Intravenous every 4-6 hours
BUT does not enter the CNS Antidote for early stage cholinesterase
inhibitor poisoning

PHARMA (TWG) NAGUIT, ROSAL, ROSALES, E., ROSALES, K., ROSALES, Q. SAMSON (TEG) CLEDERA, CONVENTO, MANGUSSAD, ROLLOM, ROMUALDO, ROQUE 13