MODULE 4│PHARM BIOSCI 6 & 7
PHARMACOLOGY
PHARMACOLOGY 1. ANATOMIC DIVISIONS OF THE NERVOUS SYSTEM
• Study of drugs
Nervous System
Drugs
• articles used in diagnosis, prevention, treatment, mitigation
of diseases.
Peripheral nervous Central nervous
CLASSIFICATION OF DRUGS system system
1. Diagnostic agents – drugs being given primarily to determine the
cause of a disease or to confirm diagnosis
Efferent division Afferent division
• Edrophonium (Tensilon®) – diagnosis of Myasthenia gravis,
differentiates myasthenic from cholinergic crisis (base on the
improvement or deterioration in the muscle strength when the drug is
given)
Myasthenic crisis – insufficient dose of the drug we are given. Autonomic system Somatic system
• Radiopharmaceuticals – Technetium 99m sestamibi for
Myocardial ischemia
• Insulin – performance of Insulin Tolerance Test to
determine reserves of growth hormone. Enteric Parasympathetic Sympathetic
2. Replenishers – given to supplement lacking endogenous
substances
• Cyanocobalamin – Mx of Pernicious Anemia (B12 Nervous System
deficiency); characterized by the presence of auto antibodies that is Central Nervous System Peripheral Nervous System
directed against their own cells, these antibodies destroy an important Afferent Neurons
cell which is responsible for producing a substance for Vitamin B12 • Sensory – enter the
absorption in the Ilium. Cyanocobalamin is given IM in as much as CNS
there is lack of the intrinsic factor in Pernicious Anemia that will allow
the absorption of B12 in the GIT.
• Insulin – for Insulin-requiring DM Efferent Neurons
• Motor – leave the CNS
3. Functional modifiers – alter normal physiologic function
processes. Efferent Neurons
• Analgesics – alter pain perception
• Antipyretic – alter effects of endogenous pyrogens a. Somatic Nervous System
• BIGGEST CLASS OF DRUGS • Single neuron
• Carries impulses going to the organs that are voluntarily
4. Chemotherapeutic agents moving such as skeletal muscles
• Drugs used to treat or inhibit growth of cells or proliferation of
nucleic acids that considered foreign to the body b. Autonomic Nervous System
• Anti-infectives (antibacterial, antiviral, antifungal, • 2-neuron set-up → CNS & Effector
antiparasitic) • Carries impulses towards the organs that are independent or
• Anti-neoplastic involuntarily moving such cardiac muscles, smooth muscles
and exocrine glands
BRANCHES OF PHARMACOLOGY
Ganglion
1. Pharmacodynamics (PD)
• What the drug does to the body
• Study of the biochemical and physiologic effects of drugs in Pre-ganglion Post-ganglion
biological systems, and the mechanism by which these
effects are produced
Effector
2. Pharmacokinetics (PK) CNS
• What the body does to the drug
• Study of processes a drug undergoes as it reaches and • Ganglion – collection of neuron cell bodies in the PNS
leaves the biological site of action
2. SYNAPTIC NEUROTRANSMISSION
3. Pharmacotherapeutics
• Study of rational use of drugs in the management of • Nervous system is not a continuous system
diseases Gaps are present
• between 2 neurons
(See Biopharmaceutics) • between a neuron and an effector
→ Synapse (interface)
AUTONOMIC PHARMACOLOGY Parts of the Synapse
A. ANATOMY AND PHYSIOLOGY OF THE ANS - Synthesis, storage and
release of neurotransmitters
- Metabolizing enzymes
1. Anatomic Divisions of the Nervous System - Auto receptors
1. Pre-synapse
2. Synaptic Neurotransmission
3. Synaptic Cleft
3. Subdivisions of Autonomic Nervous System - Metabolizing enzymes
2. Post-synapse - Majority of receptors
- Metabolizing enzymes
Module 4 – Pharmacology Page 1 of 33 RJAV 2022
,Steps Functional Difference
Neurotransmitters carry information from the pre-synaptic—sending—neuron SANS PANS
to the post-synaptic—receiving—cell. Synapses are usually formed between Fight/ Flight Rest/ Digest
nerve terminals—axon terminals—on the sending neuron and the cell body or Heart Tachycardia Bradycardia
dendrites of the receiving neuron. Eyes Mydriasis Miosis
A single axon can have multiple branches, allowing it to make synapses on
Lungs Bronchodilation Bronchoconstriction
various postsynaptic cells. Similarly, a single neuron can receive thousands of
Intestine Ileus Bowel Movement
synaptic inputs from many different presynaptic—sending—neurons.
Gall
Inside the axon terminal of a sending cell are many synaptic vesicles. These Urinary Retention Urination
bladder
are membrane-bound spheres filled with neurotransmitter molecules. There is
a small gap between the axon terminal of the presynaptic neuron and the Palms and
Sweating Generalized
membrane of the postsynaptic cell, and this gap is called the synaptic cleft. Soles
Pre-synaptic Axon terminal B. SYMPATHETIC DRUGS
cell
Synaptic vehicle 1. Natural Catecholamines
Neurotransmitter
Voltage-gated
2. Receptors
Ca2+ channel
3. Sympathomimetics
Synaptic Receptor for
neurotransmitter
3. Sympatholytics
cleft
(ligand-gated ion
channel) 1. NATURAL CATECHOLAMINES
Post-synaptic cell
• Endogenous – self-made; they are being produced inside the
When an action potential, or nerve impulse, arrives at the axon terminal, it body
activates voltage-gated calcium channels in the cell membrane. Ca2+ which is • Norepinephrine, Epinephrine, Dopamine
present at a much higher concentration outside the neuron than inside, rushes
into the cell. The Ca2+
allows synaptic vesicles to fuse with the axon terminal membrane, releasing Locations:
neurotransmitter (Exocytosis) into the synaptic cleft.
a. Sympathetic post-ganglion – particularly NE
1. Action potential reaches
Action axon terminal and b. Adrenal medulla – NE, Epi
potential depolarizes membrane
c. Brain – NE, Dopamine
arrives 2. Voltage-gated Ca2+
channel is open and Ca2+
flows in Steps
3. Ca2+ influx triggers
synaptic vesicles to release
neurotransmitter
4. Neurotransmitter binds to
receptors on target cell (in
this case, causing positive
ions to flow in
depolarization –
more likely to fire action potential
The molecules of neurotransmitter diffuse across the synaptic cleft and bind to
receptor proteins on the postsynaptic cell. Activation of postsynaptic receptors
leads to the opening or closing of ion channels in the cell membrane. This may
be depolarizing—make the inside of the cell more positive—or
hyperpolarizing—make the inside of the cell more negative—depending on
the ions involved. Drugs
3. SUBDIVISIONS OF AUTONOMIC NERVOUS SYSTEM
3 Major Subdivisions:
• Enteric Nervous System
• Sympathetic Nervous System
• Parasympathetic Nervous System
Anatomical Difference
Sympathetic NS Parasympathetic NS
Origin/ Roots of Fibers
Thoraco-Lumbar NS Cranio-Sacral NS
• T1 – T12 • Cranial: 3,7,9,10
Tyramine
• L1 – L4 • S2 – S4
Ephedrine
Length of Fibers
Amphetamine
Short: Pre-ganglionic neuron Long: Pre-ganglionic neuron Angiotensin II
Long: Post-ganglionic neuron Short: Post-ganglionic neuron α-latrotoxin
Location of Ganglion
Near the CNS Near the Effector organ
Neurotransmitters
Ach: Pre-ganglionic neuron Ach: Pre-ganglionic neuron & Guanethidine
NE: Post-ganglionic neuron Post-ganglionic neuron Guanadrel
Receptors Bretylium
Ganglia: Nicotinic Ganglia: Nicotinic
Effector: α, β, Dopa Effector: Muscarinic, Nicotinic
Module 4 – Pharmacology Page 2 of 33 RJAV 2022
,Termination Skeletal muscles
Increased inward conductance
Cell membranes
Passive Diffusion → Metabolism → Reuptake Process to K+ ions = Hypokalemia
Neuromuscular endplates Contraction = Tremors
Beta3 (β3) Receptors:
Target Response
Adipocytes Lipolysis
Dopaminergic Receptors:
Dopaminergic1 Receptor (Gs-linked)
Target Response
Renal and Splanchnic Blood
Vasodilation (↑GFR = Diuresis)
vessels
Dopaminergic2 Receptor (Gi-linked)
Target Response
Peripheral (GI tract) Relaxation (ileus; no peristalsis)
Perception and behavior
Central (Brain)
Modulation of motor activity
The vesicular monoamine transporter (VMAT) is responsible for the transport
3. SYMPATHOMIMETICS
of catecholamines to the storage vesicles, maintaining their cytosolic
concentration low. After catecholamine release to the synaptic cleft,
catecholamines are reuptaken to the presynaptic terminal by noradrenaline • Adrenergic Agonists
transporter (NET), and/or taken to extraneuronal cells by the extraneuronal • Mimicry
transporters. The most important extraneuronal transporter for catecholamines
is extraneuronal monoamine transporter (EMT). Catecholamines are Classifications
metabolized by intracellular enzymes. Monoamine oxidase (MAO) is located in
the outer membrane of mitochondria in neurons and in extraneuronal cells. Based on • Catecholamines
Catechol-O-methyl transferase (COMT) is located at extraneuronal cells. Both Chemistry • Non-catecholamines
enzymes (COMT and MAO) are the main responsible for the metabolism of
catecholamines. The enzymatic process leads to the formation of several
metabolites. To exert their actions, the catecholamines and other Based on • Direct-acting
neurotransmitters in the synaptic cleft bind to different pre-and postsynaptic Mechanism of • Indirect-acting
receptors. Such binding leads to alterations in the postsynaptic cell and Action
activation of intracellular pathways through G proteins. In presynaptic neurons, • Mixed-acting
catecholamines bind to autoreceptors and activate feed-back responses that
change their own release.
BASED ON CHEMISTRY
2. RECEPTORS
Catecholamines
Alpha (α) Receptors Catechol
Beta (β) Receptors 3,4-dihydroxybenzene group
Dopaminergic (D) Receptors • High potency in activating α and β receptors
• Metabolized by MAO and COMT
Alpha (α) Receptors: • Do not penetrate the CNS
Alpha1 (α1) Receptors Gq → Contraction
Target (Smooth muscle) Response
Vascular smooth muscle Vasoconstriction = ↑BP
Bladder, trigone & sphincter – females
Urinary Retention
Prostatic smooth muscles – males
Radial muscles (iris) Contraction = mydriasis
Contraction (piloerection) =
Pilomotor smooth muscles (skin)
goosebumps
Alpha2 (α2) Receptors
Target Response
Pre-synaptic alpha 2 (Gi-linked)
→Autoregulation (Inhibits further release of NE from the vesicles)
Central Sedation
Peripheral blood vessels Vasodilation = ↓BP Non-catecholamines
• No catechol
Beta (β) Receptors: • Not metabolized by MAO and COMT
• Longer half-lives
Beta1 (β1) Receptors (Gs-linked) • Administered orally
Target Response
(+) Inotropism
• Force of contraction
Heart (Cardiac myocytes) (+) Chromotopism
• Heart rate
(+) Dromotropism
• AV nodal conduction
Renin secretion
Kidneys
• RAAS activation =
Renal Juxtaglomerular Apparatus
Increased BP
Beta2 (β2) Receptors (Gs-linked)
Target Response
Smooth muscles
Bronchi Bronchodilation
Uterus Relaxation (tocolysis)
Blood vessels (skeletal muscles) Vasodilation
Module 4 – Pharmacology Page 3 of 33 RJAV 2022
, BASED ON MOA - Management of preterm labor (tocolytics)
- Adjunct in the management of
Direct-acting: hyperkalemia
- Non-selective
Toxic effects :
• binds and activate more than 1 general type of - Tremors
adrenergic receptor - Hyperkalemia
- Selective D1-Selective - Fenoldopam (Corlopam ®)
• binds and activates 1 general type of adrenergic Agonists - Used as an alternative for
receptor hypertensive crisis
Non-selective: Indirect-acting
Epinephrine: - Anaphylaxis, anaphylactic shock,
α1, β1, β2 anaphylactoid reaction Releasers Reuptake inhibitors
- Cardiac stimulant Enhances exocytosis of NE - Tricyclic antidepressants
- Local vasoconstrictor (+ Lidocaine) - Centrally acting
- Galucoma: Dipivefrin – lower intraocular - Tyramine - Cocaine
pressure - Ephedrine - Local Anesthetic
Norepinephrine: - Septic Shock - Amphetamine - Atomoxetine
α1, β1 - Methamphetamine - ADHD
Dopamine: - Cardiogenic shock (alternative) - Sibutramine
α1, β1, D1 - Acute Heart Failure - Methylphenidate - Obesity
Toxic Effects: - ADHD (1st line)
- Digital Necrosis: α1 - Phenmetrazine
- Ventricular tachyarrhythmias: β1 - Anorexiant
- Modafinil
Selective - Narcolepsy
α1-selective Constrictor Agents:
Agonists - Phenylephrine Mixed-acting
- Methoxamine Ephedrine For Narcolepsy
- Propyhexedrine Mephentermine and Metaraminol For Hypotension
- Tetrahydrozoline Phenylpropanolamine For Nasal congestion
- Oxymetazoline
- Nafazoline
4. SYMPATHOLYTICS
Clinical uses
- Nasal & Ophthalmic congestion • Adrenergic Antagonists
- Hypotension • Relaxation (blocking alpha receptors)
- Local vasoconstrictions • Cardiac depression (blocking beta receptors)
Toxic Effects: Classifications
- Local:
- Rhinitis medicamentosa or rebound Direct-Acting • Alpha Blockers
congestion (do not use for more than • Beta Blockers
3 days)
- Systemic: Peripherally- • Adrenergic Neuronal
- Hypertension Acting Blockers
- Urinary retention (Benign prostatic
hyperplasia)
- Tolerance (do not use for more than DIRECT-ACTING
5days)
α2-selective Anti-hypertensive: Alpha Blockers
Agonists - Clonidine α1 α2 – Nonselective, Irreversible, Noncompetitive Phenoxybenzamine
- hypertensive crisis (rapid acting) α1 α2 – Nonselective, Reversible Phentolamine
- alternative for ADHD α2 – Selective, Reversible Yohimbine
- Toxic effects: Clonidine withdrawal-
α2 – Adrenergic Selective, Reversible Prazosin
induced HTN
Doxazosin
- Methyldopa
Terazosin
- FDA approved for Pregnant women
Tamsulosin
- Toxic effects: Sedation,
Alfuzosin
Hepatotoxicity, (+) Coombs test
- Guanfacine – centrally acting
- Guanabenz – centrally acting Clinical Uses:
Phenoxybenzamine Pheochromocytoma
Anti-glaucoma - (pre-surgical)
- Apraclonidine - a catecholamine secreting tumor of
- Brimonidine cells derived from the adrenal
Non-selective - Isoproterenol medulla
β Agonists - Alternative during shock states - used prior to surgical removal of
- Management of Acute Heart Failure tumor to prevent hypertensive crisis
- Inotropic
β1-selective - Dobutamine Mastocytosis (H-blockade)
Agonists - First line for cardiogenic shock - too much masts cells that store
- Management of Acute Heart Failure histamine
- Pharmacologic stress test (with
dipyridamole) Carcinoid Tumor (5-HT blockade)
β2-selective Bronchodilators - abnormal high levels of serotonin
Agonists - SABAs (Salbutamol/Albuterol, Terbutaline, Phentolamine Pheochromocytoma
Pirbuterol, Metaproterenol) - (during surgical)
- LABAs (Salmeterol, Formoterol,
Bambuterol, Indacaterol) Raynaud Syndrome
Tocolytics Accidental local infiltration of alpha agonists and
- Ritodrine sympathomimetic poisoning
- Isoxsuprine
- Terbutaline (off-label use) Erectile Dysfunction
- Locally administered
Clinical Uses : Yohimbine Erectile dysfunction
- Management of bronchial asthma and Prazosin HTN: Prazosin, Doxazosin, Terazosin
COPD (bronchodilators) Doxazosin - Vasodilators
Module 4 – Pharmacology Page 4 of 33 RJAV 2022
PHARMACOLOGY
PHARMACOLOGY 1. ANATOMIC DIVISIONS OF THE NERVOUS SYSTEM
• Study of drugs
Nervous System
Drugs
• articles used in diagnosis, prevention, treatment, mitigation
of diseases.
Peripheral nervous Central nervous
CLASSIFICATION OF DRUGS system system
1. Diagnostic agents – drugs being given primarily to determine the
cause of a disease or to confirm diagnosis
Efferent division Afferent division
• Edrophonium (Tensilon®) – diagnosis of Myasthenia gravis,
differentiates myasthenic from cholinergic crisis (base on the
improvement or deterioration in the muscle strength when the drug is
given)
Myasthenic crisis – insufficient dose of the drug we are given. Autonomic system Somatic system
• Radiopharmaceuticals – Technetium 99m sestamibi for
Myocardial ischemia
• Insulin – performance of Insulin Tolerance Test to
determine reserves of growth hormone. Enteric Parasympathetic Sympathetic
2. Replenishers – given to supplement lacking endogenous
substances
• Cyanocobalamin – Mx of Pernicious Anemia (B12 Nervous System
deficiency); characterized by the presence of auto antibodies that is Central Nervous System Peripheral Nervous System
directed against their own cells, these antibodies destroy an important Afferent Neurons
cell which is responsible for producing a substance for Vitamin B12 • Sensory – enter the
absorption in the Ilium. Cyanocobalamin is given IM in as much as CNS
there is lack of the intrinsic factor in Pernicious Anemia that will allow
the absorption of B12 in the GIT.
• Insulin – for Insulin-requiring DM Efferent Neurons
• Motor – leave the CNS
3. Functional modifiers – alter normal physiologic function
processes. Efferent Neurons
• Analgesics – alter pain perception
• Antipyretic – alter effects of endogenous pyrogens a. Somatic Nervous System
• BIGGEST CLASS OF DRUGS • Single neuron
• Carries impulses going to the organs that are voluntarily
4. Chemotherapeutic agents moving such as skeletal muscles
• Drugs used to treat or inhibit growth of cells or proliferation of
nucleic acids that considered foreign to the body b. Autonomic Nervous System
• Anti-infectives (antibacterial, antiviral, antifungal, • 2-neuron set-up → CNS & Effector
antiparasitic) • Carries impulses towards the organs that are independent or
• Anti-neoplastic involuntarily moving such cardiac muscles, smooth muscles
and exocrine glands
BRANCHES OF PHARMACOLOGY
Ganglion
1. Pharmacodynamics (PD)
• What the drug does to the body
• Study of the biochemical and physiologic effects of drugs in Pre-ganglion Post-ganglion
biological systems, and the mechanism by which these
effects are produced
Effector
2. Pharmacokinetics (PK) CNS
• What the body does to the drug
• Study of processes a drug undergoes as it reaches and • Ganglion – collection of neuron cell bodies in the PNS
leaves the biological site of action
2. SYNAPTIC NEUROTRANSMISSION
3. Pharmacotherapeutics
• Study of rational use of drugs in the management of • Nervous system is not a continuous system
diseases Gaps are present
• between 2 neurons
(See Biopharmaceutics) • between a neuron and an effector
→ Synapse (interface)
AUTONOMIC PHARMACOLOGY Parts of the Synapse
A. ANATOMY AND PHYSIOLOGY OF THE ANS - Synthesis, storage and
release of neurotransmitters
- Metabolizing enzymes
1. Anatomic Divisions of the Nervous System - Auto receptors
1. Pre-synapse
2. Synaptic Neurotransmission
3. Synaptic Cleft
3. Subdivisions of Autonomic Nervous System - Metabolizing enzymes
2. Post-synapse - Majority of receptors
- Metabolizing enzymes
Module 4 – Pharmacology Page 1 of 33 RJAV 2022
,Steps Functional Difference
Neurotransmitters carry information from the pre-synaptic—sending—neuron SANS PANS
to the post-synaptic—receiving—cell. Synapses are usually formed between Fight/ Flight Rest/ Digest
nerve terminals—axon terminals—on the sending neuron and the cell body or Heart Tachycardia Bradycardia
dendrites of the receiving neuron. Eyes Mydriasis Miosis
A single axon can have multiple branches, allowing it to make synapses on
Lungs Bronchodilation Bronchoconstriction
various postsynaptic cells. Similarly, a single neuron can receive thousands of
Intestine Ileus Bowel Movement
synaptic inputs from many different presynaptic—sending—neurons.
Gall
Inside the axon terminal of a sending cell are many synaptic vesicles. These Urinary Retention Urination
bladder
are membrane-bound spheres filled with neurotransmitter molecules. There is
a small gap between the axon terminal of the presynaptic neuron and the Palms and
Sweating Generalized
membrane of the postsynaptic cell, and this gap is called the synaptic cleft. Soles
Pre-synaptic Axon terminal B. SYMPATHETIC DRUGS
cell
Synaptic vehicle 1. Natural Catecholamines
Neurotransmitter
Voltage-gated
2. Receptors
Ca2+ channel
3. Sympathomimetics
Synaptic Receptor for
neurotransmitter
3. Sympatholytics
cleft
(ligand-gated ion
channel) 1. NATURAL CATECHOLAMINES
Post-synaptic cell
• Endogenous – self-made; they are being produced inside the
When an action potential, or nerve impulse, arrives at the axon terminal, it body
activates voltage-gated calcium channels in the cell membrane. Ca2+ which is • Norepinephrine, Epinephrine, Dopamine
present at a much higher concentration outside the neuron than inside, rushes
into the cell. The Ca2+
allows synaptic vesicles to fuse with the axon terminal membrane, releasing Locations:
neurotransmitter (Exocytosis) into the synaptic cleft.
a. Sympathetic post-ganglion – particularly NE
1. Action potential reaches
Action axon terminal and b. Adrenal medulla – NE, Epi
potential depolarizes membrane
c. Brain – NE, Dopamine
arrives 2. Voltage-gated Ca2+
channel is open and Ca2+
flows in Steps
3. Ca2+ influx triggers
synaptic vesicles to release
neurotransmitter
4. Neurotransmitter binds to
receptors on target cell (in
this case, causing positive
ions to flow in
depolarization –
more likely to fire action potential
The molecules of neurotransmitter diffuse across the synaptic cleft and bind to
receptor proteins on the postsynaptic cell. Activation of postsynaptic receptors
leads to the opening or closing of ion channels in the cell membrane. This may
be depolarizing—make the inside of the cell more positive—or
hyperpolarizing—make the inside of the cell more negative—depending on
the ions involved. Drugs
3. SUBDIVISIONS OF AUTONOMIC NERVOUS SYSTEM
3 Major Subdivisions:
• Enteric Nervous System
• Sympathetic Nervous System
• Parasympathetic Nervous System
Anatomical Difference
Sympathetic NS Parasympathetic NS
Origin/ Roots of Fibers
Thoraco-Lumbar NS Cranio-Sacral NS
• T1 – T12 • Cranial: 3,7,9,10
Tyramine
• L1 – L4 • S2 – S4
Ephedrine
Length of Fibers
Amphetamine
Short: Pre-ganglionic neuron Long: Pre-ganglionic neuron Angiotensin II
Long: Post-ganglionic neuron Short: Post-ganglionic neuron α-latrotoxin
Location of Ganglion
Near the CNS Near the Effector organ
Neurotransmitters
Ach: Pre-ganglionic neuron Ach: Pre-ganglionic neuron & Guanethidine
NE: Post-ganglionic neuron Post-ganglionic neuron Guanadrel
Receptors Bretylium
Ganglia: Nicotinic Ganglia: Nicotinic
Effector: α, β, Dopa Effector: Muscarinic, Nicotinic
Module 4 – Pharmacology Page 2 of 33 RJAV 2022
,Termination Skeletal muscles
Increased inward conductance
Cell membranes
Passive Diffusion → Metabolism → Reuptake Process to K+ ions = Hypokalemia
Neuromuscular endplates Contraction = Tremors
Beta3 (β3) Receptors:
Target Response
Adipocytes Lipolysis
Dopaminergic Receptors:
Dopaminergic1 Receptor (Gs-linked)
Target Response
Renal and Splanchnic Blood
Vasodilation (↑GFR = Diuresis)
vessels
Dopaminergic2 Receptor (Gi-linked)
Target Response
Peripheral (GI tract) Relaxation (ileus; no peristalsis)
Perception and behavior
Central (Brain)
Modulation of motor activity
The vesicular monoamine transporter (VMAT) is responsible for the transport
3. SYMPATHOMIMETICS
of catecholamines to the storage vesicles, maintaining their cytosolic
concentration low. After catecholamine release to the synaptic cleft,
catecholamines are reuptaken to the presynaptic terminal by noradrenaline • Adrenergic Agonists
transporter (NET), and/or taken to extraneuronal cells by the extraneuronal • Mimicry
transporters. The most important extraneuronal transporter for catecholamines
is extraneuronal monoamine transporter (EMT). Catecholamines are Classifications
metabolized by intracellular enzymes. Monoamine oxidase (MAO) is located in
the outer membrane of mitochondria in neurons and in extraneuronal cells. Based on • Catecholamines
Catechol-O-methyl transferase (COMT) is located at extraneuronal cells. Both Chemistry • Non-catecholamines
enzymes (COMT and MAO) are the main responsible for the metabolism of
catecholamines. The enzymatic process leads to the formation of several
metabolites. To exert their actions, the catecholamines and other Based on • Direct-acting
neurotransmitters in the synaptic cleft bind to different pre-and postsynaptic Mechanism of • Indirect-acting
receptors. Such binding leads to alterations in the postsynaptic cell and Action
activation of intracellular pathways through G proteins. In presynaptic neurons, • Mixed-acting
catecholamines bind to autoreceptors and activate feed-back responses that
change their own release.
BASED ON CHEMISTRY
2. RECEPTORS
Catecholamines
Alpha (α) Receptors Catechol
Beta (β) Receptors 3,4-dihydroxybenzene group
Dopaminergic (D) Receptors • High potency in activating α and β receptors
• Metabolized by MAO and COMT
Alpha (α) Receptors: • Do not penetrate the CNS
Alpha1 (α1) Receptors Gq → Contraction
Target (Smooth muscle) Response
Vascular smooth muscle Vasoconstriction = ↑BP
Bladder, trigone & sphincter – females
Urinary Retention
Prostatic smooth muscles – males
Radial muscles (iris) Contraction = mydriasis
Contraction (piloerection) =
Pilomotor smooth muscles (skin)
goosebumps
Alpha2 (α2) Receptors
Target Response
Pre-synaptic alpha 2 (Gi-linked)
→Autoregulation (Inhibits further release of NE from the vesicles)
Central Sedation
Peripheral blood vessels Vasodilation = ↓BP Non-catecholamines
• No catechol
Beta (β) Receptors: • Not metabolized by MAO and COMT
• Longer half-lives
Beta1 (β1) Receptors (Gs-linked) • Administered orally
Target Response
(+) Inotropism
• Force of contraction
Heart (Cardiac myocytes) (+) Chromotopism
• Heart rate
(+) Dromotropism
• AV nodal conduction
Renin secretion
Kidneys
• RAAS activation =
Renal Juxtaglomerular Apparatus
Increased BP
Beta2 (β2) Receptors (Gs-linked)
Target Response
Smooth muscles
Bronchi Bronchodilation
Uterus Relaxation (tocolysis)
Blood vessels (skeletal muscles) Vasodilation
Module 4 – Pharmacology Page 3 of 33 RJAV 2022
, BASED ON MOA - Management of preterm labor (tocolytics)
- Adjunct in the management of
Direct-acting: hyperkalemia
- Non-selective
Toxic effects :
• binds and activate more than 1 general type of - Tremors
adrenergic receptor - Hyperkalemia
- Selective D1-Selective - Fenoldopam (Corlopam ®)
• binds and activates 1 general type of adrenergic Agonists - Used as an alternative for
receptor hypertensive crisis
Non-selective: Indirect-acting
Epinephrine: - Anaphylaxis, anaphylactic shock,
α1, β1, β2 anaphylactoid reaction Releasers Reuptake inhibitors
- Cardiac stimulant Enhances exocytosis of NE - Tricyclic antidepressants
- Local vasoconstrictor (+ Lidocaine) - Centrally acting
- Galucoma: Dipivefrin – lower intraocular - Tyramine - Cocaine
pressure - Ephedrine - Local Anesthetic
Norepinephrine: - Septic Shock - Amphetamine - Atomoxetine
α1, β1 - Methamphetamine - ADHD
Dopamine: - Cardiogenic shock (alternative) - Sibutramine
α1, β1, D1 - Acute Heart Failure - Methylphenidate - Obesity
Toxic Effects: - ADHD (1st line)
- Digital Necrosis: α1 - Phenmetrazine
- Ventricular tachyarrhythmias: β1 - Anorexiant
- Modafinil
Selective - Narcolepsy
α1-selective Constrictor Agents:
Agonists - Phenylephrine Mixed-acting
- Methoxamine Ephedrine For Narcolepsy
- Propyhexedrine Mephentermine and Metaraminol For Hypotension
- Tetrahydrozoline Phenylpropanolamine For Nasal congestion
- Oxymetazoline
- Nafazoline
4. SYMPATHOLYTICS
Clinical uses
- Nasal & Ophthalmic congestion • Adrenergic Antagonists
- Hypotension • Relaxation (blocking alpha receptors)
- Local vasoconstrictions • Cardiac depression (blocking beta receptors)
Toxic Effects: Classifications
- Local:
- Rhinitis medicamentosa or rebound Direct-Acting • Alpha Blockers
congestion (do not use for more than • Beta Blockers
3 days)
- Systemic: Peripherally- • Adrenergic Neuronal
- Hypertension Acting Blockers
- Urinary retention (Benign prostatic
hyperplasia)
- Tolerance (do not use for more than DIRECT-ACTING
5days)
α2-selective Anti-hypertensive: Alpha Blockers
Agonists - Clonidine α1 α2 – Nonselective, Irreversible, Noncompetitive Phenoxybenzamine
- hypertensive crisis (rapid acting) α1 α2 – Nonselective, Reversible Phentolamine
- alternative for ADHD α2 – Selective, Reversible Yohimbine
- Toxic effects: Clonidine withdrawal-
α2 – Adrenergic Selective, Reversible Prazosin
induced HTN
Doxazosin
- Methyldopa
Terazosin
- FDA approved for Pregnant women
Tamsulosin
- Toxic effects: Sedation,
Alfuzosin
Hepatotoxicity, (+) Coombs test
- Guanfacine – centrally acting
- Guanabenz – centrally acting Clinical Uses:
Phenoxybenzamine Pheochromocytoma
Anti-glaucoma - (pre-surgical)
- Apraclonidine - a catecholamine secreting tumor of
- Brimonidine cells derived from the adrenal
Non-selective - Isoproterenol medulla
β Agonists - Alternative during shock states - used prior to surgical removal of
- Management of Acute Heart Failure tumor to prevent hypertensive crisis
- Inotropic
β1-selective - Dobutamine Mastocytosis (H-blockade)
Agonists - First line for cardiogenic shock - too much masts cells that store
- Management of Acute Heart Failure histamine
- Pharmacologic stress test (with
dipyridamole) Carcinoid Tumor (5-HT blockade)
β2-selective Bronchodilators - abnormal high levels of serotonin
Agonists - SABAs (Salbutamol/Albuterol, Terbutaline, Phentolamine Pheochromocytoma
Pirbuterol, Metaproterenol) - (during surgical)
- LABAs (Salmeterol, Formoterol,
Bambuterol, Indacaterol) Raynaud Syndrome
Tocolytics Accidental local infiltration of alpha agonists and
- Ritodrine sympathomimetic poisoning
- Isoxsuprine
- Terbutaline (off-label use) Erectile Dysfunction
- Locally administered
Clinical Uses : Yohimbine Erectile dysfunction
- Management of bronchial asthma and Prazosin HTN: Prazosin, Doxazosin, Terazosin
COPD (bronchodilators) Doxazosin - Vasodilators
Module 4 – Pharmacology Page 4 of 33 RJAV 2022
