Introduction to neuropharmacology:

Neuropharmacology is the study of how drugs affect cellular function in the nervous system,
and the neural mechanisms through which they influence behavior. There are two main branches
of neuropharmacology:
1. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior
(neuropsychopharmacology), including the study of how drug dependence
and addiction affect the human brain.
2. Molecular neuropharmacology involves the study of neurons and their neurochemical
interactions, with the overall goal of developing drugs that have beneficial effects on
neurological function.
Both of these fields are closely connected, since both are concerned with the interactions
of neurotransmitters, neuropeptides, neurohormones, neuromodulators , enzymes, second
messengers, co-transporters, ion channels, and receptor proteins in the central and peripheral
nervous systems. Studying these interactions, researchers are developing drugs to treat many
different neurological disorders, including pain, neurodegenerative diseases such as Parkinson's
disease and Alzheimer's disease, psychological disorders, addiction, and many others.
Yeung AWK, Tzvetkov NT, Atanasov AG. When Neuroscience Meets Pharmacology: A
Neuropharmacology Literature Analysis. Front Neurosci. 2018 Nov 16;12:852. doi:
10.3389/fnins.2018.00852

NEUROTRANSMITTER AND RECEPTOR SYSTEM IN BRAIN:

 Cholinergic system:
Acetylcholine is the only neurotransmitter containing a quaternary ammonium group.
It is the neurotransmitter used in neuromuscular junctions of all vertebrates, ale preganglionic
neurons of the autonomous nervous system and all postganglionic parasympathetic neurons. In
the CNS it modulates many cortical activities such as arousal, sleep and memory consolidation.
 Synthesis and inactivation of acetylcholine
Acetylcholine (ACh) is an ester of choline and acetic acid. It is synthesised in one step by
transferring the acetyl group from acetyl-CoA to choline. This reaction is catalysed by choline
acetyltransferase.
The brain receives all its choline from the blood. Choline is mostly synthesised in the liver by a
triple methylation of ethanolamine; S-adenosylmethionine (SAM) is the donor of methyl groups.
Ethanolamine is produced by a decarboxylation of serine.
The cholinergic signal is terminated by the serine hydrolase acetylcholine esterase (AChE)
bound to the postsynaptic membrane. The hydrolysis produces choline, which is taken up by the
presynaptic neuron and recycled, and acetate. The catalytic activity of AChE depends primarily
on three amino acid residues – serine, histidine and glutamate (a similar triad exists also in serine
proteases with aspartate instead of glutamate). The hydroxyl group of serine attacks the ester
bond. AChE is not entirely specific for ACh, it also hydrolyses other choline esters.
Cholinergic signalling in the nervous system is mediate by two receptor types with several
subtypes:
1) Muscarinic receptors
These are metabotropic receptors coupled to G proteins, which then regulate ion channel
opening. The response of the postsynaptic neuron is thus relatively slow. So far five subtypes of
muscarinic receptors have been identified.
a) M1 receptors
These so called neuronal receptors are found in abundance in the CNS, particularly in the
hippocampus and cortex. This receptor mediates an excitatory response via a Gq protein starting
a signalling cascade leading to a decreased permeability for potassium. It is thought that a
decrease in their function or density is one of the causes of dementia.
b) M2 receptors
Often labelled as cardiac receptors they are expressed in cardiomyocytes but can be found in
high densities in neuronal tissues as well. They mediate an inhibitory response via a Gi protein,
which activates potassium channels (via its beta-gamma subunit dimer) thus causing membrane
hyperpolarization. This is the mechanism by which the vagus nerve exerts its negative
chronotropic effect on the sinoatrial node and the negative dromotropic effect on the
atrioventricular node. In the CNS M2 receptors act as autoreceptors on presynaptic neurons
mediating negative feedback inhibition in the cortex and the hippocampal formation.
c) M3 receptors
These receptors mediate the cholinergic stimulation of exocrine glands and the contraction of
smooth muscles in the GIT and other organs. M3 receptors are coupled with a Gq protein, which
increases intracellular calcium concentration via the activation of phospholipase C and the
formation of IP3 and DAG from PIP2. Although they exist in the CNS at a relatively low density
they can induce a potent emetic effect.
The effect of ACh on blood vessels is worth pointing out. While ACh can cause smooth muscle
contraction in blood vessels it causes vasodilation. This is not a direct effect on the smooth
muscle but rather a heterotropic inhibition of noradrenergic sympathetic activity and the
stimulation of NO production in the endothelium.
M3 receptors are being intensively studied due to their role in the development of type 2
diabetes. In the CNS they are expressed in areas responsible for the monitoring and regulation of
blood glucose levels, i.e. in parts of hypothalamus and parasympathetic nuclei of the brainstem.
In the pancreas they are expressed in beta-cells of the islets of Langerhans, which explains why
certain antipsychotic agents used to treat schizophrenia may cause blood glucose dysregulation
and increase the risk of T2D via blocking M3 receptors.
d) M4 receptors
This group of receptors is still relatively poorly studied. Their mechanisms of effect is similar to
M2 receptors (Gi-protein activating K+ channels). They are found mainly in the striatum, where
they function mainly as regulatory autoreceptors on cholinergic neurons (the same role as M2
receptors in the hippocampus and other cortical regions).
In the striatum M4 receptors attenuate the activity of excitatory D1 receptors, through which
dopamine increases the activity of the extrapyramidal motor system. The physiological
implications of this interaction are unclear.
e) M5 receptors
Similar to M1 and M3 receptors M5 receptors are couple with a Gq-protein. Most studies on M5
receptors to date were performed in vitro.
2) Nicotinic receptors
These are ionotropic receptors opening cation channel permeable for sodium and potassium, in
some subtypes also for calcium. The basic division is into a muscular type (NM receptor) present
mostly in the neuromuscular junction and a neuronal type (NM) found in all postsynaptic
terminals in autonomic ganglia. In the CNS NM receptors function as heteroreceptors for other
systems (GABA, serotonin, glutamate, dopamine). They increase the permeability for calcium
and increase the amount of released neurotransmitters.
Cholinergic neurons are found mainly in the basal nucleus of Meynert and in septal nuclei.
These neurons project into the cortex and the hippocampus. They play a role in the activation of
certain cortical areas and in short term memory consolidation. The neurons of the basal nucleus
and medial septum are damaged in Alzheimer’s disease.
Another group of cholinergic neurons can be found in the tegmentum of the brainstem, which
send their projections into the cerebellum, hypothalamus and lower portions of the CNS. These
affect arousal, sleep cycle and are important for the initiation of the REM sleep phase.
There are cholinergic interneurons in the striatum, which form a part of the basal ganglia circuit
and thus play a role in the regulation of posture, movement initiation and selection of appropriate
movement patterns.

 Noradrenergic system
Noradrenaline in the CNS mainly regulates the activity of other neurotransmitter systems.
Noradrenergic pathways increase or decrease the excitability of target areas depending on the
receptors expressed and other poorly understood mechanisms. Noradrenergic pathways can thus
regulate both the excitatory function of glutamate and the inhibitory function of GABA.
Noradrenaline binds to specific receptors in the target cell’s membrane. There are four subtypes
of adrenergic receptors in the CNS:
1) α1 receptor
Present in postsynaptic neurons, mediates excitatory effects of noradrenaline.
2) α2 receptor
Present mainly in presynaptic terminals and mediates inhibitory effects. Its main role is in
feedback inhibition of noradrenaline release in the synapse.
3) β1 receptor
Neuronal receptor with excitatory effects.
4) β2 receptor
In the CNS mainly expressed in glial cells. Latest research shows that beta-2 receptors mediates
the integration of the nervous and immune systems. The exact physiological role is being
studied.
Noradrenergic neurons are found in the brainstem, particularly in the locus coeruleus (group A6),
tegmentum and the reticular formation of the medulla and pons (groups A1, A2, A5, A7).
1) Locus coeruleus
Axons of neuron in the locus coeruleus project virtually to all CNS regions. This system
modulates the excitability of other projection systems and regulates attention, arousal, sleep
cycle and response to stress. Projections into association cortical areas influence emotional
behaviour.
2) Neuronal groups of the tegmentum and reticular formation
Neurons of these groups project into the spinal cord, brainstem, hypothalamus and the limbic
system, particularly into regions responsible for the regulation of visceral functions.
In the spinal cord they regulate the excitability of anterior horn motoneurons.
The reticular formation contains a smaller group of neurons releasing adrenaline with projections
similar to those of locus coeruleus. It is thought that they cooperate with noradrenergic neurons
in the regulation of alarm reaction and adaptation to stress.
Clinical correlation:
The catecholaminergic hypothesis aims to explain the pathogenesis of affective disorders such as
depression primarily as an hypoactivity of noradrenergic projections from locus coeruleus into
certain cortical areas (with a concomitant disorder of the serotonergic system).

 Dopaminergic system
Dopamine in the CNS plays an important role in the regulation of motor functions, initiation of
behavioural patterns and modulation of visceral functions.
Five dopamine receptors have been identified to date, which are all coupled to a G-protein
regulating adenylate cyclase activity. They can be divided into two groups depending on whether
they activate AC via a Gs protein (D1, D5) or inhibit it via a Gi protein (D2, D3, D4). The
density of various receptor subtypes differs in different areas of the CNS, e.g. cortical motor
areas are rich in D2 receptors while the limbic system mainly expresses D3 and D4 receptors.
Adrenaline and noradrenaline act as partial agonists on most dopamine receptors.
Dopaminergic neurons can be found in the mesencephalon and hypothalamus. From a functional
point of view several distinct dopaminergic projections are described.
1) Nigrostriatal projection
Neurons form the pars compacta of substantia nigra project mainly into the striatum, globus
pallidus and putamen and as such influence the functioning of basal ganglia. They play a role in
the planning and execution of cortical activities with their main effect on motor cortex.
Decreased function of this projection manifests as tremor at rest, bradykinesis, muscle stiffness
and impaired posture. Damage to these neurons may be caused by idiopathic degenerative
processes (Parkinson’s disease) or atherosclerotic narrowing of the blood vessels (parkinsonism).
2) Mesolimbic projections
Dopaminergic neurons from the ventral tegmentum and mesencephalic reticular formation
project into nucleus accumbens, amygdala and hippocampus. They play a role in motivation,
reward and punishment, instinctive behaviour and addiction. Their increased activity leads to
stereotypical behavioural patterns, repeated movements, etc.
3) Mesocortical projections
Some neurons of the ventral tegmentum and mesencephalic reticular formation also project into
prefrontal cortical areas. They influence planning and execution of frontal cortex activities (e.g.
attention) and affect initiation of behaviour.
Mesolimbic and mesocortical projections are closely related and are the target of some
antipsychotic drugs in the treatment of schizophrenia, obsessive-compulsive disorder, attention
deficit/hyperactivity disorder and Tourette’s syndrome.
4) Tuberoinfundibular projections
Inhibit prolactin secretion.
5) Intrahypothalamic projection
Plays a role in modulating various visceral functions.

 Serotonergic system
The serotonergic system plays a similar role in the CNS as the noradrenergic system. It regulates
a range of functions and modulates the activity of other projection systems. It often innervates
the same structures and functionally complements noradrenergic afferents.
Seven types of serotonin receptors have been identified to date, 5-HT1-7R, some of which are
inhibitory and some excitatory. The effect of serotonin depends on their localisation and the
types of receptors expressed.
Serotonergic neurons can be found in raphe nuclei of the reticular formation, which can be
divided into a rostral past with ascendent projections and a caudal part with descendent
projections.
1) Ascendent serotonergic system (nc. raphe dorsalis, nc. raphe pontis centralis superior)
This system projects into the cortex, some limbic structures (hippocampus, amygdala), basal
ganglia, many hypothalamic nuclei and areas and some thalamic nuclei.
It is important for the regulation of emotional behaviour, hypothalamic functions and the sleep
cycle. It also modulates information processing in sensory areas (e.g. visual cortex).
2) Descendent serotonergic system (nc. raphe pontis, nc. raphe magnus, nc. raphe obscurus)
Projections from these structures project mainly to more caudal parts of the CNS: brainstem,
cerebellum and spinal cord.
Caudal neurons influence pain perception via projection into posterior horns of the spinal cord.
An increased activity of the serotonergic system potentiates the effect of analgesics and is
essential for the effect of opiates. Their projections also modulate the excitability of
preganglionic neurons of the autonomous nervous system and stimulate motor neurons in the
anterior horns of the spinal cord.
Clinical correlation:
Drugs in the group of specific serotonin re-uptake inhibitors (SSRI) increase the activity of the
serotonergic system and are used to treat patients with unipolar depression. Unfortunately they
also decrease libido and cause food intake disorders, usually hyperphagia.

 Synthesis and inactivation of serotonin

Serotonin is derived from L-tryptophan, chemically it is 5-hydroxytryptamine. Its synthesis
occurs in two steps:
1) Tryptophan hydroxylation
Tryptophan is hydroxylated to 5-hydroxytryptamine, the reaction is catalysed by tryptophan
hydroxylase, which is the rate limiting enzyme of serotonin synthesis.
2) Decarboxylation
Decarboxylation of 5-hydroxytryptophan gives rise to 5-hydroxytryptamine, i.e. serotonin, which
is thus a biogenic amine (together with all catecholamines). This reaction is catalysed by
aromatic L-amino acid decarboxylase (LAAD, see catecholamine synthesis), in this case also
called 5-hydroxytryptophan decarboxylase.
Serotonergic neurotransmission is terminated by the reuptake of serotonin and its subsequent
intracellular metabolism. The inactivation of serotonin is catalysed by two enzymes –
monoamine oxidase (MAO) and aldehyde dehydrogenase (see catecholamine inactivation).
The product of serotonin inactivation is 5-hydroxyindoleacetic acid, which is mostly excreted in
urine conjugated with glucuronic acid. It is used as a diagnostic marker for neuroendocrine
tumours secreting serotonin (formerly carcinoid).
Serotonin also starts another metabolic pathway leading to the hormone melatonin. The amino
group of serotonin is first acetylated and the resulting N-acetylserotonin is the methylated on the
indole hydroxyl group to form melatonin.
Historical note:
The name serotonin points to its discovery as the substance in the serum, which affects smooth
muscle tone.

Patrik Maďa and Josef Fontana

http://fblt.cz/en/skripta/regulacni-mechanismy-2-nervova-regulace/5-neurotransmisni-systemy/

 Brain disorders and names of drug to treat them:

Anxiety:
Anxiety are among the most common mental disorders. Anxiety is an unpleasant state of tension,
apprehension, or uneasiness.The physical symptoms of severe anxiety are similar to those of fear
(such as tachycardia, sweating, trembling, and palpitations) and involve sympathetic activation.

 Drugs of anxiety:
1. Benzodiazepines
 Mechanism of action
The targets for benzodiazepine actions are the γ-aminobutyric acid (gabaa) receptors. The gabaa
receptors are composed of a combination of five α, β, and γ subunits that span the postsynaptic
membrane. For each subunit, many subtypes exist (for example, there are six subtypes of the α
subunit). Binding of gaba to its receptor triggers an opening of the central ion channel, allowing
chloride through the pore. The influx of chloride ions causes hyperpolarization of the neuron and
decreases neurotransmission by inhibiting the formation of action potentials. Benzodiazepines
modulate gaba effects by binding to a specific, high-affinity site (distinct from the gaba-binding
site) located at the interface of the α subunit and the γ subunit on the gabaa receptor .These
binding sites are sometimes labeled “benzodiazepine (bz) receptors.” Common bz receptor
subtypes in the cns are designated as bz1 or bz2 depending on whether the binding site includes
an α1 or α2 subunit, respectively.Benzodiazepines increase the frequency of channel openings
produced by gaba.Binding of a benzodiazepine to its receptor site increases the affinity of gaba
for the gaba-binding site (and vice versa). The clinical effects of the various benzodiazepines
correlate well with the binding affinity of each drug for the gaba receptor–chloride ion channel
complex.

 Indications:
It is indicated in Anxiety disorders, Sleep disorders, Amnesia, Seizures
  Pharmacokinetics
1. Absorption and distribution:The benzodiazepines are lipophilic. They are rapidly and
completely absorbed after oral administration, distribute throughout the body and penetrate into
the CNS.
2. Duration of action:The half-lives of the benzodiazepines are important clinically, because
the duration of action may determine the therapeutic usefulness.
3. Fate:Most benzodiazepines, including chlordiazepoxide and diazepam, are metabolized by the
hepatic microsomal system to compounds that are also active.

 Adverse effects:
Drowsiness , confusion, ataxia

 Drugs:
Alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam,
midazolam oxazepam, quazepam, temazepam, triazolam

2. Benzodiazepine antagonist
 Drug:
 Flumazenil
Flumazenil is a gaba receptor antagonist that can rapidly reverse the effects of benzodiazepines.
The drug is available for intravenous (iv) administration only. Onset is rapid, but the duration is
short, with a half-life of about 1 hour. Frequent administration may be necessary to maintain
reversal of a long-acting benzodiazepine. Administration of flumazenil may precipitate
withdrawal in dependent patients or cause seizures if a benzodiazepine is used to control seizure
activity. Seizures may also result if the patient has a mixed ingestion with tricyclic
antidepressants or antipsychotics.
 Adverse effects:
Dizziness, nausea, vomiting, and agitation.

3. Other anxiolytic drugs

 Antidepressant
Antidepressants many antidepressants are effective in the treatment of chronic anxiety disorders
and should be considered as first-line agents.selective serotonin reuptake inhibitors (SSRIS, such
as escitalopram or paroxetine) or serotonin/norepinephrine reuptake inhibitors (SNRIS), such as
venlafaxine or duloxetine) may be used alone or prescribed in combination with a low dose of a
benzodiazepine during the first weeks of treatment . After 4 to 6 weeks, when the antidepressant
begins to produce an anxiolytic effect, the benzodiazepine dose can be tapered. Long-term use of
antidepressants and benzodiazepines for anxiety disorders is often required to maintain ongoing
benefit and prevent relapse.
  Buspirone
Buspirone is useful for the chronic treatment of gad and has an efficacy comparable to that of
the benzodiazepines. It has a slow onset of action and is not effective for short-term or “as-
needed” treatment of acute anxiety states. The actions of buspirone appear to be mediated by
serotonin (5-ht1a) receptors, although it also displays some affinity for d2 dopamine receptors
and 5-ht2a serotonin receptors. Thus, its mode of action differs from that of the benzodiazepines.
In addition, buspirone lacks the anticonvulsant and muscle-relaxant properties of the
benzodiazepines.
 Adverse effects:
Headaches, dizziness, nervousness, nausea, and light-headedness. Sedation and psychomotor and
cognitive dysfunction are minimal, and dependence is unlikely.

 Barbiturates
 Mechanism of action
The sedative–hypnotic action of the barbiturates is due to their interaction with gabaa receptors,
which enhances gabaergic transmission. The binding site of barbiturates on the gaba receptor is
distinct from that of the benzodiazepines. Barbiturates potentiate gaba action on chloride entry
into the neuron by prolonging the duration of the chloride channel openings. In addition,
barbiturates can block excitatory glutamate receptors. Anesthetic concentrations of pentobarbital
also block hih-frequency sodium channels. All of these molecular actions lead to decreased
neuronal activity.
 Indications:
It is indicated in Anesthesia, mild sedatives to relieve anxiety, nervous tension, and insomnia.
 Pharmacokinetics
barbiturates are well absorbed after oral administration and distribute throughout the body. All
barbiturates redistribute from the brain to the splanchnic areas, to skeletal muscle, and, finally, to
adipose tissue. This movement is important in causing the short duration of action of thiopental
and similar short-acting derivatives. Barbiturates readily cross the placenta and can depress the
fetus. These agents are metabolized in the liver, and inactive metabolites are excreted in urine.
 Adverse effects
drowsiness, impaired concentration, and mental and physical sluggishness
amobarbital amytal pentobarbital nembutal phenobarbital luminal sodium secobarbital seconal
thiopental pentothal

Depression:
The symptoms of depression are feelings of sadness and hopelessness, as well as the inability to
experience pleasure in usual activities, changes in sleep patterns and appetite, loss of energy, and
suicidal thoughts.
 Mechanism of action of antidepressants:
Most clinically useful antidepressant drugs potentiate, either directly or indirectly, the actions of
norepinephrine and/or serotonin (5-ht) in the brain. This, along with other evidence, led to the
biogenic amine theory, which proposes that depression is due to a deficiency of monoamines,
such as norepinephrine and serotonin, at certain key sites in the brain. Conversely, the theory
proposes that mania is caused by an overproduction of these neurotransmitters. However, the
biogenic amine theory of depression and mania is overly simplistic.

 Antidepressant:
1. Selective serotonin reuptake inhibitors (SSRIS)
The SSRIS block the reuptake of serotonin, leading to increased concentrations of the
neurotransmitter in the synaptic cleft. Antidepressants, including ssris, typically take at least 2
weeks to produce significant improvement in mood, and maximum benefit may require up to 12
weeks or more.

 Pharmacokinetics
All of the SSRIS are well absorbed after oral administration. Peak levels are seen in
approximately 2 to 8 hours on average. Food has little effect on absorption (except with
sertraline, for which food increases its absorption). The majority of SSRIS have plasma half-
lives that range between 16 and 36 hours. Metabolism by cytochrome p450 (cyp450)–dependent
enzymes and glucuronide or sulfate conjugation occur extensively. Fluoxetine differs from the
other members of the class by having a much longer half-life (50 hours), and the halflife of its
active metabolite s-norfluoxetine is quite long, averaging 10 days. Fluoxetine and paroxetine are
potent inhibitors of a cyp450 isoenzyme (cyp2d6) responsible for the elimination of tcas,
antipsychotic drugs, and some antiarrhythmic and β-adrenergic antagonist drugs. Other cyp450
isoenzymes (cyp2c9/19, cyp3a4, cyp1a2) are involved with ssri metabolism and may also be
inhibited to various degrees by the ssris

 Indications:
The primary indication for SSRIS is depression, for which they are as effective as the TCAS. A
number of other psychiatric disorders also respond favorably to SSRIS, including obsessive–
compulsive disorder, panic disorder, generalized anxiety disorder, posttraumatic stress disorder,
social anxiety disorder, premenstrual dysphoric disorder, and bulimia nervosa (only fluoxetine is
approved for bulimia).

 Adverse effects:
Headache, sweating, anxiety and agitation, gastrointestinal (gi) effects (nausea, vomiting,
diarrhea), weakness and fatigue, sexual dysfunction, changes in weight, sleep disturbances
(insomnia and somnolence)
  Drugs:
Citalopram, escitalopram, fluoxetine, fluvoxamin, crparoxetine, sertraline

2. Serotonin/norepinephrine reuptake inhibitors (SNRIS)

They inhibit the reuptake of both serotonin and norepinephrine.These agents, termed SNRIS,
may be effective in treating depression in patients in whom SSRIS are ineffective. Both SNRIS
and the tcas, with their dual inhibition of both serotonin and norepinephrine reuptake, are
sometimes effective in relieving pain associated with diabetic peripheral neuropathy,
postherpetic neuralgia, fibromyalgia, and low back pain.

 Adverse effects:
Nausea, dry mouth, and constipation. Insomnia, dizziness, somnolence, sweating, and sexual
dysfunction are also seen. Duloxetine may increase blood pressure or heart rate.

 Drugs:
Desvenlafaxine, duloxetine , venlafaxine

3. Atypical antidepressants
The atypical antidepressants are a mixed group of agents that have actions at several different
sites.
 Drugs:
Bupropion , mirtazapine, nefazodone , trazodone , vilazodone , and vortioxetine

1. Bupropion
It is a weak dopamine and norepinephrine reuptake inhibitor that is used to alleviate the
symptoms of depression. Bupropion is also useful for decreasing cravings and attenuating
withdrawal symptoms of nicotine in patients trying to quit smoking. Bupropion is metabolized
by the cyp2b6 pathway. Mirtazapine mirtazapine enhances serotonin and norepinephrine
neurotransmission by serving as an antagonist at presynaptic α2 receptors. Additionally, some of
the antidepressant activity may be related to antagonism at 5-ht2 receptors. It is sedating because
of its potent antihistaminic activity, but it does not cause the antimuscarinic side effects of the
TCAS, or interfere with sexual function like the SSRIS.
 Adverse effects:
Dry mouth, sweating, nervousness, tremor, and a dosedependent increased risk for seizures. It
has a very low incidence of sexual dysfunction.

2. Nefazodone and trazodone

These drugs are weak inhibitors of serotonin reuptake. Their therapeutic benefit appears to be
related to their ability to block postsynaptic 5-ht2a receptors. Both agents are sedating, probably
because of their potent histamine h1 -blocking activity.
  Adverse effects:
Increased appetite and weight gain

3. Vilazodone
It is a serotonin reuptake inhibitor and a 5-ht1a partial agonist. Although the extent to which the
5-ht1a receptor activity contributes to its therapeutic effects is unknown, this possible
mechanism of action renders it unique from that of the ssris.

4. Vortioxetine
It utilizes a combination of serotonin reuptake inhibition, 5-ht1a agonism, and 5-ht3 and 5-ht7
antagonism as its suggested mechanisms of action to treat depression. It is unclear to what extent
the activities other than inhibition of serotonin reuptake influence the overall effects of
vortioxetine.
 Adverse effects
nausea, vomiting, and constipation
Bupropion wellbutrin, zyban mirtazapine remeron nefazodone trazodone desyrel

4 Tricyclic antidepressants (TCAS)

 Mechanism of action
1. Inhibition of neurotransmitter reuptake: TCAS and amoxapine are potent inhibitors of the
neuronal reuptake of norepinephrine and serotonin into presynaptic nerve terminals. Maprotiline
and desipramine are relatively selective inhibitors of norepinephrine reuptake.
2. Blocking of receptors: TCAS also block serotonergic, α-adrenergic, histaminic, and
muscarinic receptors. It is not known if any of these actions produce the therapeutic benefit of
the tcas. However, actions at these receptors are likely responsible for many of their adverse
effects. Amoxapine also blocks 5-ht2 and dopamine d2 receptors.

 Indications:
the TCAS are effective in treating moderate to severe depression. Some patients with panic
disorder also respond to tcas. Imipramine has been used to control bed-wetting in children older
than 6 years of age; however, it has largely been replaced by desmopressin and
nonpharmacologic treatments (enuresis alarms).

 Pharmacokinetics
TCAs are well absorbed upon oral administration. Because of their lipophilic nature, they are
widely distributed and readily penetrate into the CNS. As a result of their variable first-pass
metabolism in the liver, TCAs have low and inconsistent bioavailability. These drugs are
metabolized by the hepatic microsomal system (and, thus, may be sensitive to agents that induce
or inhibit the cyp450 isoenzymes) and conjugated with glucuronic acid. Ultimately, the tcas are
excreted as inactive metabolites via the kidney
 Adverse effects
Blockade of muscarinic receptors leads to blurred vision, xerostomia (dry mouth), urinary
retention, sinus tachycardia, constipation, and aggravation of angle-closure glaucoma.
 Drugs
Amitriptyline, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline,
protriptyline, trimipramine.

5 Monoamine oxidase inhibitors (MAOIs)

 Mechanism of action
most MAOIs, such as phenelzine, form stable complexes with the enzyme, causing irreversible
inactivation. This results in increased stores of norepinephrine, serotonin, and dopamine within
the neuron and subsequent diffusion of excess neurotransmitter into the synaptic space.These
drugs inhibit not only mao in the brain but also mao in the liver and gut that catalyzes oxidative
deamination of drugs and potentially toxic substances, such as tyramine, which is found in
certain foods. The MAOIs, therefore, show a high incidence of drug–drug and drug–food
interactions. Selegiline administered as the transdermal patch may produce less inhibition of gut
and hepatic MAO at low doses because it avoids first-pass metabolism.

 Indications:
The MAOIs are indicated for depressed patients who are unresponsive or allergic to TCAS and
SSRIS or who experience strong anxiety.
 Drugs:
Isocarboxazid, phenelzine, selegiline, tranylcypromine.

Psychosis is an abnormal condition of the mind that results in difficulties determining what is
real and what is not
Schizophrenia is a type of chronic psychosis characterized by delusions, hallucinations (often in
the form of voices), and thinking or speech disturbances.

First-generation antipsychotic (low potency)

First-generation antipsychotics the first-generation antipsychotic drugs (also called conventional,
typical, or traditional antipsychotics) are competitive inhibitors at a variety of receptors, but their
antipsychotic effects reflect competitive blocking of dopamine d2 receptors. First-generation
antipsychotics are more likely to be associated with movement disorders known as
extrapyramidal symptoms (eps), particularly drugs that bind tightly to dopaminergic
neuroreceptors, such as haloperidol [hal-oh-per-i-dol]. Movement disorders are less likely with
medications that bind weakly, such as chlorpromazine [klor-proe-ma-zeen]. No one drug is
clinically more effective than another.
 chlorpromazine thorazine prochlorperazine compazine thioridazine
first-generation antipsychotic (high potency) fluphenazine prolixin haloperidol haldol pimozide
orap thiothixene navane

second-generation antipsychotic
Mechanism of action
1. Dopamine antagonism: all of the first-generation and most of the second-generation
antipsychotic drugs block d2 dopamine receptors in the brain and the periphery (figure 11.2).
2. Serotonin receptor–blocking activity: most of the secondgeneration agents appear to exert part
of their unique action through inhibition of serotonin receptors (5-ht), particularly 5-ht2a
receptors. Clozapine has high affinity for d1 , d4 , 5-ht2 , muscarinic, and α-adrenergic receptors,
but it is also a weak dopamine d2 receptor antagonist (figure 11.3). Risperidone [rispear-ih-dohn]
blocks 5-ht2a receptors to a greater extent than it does d2 receptors, as does olanzapine [oh-lanz-
ah-peen]. The second-generation antipsychotic aripiprazole [a-rih-pip-razole] is a partial agonist
at d2 and 5-ht1a receptors, as well as an antagonist of 5-ht2a receptors. Quetiapine [qwe-ty-uh-
peen] blocks d2 receptors more potently than 5-ht2a receptors but is relatively weak at blocking
either receptor. Its low risk for eps may also be related to the relatively short period of time it
binds to the d2 receptor.

Therapeutic uses 1. Treatment of schizophrenia, 2. Prevention of nausea and vomiting:

Chlorpromazine is used to treat intractable hiccups. Pimozide [pim-oh-zide] is primarily
indicated for treatment of the motor and phonic tics of tourette disorder.

Absorption and metabolism after oral administration, the antipsychotics show variable
absorption that is unaffected by food (except for ziprasidone [zi-pras-i-done] and paliperidone,
the absorption of which is increased with food). These agents readily pass into the brain and have
a large volume of distribution. They are metabolized to many different metabolites, usually by
the cytochrome p450 system in the liver, particularly the cyp2d6, cyp1a2, and cyp3a4
isoenzymes.

Adverse effects adverse effects of the antipsychotic drugs can occur in practically all patients and
are significant in about 80%
Extrapyramidal effects, tardive dyskinesia: neuroleptic malignant syndrome: drowsiness
Aripiprazole abilify asenapine saphris clozapine clozaril iloperidone fanapt lurasidone latuda
olanzapine zyprexa quetiapine seroquel paliperidone invega risperidone risperdal ziprasidone
geodon

Epilepsy is the third most common neurologic disorder after cerebrovascular and alzheimer’s
disease. Epilepsy is not a single entity but an assortment of different seizure types and syndromes
originating from several mechanisms that have in common the sudden, excessive, and
synchronous discharge of cerebral neurons. This abnormal electrical activity may result in a
variety of events, including loss of consciousness, abnormal movements, atypical or odd
behavior, and distorted perceptions that are of limited duration but recur if untreated. The site of
origin of the abnormal neuronal firing determines the symptoms that are produced. For example,
if the motor cortex is involved, the patient may experience abnormal movements or a generalized
convulsion. Seizures originating in the parietal or occipital lobe may include visual, auditory, and
olfactory hallucinations.

Mechanism of action of antiepilepsy medications drugs reduce seizures through such

mechanisms as blocking voltage-gated channels (na+ or ca2+), enhancing inhibitory γ-
aminobutyric acid (gaba)-ergic impulses and interfering with excitatory glutamate transmission.
Some antiepilepsy medications appear to have multiple targets within the cns, whereas the
mechanism of action for some agents is poorly defined. Antiepilepsy medications suppress
seizures but do not “cure” or “prevent” epilepsy.
Sedation nausea and vomiting ataxia rash hyponatremia na+ weight gain or weight loss
teratogenicity osteoporosis
Approved before 1990
Carbamazepine tegretol diazepam valium divalproex depakote ethosuximide zarontin felbamate
felbatol gabapentin neurontin lacosamide vimpat lamotrigine lamictal levetiracetam keppra
lorazepam ativan oxcarbazepine trileptal phenobarbital luminal phenytoin dilantin fosphenytoin
cerebyx primidone mysoline
Approved after 1990
Clobazam onfi perampanel fycompa pregabalin lyrica ezogabine potiga eslicarbazepine aptiom
Felbamate felbatol gabapentin neurontin lacosamide vimpat lamotrigine lamictal levetiracetam
keppra lorazepam ativan oxcarbazepin

Anesthesia is a reversible state of central nervous system (cns) depression, causing loss of
response to and perception of stimuli. For patients undergoing surgical or medical procedures,
anesthesia provides five important benefits: • sedation and reduced anxiety • lack of awareness
and amnesia • skeletal muscle relaxation • suppression of undesirable reflexes • analgesia
because no single agent provides all desirable properties, several categories of drugs are
combined to produce optimal anesthesia . Preanesthetics help calm patients, relieve pain, and
prevent side effects of subsequently administered anesthetics or the procedure itself.
Neuromuscular blockers facilitate tracheal intubation and surgery. Potent general anesthetics are
delivered via inhalation and/or intravenous (iv) injection. Except for nitrous oxide, inhaled
anesthetics are volatile, halogenated hydrocarbons. Iv anesthetics consist of several chemically
unrelated drug types commonly used to rapidly induce anesthesia.
Preanesthetic medications antacids anticholinergics antiemetics antihistamines benzodiazepines
opioids
general anesthetics:
Mechanism
General anesthetics increase the sensitivity of the γ-aminobutyric acid (gabaa) receptors to the
inhibitory neurotransmitter gaba. This increases chloride ion influx and hyperpolarization of
neurons. Postsynaptic neuronal excitability and, thus, cns activity are diminished (figure 13.8).
Unlike other anesthetics, nitrous oxide and ketamine do not have actions on gabaa receptors.
Their effects are likely mediated via inhibition of the n-methyl-d-aspartate (nmda) receptors.

Uses
It is a potent bronchodilator. Halothane relaxes both skeletal and uterine muscles and can be used
in obstetrics when uterine relaxation is indicated. Desflurane is not used for inhalation induction

Pharmacokinetics: halothane is oxidatively metabolized in the body to tissue-toxic hydrocarbons

(for example, trifluoroethanol) and bromide ion. Sevoflurane is metabolized by the liver
Adverse effects: a. Cardiac effects: malignant hyperthermia:
inhaled suprane halothane
Fluothane forane nitrous oxide nitrous oxide ultane

general anesthetics:
Uses
Propofol [pro-puh-fol] is an iv sedative/hypnotic used for induction and/or maintenance of
anesthesia. The benzodiazepines are used in conjunction with anesthetics for sedation
intravenous barbiturates benzodiazepines dexmedetomidine precedex etomidate amidate
ketamine ketalar opioids propofol diprivan
neuromuscular blockers
Neuromuscular blockers are used to abolish reflexes to facilitate tracheal intubation and provide
muscle relaxation as needed for surgery. Their mechanism of action is blockade of nicotinic
acetylcholine receptors in the neuromuscular junction.
Cisatracurium, pancuronium, rocuronium, succinylcholine, vecuronium
Local anesthetics:
Local anesthetics block nerve conduction of sensory impulses and, in higher concentrations,
motor impulses from the periphery to the cns. Na+ ion channels are blocked to prevent the
transient increase in permeability of the nerve membrane to na+ that is required for an action
potential (figure 13.12). When propagation of action potentials is prevented, sensation cannot be
transmitted from the source of stimulation to the brain. Delivery techniques include topical
administration, infiltration, peripheral nerve blocks, and neuraxial (spinal, epidural, or caudal)
blocks. Small, unmyelinated nerve fibers for pain, temperature, and autonomic activity are most
sensitive. Structurally, local anesthetics all include a lipophilic group joined by an amide or ester
linkage to a carbon chain, which, in turn, is joined to a hydrophilic group
Metabolism biotransformation of amides occurs primarily in the liver. Prilocaine [pry-low-cane],
a dental anesthetic, is also metabolized in the plasma and kidney, and one of its metabolites may
lead to methemoglobinemia. Esters are biotransformed by plasma cholinesterase
(pseudocholinesterase). Onset and duration of action the onset and duration of action of local
anesthetics are influenced by several factors including tissue ph, nerve morphology,
concentration, pka, and lipid solubility of the drug
Amides bupivacaine marcaine lidocaine xylocaine mepivacaine carbocaine ropivacaine naropin
Local anesthetics: esters chloroprocaine nesacaine procaine novocaine tetracaine pontocaine

Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically
they are primarily used for pain relief, including anesthesia. Other medical uses include
suppression of diarrhea, replacement therapy for opioid . The major effects of the opioids are
mediated by three receptor families, which are commonly designated as μ (mu), κ (kappa), and δ
(delta). Each receptor family exhibits a different specificity for the drug(s) it binds. The analgesic
properties of the opioids are primarily mediated by the μ receptors that modulate responses to
thermal, mechanical, and chemical nociception. The κ receptors in the dorsal horn also contribute
to analgesia by modulating the response to chemical and thermal nociception.

STRONG AGONISTS
Morphine 1. Mechanism of action: Morphine and other opioids exert their major effects by interacting
stereospecifically with opioid receptors on the membranes of certain cells in the CNS and other
anatomic structures, such as the gastrointestinal (GI) tract and the urinary bladder. Morphine also acts
at κ receptors in lamina I and II of the dorsal horn of the spinal cord. It decreases the release of
substance P, which modulates pain perception in the spinal cord. Morphine also appears to inhibit the
release of many excitatory transmitters from nerve terminals carrying nociceptive (painful) stimuli.

. Pharmacokinetics:
a. Administration: Because significant first-pass metabolism of morphine occurs in the liver,
intramuscular, subcutaneous, and IV injections produce the most reliable responses.

Distribution: Morphine rapidly enters all body tissues, including the fetuses of pregnant women.
Fate: Morphine is conjugated with glucuronic acid in the liver to two main metabolites. Morphine-6-
glucuronide is a very potent analgesic, whereas morphine-3-glucuronide does not have analgesic
activity, but is believed to cause the neuroexcitatory effects seen with high doses of morphine. The
conjugates are excreted primarily in urine, with small quantities appearing in bile. The duration of action
of morphine is 4 to 5 hours when administered systemically

s.e With most μ agonists, severe respiratory depression can occur and may result in death from acute
opioid overdose. Respiratory drive may be suppressed in patients with emphysema or cor pulmonale.
Alfentanil ALFENTA Fentanyl ABSTRAL, ACTIQ, DURAGESIC, Heroin Hydrocodone
LORTAB, VICODIN, VARIOUS Hydromorphone DILAUDID, EXALGO Meperidine
DEMEROL Methadone DOLOPHINE Morphine AVINZA, KADIAN, MS CONTIN,
ORAMORPH Oxycodone OXYCONTIN Oxymorphone OPANA Remifentanil ULTIVA
Sufentanil SUFENTA Tapentadol NUCYNTA
MODERATE/LOW AGONISTS Codeine
MIXED AGONIST–ANTAGONIST AND

PARTIAL AGONISTS
Partial agonists bind to the opioid receptor, but have less intrinsic activity than full agonists (see Chapter
2). There is a ceiling to the pharmacologic effects of these agents. Drugs that stimulate one receptor but
block another are termed mixed agonist–antagonists. The effects of these drugs depend on previous
exposure to opioids. In individuals who have not received opioids (naïve patients), mixed agonist–
antagonists show agonist activity and are used to relieve pain. In the patient with opioid dependence,
the agonist–antagonist drugs may show primarily blocking effects (that is, produce withdrawal
symptoms).
Adverse effects
In higher doses, the drug causes respiratory depression and decreases the activity of the GI tract. High
doses increase blood pressure and can cause hallucinations, nightmares, dysphoria, tachycardia, and
dizziness.
Buprenorphine BUPRENEX, SUBUTEX Butorphanol Nalbuphine NUBAIN Pentazocine
TALWIN

ANTAGONISTS
The opioid antagonists bind with high affinity to opioid receptors, but fail to activate the receptor-
mediated response. Administration of opioid antagonists produces no profound effects in normal
individuals. However, in patients dependent on opioids, antagonists rapidly reverse the effect of
agonists, such as morphine or any full μ agonist, and precipitate the symptoms of opioid withdrawal.

Pharmacokinetics
Within 30 seconds of IV injection of naloxone, the respiratory depression and coma characteristic of high
doses of morphine are reversed, causing the patient to be revived and alert. Naloxone has a half-life of
30 to 81 minutes. Naltrexone has a longer duration of action than naloxone, and a single oral dose of
naltrexone blocks the effect of injected heroin for up to 24 hours.
Naloxone NARCAN Naltrexone REVIA, VIVITROL

OTHER ANALGESICS
Tapentadol Tapentadol [ta-PEN-ta-dol], a centrally acting analgesic, is an agonist at the μ opioid receptor
and an inhibitor of norepinephrine reuptake. It has been used to manage moderate to severe pain, both
chronic and acute. Tapentadol is mainly metabolized to inactive metabolites via glucuronidation, and it
does not inhibit or induce the CYP450 enzyme system. Because tapentadol does not produce active
metabolites, dosing adjustment is not necessary in mild to moderate renal impairment. Tapentadol
should be avoided in patients who have received MAOIs within the last 14 days. It is available in an
immediate-release and extended-release formulation. B. Tramadol Tramadol [TRA-ma-dole] is a
centrally acting analgesic that binds to the μ opioid receptor. The drug undergoes extensive metabolism
via CYP450 2D6, leading to an active metabolite with a much higher affinity for the μ receptor than the
parent compound. In addition, it weakly inhibits reuptake of norepinephrine and serotonin. It is used to
manage moderate to moderately severe pain. Its respiratorydepressant activity is less than that of
morphine. Naloxone can only partially reverse the analgesia produced by tramadol or its active
metabolite. Anaphylactoid reactions have been reported. Overdose or drug–drug interactions with
medications, such as SSRIs, MAOIs, and tricyclic antidepressants, can lead to toxicity manifested by CNS
excitation and seizures. As with other agents that bind the μ opioid receptor, tramadol has been
associated with misuse and abuse.
Tramadol ULTRAM
Parkinsonism is a progressive neurological disorder of muscle movement, characterized by
tremors, muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary
movements), and postural and gait abnormalities. Most cases involve people over the age of 65,
among whom the incidence is about 1 in 100 individuals. A. Etiology The cause of Parkinson’s
disease is unknown for most patients. The disease is correlated with destruction of dopaminergic
neurons in the substantia nigra with a consequent reduction of dopamine actions in the corpus
striatum, parts of the basal ganglia system that are involved in motor control.

DRUGS
Many currently available drugs aim to maintain CNS dopamine levels as constant as possible.
These agents offer temporary relief from the symptoms of the disorder, but they do not arrest or
reverse the neuronal degeneration caused by the disease.
Amantadine SYMMETREL Apomorphine APOKYN Benztropine COGENTIN Biperiden
AKINETON Bromocriptine PARLODEL Carbidopa LODOSYN Entacapone COMTAN
Levodopa (w/Carbidopa) SINEMET, PARCOPA Pramipexole MIRAPEX Procyclidine
KEMADRIN Rasagiline AZILECT Ropinirole REQUIP Rotigotine NEUPRO Selegiline
(Deprenyl) ELDEPRYL, ZELAPAR Tolcapone TASMAR Trihexyphenidyl ARTANE
Dementia of the Alzheimer type has three distinguishing features: 1) accumulation of senile
plaques (β-amyloid accumulations), 2) formation of numerous neurofibrillary tangles, and 3) loss
of cortical neurons, particularly cholinergic neurons. Current therapies aim to either improve
cholinergic transmission within the CNS or prevent excitotoxic actions resulting from
overstimulation of NMDA-glutamate receptors in selected areas of the brain. Pharmacologic
intervention for Alzheimer’s disease is only palliative and provides modest short-term benefit.
None of the available therapeutic agents alter the underlying neurodegenerative process.
Donepezil ARICEPT Galantamine RAZADYNE Memantine NAMENDA Rivastigmine
EXELON