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 Trade Name: generic

 Drug Class: Antihypertensive (monoamine depletor)
 Mechanism of Action:
 A selective competitive inhibitor of the monoamine vesicular monoamine uptake transporter
(VMAT2) that transports cytosolic norepinephrine & epinephrine into presynaptic storage vesicles
found in sympathetic nerve terminals (as well as dopamine, serotonin & histamine into storage vesicles
in the CNS).
 Binds to the same site on VMAT2 as intracellular monoamines, producing a competitive inhibition of
monoamine (e.g. norepinephrine) transport into synaptic storage vesicles (Wimalasena, 2011).
 Produces a depletion of releasable neuronal monomamine neurotransmitters
 Reserpine's effects produce a reduction in blood pressure due to a decreased cardiac output & decreased
peripheral vascular resistance
 Indications:
 Hypertension
 JNC8: an alternative drug for treating hypertension (not recommended for initial
treatment)(James et al, 2014)
 Side Effects:
 Sedation
 Depression (suicidal tendencies)
 Parkinsonism symptoms
 Pharmacokinetics:
 Reserpine readily crosses the blood brain barrier & depletes cerebral catecholamine stores. This can
cause side effects such as those listed above.
 Notes on VMATs & Reserpine:
 VMAT1 is another isoform of VMAT expressed preferentially in large dense core vesicles of
neuroendocrine cells, including chromaffin cells of the adrenal medulla. However expression of
VMAT1 appears to be species-dependent, in that VMAT1 is the major transporter in the rat adrenal
medulla, while bovine cells express VMAT2 in the adrenal medulla (see Wimalasena, 2011).
 The vesicular acetylcholine transporter (VAChT) is a different transporter responsible for transport of
cytoplasmic acetylcholine into storage vesicles in cholinergic neurons (Erickson & Varoqui, 2000).
 Reserpine is the active ingredient of a herbal tranquillizer from Rauwolfia serpentina discovered by
ancient Indian physicians.
 Clinically, reserpine is “primarily of historical importance”, although it is available for use in
patients with resistant hypertension, and has been used for many years in animal experiments to deplete
catecholamine levels.
 Two other drugs with a similar mechanism of action (tetrabenazine & deutetrabenazine) are used in the
treatment of hyperkinetic movement disorders, such as Huntington's chorea.

Reserpine's mechanism of action is through inhibition of the ATP/Mg2+ pump responsible for the sequestering of
neurotransmitters into storage vesicles located in the presynaptic neuron. The neurotransmitters that are not sequestered in
the storage vesicle are readily metabolized by monoamine oxidase (MAO) causing a reduction in catecholamines

mon·o·a·mine ox·i·dase
1. an enzyme (present in most tissues) that catalyzes the oxidation and inactivation of monoamine neurotransmitters.
Blocking this enzyme helps relieve depression. If you take an MAOI and you eat high-tyramine foods, tyramine can
quickly reach dangerous levels. ... Tyramineoccurs naturally in small amounts in protein-containing foods. As these
foods age, the tyramine levels increase.

MAOIs and diet: Is it necessary to restrict tyramine? - Mayo Clinic


Tyramine (TIE-ruh-meen) is an amino acid that helps regulate blood pressure. ... Medications called monoamine oxidase
inhibitors (MAOIs) block monoamine oxidase, which is an enzyme that breaks down excess tyramine in the body.
Blocking this enzyme helps relieve depression.
How MAO-B inhibitors work

MAO is an enzyme found throughout the cells in the body. There are two types of MAOs: MAOs in the intestines are
predominantly type A, while most of the MAOs in the brain are type B. In the brain, MAO-B plays an important role in
the breakdown of neurotransmitters (chemical messengers) like dopamine. MAO inhibitors (MAOI) block the action of
the enzyme.3

The motor symptoms of Parkinson’s are caused by the reduction in dopamine, which transmits signals in the brain to
produce smooth, purposeful movement. As PD damages and destroys the neurons (nerve cells) that produce dopamine, the
motor symptoms of PD appear. Levodopa therapy provides the precursor to dopamine – it is the substance that is used to
make dopamine. Adding an MAO-B inhibitor slows the breakdown of levodopa and dopamine in the brain, and may boost
the effect of levodopa.1

Eicosanoid Synthesis
All mammalian cells except erythrocytes synthesize eicosanoids. These molecules are extremely potent, able to
cause profound physiological effects at very dilute concentrations. All eicosanoids function locally at the site of synthesis,
through receptor-mediated G-protein linked signaling pathways.
Two main pathways are involved in the biosynthesis of eicosanoids, the cyclic and the linear pathways. The
prostaglandins and thromboxanes are synthesized by the cyclic pathway, the leukotrienes are synthesized by the linear
The cyclic pathway is initiated through the action of prostaglandin G/H synthase, PGS (also called prostaglandin-
endoperoxide synthetase). This enzyme possesses two activities, cyclooxygenase (COX) and peroxidase. There are two
forms of the COX activity in humans, COX-1 and COX-2. COX-1 (PGS-1) is expressed constitutively in gastric mucosa,
kidney, platelets, and vascular endothelial cells. COX-2 (PGS-2) is inducible and is expressed in macrophages and
monocytes in response to inflammation. The primary triggers for COX-2 induction in monocytes and macrophages are
platelet-activating factor, PAF and interleukin-1, IL-1. Both COX-1 and COX-2 catalyze the 2-step conversion of
arachidonic acid to PGG2 and then to PGH2. The gene encoding COX-1 is identified as the PTGS1 gene and that encoding
COX-2 is the PTGS2 gene. The PTGS1 gene is located on chromosome 9q33.2 and is composed of 16 exons that
generates seven alternatively spliced mRNAs that collectively encode six protein isoforms. The PTGS2 gene is located
on chromosome 1q31.1 and is composed of 10 exons that encode a precursor protein of 604 amino acids.

Prostaglandin and Thromboxane Synthesis

Synthesis of the clinically relevant prostaglandins and thromboxanes from arachidonic acid.Numerous stimuli
(e.g. epinephrine, thrombin and bradykinin) activate PLA2 which hydrolyzes arachidonic acid from cellular membrane
phospholipids. As shown, the bradykinin type 2 receptor (encoded by the BDKRB2 gene) is coupled to both G i/0- and
Gq-type G-protein activation with the net effect that there is increased intracellular calcium and activation of PKC. Both
PKC phosphorylation and the Ca2+ ions activate the ER membrane-associated cPLA2 isoforms which, when activated,
hydrolyze arachidonic acid from PIP2. Arachidonic acid is converted to PGH2 via the action of the bi-functional enzymes
COX-1 and COX-2 (also called prostaglandin G/H synthase, PGS or prostaglandin endoperoxide synthetase). The
prostaglandins are identified as PG and the thromboxanes as TX. Prostaglandin PGI2 is also known as prostacyclin.
PGE2 is synthesized from PGH2 via the action of one of several PGE synthases, where PGE synthase (encoded by the
PTGES gene) appears to be the key enzyme. Two forms of PGD2 synthases have been identified that convert PGH2 to
PGD2. One is encoded by the HPGDS (hematopoietic prostaglandin D synthase) gene and the other is encoded by the
PTGDS (prostaglandin D2 synthase) gene. The enzyme encoded by the HPGDS gene is a member of the large family of
cytosolic glutathione S-transferase enzymes. Prostacyclin (PGI2) is synthesized from PGH2 via the action of prostacyclin
synthase (encoded by the PTGIS gene). Prostaglandin F synthase 1 (encoded by the PGFS gene) converts PGH2 to
PGF2α and it can also convert PGD2 to 9α,11β-PGF2α,β. The principal thromboxane (TXA2) is derived from PGH2 via the
action of thromboxane A synthase 1 encoded by the TBXAS1 gene. The formation of TXB2 results from degradation of
TXA2 and is known to play a role in the hepatotoxicity of acetominophen. The three most physiologically significant
cyclic eicosanoids are enclosed in the red boxes. Green arrows denote positive effects. The subscript 2 in each molecule
refers to the number of carbon-carbon double bonds present. LPI: lysophosphatidylinositol. Place mouse over structure
names to see the structure.

Leukotriene Synthesis
The linear pathway is initiated through the action of arachidonate lipoxygenases (LOXs) of which there are three
forms, 5-LOX, 12-LOX and 15-LOX. The official names for these three enzymes are arachidonate 5-lipoxygenase,
arachidonate 12-lipoxygenase, and arachidonate 15-lipoxygenase. The 5-LOX enzyme is encoded by the ALOX5 gene
which is located on chromosome 10q11.21 and is composed of 14 exons that generate five alternatively spliced mRNAs
each of which encode a distinct protein isoform. The 12-LOX enzyme is encoded by the ALOX12 gene which is located
on chromosome 17p13.1 and is composed of 14 exons that encode a protein of 663 amino acids. The 15-LOX enzyme is
encoded by the ALOX15 gene which is located on chromosome 17p13.2 and is composed of 14 exons that encode a
protein of 662 amino acids. It is 5-LOX that gives rise to the leukotrienes. The leukotrienes are synthesized by several
different cell types including white blood cells (leukocytes, hence the derivation of the name of the compounds), mast
cells, lung, spleen, brain and heart. The activities of 12-LOX and 15-LOX are involved in the synthesis of the lipoxins.

Synthesis of the clinically relevant leukotrienes from arachidonic acid. The leukotrienes are identified as LT.
Numerous stimuli (e.g. epinephrine, thrombin and bradykinin) activate PLA2 which hydrolyzes arachidonic acid from
cellular membrane phospholipids. As shown, the bradykinin receptor (specifically BDKR2) is coupled to both G i/0 and
Gq G-protein activation with the net effect that there is increased intracellular calcium and activation of PKC. Both PKC
phosphorylation and the Ca2+ ions activate the ER membrane-associated cPLA2 isoforms which, when activated,
hydrolyze arachidonic acid from PIP2. The enzyme, 5-lipoxygenase (5-LOX) in association with the protein, 5-LOX
activating protein (FLAP), catalyzes the conversion of arachidonic acid, first to 5-hydroperoxyeicosatetraenoic acid (5-
HPETE) which spontaneously reduces to 5-hydroxyeicosatetraenoic acid (5-HETE), and then to LTA4. LTA4 is unstable
and is converted to LTB4 in neutrophils and monocytes harboring LTA4 hydrolase. LTB4 is enclosed in a red box to
denote its critical significance as one of the most potent inflammation-mediating lipids. In mast cells and eosinophils,
which harbor LTC4 synthase, LTA4 is converted to LTC4. The leukotrienes LTC4, LTD4, LTE4 and LTF4 are known as
the peptidoleukotrienes or the cysteinyl leukotrienes because of the presence of amino acids. The peptidoleukotrienes,
LTC4, LTD4 and LTE4 are components of slow-reacting substance of anaphylaxis (SRSA). SRSA was originally
identified as an activity released from sensitized lung after immunologic challenge. Green arrows denote positive effects.
LPI: lysophosphoinositol. The subscript 4 in each molecule refers to the number of carbon-carbon double bonds present.
Place mouse over structure names to see the structure.
Lipoxin Synthesis
The lipoxins are synthesized through the concerted actions of 15-LOX (acting on arachidonic acid in epithelial cells,
such as in the airway) followed by 5-LOX in leukocytes or through the actions of 5-LOX in leukocytes followed by 12-
LOX action in platelets. Details of the functions of the lipoxins can be found in the Lipid-Derived Inflammatory
Modulators page.

Acetylcholine Receptors

Two Types of Receptors

There are two types of acetylcholine receptors (AChR) that bind acetylcholine and transmit its signal: muscarinic AChRs
and nicotinic AChRs, which are named after the agonists muscarine and nicotine, respectively. These receptors are
functionally different, the muscarinic type being G-protein coupled receptors (GPCRs) that mediate a slow metabolic
response via second messenger cascades, while the nicotinic type are ligand-gated ion channels that mediate a fast
synaptic transmission of the neurotransmitter.

Muscarinic Cholinergic Receptors

Amanita muscaria

Muscarinic receptors are characterised through their interaction with muscarine, a water-soluble toxin derived from the
mushroom Amanita muscaria that causes substantial activation of the peripheral sympathetic nervous system through its
binding to muscarinic AChRs, resulting in convulsions and even death. The muscarinic AChRs occur primarily in the
CNS, and are part of a large family of G-protein-coupled receptors (‘G proteins’), which use an intracellular secondary
messenger system involving an increase of intracellular calcium to transmit signals inside cells. Binding of acetylcholine
to a muscarinic AChR causes a conformational change in the receptor that is responsible for its association with and
activation of an intracellular G protein, the latter converting GTP to GDP in order to become activated and dissociate from
the receptor. The activated G protein can then act as an enzyme to catalyse downstream intracellular events.

Muscarinic receptors are involved in a large number of physiological functions including heart rate and force,
contraction of smooth muscles and the release of neurotransmitters. There are five subtypes of muscarinic AChRs based
on pharmacological activity: M1-M5. All five are found in the CNS, while M1-M4 are also found in various tissues: M1
AChRs are common in secretory glands; M2 AChRs are found in cardiac tissue; M3 AChRs are found in smooth muscles
and in secretion glands. M1, M3 and M5 receptors cause the activation of phospholipase C, generating two secondary
messengers (IP3 and DAG) eventually leading to an intracellular increase of calcium, while M2 and M4 inhibit adenylate
cyclase, thereby decreasing the production of the second messenger cAMP. The activation of the M2 receptor in the heart
is important for closing calcium channels in order to reduce the force and rate of contraction.

Nicotinic cholinergic receptors

Nicotinic receptors are characterised through their interaction with nicotine in tobacco. The nicotinic AChRs are
ligand-gated ion channels that form pores in cells’ plasma membranes, mediating fast signal transmission at synapses.
Nicotinic AChRs are involved in a wide range of physiological processes, and can be either neuronal or muscle-type.
Muscle-type nicotinic AChRs are localised at neuromuscular junctions, where an electrical impulse from a neuron to a
muscle cell signals contraction and is responsible for muscle tone; as such, these receptors are targets for muscle relaxants.
The many types of neuronal nicotinic AChRs are located at synapses between neurons, such as in the CNS where they are
involved in cognitive function, learning and memory, arousal, reward, motor control and analgesia.

The binding of acetylcholine to nicotinic AChRs brings about their activation. When two molecules of
acetylcholine bind a nicotinic AchR, a conformational change occurs in the receptor, resulting in the formation of an ion
pore. At the neuromuscular junction, the opening of a pore produces a rapid increase in the cellular permeability of
sodium and calcium ions, resulting in the depolarisation and excitation of the muscle cell, thereby producing a muscular

The activation of neuronal nicotinic AChRs also causes the movement of cations through the opening of an ion channel,
with the influx of calcium ions affecting the release of neurotransmitters. Nicotinic AChRs on a postganglionic neuron
are responsible for the initial fast depolarisation of that neuron. However, the subsequent hyperpolarisation and slow
depolarisation, which represent the recovery of the postganglionic neuron from stimulation, are mediated by muscarinic
AChR types M2 and M1, respectively. The binding of nicotine can activate nicotinic AChRs, modifying the neurons in
two ways: the depolarisation of the membrane through the movement of cations results in an excitation of the neuron,
while the influx of calcium acts through intracellular cascades affect the regulation of certain genes and the release of

Nicotinic AChRs are composed of five types of subunits: alpha (a1-a10), beta (b2-b5), delta, epsilon and gamma.
These subunits are found in different combinations in different types of nicotinic AChRs:

Ø Muscle nicotinic AChRs (adult neuromuscular junction): a1-e-a1-b1-d

Ø Muscle n

Muscle relaxation: Mechanism


In the resting state, the electrical potential of the inside of a nerve cell is negative with respect with the outside. When the
action potential depolarizes the nerve terminal, an influx of calcium diffuse into the cell via channels. The entry of
calcium facilitates the release of acetylcholine (ACh). These ACh molecules then diffuse across the synaptic cleft and
bind to the nicotinic cholinergic receptors at the motor end-plate. This depolarizes the end-plate generating an action
potential propagating the activation of sodium channels throughout the muscle fiber.

Neuromuscular blocking agents work at the neuromuscular junction. There are two types, depolarizing and
nondepolarizing.Depolarizing muscle relaxants acts as ACh receptor agonists. They bind to the ACh receptors and
generate an action potential. However, because they are not metabolized by acetylcholinesterase, the binding of this drug
to the receptor is prolonged resulting in an extended depolarization of the muscle end-plate. As the muscle relaxant
continues to bind to the ACh receptor, the end plate cannot repolarize, resulting in a phase I block. The ACh receptor can
also undergo conformational and ionic changes after a period of time, resulting in a phase II block.
Nondepolarizing muscle relaxants act as competitive antagonists. They bind to the ACh receptors but unable to induce ion
channel openings. They prevent ACh from binding and thus end plate potentials do not develop.

When there is a compensatory increase in the number of ACh receptors extrajunctional isoforms of the receptor such as in
certain disease states, there is an increased sensitivity to depolarizing relaxants and resistance to nondepolarizers. In states
where there are fewer ACh receptors, the opposite occurs where there is resistance to the depolarizers and increased
sensitivity to the nondepolarizers.

Neuromuscular Activation

Influx of Ca++ in nerve terminals leads to release of AChACh binds nicotinic receptors at motor endplate and causes
depolarization / Na+ entryAction potential caused by Na+ depolarizes muscle fibers

Trace: • depolarizing_nm_blocker

Depolarizing Neuromuscular Blocker


Trade Name: Anectine ®

Drug Class: Depolarizing Neuromuscular Blocker

Mechanism of Action:

In the motor endplate it combines with nicotinic receptors to produce depolarization which can be observed as
uncontrolled focal muscle contractions (fasciculations). Subsequent transmission across the NMJ is inhibited as long as
succinylcholine remains at the nicotinic receptor sites.

A depolarized post-junctional membrane (resulting in inactivation of Na channels) causes the postjunctional membrane to
become unresponsive to ACh released by motor neurons. This is referred to as “Phase I block” & produces a characteristic
reduction in contractile response (with no fade) during a train of four stimuli.

In less than a minute after IV administration a flaccid paralysisdevelops due to the development of a desensitized state
where the membrane becomes repolarized, but insensitive to ACh (due to receptor desensitization). This is referred to as
“Phase II block” and responds to a train of four stimuli with a “fade” pattern similar to that produced by non-depolarizing
neuromuscular blockers.

Succinylcholine's effects at muscarinic & nicotinic receptors outside of the NMJ are responsible for numerous side effects.

With a single IV dose, the period of flaccid paralysis lasts less than 10 minutes, and is terminated due to rapid hydrolysis
of succinylcholine by cholinesterase in the plasma & liver.


Adjunct to general anesthesia to facilitate endotracheal intubation and relax skeletal muscle during surgery or mechanical

It has a more rapid onset of actionas well as a short duration of action compared to most nondepolarizing neuromuscular
blockers, making it a drug of choice for emergency cases where rapid endotracheal intubation is necessary.

rapid onset of action is useful when rapid sequence intubation is necessary to protect the airway (e.g. from aspiration of
stomach contents)

short duration of action is useful if intubation attempts are unsuccessful. An agent that wears off quickly minimizes the
time period of bag-mask ventilation needed to support the patient.


Genetic disorders of plasma pseudocholinesterase

reduced activity of plasma pseudocholinesterase caused by drugs or genetic mutations can result in prolonged responses to
the muscle relaxant effects of succinylcholine (including paralysis of the diaphragm)
Family history of malignant hyperthermia

Recent burns or trauma

Myopathies with elevated CPK levels

Acute narrow-angle glaucoma or penetrating eye injuries

Side Effects:

Succinylcholine's stimulatory effect can cause hyperkalemia. It should not be given to patients 24 to 72 hrs after major
burns or trauma because it may cause acute hyperkalemia, hyperkalemic rhabdomyolysis & cardiac arrest.

It has also produced acute hyperkalemia & cardiac arrest in otherwise healthy boys with unrecognized muscular
dystrophy, causing the FDA to issue a warning about its use in children (it should not be used in children except for
emergency control of the airway).

Heavily muscled patients can suffer from muscle pain due to muscle fasiculations, as well as an increased risk for
regurgitation & aspiration of gastric contents caused by increases in intragastric pressure.

Succinylcholine can cause a rapid increase in intraocular pressuredue to effects on ocular blood vessels & myofibrils.

It can cause cardiac arrhythmias(increase or decrease in heart rate) because of its effects on muscarinic receptors and
nicotinic-ganglionic receptors.

There is an increased risk for potentially fatal malignant hyperthermia.


Given i.v. or i.m.

Metabolized by plasma pseudocholinesterase

normal duration of action 4-30 min (depending on dose, route of administration & presence of normal
pseudocholinesterase activity).

Major drug Interactions:

Aminoglycoside antibiotics(additive skeletal muscle blockade)

Cholinesterase inhibitors (can inhibit pseudocholinesterase, and reduce metabolism of succinylcholine, which may
prolong neuromuscular blockade)(Ramirez et al, 2005)


Succinylcholine is the only depolarizing type NMJ blocker in clinical use in the USA


Hibbs RE, Zambon AC (2011): Agents Acting at the Neuromuscular Junction and Autonomic Ganglia (Chapter 11).
In: Goodman & Gilman's Pharmacological Basis for Therapeutics. 12e. McGraw-Hill (Access Medicine).

Kruidering-Hall M, Campbell L (2012): Skeletal Muscle Relaxants. (Chapter 27). In: Basic and Clinical Pharmacology.
12e. B Katzung, SB Masters AJ Trevor (Editors)

Morgan GE Jr, Mikhail MS, Murray MJ (2006): Neuromuscular Blocking Agents (Chapter 9) In: Clinical Anesthesiology.
4th Edition. Morgan GE Jr, Mikhail MS, Murray MJ (Editors). McGraw-Hill (Access Medicine).

Trace: • amphetamines

Amphetamines (Drug Class)

Trade Names: Adderall, Dexedrine ®

Drug Class: CNS Stimulant, Indirectly Acting Sympathomimetic

Mechanism of Action:

The D-isomer (Dextroamphetamine) is more potent than the L-isomer


increases the release of norepinephrine, dopamine & serotonin from nerve terminals

amphetamines bind to presynaptic membrane transporters responsible for the reuptake of norepinephrine (NET),
dopamine (DAT), and serotonin (SERT), with uptake of amphetamine resulting in efflux of these monoamines from the
cytoplasmic pool into the extracellular space(Sandtner et al, 2014).

Amphetamine causes the intracellular vesicular release of catecholamines within the nerve terminal causing redistribution
of monoamines from the storage vesicles into the cytoplasmic pool (Sulzer et al, 1995; Wallace, 2012).


can compete with monoamines for reuptake (competitive substrate)

MAO inhibition - high doses of amphetamines inhibit MAO; to what extent this contributes to clinical effects is debated
(Wallace, 2012)

evidence suggests that amphetamines may have species-dependent direct effects that may also contribute to their systemic
effects. Recent studies have identified a new class of G-protein coupled trace-amine associated receptors (encoded by the
TAAR1 gene) involved in mediating direct effects (Miller, 2011).


attention-deficit disorders




Contraindicated for long-term use for treating obesity (due to development of tolerance &/or drug dependence)

Amphetamines have a high potential for abuse. Administration for prolonged periods of time may result in drug
dependence. Misuse may cause sudden death and cardiovascular adverse events.


Dexedrine - PO, completely absorbed in 3 hr. Duration: PO, 4-24 hr; t1/2, adults: 10-12 hr; children: 6-8 hr.

Roughly half of a dose of amphetamine undergoes oxidation to metabolites by hepatic P-450 metabolism (2D6), while the
remainder is cleared by the kidney.

Metabolites and unchanged amphetamine is eliminated in urine. Acidification will increase excretion, while alkalinization
will decrease it.

Major drug Interactions:

MAO inhibitors will increase effects & toxicity

Schedule II drug with high abuse potential


Biaggioni I, Robertson D (2015): Adrenoceptor Agonists & Sympathomimetic Drugs (Chapter 9). In: Basic and Clinical
Pharmacology. 13th Ed. B Katzung, AJ Trevor (Editors); McGraw-Hill.

Miller GM (2011): The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine
transporters and dopaminergic activity. J Neurochemistry 116(2): 164-176. DOI: 10.1111/j.1471-4159.2010.07109.x

Sandtner W et al (2014): A quantitative model of amphetamine action on the 5-HT transporter. Br J Pharmacol.
171(4):1007-18. doi: 10.1111/bph.12520.

Sulzer D et al (1995): Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse
transport. J Neurosci. 15(5 Pt 2):4102-8.

Wallace LJ (2012): Effects of amphetamine on subcellular distribution of dopamine and DOPAC. Synapse. 2012
Jul;66(7):592-607. doi: 10.1002/syn.21546.

rxlist.com (Dexedrine ®)


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Trace: • amphetamines • tyramine


Drug Class: Indirectly Acting Sympathomimetic (a byproduct of tyrosine metabolism)

Mechanism of Action:

Tyramine is taken up into nerve terminals by NET (the norepinephrine reuptake transporter) and causes the release of
catecholamines. It has been proposed that this results from reverse transport of NET (Broadley, 2010).

The effects of tyramine are increased in the presence of MAO inhibitors. MAO present in nerve terminals metabolizes
both cytosolic amines, such as norepinephrine, as well as tyramine, converting them to inactive metabolites. Normally the
bioavailability of dietary tyramine (which is present in red wine & cheese) is relatively low due to the high expression of
MAO in the GI tract and liver. However, when MAO is inhibited, high levels of tyramine can be absorbed, resulting in a
“hypertensive crisis” due to the indirect release of norepinephrine from nerve terminals.


Tyramine is readily metabolized by MAO in the liver and is normally inactive when taken orally because of a high first-
pass effect (low bioavailability).

If administered parentally, or if taken orally while taking MAO inhibitors, it produces effects similar to norepinephrine,
and can possibly cause a hypertensive crisis.

Tyramine causes the release of catecholamines from a small pool, and repeated exposure may result in tachyphylaxis (a
rapidly developing form of tolerance).

Major drug Interactions:

Indirectly acting sympathomimetic amines must be taken up into the nerve terminal to promote release. Thus agents that
inhibit the NET uptake pump (e.g. cocaine or imipramine) antagonize responses to indirectly acting sympathomimetics.

Agents that cause depletion of catecholamines from the sympathetic nerve terminals (e.g., reserpine) can also antagonize
indirectly acting agents (such as tyramine) because there is a lack of catecholamines to be released. However, since
catecholamine depletion takes some time to develop, reserpine-like drugs must be given several hours to days in advance
of tyramine for this interaction to be observable.

The pharmacodynamics of cocaine involve the complex relationships of neurotransmitters (inhibiting monoamine uptake
in rats with ratios of about: serotonin:dopamine = 2:3, serotonin:norepinephrine = 2:5).[59][10] The most extensively studied
effect of cocaine on the central nervous system is the blockade of the dopamine transporter protein.
Dopamine transmitter released during neural signaling is normally recycled via the transporter; i.e., the transporter binds
the transmitter and pumps it out of the synaptic cleft back into the presynaptic neuron, where it is taken up into
storage vesicles. Cocaine binds tightly at the dopamine transporter forming a complex that blocks the transporter's
function. The dopamine transporter can no longer perform its reuptake function, and thus dopamine accumulates in
the synaptic cleft. The increased concentration of dopamine in the synapse activates post-synaptic dopamine receptors,
which makes the drug rewarding and promotes the compulsive use of cocaine.[60]
Cocaine affects certain serotonin (5-HT) receptors; in particular, it has been shown to antagonize the 5-HT3 receptor,
which is a ligand-gated ion channel. The overabundance of 5-HT3 receptors in cocaine conditioned rats display this trait,
however the exact effect of 5-HT3 in this process is unclear.[61] The 5-HT2 receptor (particularly the subtypes 5-HT2AR,
5-HT2BR and 5-HT2CR) are involved in the locomotor-activating effects of cocaine.[62]
Cocaine has been demonstrated to bind as to directly stabilize the DAT transporter on the open outward-facing
conformation. Further, cocaine binds in such a way as to inhibit a hydrogen bond innate to DAT. Cocaine's binding
properties are such that it attaches so this hydrogen bond will not form and is blocked from formation due to the tightly
locked orientation of the cocaine molecule. Research studies have suggested that the affinity for the transporter is not what
is involved in habituation of the substance so much as the conformation and binding properties to where and how on the
transporter the molecule binds.[63]
Sigma receptors are affected by cocaine, as cocaine functions as a sigma ligand agonist.[64] Further specific receptors it has
been demonstrated to function on are NMDA and the D1 dopamine receptor.[65]
Cocaine also blocks sodium channels, thereby interfering with the propagation of action potentials;[66][39] thus,
like lignocaine and novocaine, it acts as a local anesthetic. It also functions on the binding sites to the dopamine and
serotonin sodium dependent transport area as targets as separate mechanisms from its reuptake of those transporters;
unique to its local anesthetic value which makes it in a class of functionality different from both its own derived
phenyltropanes analogues which have that removed. In addition to this cocaine has some target binding to the site of the
Kappa-opioid receptor as well.[67] Cocaine also causes vasoconstriction, thus reducing bleeding during minor surgical
procedures. The locomotor enhancing properties of cocaine may be attributable to its enhancement of dopaminergic
transmission from the substantia nigra.[citation needed] Recent research points to an important role of circadian
mechanisms[68] and clock genes[69] in behavioral actions of cocaine.
Cocaine can often cause reduced food intake, many chronic users lose their appetite and can experience severe
malnutrition and significant weight loss. Cocaine effects, further, are shown to be potentiated for the user when used in
conjunction with new surroundings and stimuli, and otherwise novel environs.[70]
Cocaine has a short half life of 0.7-1.5 hours and is extensively metabolized by cholinesterase enzymes (primarily in
the liver and plasma), with only about 1% excreted unchanged in the urine.[9] The metabolism is dominated
by hydrolytic ester cleavage, so the eliminated metabolites consist mostly of benzoylecgonine (BE), the major metabolite,
and other significant metabolites in lesser amounts such as ecgonine methyl ester (EME) and ecgonine.[9] Further minor
metabolites of cocaine include norcocaine, p-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine (pOHBE),
and m-hydroxybenzoylecgonine.[71] If consumed with alcohol, cocaine combines with alcohol in the liver to
form cocaethylene.[9] Studies have suggested cocaethylene is both more euphoric, and has a higher cardiovascular toxicity
than cocaine by itself.[9]
Depending on liver and kidney function, cocaine metabolites are detectable in urine. Benzoylecgonine can be detected in
urine within four hours after cocaine intake and remains detectable in concentrations greater than 150 ng/mL typically for
up to eight days after cocaine is used. Detection of cocaine metabolites in hair is possible in regular users until the sections
of hair grown during use are cut or fall out.[citation needed]

Tyramine is found in relatively high concentrations in fermented foods such as cheese, sausage, pepperoni, salami, pickled
or smoked fish & yeast supplements. Small amounts are found in red wine & chicken liver as well; See Table 9-5 in (
Biaggioni & Robertson (2012)).


Biaggioni I, Robertson D (2015): Adrenoceptor Agonists & Sympathomimetic Drugs (Chapter 9). In: Basic and Clinical
Pharmacology. 13th Ed. B Katzung, AJ Trevor (Editors); McGraw-Hill.

Broadley KJ (2010): The vascular effects of trace amines and amphetamines. Pharmacol Ther. 125(3):363-75. doi:

See also: Epigenetics of cocaine addiction
Cocaine addiction occurs through ΔFosB overexpression in the nucleus accumbens, which results in
altered transcriptional regulation in neurons within the nucleus accumbens.
ΔFosB levels have been found to increase upon the use of cocaine.[53] Each subsequent dose of cocaine continues to
increase ΔFosB levels with no ceiling of tolerance. Elevated levels of ΔFosB leads to increases in brain-derived
neurotrophic factor (BDNF) levels, which in turn increases the number of dendritic branches and spines present on
neurons involved with the nucleus accumbens and prefrontal cortex areas of the brain. This change can be identified rather
quickly, and may be sustained weeks after the last dose of the drug.
Transgenic mice exhibiting inducible expression of ΔFosB primarily in the nucleus accumbens and dorsal
striatum exhibit sensitized behavioural responses to cocaine.[54] They self-administer cocaine at lower doses than
control,[55] but have a greater likelihood of relapse when the drug is withheld.[55][56] ΔFosB increases the expression
of AMPA receptorsubunit GluR2[54] and also decreases expression of dynorphin, thereby enhancing sensitivity to
Cocaine acts by inhibiting the reuptake of serotonin, norepinephrine, and dopamine.[10] This results in greater
concentrations of these three neurotransmitters in the brain.[10] It can easily cross the blood–brain barrier and may lead to
the breakdown of the barrier.[15][16]Cocaine is a naturally occurring substance found in the coca plant which is mostly
grown in South America.[9] In 2013, 419 kilograms were produced legally.[17] It is estimated that the illegal market for
cocaine is 100 to US$500 billion each year.[10] With further processing crack cocaine can be produced from cocaine.[10]

Membrane Potentials
In cells of all types, there is an electrical potential difference between the inside of the cell and the surrounding
extracellular fluid. This is termed the membrane potential of the cell. While this phenomenon is present in all cells, it is
especially important in nerve and muscles cells, because changes in their membrane potentials are used to code and
transmit information.

First, what is an electrical potential difference? An electrical potential difference exists between two locations when there
is a net separation of charge between the two locations. This is illustrated in the figure on the right. Electrical potentials
are measured in units of volts. (A volt is defined in terms of energy per unit charge; that is, one volt is equal to one

When a nerve or muscle cell is at "rest", its membrane potential is called the resting membrane potential. In a typical
neuron, this is about –70 millivolts (mV). The minus sign indicates that the inside of the cell is negative with respect to
the surrounding extracellular fluid.

It is essential to realize that only a very small number of negative and positive ions need to be separated by the membrane
to create the resting membrane potential. For example, for each pair of negative and positive ions separated by the
membrane, there are roughly 1000 pairs of positive and negative ions within the cytosol of the neuron.
Thus, two energetic factors influence the movement of an ion across a membrane.

The concentration gradient

The electrical potential difference
The concentration gradient, of course, applies to uncharged molecules too. But with ions, we must always consider the
electrical potential difference as well. Thus, the total energy change for the movement of an ion across the membrane is
the the sum of the energy change due to the concentration gradient and the energy change due to electrical potential
difference. These two factors may act in the same direction or in opposite directions.

If some event, such as the opening of a gated ion channel, causes the membrane potential to become less negative, this is
termed depolarization. Conversely, if some factor causes the membrane potential to become more negative, this is termed

When a chloride channel is opened, allowing for chloride ions to enter a neuron, what is the psychological result? | eNotes
In order to understand the physiological result of chloride channels opening in neurons, one must first understand how
action potential generation occurs. Action potentials are short electrical events that generate signals, which can then be
communicated to other neurons at meeting points called synapses. These signals are passed on from one neuron to the
next via the release of chemicals known as neurotransmitters from the axon of the signal generating neuron. These
neurotransmitters act on specific receptors located on dendrites of the receiving neuron. Many neurotransmitters exist, and
each type can activate a specific channel or set of channels leading to either the generation of another action potential or
the inhibition of further signaling.

Action potentials are generated via changes in the electrochemical gradient of neurons. This gradient is generated by
differences between the intracellular and extracellular concentrations of key ions such as sodium, potassium, calcium, and
chloride. In neurons this resting potential typically lies around -70 millivolts (mV). The concentration for sodium is higher
outside of the neuron (about 150 milliMolar (mM)) and lower on the inside of the neuron (about 15mM). The opposite is
true in the case of potassium with the internal concentration being higher (about 150 mM), while the external
concentration is lower (about 5.5 mM). Since neuronal membranes are considered leaky, ions are able to diffuse along
concentration gradients towards the side of the neuron that has a lower concentration. Because of this, neurons rely on the
sodium/potassium ATPase exchange pump to maintain resting potential. This is done via the exchange of 3 sodium ions
being pumped out the cell for 2 potassium ions being pumped into the cell and requires ATP for activation.

In order for an action potential to be generated the membrane potential must typically be raised to -55 mV. This is done
through the activation and opening of channels, via neurotransmitters, that conduct positive sodium ions into the cell. It is
at this point, referred to as the "threshold potential," that depolarization occurs and an action potential is generated. This
point is also typically referred to as the point of no return. Upon reaching a membrane potential of -55mV, voltage gated
channels located on the cell surface of the neuron that are responsible for allowing sodium into the neuron begin to open.
This opening leads to a large influx of positively charged sodium ions into the neuron causing an action potential to be
generated. After a quick period, slow opening potassium channels begin to allow potassium ions to flow out of the cell,
thus decreasing the amount of positive charge inside the neuron and restoring the resting membrane potential, allowing
later action potentials to be generated.

In the specific case of chloride ions, these ions are present in a much lower concentration inside the neuron (around 4
mM) than outside the neuron (around 100 mM). Unlike sodium and potassium, chloride is a negatively charged ion.
Therefore, in the resting state chloride defuses down its concentration gradient and into the cell. In some cases, chloride
ions are pumped back across the cell surface to maintain resting membrane potential. In the specific case of a chloride
channel opening (presumably through neurotransmitter activation), the influx of chloride into the neuron would decrease
the resting membrane potential driving it more negative than -65mV. This is referred to as hyperpolarization. This
phenomenon is known as an inhibitory postsynaptic potential. As the name implies, and because threshold potential does
not change, this chloride ion influx makes it more difficult for depolarization of neurons, and for action potential firing to
occur. Hope this helps!

Further Reading:
This higher-level question implies that you already know the basics of how nerve cells operate--that nerve cells carry
messages to other parts of the body both electrically, along the axon, and chemically, across the gap between nerve cells.
This gap is called the synapse. Nerve cell "firing" happens when the difference in electrical charge between the inside and
the outside of the neuron's cell membrane is great enough. The nerve cell can then "fire"; this is an all-or-nothing

Chloride channels, when opened, appear to be one of the ways that positively charged ions are moved inside the cell, and
negatively charged ions out, until the charge difference is great enough that the nerve impulse can be generated. This is an
area currently under study, as problems with the channels may be implicated in seizure diseases such as epilepsy. The
links below give a lot more detail.

Further Reading

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Cardiovascular Pharmacology Concepts

Richard E. Klabunde, PhD

Clinical Disorders:

Heart Failure
Systemic Hypertension
Pulmonary Hypertension
Myocardial Infarction
Therapeutic Classes:

Mechanism Classes:

Click here to see list

Also Visit
Cardiovascular Physiology Concepts textbook cover

Click here for information on Cardiovascular Physiology Concepts, 2nd edition, a textbook published by Lippincott
Williams & Wilkins (2011)

Cardiovascular Physiology Concepts textbook cover

Click here for information on Normal and Abnormal Blood Pressure, a textbook published by Richard E. Klabunde (2013)

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Antiarrhythmic Drugs

Therapeutic Use and Rationale

The ultimate goal of antiarrhythmic drug therapy is to restore normal rhythm and conduction. When it is not possible to
revert to normal sinus rhythm, drugs may be used to prevent more serious and possibly lethal arrhythmias from occurring.
Antiarrhythmic drugs are used to:

decrease or increase conduction velocity

alter the excitability of cardiac cells by changing the duration of the effective refractory period
suppress abnormal automaticity
All antiarrhythmic drugs directly or indirectly alter membrane ion conductances, which in turn alters the physical
characteristics of cardiac action potentials. For example, some drugs are used to block fast sodium channels. These
channels determine how fast the membrane depolarizes (phase 0) during an action potential. Since conduction velocity is
related to how fast the membrane depolarizes, sodium channel blockers reduce conduction velocity. Decreasing
conduction velocity can help to abolish tachyarrhythmias caused by reentry circuits. Other types of antiarrhythmic drugs
affect the duration of action potentials, and especially the effective refractory period. By prolonging the effective
refractory period, reentry tachycardias can often be abolished. These drugs typically affect potassium channels and delay
repolarization of action potentials (phase 3). Drugs that block slow inward calcium channels are used to reduce pacemaker
firing rate by slowing the rate of rise of depolarizing pacemaker potentials (phase 4 depolarization). These drugs also
reduce conduction velocity at the AV node, because those cells, like SA nodal cells, depend on the inward movement of
calcium ions to depolarize.

Because sympathetic activity can precipitate arrhythmias, drugs that block beta1-adrenoceptors are used to inhibit
sympathetic effects on the heart. Because beta-adrenoceptors are coupled to ion channels through defined signal
transduction pathways, beta-blockers indirectly alter membrane ion conductance, particularly calcium and potassium

In the case of AV block, drugs that block vagal influences (e.g., atropine, a muscarinic receptor antagonist) are sometimes
2used. AV block can occur during beta-blocker treatment and therefore simply removing a beta-blocker in patients being
treated with such drugs may normalize AV conduction.

Sometimes ventricular rate is excessively high because it is being driven by atrial flutter or fibrillation. Because it is very
important to reverse ventricular tachycardia, drugs are often used to slow AV nodal conduction. Calcium channel blockers
and beta-blockers are useful for this indication. Digitalis, because of its ability to activate the vagus nerve
(parasympathomimetic effect), can also be used to reduce AV conduction velocity in an attempt to normalize ventricular
rate during atrial flutter or fibrillation.

Classes of Drugs Used to Treat Arrhythmias

Classes of drugs used in the treatment of arrhythmias are given below. Clicking on the drug class will link you to the
page describing the pharmacology of that drug class and specific drugs. Please note that many of the drugs comprising the
first five listed classes have considerable overlap in their pharmacologic properties.
Antiarrhythmic drug classes:
Class I - Sodium-channel blockers
Class II - Beta-blockers
Class III - Potassium-channel blockers
Class IV - Calcium-channel blockers
Miscellaneous - adenosine
- electrolyte supplement (magnesium and potassium salts)
- digitalis compounds (cardiac glycosides)
- atropine (muscarinic receptor antagonist)
Click here to see a table summarizing the types of drugs that may be used to treat different types of arrhythmias.

Revised 03/14/07

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. Depolarization
Sensory neurons, like the ones that sense light in your eyes, are activated by a stimulus, like light. Other neurons in your
brain are activated by chemicals called neurotransmitters that are sent in between neurons.

So, as you're reading this, light is hitting sensory neurons in your eyes. The light causes channel proteins to open on the
cell membrane. These proteins allow positively charged ions, like sodium and calcium, to enter the cell.

Your brain and other neurons are electrical organs. Electricity surges through their long axons, just like electricity moves
through a wire in your house. All cells have a normal membrane potential, called the resting potential. When ions enter or
leave the cell, the membrane potential changes.

So, when positive ions enter the cell, it causes an increase in the membrane potential of the cell. The membrane potential
increases until the threshold potential is reached. Then voltage-gated sodium channels open and allow sodium to come
rushing into the neuron at the junction of the axon and cell body.

At this point, the cell undergoes depolarization, which is a rapid increase in membrane potential. This response is all or
none, meaning that once the depolarization starts, it goes on for a set amount of time, then the sodium channels slam shut,
preventing the axon from depolarizing.

2. Repolarization
After the action potential is sent down the axon, the initial segment needs to be reset to start a new impulse. This phase is
called repolarization. When the membrane potential increases to a certain level, voltage-gated potassium channels open.
Potassium also has a positive charge, but when the channels open, potassium rushes out of the cell. Since a positive ion is
leaving, it makes the cell more negative.

3. Hyperpolarization
Eventually the cell gets so negative, it actually overshoots the original resting potential. This is called hyperpolarization.
During this phase, the membrane potential is more negative than it would normally be. This makes it harder for a neuron
to reach the threshold to send a signal than normal, limiting the number of signals that can be sent back to back. This is
called the refractory period, where it's more difficult for a cell to start an action potential.