Drugs affecting the cns psychopharmacology by pharmacologist l mweetwa

CNS Pharmacology
L.Mweetwa-Pharmacologist
University of Zambia
Dept of Pharmacy
Faculty of Medicine
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY

Dept of Pharmacy
PHARMACY FACULTY
Faculty of Medicine

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A gap between two neurons

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Mostly chemical

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Rarely electrical
 Mostly present in lower animals
 Gap junctions

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Synapses could be
 Axo-dendritic
 Axo-somatic
 Axo-axonic
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Presynaptic membrane
 Contains neurotransmitter

vesicles
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Synaptic cleft

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Postsynaptic membrane
 Contains receptors for the

neurotransmitter
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Action potential passes from the presynaptic
neuron to the postsynaptic neuron
Although an axon conducts both ways, conduction
through synapse is one way
A neuron receives more than 10000 synapses

Postsynaptic activity is an integrated function
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Chemicals that facilitate signal transmission across a synapse

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Neurotransmitters are released on the presynaptic side and bind to
receptors on the postsynaptic side

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Earliest neurotransmitter discovered was acetylcholine

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There are different chemical types
 Amines
▪ Norepinephrine, Epinephrine, dopamine, serotonin (5HT), histamine
 Amino acids
▪ GABA, Glycine, Glutamate, Aspartate
 Peptides
▪ Beta endorphin, enkephalins, dynorphin
 Others
▪ Acetylcholine, nitric oxide
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“At rest”, the synapse contains numerous synaptic vesicles filled
with neurotransmitter

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Intracellular calcium levels are very low

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Arrival of an action potential causes opening of voltage-gated
calcium channels

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Calcium enters the synapse

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Calcium triggers exocytosis and release of neurotransmitter

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Vesicles are recycled by endocytosis
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Ca2+

Ca2+

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Once released, the neurotransmitter molecules diffuse across the
synaptic cleft
 When they “arrive” at the postsynaptic membrane, they bind to
neurotransmitter receptors
 Two main classes of receptors:
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 Ligand-gated ion channels
 transmitter molecules bind on the outside, cause the channel to open and become
permeable to either sodium, potassium or chloride
 G-protein-coupled receptors
 G-protein-coupled receptors have slower, longer-lasting and diverse postsynaptic
effects. They can have effects that change an entire cell’s metabolism
 or an enzyme that activates an internal metabolic change inside the cell
 activate cAMP
 activate cellular genes: forms more receptor proteins
 activate protein kinase: decrease the number of proteins

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Excitation
 1. Na+ influx cause accumulation of positive

charges causing excitation
 2. Decreased K+ efflux or Cl- influx
 3. Various internal changes to excite cell,

increase in excitatory receptors, decrease in
inhibitory receptors.
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Inhibition
 1. Efflux of K+
 2. Influx of Cl 3. activation of receptor enzymes to inhibit

metabolic functions or to increase inhibitory
receptors or decrease excitatory receptors
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Excitatory effects of neurotransmitters
 EPSP: excitatory post synaptic potential

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Inhibitory effects of neurotransmitters
 IPSP: inhibitory post synaptic potential

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Synaptic integration

 On average, each neuron in the brain receives about

10,000 synaptic connections from other neurons

 Many (but probably not all) of these connections

may be active at any given time

 Each neuron produces only one output
 One single input is usually not sufficient to trigger

this output

 The neuron must integrate a large number of

synaptic inputs and “decide” whether to produce an
output or not
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 First neurotransmitter discovered in 1921
 secreted by motor neurons, autonomic nerves, large

pyramidal cells of the motor cortex, basal ganglia
(caudate & putamen), hippocampus.
 It is generally excitatory
 receptors
▪ nicotinic (autonomic ganglia, NMJ) - Na influx
▪ muscarinic (parasympathetc terminal)
 sub types: M1(brain), M2, M3, M4, M5
 second messenger cAMP
 Common Ach blockers: plant poison (curare), botulinum toxin (food poison)
 Loss of Ach neurons in Alzheimer’s patients
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 present in the autonomic nerves, brain stem,

hypothalamus, locus ceruleus of the pons
 Mostly it causes excitation but sometimes inhibition also
happens
 Increases BP and HR
 control the overall activity of the brain and the mood
 receptors
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1, 2, 1, 2, 3
 second messenger: cAMP

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present in the cerebral cortex, hypothalamus
secreted by neurons in the basal ganglia
Mainly inhibitory
Involved in the reward mechanisms in the brain
Drugs like cocaine, opium, heroin, and alcohol
increase the levels of dopamine
receptors:
 D1, D2, D3, D4, D5
 second messenger: cAMP

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Increased levels associates with schizophrenia, low levels are associated with Parkinsonism

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Present in the basal ganglia
Also present in the spinal cord, cerebellum &
many other areas of the Cortex
Major inhibitory neurotransmitter of the
brain occurring in 30-40% of all synapses
receptors
▪ GABAA increase Cl- influx
▪ GABAB act via G proteins, increase K+ influx

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Low GABA levels are associated with anxiety and epilepsy
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Present in the synapses of the spinal cord,
interneurons
also present in the retina
Inhibitory (increase Cl influx)
by its action on NMDA receptors it is
excitatory

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Excitatory amino acids
 glutamate is present in presynaptic terminals in the sensory pathways

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and other cortical areas
Involved in the stretch reflex
present in basal ganglia
Main excitatory neurotransmitter in brain & spinal cord
aspartate is present in cortical pyramidal cells & visual cortex
receptors: metabotropic receptors, kainate, AMPA, NMDA
NMDA receptors are present in hippocampus, involved in memory &
learning

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Increased levels are associated with certain neurological diseases

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secreted by the nuclei originating in the
median raphe of the brain stem and
terminate in dorsal horn of the spinal cord
and hypothalamus
Inhibitory
Control the mood of the person and
important in sleep
also present in GIT, platelets & limbic system
receptors: 1A, 1B, 1D, 2A, 2C, 3, 4
Low levels are associated with depression
and other psychiatric disorders. May be
involved in migraine
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histamine:
 present in pathways from hypothalamus to

cortical areas & spinal cord
 receptors: H1, H2, H3 (all present in brain)
 functions related to arousal, sexual behaviour,
drinking, pain
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Substance P
 found in primary nerve ending in the spinal cord
 mediator of pain in the spinal cord
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synthesized by ribosomes in the cell body

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ER and Golgi apparatus enzymatically split the large
molecule into smaller precursor or active molecules

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Golgi apparatus makes vesicles

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these vesicles are transported through the axoplasm slowly

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remain in the terminal

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release by a process similar to the other neurotransmitter
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however vesicle is autolysed and not reused

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quantity of neuropeptides released is smaller than that of
other neurotransmitters

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but the neuropeptides are thousand times more potent

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they also cause much more prolonged action

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generally only one type of small molecule neurotransmitter
is released by a neuron

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several neuropeptides could be released
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Removal of neurotransmitter:
by diffusion into the surrounding fluids
enzymatic destruction (Ach)
active transport re-uptake into the presynaptic terminal

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Actions
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prolonged closure of Ca pores
prolonged changes in cell metabolism
deactivation of specific genes
prolonged changes in excitatory or inhibitory
receptors
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Endorphin

 present in pituitary, earliest discovered opioid peptide

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enkephalins: met-enkephalin, leu-enkephalin

 present at substantia gelatinosa in the spinal cord & brain stem

reticular nuclei
 widely distributed

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dynorphin

 recently discovered
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opioid peptides are involved in the descending pain inhibitory pathway

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receptors: , ,

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Substance P
ACTH
Oxytocin
Glucagon
Somatostatin
VIP
Prolactin
LH
TRH
Releasing hormones,

– GH
– Gastrin
– CCK
– Neurotensin
– Insulin
– Angiotesin II
– Bradykinin
– Calcitonin gene
related peptide
(CGRP)
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nitrous oxide (NO)
 present in brain
 probably involved in memory

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Neurotransmitters transmit an impulse from
one neuron to another

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Neuromodulator modulate regions or
circuits of the brain

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They affect a group of neurons, causing a
modulation of that group

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Neuromodulators alter neuronal activity by
amplifying or dampening synaptic activity
 eg. dopamine, serotonin, acetylcholine,

histamine, glutamate

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This is a modified
synapse
 Consists of
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 Presynaptic membrane

(nerve terminal)
 Synaptic cleft
 Postsynaptic membrane
(motor end plate)

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Terminal has synaptic vesicles and mitochondria
Mitochondria (ATP) are present inside the presynaptic
terminal

Vesicles containing neurotransmitter (Ach)

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Presynaptic membrane contain voltage-gated
Ca channels
The quantity of neurotransmitter released is
proportional to the number of Ca entering the
terminal
Ca ions binds to the protein molecules on the
inner surface of the synaptic membrane called
release sites
Neurotransmitter binds to these sites and
exocytosis occur
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Postsynaptic membrane contain receptors for the
neurotransmitter released
eg: Acetylcholine receptor
Na+

Ach

•This receptor is Ach-gated
Na+ channel
•When Ach binds to this,
Na+ channel opens up
•Na+ influx occurs

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Na+ influx causes depolarisation of the
membrane
 End Plate Potential (EPP)
▪ This is a graded potential
▪ Once this reaches the threshold level
▪ AP is generated at the postsynaptic membrane

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An average human end plate contains 15-40
million Ach receptors

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Each nerve impulse release 60 Ach vesicles

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Each vesicle contains about 10,000 molecules
of Ach

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Ach is released in quanta (small packets)
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Even at rest small quanta are released

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Which creates a minute depolarising spike
called Miniature End Plate Potential (MEPP)

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When an impulse arrives at the NMJ quanta
released are increased in several times
causing EPP

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After the Ach binding is over

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Cholinesterase present in the synaptic cleft
will hydrolyse Ach into choline and acetate

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Choline is reuptaken to the presynaptic
terminal

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AchE is also found in RBC membranes
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A cellular process responsible for movement of
mitochondria, lipids, synaptic vesicles, proteins, and other
organelles to and from a neuron's cell body, through the
axoplasm

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anterograde transport
 movement toward the synapse is called

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retrograde transport
 Movement toward the cell body

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NMJ not well developed

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Smooth muscle does not depend on motor neurons to be stimulated

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However, motor neurons (of the autonomic system) reach smooth
muscle and can stimulate it — or relax it — depending on the
neurotransmitter they release (e.g. noradrenaline or nitric oxide, NO))

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Smooth muscle can also be made to contract
 by other substances released in the vicinity (paracrine stimulation)
 Example: release of histamine causes contraction of the smooth muscle lining our
air passages (triggering an attack of asthma)
 by hormones circulating in the blood
 Example: oxytocin reaching the uterus stimulates it to contract to begin childbirth.

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The contraction of smooth muscle tends
to be slower than that of striated muscle

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It also is often sustained for long periods
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L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA
SCHOOL OF MEDICINE , PHARMACY FACULTY

CNS Pharmacology

Dept of Pharmacy
Faculty of Medicine

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Parkinsonism is a progressive degenerative,
extrapyramidal disorder of muscle movement, due
to dysfunction in basal ganglia, comprising four
cardinal features:
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Bradykinesia or hypokinesia.
Muscle rigidity.
Resting tremor.
Impairment of postural balance leading to disturbances of
gait, and falling. The secondary manifestations are masklike face, siallorrhoea, difficulty in speech, slowing of
mental process and dementia.
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It is slowness in initiating and carrying out
voluntary movements. It is called poverty and
suppression of voluntary movements. It is
caused partly by muscle rigidity and partly by
inertia of the motor system, which means
that motor activity is difficult to stop as well
as to initiate. It is hard to start walking, and
once in progress, the patient can not stop
quickly.
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Rigidity is due to increased muscle tone. The
rigidity affects the opposing muscles equally,
flexors and extensors. Rigidity is detectable
as an increased resistance in passive limb
movement.

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Tremors are defined as rhythmic oscillatory
movements caused by the opposing muscles
around a joint. Tremors of Parkinsonism are
slow. Hand tremors involve all the fingers and
thumb (pill rolling tremor) which tend to
diminish during voluntary activity. The
“resting tremors” are present at rest and
disappear (abate) during voluntary
movements.
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Dyskinesia: Abnormal involuntary movements
Chorea: It consists of irregular, unpredictable, involuntary
muscle jerks that occur in different parts of the body and
impaired voluntary activity.
Athetosis: Abnormal movements are slow and writhing in
character

Dystonia: The abnormal movements are slow in character
and are sustained so that they are regarded as abnormal
postures
Tics: They are coordinated abnormal movements that tend
to occur repetitively particularly about the face and head,
especially in children
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The degeneration of neurons occurs in substantia nigra pars
compacta and the nigrostriatal tract that are dopaminergic
and inhibit the activity of striatal GABA ergic neurons. This
results in deficiency of dopamine in striatum which controls
muscle tone and coordinates movements. Nerve fibers from
cerebral cortex and thalamus secrete acetylcholine in the
neostriatum causing excitatory effects that initiate and
regulate gross intentional movements of the body. In
Parkinson’s disease, due to deficiency of dopamine in
striatum, an imbalance between dopaminergic (inhibitory)
and cholinergic (excitatory) system occurs, leading to
excessive excitatory actions of cholinergic neurons on
striatal GABA ergic neurons.
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Substantia Nigra:
 The substantia nigra pars compacta is the source

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dopaminergic neurons that travel through nigrostriatal
tract to terminate in the striatum. These dopaminergic
neurons from the substantia nigra fire tonically, to
produce a sustained influence on motor activity.

Striatum:

 The striatum is connected to the substantia nigra par

reticulata by neurons that secrete the inhibitory
transmitter GABA at their endings in the substantia nigra.
In turn, cells of the substantia nigra send neurons back to
the striatum, secreting the inhibitory transmitter
dopamine at their endings. Nerve fibers from the cerebral
cortex and thalamus secrete Acetylcholine in the
neostriatum causing excitatory effects.
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In Parkinson’s disease dopaminergic
inhibitory activity is reduced and cholinergic
excitatory activity is increased. Therefore,
therapy is aimed at restoring dopamine in the
basal ganglia and antagonizing the excitatory
effects of cholinergic neurons.

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Drug therapy is aimed at restoring the
balance between the dopaminergic and
cholinergic components, which is achieved
by:
 Increasing the central dopaminergic activity

OR
 Decreasing the central cholinergic activity
OR BOTH.
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Idiopathic Parkinson's disease
 Idiopathic Parkinson's disease - or Parkinson's - is
the most common type of parkinsonism. Unlike
some other forms which have specific causes it is
not known why idiopathic Parkinson's occurs.
 The main symptoms of idiopatic Parkinson's are
tremor, rigidity and slowness of movement.
 Symptoms and the rate at which the condition
progresses vary from person to person. This can
make diagnosis difficult.
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Vascular parkinsonism is one of the atypical forms of
parkinsonism.
The most likely causes of vascular parkinsonism are
hypertension and diabetes. A stroke (cerebrovascular
accident), cardiac disease or carotid artery pathology
(another form of stroke) may also be involved.
Symptoms of vascular parkinsonism may include
difficulty speaking, making facial expressions or
swallowing.
Other signs can include problems with memory or
confused thought, cognitive problems and
incontinence.
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A small number (around 7%) of people diagnosed with parkinsonism
have developed their symptoms following treatment with particular
medications.
Drugs - known as neuroleptic drugs - used to treat schizophrenia and
other psychotic disorders block dopamine. These drugs are thought to be
the biggest cause of drug-induced parkinsonism.
Dopamine is a chemical in the brain which allows messages to be sent to
the parts of the brain that co-ordinate movement.
The symptoms of Parkinson's appear when the level of dopamine falls.
The symptoms of drug-induced parkinsonism tend to be static. Only in
rare cases do they change in the manner that the symptoms of
Parkinson's do.
Most people will recover within months, and often within hours or days,
of stopping the drug that caused the dopamine block.
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Dementia with Lewy bodies is similar, in some ways, to
Parkinson's and Alzheimer's.
Symptoms differ slightly from Parkinson's and include
problems with memory and concentration, attention,
language and the ability to carry out simple actions.
People who have dementia with Lewy bodies commonly
experience visual hallucinations and some Parkinson's-type
symptoms, such as slowness of movement, stiffness and
tremor.
Dementia with Lewy bodies is also a progressive condition,
which means that the symptoms can become worse over
time. Currently, there is no cure or treatment for the
condition.
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There is no conclusive evidence that Parkinson's is a
hereditary condition that can be passed on within families,
apart from in exceptionally rare cases.
It is thought that although it is not directly inherited, some
people may have genes that increase the possibility of
developing Parkinson's.
People who have genes that are prone to Parkinson's may be
more likely to develop the condition when combined with
other factors, such as environmental toxins or viruses.
At present, it is estimated that up to 5% of people with
Parkinson's may have a genetic cause.
The role genetics may play in the development of
Parkinson's is currently the subject of much research.

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Juvenile Parkinson's is a term used when the
condition affects people under the age of 20.

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Causes of parkinsonism:
Idiopathic PD:
- Due to loss of dopaminergic neurons of the
substantia nigra
- Progressive loss of dopamine-containing neurons is a
feature of normal aging; however, most people do not
lose the 70% to 80% of dopaminergic neurons required
to cause symptomatic PD
- Death frequently results from complications of
immobility, including aspiration pneumonia or
pulmonary embolism
2) Secondary PD:
L stroke, and UNIVERSITY OF ZAMBIA SCHOOL OF dopaminee.g., following Mweetwa-Pharmacologist - intoxication withMEDICINE ,
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1)

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Aim of treatment is to enhance dopaminergic
pathway or inhibit cholinergic pathway in the
brain

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-Amantadine
-Antimuscarinic agents e.g
benztropine,biperiden,trihexyphenidyl
 Bromocriptine
 Carbidopa
 Deprenyl (selegilline)
 Levodopa
 Pramipexole
 Ropinirole
 Tolcapone
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Levodopa is (the most effective drug used in the treatment of parkinsonism)
Chemistry:
• It is the metabolic precursor of dopamine
Mechanism of action:
•
In the brain, levodopa is converted to dopamine by decarboxylation
primarily within the presynaptic terminals of dopaminergic neurons in the
stratium (by action of L-aromatic amino acid decarboxylase). The
dopamine produced is responsible for the therapeutic effectiveness of the
drug in PD; after release, it is either transported back into dopaminergic
terminals by the presynaptic uptake mechanism or metabolized by the
actions of MAO and catechol-O-methyltransferase (COMT) .

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If levodopa is administered alone, the drug is
largely decarboxylated by enzymes in the
peripheral sites so that little unchanged drug
reaches the cerebral circulation.
In addition, dopamine release into the
circulation by peripheral conversion of
levodopa produces undesirable effects,

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•

In practice, levodopa is administered in combination
with a peripherally acting inhibitor of aromatic Lamino acid decarboxylase, such as carbidopa, that do
not penetrate into the CNS.

•

Inhibition of peripheral decarboxylase markedly
increases the fraction of administered levodopa that
crosses the blood-brain barrier and reduces the
incidence of peripheral side effects.

•

The most commonly prescribed form of
carbidopa/levodopa is the 25/100 form, containing 25
mg carbidopa and 100 mg levodopa.
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Adverse effects:
A) Central:
1)
long-term therapy leads to "wearing off" phenomenon: each
dose of levodopa improves mobility for 1 to 2 hours, but
rigidity and akinesia return at the end of the dosing interval.
Increasing the dose and frequency of administration can
improve this situation, but this often is limited by the
development of dyskinesias (excessive and abnormal
involuntary movements). Patients may fluctuate between
being "off," having no beneficial effects from their
medications, and being "on" but with dyskinesias, a situation
called the on/off phenomenon.
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2) Mental effects
Depression, anxiety, agitation, insomnia,
delusions, hallucinations, euphoria
3) Dyskinesias (excessive and abnormal
involuntary movements) as chorea and tremor

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Peripheral:
Due to formation of dopamine peripherally
1. The most common peripheral side effects are
anorexia, nausea, and vomiting (likely due to
dopamine’s stimulation of the chemoreceptor
trigger zone in the medulla oblongata).
2. Cardiovascular side effects in the form of
orthostatic hypotension and cardiac arrhythmias
 Abrupt withdrawal of levodopa may precipitate
the neuroleptic malignant syndrome.
B.

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Drug Interactions:
1. Pharmacologic doses of pyridoxine (vitamin B6)
enhance the extracerebral metabolism of
levodopa and prevent its therapeutic effect unless
a peripheral decarboxylase inhibitor is also
taken.
2.

Levodopa should not be given to patients taking
monoamine oxidase A inhibitors or within 2
weeks of their discontinuance, because such a
combination can lead to hypertensive crises.
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Contraindications
1. Psychotic patients
2. Angle-closure glaucoma
3. Cardiac disease
4. Peptic ulcer
5. Melanoma

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•
1)

Four orally administered dopamine-receptor
agonists are available for treatment of PD:
Ergot derivatives: as bromocriptine or
pergolide

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Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a
number of pharmacologic effects. Five dopamine receptor types from two
dopaminergic subfamilies have been identified. The dopaminergic D1 receptor
subfamily consists of D1 and D5 subreceptors, which are associated with
dyskinesias. The dopaminergic D2 receptor subfamily consists of D2, D3 and
D4 subreceptors, which are associated with improvement of symptoms of
movement disorders. Thus, agonist activity specific for D2 subfamily receptors,
primarily D2 and D3 receptor subtypes, are the primary targets of dopaminergic
antiparkinsonian agents. It is thought that postsynaptic D2 stimulation is
primarily responsible for the antiparkinsonian effect of dopamine agonists, while
presynaptic D2 stimulation confers neuroprotective effects. This semisynthetic
ergot derivative exhibits potent agonist activity on dopamine D2-receptors. It
also exhibits agonist activity (in order of decreasing binding affinity) on 5hydroxytryptamine (5-HT)1D, dopamine D3, 5-HT1A, 5-HT2A, 5-HT1B, and 5HT2Creceptors, antagonist activity on α2A-adrenergic, α2C, α2B, and dopamine
D1 receptors, partial agonist activity at receptor 5-HT2B, and inactivates
dopamine D4 and 5-HT7 receptors.

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The dopamine D2 receptor is a 7-transmembrane G-protein coupled
receptor associated with Gi proteins. In lactotrophs, stimulation of
dopamine D2 receptor causes inhibition of adenylyl cyclase, which
decreases intracellular cAMP concentrations and blocks IP3-dependent
release of Ca2+ from intracellular stores. Decreases in intracellular
calcium levels may also be brought about via inhibition of calcium influx
through voltage-gated calcium channels, rather than via inhibition of
adenylyl cyclase. Additionally, receptor activation blocks
phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase
phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf
and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopaminestimulated growth hormone release from the pituitary gland is mediated
by a decrease in intracellular calcium influx through voltage-gated
calcium channels rather than via adenylyl cyclase inhibition. Stimulation
of dopamine D2receptors in the nigrostriatal pathway leads to
improvements in coordinated muscle activity in those with movement
disorders.
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E.g ropinirole
Mechanism of action
Ropinirole binds the dopamine receptors D3 and D2.
Although the precise mechanism of action of
ropinirole as a treatment for Parkinson's disease is
unknown, it is believed to be related to its ability to
stimulate these receptors in the striatum. This
conclusion is supported by electrophysiologic studies
in animals that have demonstrated that ropinirole
influences striatal neuronal firing rates via activation
of dopamine receptors in the striatum and the
substantia nigra, the site of neurons that send
projections to the striatum.



PHARMACY FACULTY

Adverse effects:
I. Central:
•
Dyskinesias , mental Disturbances
Peripheral:
A) Gastrointestinal Effects:
• Anorexia and nausea and vomiting
B) Cardiovascular effects:
1. postural hypotension
2. cardiac arrhythmias
3. peripheral vasospasm (with ergot derivatives)

II.

PHARMACY FACULTY

Contraindications
1. Psychotic patients
2. Angle-closure glaucoma
3. Cardiac disease
4. Peptic ulcer
5. Peripheral vascular disease (ergot
derivatives).

PHARMACY FACULTY

Two types of monoamine oxidase (MAO) have been distinguished. Monoamine oxidase (A)
metabolizes norepinephrine and serotonin; monoamine oxidase (B) metabolizes dopamine.
Selegiline:
Mechanism of action:
•
It is therefore used as adjunctive therapy for patients with a declining response to levodopa.

Although the mechanisms for selegiline's beneficial action in the treatment of Parkinson's disease
are not fully understood, the selective, irreversible inhibition of monoamine oxidase type B
(MAO-B) is thought to be of primary importance. MAO-B is involved in the oxidative deamination
of dopamine in the brain. Selegiline binds to MAO-B within the nigrostriatal pathways in the
central nervous system, thus blocking microsomal metabolism of dopamine and enhancing the
dopaminergic activity in the substantial nigra. Selegiline may also increase dopaminergic activity
through mechanisms other than inhibition of MAO-B. At higher doses, selegiline can also inhibit
monozmine oxidase type A (MAO-A), allowing it to be used for the treatment of depression.
Side effects:
•
May cause insomnia when taken later during the day.
Drug interactions:
•
It should not be taken by patients receiving tricyclic antidepressants, or serotonin reuptake
inhibitors because of the risk of acute toxic interactions.
•
The adverse effects of levodopa may be increased by selegiline.

PHARMACY FACULTY

COMT inhibitors
Periphery

CNS (striatum)

3-O-Methyldopa
tolcapone

x

COMT

L-DOPA
carbidopa

x

AAD

Dopamine

DOPAC
selegiline

L-DOPA

AAD

tolcapone

x MAO-B
Dopamine

x

COMT

3-Methoxy
tyramine

PHARMACY FACULTY

Tolcapone
• Mechanism of action:
1.
Inhibit catechol O methyl transferase (COMT) which is
responsible for the conversion of dopa into methyl dopa.
Elevated levels of methyldopa decreases the response to
levodopa, because methyldopa competes with levodopa for
an active carrier mechanism that governs its transport
across the blood-brain barrier.
2. prolong the action of levodopa by diminishing its
peripheral metabolism.
•
•

These agents may be helpful in patients receiving levodopa
to reduce dose and decrease fluctuations in response
Side effects are similar to levodopa
PHARMACY FACULTY

Amantadine, an antiviral agent. Its mode of action in parkinsonism is unclear
Clinical Use
• Amantadine is less potent than levodopa and its effects disappear after only a few
weeks of treatment
• Mechanism of Action
 The mechanism of its antiparkinsonic effect is not fully understood, but it
appears to be releasing dopamine from the nerve endings of the brain cells,
together with stimulation of norepinephrine response. It also has NMDA receptor
antagonistic effects. The antiviral mechanism seems to be unrelated
Adverse Effects
1.
Central nervous system effects 2. Peripheral edema
3.Headache 4. Heart failure . 5.postural hypotension
6. urinary retention 7. gastrointestinal disturbances (eg, anorexia, nausea, constipation, and dry
mouth).
Contraindications
•
Amantadine should be used with caution in patients with a history of seizures or heart failure.
PHARMACY FACULTY

Benztropine
Mechanism of Action
Benztropine is a selective M1 muscarinic acetylcholine
receptor antagonist. It is able to discriminate between the
M1 (cortical or neuronal) and the peripheral muscarinic
subtypes (cardiac and glandular). Benztropine partially
blocks cholinergic activity in the CNS, which is responsible
for the symptoms of Parkinson's disease. It is also thought
to increase the availability of dopamine, a brain chemical
that is critical in the initiation and smooth control of
voluntary muscle movement.
Clinical Use
 Antimuscarinic drugs may improve the tremor and rigidity
of parkinsonism but have little effect on bradykinesia.




PHARMACY FACULTY

Adverse Effects
1) Central nervous system effects, including drowsiness,
restlessness, confusion, agitation, hallucinations, and mood
changes. Dyskinesias occur in rare cases
2) Atropine – like actions: dryness of the mouth, blurring of
vision, urinary retention, nausea and vomiting, constipation,
tachycardia, palpitations, and cardiac arrhythmias.
withdrawal should be gradual in order to prevent acute
exacerbation of parkinsonism.
Contraindications
1. Prostatic hyperplasia,
2. Obstructive gastrointestinal disease (eg, paralytic ileus)
3. Angle-closure glaucoma.

PHARMACY FACULTY

CNS Pharmacology
2.Anxiolytic and Hypnotic Drugs
 L.Mweetwa-Pharmacologist


 Dept of Pharmacy
 Faculty of Medicine



PHARMACY FACULTY




Def:
Anxiety is an unpleasant state of tension,
apprehension or uneasiness arising from
unknown source. Anxiety is the most
common mental disorder.

PHARMACY FACULTY

SEDATION
 Reduction of anxiety
 Calming effect
ANXIOLYTIC
 Drug that reduces anxiety
 Sedative
HYPNOSIS
 Induction of sleep
PHARMACY FACULTY






Verbal complaints. The patient says he/she
is anxious, nervous, edgy.
Somatic and autonomic effects. The
patient is restless and agitated, has
tachycardia, increased sweating, weeping
and often gastrointestinal disorders.
Social effects. Interference with normal
productive activities.
PHARMACY FACULTY

Generalized anxiety disorder (GAD): People
suffering from GAD have general symptoms of
motor tension, autonomic hyperactivity, etc. for at
least one month.
Phobic anxiety:
Simple phobias. Agoraphobia, fear of animals, etc.
Social phobias.
Panic disorders: Characterized by acute attacks of
fear as compared to the chronic presentation of
GAD.
Obsessive-compulsive behaviors: These patients
show repetitive ideas (obsessions) and behaviors
(compulsions).
PHARMACY FACULTY

1). Medical:
a) Respiratory
b) Endocrine
c) Cardiovascular
d) Metabolic
e) Neurologic.
PHARMACY FACULTY

2). Drug-Induced:
 Stimulants

▪ Amphetamines, cocaine, TCAs, caffeine.
 Sympathomimetics
▪ Ephedrine, epinephrine, pseudoephedrine
phenylpropanolamine.
 AnticholinergicsAntihistaminergics
▪ Trihexyphenidyl, benztropine, meperidine
diphenhydramine, oxybutinin.
 Dopaminergics
▪ Amantadine, bromocriptine, L-Dopa,
carbid/levodopa.
PHARMACY FACULTY

 Miscellaneous:

▪ Baclofen, cycloserine, hallucinogens,
indomethacin.

3). Drug Withdrawal:
▪ BDZs, narcotics, BARBs, other
sedatives, alcohol.

PHARMACY FACULTY

Strategy for treatment
Reduce anxiety without causing sedation.

PHARMACY FACULTY

1) Benzodiazepines (BZDs):

2)
3)

4)

5)

Alprazolam, diazepam, oxacepam, triazolam
Barbiturates:
Pentobarbital, phenobarbital
Alcohols:
Ethanol, chloral hydrate, paraldehyde,
trichloroethanol,
Imidazopyridine Derivatives:
Zolpidem
Pyrazolopyrimidine
Zaleplon
PHARMACY FACULTY

6) Propanediol carbamates:
Meprobamate

7) Piperidinediones
Glutethimide

8) Azaspirodecanedione
Buspirone

9) -Blockers**
Propranolol

10) 2-AR partial agonist**
ClonidineL Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY

Others:
11) Antyipsychotics **
Ziprasidone
12) Antidepressants **
TCAs, SSRIs

13) Antihistaminic drugs **
Dephenhydramine
PHARMACY FACULTY

The benzodiazepines are the most
important sedative hypnotics.

Developed to avoid undesirable
effects of barbiturates (abuse
liability).
PHARMACY FACULTY



Benzodiazepines (BDZs) bind to the gamma
sub-unit of the GABA-A receptor. Their
binding causes an allosteric (structural)
modification of the receptor that results in an
increase in GABA A receptor activity. BDZs do
not substitute for GABA, which bind at the
alpha sub-unit, but increase the frequency of
channel opening events which leads to an
increase in chloride ion conductance and
inhibition of the action potential
PHARMACY FACULTY






BDZ have no antipsychotic activity nor any
analgesic action and do not affect the
autonomic nervous system.
Actions
1. Reduction of anxiety: at low dose they
reduce anxiety by selectively inhibiting
neuronal circuits in the limbic system of the
brain
PHARMACY FACULTY







2. Sedative and Hypnotic action: All BDZ have
sedative action and some produce hypnosis at
higher doses.
3. Anticonvulsant action: Several BDZ have
anticonvulsant action and used to treat epilepsy
and seizure disorders.
4. Muscle relaxant: The benzodiazepines relax
spasticity of skeletal muscle probably by
increasing presynaptic inhibition in the spinal
cord.
PHARMACY FACULTY






Pharmacokinetic variation and duration of
action influence the choice of BDZ
1. Anxiety disorders associated with
depression: longer acting drugs such
diazepam are often preferred alprazolam is
effective but may cause withdrawal
reactions.
2. Muscular disorders: such as muscle strain,
cerebral palsy diazepam is effective.
PHARMACY FACULTY





3. Seizures: Clonazepam is useful in chronic
treatment of epilepsy, whereas diazepam is
the drug of choice in terminating grand mal
epileptic seizures and status epilepticus.
Chlordiazepoxide, Clorazepate, diazepam
and oxazepam are useful in the acute
treatment of alcohol withdrawal.

PHARMACY FACULTY



4. Sleep disorders: Not all BDZ have
hypnotic action although all have sedative or
calming action. Drugs of choice for sleep
disorders include, long acting - flurazepam,
intermediate acting – temazepam and short
acting triazolam

PHARMACY FACULTY



Psychological and Physical dependence BDZ
can develop due to prolonged high dosage
use over a prolonged period and abrupt
discontinuation. Because of long half-lives of
some BDZ, withdrawal symptoms may not
occur until after a number of days.

PHARMACY FACULTY






Drowsiness and Confusion
Cognitive impairment
Early morning insomnia
Tolerance

PHARMACY FACULTY

Flumazenil
Mechanism of action
Flumazenil, an imidazobenzodiazepine derivative,
antagonizes the actions of benzodiazepines on
the central nervous system. Flumazenil
competitively inhibits the activity at the
benzodiazepine recognition site on the
GABA/benzodiazepine receptor complex.
Flumazenil is a weak partial agonist in some
animal models of activity, but has little or no
agonist activity in man.



PHARMACY FACULTY

Although BDZs are highly protein bound
(60-95%),
few
clinically
significant
interactions.*
High lipid solubility  high rate of entry
into CNS  rapid onset.
*The only exception is chloral hydrate

PHARMACY FACULTY

Hepatic metabolism. Almost all BDZs
undergo
microsomal
oxidation
(Ndealkylation and aliphatic hydroxylation)
and conjugation (to glucoronides).
Rapid tissue redistribution  long acting
 long half lives and elimination half lives
(from 10 to > 100 hrs).
All BDZs cross the placenta  detectable
in breast milk  may exert depressant
effects on the CNS of the lactating infant.
PHARMACY FACULTY

Many have active metabolites with halflives greater than the parent drug.
Prototype drug is diazepam (Valium),
which has active metabolites (desmethyldiazepam and oxazepam) and is long
acting (t½ = 20-80 hr).
Differing times of onset and elimination
half-lives (long half-life => daytime
sedation).
PHARMACY FACULTY

From Katzung, 1998
PHARMACY FACULTY







Keep in mind that with formation of active
metabolites, the kinetics of the parent drug
may not reflect the time course of the
pharmacological effect.
Estazolam, oxazepam, and lorazepam,
which are directly metabolized to
glucoronides have the least residual
(drowsiness) effects.
All of these drugs and their metabolites are
excreted in urine.
PHARMACY FACULTY







BDZs have a wide margin of safety if used
for short periods. Prolonged use may cause
dependence.
BDZs have little effect on respiratory or
cardiovascular function compared to BARBS
and other sedative-hypnotics.
BDZs depress the turnover rates of
norepinephrine (NE), dopamine (DA) and
serotonin (5-HT) in various brain nuclei.
PHARMACY FACULTY



Drug overdose is treated with flumazenil (a BDZ
receptor antagonist, short half-life), but respiratory
function should be adequately supported and
carefully monitored.



Seizures and cardiac arrhythmias may occur
following flumazenil administration when BDZ are
taken with TCAs.



Flumazenil is not effective against BARBs
overdose.
PHARMACY FACULTY









BDZ's have additive effects with other CNS
depressants (narcotics), alcohol => have a
greatly reduced margin of safety.
BDZs reduce the effect of antiepileptic
drugs.
Combination of anxiolytic drugs should be
avoided.
Concurrent use with antihistaminic and
anticholinergic drugs as well as the
consumption of alcohol should be avoided.
SSRI’s and oral contraceptives decrease
metabolism of BDZs.
PHARMACY FACULTY




Mechanism of action
Barbiturates act on GABAA receptors, increasing
synaptic inhibition. This has the effect of
elevating seizure threshold and reducing the
spread of seizure activity from a seizure focus.
Barbiturates may also inhibit calcium channels,
resulting in a decrease in excitatory transmitter
release. The sedative-hypnotic effects of
Barbiturates are likely the result of polysynaptic
midbrain reticular formation, which controls
CNS arousal.
PHARMACY FACULTY






1. Depression of CNS: is dose dependant
2. Respiratory Depression: barbiturates
suppress the hypoxic and chemoreceptor
response to CO2 and over dosage is followed
by respiratory depression and death.
3. Enzyme induction: they induce Cyt-P450
microsomal enzymes in the liver and reduce
the action of many drugs administered
together with barbiturates.
PHARMACY FACULTY





1. Anaesthesia: e.g short acting drugs like
thiopental.
2. Anticonvulsant : e.g Phenobarbital
3. Anxiety : used as a mild sedative to relieve
anxiety nervous tension and insomnia.

PHARMACY FACULTY

Rapid absorption following oral
administration.
 Rapid onset of central effects.
 Extensively metabolized in liver (except
phenobarbital), however, there are no
active metabolites.
 Phenobarbital is excreted unchanged.
Its excretion can be increased by
alkalinization of the urine.


PHARMACY FACULTY

In the elderly and in those with limited
hepatic function, dosages should be
reduced.
 Phenobarbital and meprobamate cause
autometabolism by induction of liver
enzymes.


PHARMACY FACULTY

Strong physiological dependence may
develop upon long-term use.
 Depression of the medullary respiratory
centers is the usual cause of death of
sedative/hypnotic overdose. Also loss
of brainstem vasomotor control and
myocardial depression.


PHARMACY FACULTY









Withdrawal is characterized by increase
anxiety, insomnia, CNS excitability and
convulsions.
Drugs with long-half lives have mildest
withdrawal (.
Drugs with quick onset of action are most
abused.
No medication against overdose with
BARBs.
Contraindicated in patients with porphyria.
PHARMACY FACULTY

Buspirone
 Chloral hydrate
 Hydroxyzine
 Meprobamate (Similar to BARBS)
 Zolpidem (BZ1 selective)
 Zaleplon (BZ1 selective)


PHARMACY FACULTY








Most selective anxiolytic currently available.
The anxiolytic effect of this drug takes
several weeks to develop => used for GAD.
Buspirone does not have sedative effects
and does not potentiate CNS depressants.
Has a relatively high margin of safety, few
side effects and does not appear to be
associated with drug dependence.
No rebound anxiety or signs of withdrawal
when discontinued.
PHARMACY FACULTY

Side effects:
• Tachycardia, palpitations,
nervousness, GI distress and
paresthesias may occur.
• Causes a dose-dependent pupillary
constriction.

PHARMACY FACULTY

Mechanism of Action:
• Buspirone binds to 5-HT type 1A serotonin receptors on

presynaptic neurons in the dorsal raphe and on postsynaptic
neurons in the hippocampus, thus inhibiting the firing rate of
5-HT-containing neurons in the dorsal raphe. Buspirone also
binds at dopamine type 2 (DA2) receptors, blocking
presynaptic dopamine receptors. Buspirone increases firing in
the locus ceruleus, an area of brain where norepinephrine cell
bodies are found in high concentration. The net result of
buspirone actions is that serotonergic activity is suppressed
while noradrenergic and dopaminergic cell firing is enhanced.
PHARMACY FACULTY









Not effective in panic disorders.
Rapidly absorbed orally.
Undergoes extensive hepatic metabolism
(hydroxylation and dealkylation) to form
several active metabolites (e.g. 1-(2pyrimidyl-piperazine, 1-PP)
Well tolerated by elderly, but may have slow
clearance.
Analogs: Ipsapirone, gepirone, tandospirone.
PHARMACY FACULTY







Structurally unrelated but as effective as
BDZs.
Minimal muscle relaxing and anticonvulsant
effect.
Rapidly metabolized by liver enzymes into
inactive metabolites.
Dosage should be reduced in patients with
hepatic dysfunction, the elderly and patients
taking cimetidine.
PHARMACY FACULTY

Mechanism of Action:
• Zolpidem

modulates the alpha-subunit,
known as the benzodiazepine receptor, within
the GABAA receptor chloride channel
macromolecular
complex.
Unlike
the
benzodiazepines,which
non-selectively
interact with all three alpha-receptor
subtypes, Zolpidem preferentially binds to the
alpha-1 receptor.
• Actions are antagonized by flumazenil
PHARMACY FACULTY




Mechanism of action
Hydroxyzine competes with histamine for
binding at H1-receptor sites on the effector
cell surface, resulting in suppression of
histaminic edema, flare, and pruritus. The
sedative properties of hydroxyzine occur at
the subcortical level of the CNS. Secondary to
its central anticholinergic actions,
hydroxyzine may be effective as an
antiemetic.
PHARMACY FACULTY






Chloral hydrate
Is used in institutionalized patients. It
displaces warfarin (anti-coagulant) from
plasma proteins.
Extensive biotransformation.

PHARMACY FACULTY

2-Adrenoreceptor Agonists (eg. Clonidine)
• Antihypertensive.
• Has been used for the treatment of panic
attacks.
• Has been useful in suppressing anxiety
during the management of withdrawal from
nicotine and opioid analgesics.
• Withdrawal from clonidine, after protracted
use, may lead to a life-threatening
hypertensive crisis.
PHARMACY FACULTY

-Adrenoreceptor Antagonists
(eg. Propranolol)
• Use to treat some forms of anxiety,

particularly when physical (autonomic)
symptoms (sweating, tremor, tachycardia)
are severe.
• Adverse effects of propranolol may
include:
lethargy,
vivid
dreams,
hallucinations.
PHARMACY FACULTY

1. Generalized Anxiety Disorder
Diazepam, lorazepam, alprazolam, buspirone
2. Phobic Anxiety
a. Simple phobia. BDZs
b. Social phobia. BDZs

3. Panic Disorders
TCAs and MAOIs, alprazolam

4. Obsessive-Compulsive Behavior
Clomipramine (TCA), SSRI’s
5. Posttraumatic Stress Disorder (?)
Antidepressants, buspirone
PHARMACY FACULTY



THANK You End

PHARMACY FACULTY

CNS Pharmacology
3. CNS Stimulants







PHARMACY FACULTY



We will look at two groups of drugs that act
primarily to stimulate the central nervous
system, i.e Psychomotor stimulants and
Psychotomimetic drugs.

PHARMACY FACULTY

L MWEETWA-Pharmacologist
UNIVERSITY OF ZAMBIA
PHARMACY FACULTY

Few clinical uses, Important as drugs of abuse.
Factors that limit the therapeutic usefulness include:
1.
Dependence: Psychological and physiological.
2.
Tolerance to the euphoric and anorectic effects
are classified according to their action into:
1.
Psychomotor stimulants
2.
Hallucinogen (psychotomimetic or psychedelics) drugs

PHARMACY FACULTY

1. Psychomotor stimulants
cause: Excitement, Euphoria, Decrease feeling of fatigue &
Increase motor activity
Ex., Methylxanthines (caffeine, theobromine, theophylline), nicotine,
cocaine, amphetamine, atomoxetine, modafinil, methylphenidate.

2. Hallucinogens (psychotomimetic):
Affect thought, perception, and mood, therefore produce
 profound changes in thought patterns & mood,
 little effect on the brain stem & spinal cord
Ex., Lysergic acid diethylamide (LSD), Phencyclidine (PCP),
Tetrahydrocannabinol (THC), Rimonabant.

PHARMACY FACULTY

Q. What are Stimulants?
Answer. Chemical stracture are similar to monoamine
neurotransmitters. All are indirect-acting
sympathomimetics:
1.
Many CNS stimulants release catecholamines, Therefore, their
effects are abolished by prior treatment with reserpine or guanethidine

Ex: amphetamine, dextroamphetamine, methamphetamine,
methylphenidate (Ritalin), ephedrine, pseudoephedrine (a
stereoisomer of ephedrine), tyramine.
2.
Other CNS stimulants block the reuptake of
catecholamines (NE and DA) and serotonin:
EX. Cocaine, sibutramine (reduct)®, modafinil

PHARMACY FACULTY

3.

Drugs with stimulant effects; however, they are marketed
as antidepressants include:
Atomoxetine– a relatively selective NE reuptake inhibitor (ADHD),
Bupropion – blocks the reuptake of both NE and DA.

The methylxanthines are adenosine receptor antagonists.
Drugs within this class are NOT generally considered
“psychomotor” stimulants, but they have distinct
stimulant effects caffeine, theophylline.
NB: MAO and COMT inhibitors (indirect-acting adrenergic
agonists), but they are not traditionally considered to be
stimulants.
4.

PHARMACY FACULTY

Obesity (anorectic agents).
Attention Deficit Hyperactivity Disorder (ADHD); lack the
ability to be involved in any one activity for longer than a few
minutes.
Narcolepsy: It is a relatively rare sleep disorder, that is
characterized by uncontrollable bouts of sleepiness during the
day. It is sometimes accompanied by catalepsy, a loss in muscle
control, or even paralysis brought on by strong emotion, such
as laughter.
Contraindications: patients with anorexia, insomnia, asthenia,
psychopathic personality, a history of homicidal or suicidal
tendencies.
PHARMACY FACULTY

A. methylxanthines
1.
Theophylline (found in tea) : long-acting, prescribed for
night-time asthma
2.
Theobromine: found in cocoa.
3.
Caffeine: (short-acting) the most widely consumed
 found in coffee (200 mg/cup),
 carbonated soft drinks (60 mg/can),
 cocoa and chocolate

PHARMACY FACULTY

several mechanism have been proposed
Mechanism of action of methylxanthine
1-It inhibits phosphodiesterase enz. → ↑ cAMP

↓calcium in
↑ calcium in
Smooth muscles
CNS & heart
2- Adenosine (A1, A2 and A3) receptors antagonist almost

equally, which explains many of its cardiac effects
A2 receptors antagonist responsible for CNS stimulation &
smooth muscles relaxation

PHARMACY FACULTY

a. CNS:
 decrease in fatigue, increased alertness: 100-200 mg caffeine in 1 or 2 cups

of coffees
 Anxiety & tremors- 1.5 g of caffeine: 12-15 cups of coffee
 Spinal cord stimulation: 2-5 g (very high dose)

Tolerance can rapidly develop
Withdrawal symptoms: feeling of fatigue & sedation.

b. CVS; at high dose of caffeine +ve inotropic and chronotropic effects on the
heart, ↑COP
c. Diuretic action: mild ↑ urinary output of Na+, Cl- and K+
d. Gastric mucosa: all methylxanthines stimulate secretion of HCl
e. Respiratory smooth muscle: bronchodilator, Rx asthma replaced by βagonists, corticosteroids.



PHARMACY FACULTY

Pharmacokinetics





The methylxanthines are well absorbed orally.
Caffeine distributes throughout the body, including the
brain. The drugs cross the placenta to the fetus and is
secreted into the mother's milk.
All are metabolized in the liver, generally by the CYP1A2
pathway, the metabolites are then excreted in the urine.

Adverse effects





Moderate doses: insomnia, anxiety, agitation
High doses: emesis, convulsion
Lethal dose (10 gm of caffeine): cardiac arrhythmia
Suddenly stop: lethargy, irritability, headache
PHARMACY FACULTY






Nicotine is the active ingredient in tobacco.
Used in smoking cessation therapy,
Nicotine remains important, because:
 it is 2nd only to caffeine as the most widely used CNS

stimulant
 and 2nd only to alcohol as the most abused drug.
Actions of Nicotine:
Low dose: ganglionic depolarization
High dose: ganglionic blockade

PHARMACY FACULTY

I. CNS:
1. Low dose: euphoria, arousal, relaxation, improves attention,
learning, problem solving and reaction time.
2. High dose: CNS paralysis, severe hypotension (medullary
paralysis)
II. Peripheral effects:
 Stimulation of sympathetic ganglia and adrenal medulla→↑
BP and HR (harmful in HTN patients)
 Stimulation of parasympathetic ganglia→↑ motor activity of
the bowel
 At higher doses, BP falls & activating ceases in both GIT and
bladder
PHARMACY FACULTY

highly lipid soluble absorbed everywhere (oral mucosa, lung,
GIT, skin).
 Crosses the placental membrane, secreted with milk.
 Most cigarettes contain 6-8 mg of nicotine, by inhaling
tobacco smoke, the average smoker takes in 1 to 2 mg of
nicotine per cigarette.
 the acute lethal dose is 60 mg,
 90% of nicotine inhaled in smoke is absorbed.
 Tolerance to toxic effects of nicotine develops rapidly.


PHARMACY FACULTY

CNS; irritability and tremors
Intestinal cramps, diarrhea
↑HR & BP
Withdrawal syndrome: nicotine is
addictive substance,
 physical dependence on nicotine
develops rapidly and can be severe.
 Bupropion: can reduce the craving
for cigarettes
 Transdermal patch and chewing
gum containing nicotine




PHARMACY FACULTY






partial agonist at Nn receptor in CNS.
It produces less euphoric effects than
those produced by nicotine itself
(nicotine is full agonist at these
receptors).
Thus, it is useful as an adjunct in the
management of smoking cessation in
patients with nicotine withdrawal
symptom.

PHARMACY FACULTY

1. Mechanism of action: blockade
of reuptake of the monoamines
(NE, serotonin and dopamine)
Thus, potentiates and prolongs
the CNS and peripheral actions of
these monoamines.

PHARMACY FACULTY





Initially produces the intense
euphoria by prolongation of
dopaminergic effects in the brain’s
pleasure system (limbic system).
Chronic intake of cocaine depletes
dopamine. This depletion triggers
the vicious cycle of craving for
cocaine that temporarily relieves
severe depression.

PHARMACY FACULTY

a. CNS-behavioral effects result from powerful stimulation of
cortex and brain stem.
 Cocaine acutely increase mental awareness and produces a
feeling of wellbeing and euphoria similar to that produced
by amphetamine.
 Like amphetamine, cocaine can produce hallucinations and
delusions of paranoia or grandiosity.
 Cocaine increases motor activity, and at high doses, it
causes tremors and convulsions, followed by respiratory
and vasomotor depression.

PHARMACY FACULTY

b. Sympathetic NS: peripherally potentiate the action of NE→
fight or flight
c. Hyperthermia:
 impair sweating & cutaneous vasodilation
 ↓Perception of thermal discomfort
d. local anesthetic action: blockade of voltage-activated Na+
channel.
 Cocaine is the only LA that causes vasoconstriction, chronic
inhalation of cocaine powder → necrosis and perforation of
the nasal septum
 Cocaine is often self-administered by chewing, intranasal
snorting, smoking, or intravenous (IV) injection.
PHARMACY FACULTY



Anxiety reaction that includes: hypertension, tachycardia,
sweating, and paranoia.

Because of the irritability, many users take cocaine with alcohol. A product of
cocaine metabolites and ethanol is cocaethylene, which is also psychoactive
and cause cardiotoxicity.
 Depression: Like all stimulant drugs, cocaine stimulation of the CNS is
followed by a period of mental depression.
 Addicts withdrawing from cocaine exhibit physical and emotional
depression as well as agitation. The latter symptom can be treated with
benzodiazepines or phenothiazines.
 Toxic effects:
 Seizures RX I.V diazepam
 fatal cardiac arrhythmias. propranolol

PHARMACY FACULTY

Is a non catecholamine, (shows neurologic and clinical
effects quite similar to those of cocaine),
 dextroamphetamine is the major member of this class
compounds.
 methamphetamine (speed) is a derivative of amphetamine
that can be smoked and it is preferred by many abusers.
 Methylenedioxymethamphetamine (also known as
MDMA, or Ecstasy) is a synthetic derivative of
methamphetamine with both stimulant and hallucinogenic
properties.


PHARMACY FACULTY

Amphetamine, act by
 releasing intracellular

stores of catecholamines.
 also inhibits MAO, high
level CAOs are readily
released into synaptic
spaces.

PHARMACY FACULTY

a. CNS: the major behavioral effects of amphetamine result
from a combination of its dopamine and NE release
enhancing properties.
 Amphetamine stimulates the entire cerebrospinal axis,
brainstem, and medulla.
 This lead to increase alertness, decrease fatigue, depressed
appetite, and insomnia.
b. Sympathetic Nervous System: indirectly stimulating the
receptors through NE release.

PHARMACY FACULTY






Amphetamine, methylphenidate.
Recently, a new drug, modafinil and its R-enantiomer
derivative, armodafinil, have become available to treat
narcolepsy.
Modafinil produces fewer psychoactive and euphoric effects
as well as, alterations in mood, perception, thinking, and
feelings typical of other CNS stimulants.

PHARMACY FACULTY

The amphetamines may cause addiction, dependence,
tolerance, and drug seeking behavior.
a. CNS: insomnia, irritability, weakness, dizziness, tremor,
hyperactive reflex, confusion, delirium, panic states, and suicidal
tendencies, especially in mentally ill patients.
-Chronic amphetamine use produce a state of “amphetamine
psychosis” that resembles the psychotic episodes associated
with schizophrenia.
-Whereas long-term amphetamine is associated with psychic
and physical dependence, tolerance to its effects may occur
within a few weeks.
PHARMACY FACULTY

Overdoses are treated with chlorpromazine or haloperidol,
which relieve the CNS symptoms as well as the HTN because
of their α–blocking effects.
The anorectic effect of amphetamine is due to its action in the
lateral hypothalamic feeding center.
b. CVS: palpitations, cardiac arrhythmia, HTN, anginal pain,
and circulatory collapse. Headache, chills, and excess
sweating may also occur.
c. GIT: anorexia, nausea, vomiting, abdominal cramps, and
diarrhea.
Contraindications: HTN, CV diseases, Hyperthyroidism,
Glaucoma, Patients with a history of drug abuse

PHARMACY FACULTY





approved for ADHD in children and adults.
It is a NE reuptake inhibitor (should not be taken by
individual on MAOI).
It is not habit forming and is not a controlled substance.

PHARMACY FACULTY

It has CNS stimulant properties similar to those of
amphetamine and may also lead to abuse, although its
addictive potential is controversial.
 It is taken daily by 4-6 million children in the USA. The
pharmacologically active isomer, Dexmethylphenidate, has
been approved in the USA for the Rx of ADHD.
 Methylphenidate is a more potent dopamine transport
inhibitor than cocaine, thus making more dopamine
available.
 It has less potential for abuse than cocaine, because it enters
the brain much more slowly than cocaine and, does not
increase dopamine levels as rapidly.


PHARMACY FACULTY





Methylphenidate has been used for several decades in the
treatment of ADHD in children aged 6 to 16.
It is also effective in the treatment of narcolepsy.
Unlike methylphenidate, dexmethylphenidate is not
indicated in the treatment of narcolepsy.

PHARMACY FACULTY

GIT effects are the most common; abdominal pain and nausea.
Other reactions include anorexia, insomnia, nervousness, and
fever.
 In seizure patients, methylphenidate seems to increase the
seizure frequency, especially if the patient is taking
antidepressants.
 Methylphenidate is contraindicated in patients with
glaucoma.



PHARMACY FACULTY





A few drugs have the ability to induce altered perceptual
states reminiscent of dreams, are accompanied by bright,
colourful changes in the environment and by a plasticity of
constantly changing shapes and colour.
The individual under the influence of these drugs is
incapable of normal decision making, because the drug
interferes with rational thought.

PHARMACY FACULTY






Multiple sites in the CNS are affected by lysergic acid
diethylamide (LSD).
The drug shows serotonin (5-HT) agonist activity at
presynaptic 5-HT1 receptors in the midbrain, and also
stimulates 5-HT2 receptors.
Activation of the sympathetic nervous system occurs, which
causes pupillary dilation, increased BP, piloerection, and
increased body temperature.

PHARMACY FACULTY





include hyperreflexia, nausea, and muscular weakness.
High doses may produce long-lasting psychotic changes in
susceptible individuals.
Haloperidol and other neuroleptics can block the
hallucinatory action of LSD and quickly abort the syndrome.

PHARMACY FACULTY

The main psychoactive alkaloid contained in marijuana is
tetrahydrocannabinol (THC), which is available as
dronabinol.
 THC can produce euphoria, followed by drowsiness and
relaxation.
 affect short-term memory and mental activity,
 decreases muscle strength
 and impairs highly skilled motor activity, such as that
required to drive a car.
 Its wide range of effects includes:
appetite stimulation, xerostomia, visual hallucinations,
delusions, and enhancement of sensory activity


PHARMACY FACULTY

THC receptors, designated CB1 receptors, have been found
on inhibitory presynaptic nerve terminals. CB1 is coupled to
a G protein.
 Interestingly, endocannabinoids have been identified in the
CNS.
 These compounds, which bind to the CB1 receptors, are
membrane-derived and are synthesized on demand, and
they may act as local neuromodulators.
 The action of THC is believed to be mediated through the
CB1 receptors but is still under investigation.


PHARMACY FACULTY









The effects of THC appear immediately after the drug is
smoked, but maximum effects take about 20 minutes. By 3
hours, the effects largely disappear.
Dronabinol is administered orally and has a peak effect in 2
to 4 hours. Its psychoactive effects can last up to 6 hours,
but its appetite-stimulant effects may persist for 24 hours.
It is highly lipid soluble and has a large volume of
distribution.
THC itself is extensively metabolized by the mixedfunction oxidases.
Elimination: is largely through the biliary route.

PHARMACY FACULTY

as an appetite stimulant for patients with acquired
immunodeficiency syndrome who are losing weight.
2. It is also sometimes given for the severe emesis caused by
some cancer chemotherapeutic agents.
Adverse effects: include increased heart rate, decreased
blood pressure, and reddening of the conjunctiva.
 At high doses, a toxic psychosis develops. Tolerance and
mild physical dependence occur with continued, frequent
use of the drug.
1.

PHARMACY FACULTY

Rimonabant: The CB1-receptor antagonist,
1. Obesity (decrease appetite and body weight in humans).
2. induce psychiatric disturbances, such as anxiety and
depression, during clinical trials.

PHARMACY FACULTY







Phencyclidine (also known as PCP, or “angel dust”)
inhibits the reuptake of dopamine, 5-HT, and
norepinephrine.
The major action of phencyclidine is to block the ion
channel regulated by the NMDA subtype of glutamate
receptor. This action prevents the passage of critical ions
(particularly Ca2+) through the channel.
Phencyclidine also has anticholinergic activity but,
surprisingly, produces hypersalivation.

PHARMACY FACULTY





Phencyclidine, an analog of ketamine, causes dissociative
anesthesia (insensitivity to pain, without loss of
consciousness) and analgesia.
At increased dosages, anesthesia, stupor, or coma result,
but strangely, the eyes may remain open. Increased
sensitivity to external stimuli exists, and the CNS actions
may persist for a week.

PHARMACY FACULTY

CNS Pharmacology
4. Anesthetics







PHARMACY FACULTY



General anesthesia (GA) is the state produced
when a patient receives medications for
amnesia, analgesia, muscle paralysis, and
sedation. An anesthetized patient can be
thought of as being in a controlled, reversible
state of unconsciousness. Anesthesia enables a
patient to tolerate surgical procedures that
would otherwise inflict unbearable pain,
potentiate extreme physiologic exacerbations,
and result in unpleasant memories.
PHARMACY FACULTY

The combination of anesthetic agents used for
general anesthesia often leaves a patient with
the following clinical constellation:
 1. Unarousable even secondary to painful stimuli
 2. Unable to remember what happened
(amnesia)
 3. Unable to maintain adequate airway
protection and/or spontaneous ventilation as a
result of muscle paralysis
 4. Cardiovascular changes secondary to
stimulant/depressant effects of anesthetic
agents


PHARMACY FACULTY













General anesthesia uses intravenous and inhaled agents to allow
adequate surgical access to the operative site. A point worth noting is
that general anesthesia may not always be the best choice; depending
on a patient’s clinical presentation, local or regional anesthesia may be
more appropriate.
Anesthesia providers are responsible for assessing all factors that
influence a patient's medical condition and selecting the optimal
anesthetic technique accordingly. Attributes of general anesthesia
include the following:
Advantages Reduces intraoperative patient awareness and recall
Allows proper muscle relaxation for prolonged periods of time
Facilitates complete control of the airway, breathing, and circulation
Can be used in cases of sensitivity to local anesthetic agent
Can be administered without moving the patient from the supine
position
Can be adapted easily to procedures of unpredictable duration or extent
Can be administered rapidly and is reversible
PHARMACY FACULTY








Disadvantages Requires increased complexity of care and
associated costs
Requires some degree of preoperative patient preparation
Can induce physiologic fluctuations that require active
intervention
Associated with less serious complications such as nausea
or vomiting, sore throat, headache, shivering, and delayed
return to normal mental functioning
Associated with malignant hyperthermia, a rare, inherited
muscular condition in which exposure to some (but not all)
general anesthetic agents results in acute and potentially
lethal temperature rise, hypercarbia, metabolic acidosis,
and hyperkalemia
PHARMACY FACULTY







1. Relieve anxiety- Benzodiazepines
2. Relax Muscles- Muscle relaxants
3. Prevention of fluids into the respiratory
tract- Anticholinergics
4. Rapid Induction of anesthesia- Short
acting Barbiturates
5. Prevention of Post Surgical vomitingantiemetic drugs
PHARMACY FACULTY

Ether Operation 1846

PHARMACY FACULTY



General anesthesia includes:
 Analgesia
 Amnesia

 Loss of consciousness
 Inhibition of sensory and autonomic reflexes
 Skeletal muscle relaxation.
 For the purpose of this lecture, only commonly

used anesthetic drugs will be discussed in details.
PHARMACY FACULTY



Anesthetics depress activity of neurons in
many regions of the brain.



A primary target of many anesthetics is the
GABAA receptor channel



Anesthetics directly activate GABAA
receptors, but can also facilitate the action of
GABA.
PHARMACY FACULTY



Ketamine does not affect GABAA it
antagonizes glutamic acid on NMDA
receptor.



Inhaled anesthetics also cause membrane
hyperpolarization via activation of potassium
channels.

PHARMACY FACULTY

1.

Analgesia: first analgesia, later analgesia
and amnesia.

2.

Excitement: delirium, excitement, irregular
respiration, vomiting & incontinency.

PHARMACY FACULTY

3.

Surgical Anesthesia: the recurrence of
regular respiration.
The most reliable indication is loss of the
eyelash reflex and regular respiratory
pattern.

4.

Medullary Depression: severe depression of
the vasomotor and respiratory center.
PHARMACY FACULTY



MAC stands for: Minimum Alveolar
Anesthetic Concentration



In steady state, the partial pressure of an
inhaled anesthetic in the brain equals that in
the lung



MAC is the concentration that results in
immobility in 50% of patients when exposed
to a noxious stimulus (eg, surgical incision).
PHARMACY FACULTY






MAC values decrease in elderly patients and
with hypothermia, but are not affected by
sex, height, and weight.
Presence of adjuvant drugs can reduce MAC
dramatically.
Nitrous oxide can be used as a "carrier" gas at
40% of its MAC, decreasing the anesthetic
requirement of other inhaled anesthetics to
70% of their MAC
PHARMACY FACULTY



The rate at which a given concentration of
anesthetic in the brain is reached depends on:
 Solubility properties

 Concentration in the inspired air
 Pulmonary ventilation
 Pulmonary blood flow
 Arteriovenous concentration gradient
PHARMACY FACULTY



Blood:gas partition coefficient defines the
relative affinity of an anesthetic for the blood
compared to air.



The partition coefficients for poorly soluble
gases are < 0.5 and for very soluble gases can
be more than 10

PHARMACY FACULTY



If blood solubility is low, few molecules raise
the arterial tension quickly and vice versa



Compounds that are not very soluble in
blood, rapidly equilibrate with the brain and
have fast onset of action.

PHARMACY FACULTY



It is directly proportionate to the rate of
induction of anesthesia by increasing the rate
of transfer into the blood.

PHARMACY FACULTY



The rise of gas tension in arterial blood is
directly dependent on both the rate and
depth of ventilation.



Increase in ventilation has a slight effect for
gases with low blood solubility but
significantly increases tension of agents with
moderate or high blood solubility.
PHARMACY FACULTY



Increase in pulmonary blood flow (increased
cardiac output) slows the rate of rise in
arterial tension.

PHARMACY FACULTY



Pulmonary veins contain less anesthetic than
arteries. The greater this difference, the more
has been taken up by the body and
achievement of equilibrium with the brain is
more delayed.

PHARMACY FACULTY



One of the most important factors governing
rate of recovery is the blood:gas partition
coefficient



Elimination by hyperventilation is limited
since the concentration in the lungs cannot
be reduced below zero.

PHARMACY FACULTY



Gases that are relatively insoluble in blood
and brain are eliminated faster.



The duration of exposure to the anesthetic
have a marked effect on the time of recovery,
especially for more soluble gases.

PHARMACY FACULTY





Despite their solubilities, the elimination of
halothane is more rapid than enflurane
because 40% of halothane versus 10% of
enflurane is metabolized.
Sevoflurane is degraded by contact with the
carbon dioxide absorbent in anesthesia
machines, yielding "compound A" that causes
renal damage if high concentrations are
absorbed.
PHARMACY FACULTY



In terms of the extent of metabolism of
inhaled anesthetics, the rank order is:
Methoxyflurane > Halothane > Enflurane >
Sevoflurane > Isoflurane > Desflurane >
Nitrous Oxide

PHARMACY FACULTY



All gases decrease arterial pressure in direct
proportion to their alveolar concentration.



Halothane and enflurane reduce cardiac
output



Isoflurane, desflurane, and sevoflurane
decrease systemic vascular resistance



Bradycardia is often seen with halothane
(vagal stimulation).
PHARMACY FACULTY



Nitrous oxide in combination with potent
gases produces sympathetic stimulation that
minimizes cardiac depressant effects.



Halothane & isoflurane sensitize the
myocardium to catecholamines. Arrhythmias
may occur in patients with cardiac disease who
are given sympathomimetics or are anxious.

PHARMACY FACULTY







All gases are respiratory depressants but it is
lessened by surgical stimulation.
Isoflurane and enflurane are the most
depressant.
Inhaled anesthetics decrease the ventilatory
response to hypoxia.
Concentrations that still exist during recovery
depress the increase in ventilation during
hypoxia.
PHARMACY FACULTY



Inhaled anesthetics are bronchodilators.



Halothane and sevoflurane the anesthetics of
choice in patients with airway problems.



The pungency of enflurane may elicit breath
holding, which can decrease the speed of
induction.

PHARMACY FACULTY






Most volatile agents decrease cerebral
vascular resistance, increase cerebral blood
flow and ICP.
It is prudent not to use enflurane in patients
with a history of seizure.
Nitrous oxide has analgesic and amnesic
actions which in combination with other
agents is useful in general and dental
anesthesia.
PHARMACY FACULTY



Kidney
 All gases decrease GFR and renal plasma flow in spite of

well-maintained or even increased perfusion pressures


Liver
 All gases decrease hepatic blood flow from 15% to 45%.



Uterine smooth muscle
 The halogenated gases are potent uterine muscle

relaxants. (Useful for intrauterine fetal manipulation or
manual extraction of a retained placenta).
PHARMACY FACULTY



Hepatotoxicity
 Hepatotoxicity due to halothane is one in 20,000–

35,000. Obese patients having several exposures
to halothane are more susceptible.


Nephrotoxicity
 Metabolism of methoxyflurane releases

nephrotoxic inorganic fluoride so it is obsolete for
most purposes.
PHARMACY FACULTY



Malignant hyperthermia
 It is an autosomal dominant genetic disorder of

skeletal muscle occurs by inhaled agents and muscle
relaxants (eg,succinylcholine).
 Consists of: the rapid onset of tachycardia,
hypertension, severe muscle rigidity, hyperthermia,
hyperkalemia and acidosis
 Treatment consists of correction of metabolic
disturbances and administration of dantrolene.
PHARMACY FACULTY



Reproduction
 Female operating room personnel have a higher

than expected incidence of miscarriages but the
evidence is not strong.


Hematotoxicity
 Prolonged exposure to nitrous oxide causes

megaloblastic anemia especially in poorly
ventilated dental operating suites.
PHARMACY FACULTY





Intravenous anesthetics have an onset of
action faster than the fastest of the gaseous
agents so they are used for induction of
anesthesia.
Consist of:
 Barbiturates (thiopental, methohexital)
 Propofol
 Etomidate
 Ketamine
PHARMACY FACULTY



Thiopental can produce loss of consciousness
(hypnosis) in one circulation time.



Because of its rapid removal from brain tissue a
single dose of thiopental is so short-acting.



Large doses of thiopental decreases blood pressure
and cardiac output and depresses respiration



Cerebral blood flow is decreased. (A desirable drug
for patients with head trauma or brain tumors)
PHARMACY FACULTY



Its onset of action is similar to thiopental but
recovery is more rapid (similar to the shortestacting inhaled anesthetics).



Postoperative nausea and vomiting is less common
because propofol has antiemetic actions.



Because of strong negative inotropic effects,
propofol causes a marked decrease in blood
pressure and is a respiratory depressant.
PHARMACY FACULTY



Etomidate causes minimal cardiovascular and
respiratory depression.



Etomidate produces a rapid loss of consciousness
and rapid recovery (< 5 minutes).



Etomidate causes a high incidence of pain on
injection, myoclonus, and postoperative nausea and
vomiting.



Etomidate may cause adrenocortical suppression
and decrease in hydrocortisone after a single dose.
PHARMACY FACULTY







Ketamine produces dissociative anesthesia,
characterized by: catatonia, amnesia, and
analgesia, with or without loss of
consciousness.
Ketamine is the only intravenous anesthetic
that possesses analgesic properties and
produces cardiovascular stimulation.
Ketamine markedly increases cerebral blood
flow and intracranial pressure.
PHARMACY FACULTY



Ketamine may produce postoperative
sensory and perceptual illusions,
disorientation and vivid dreams (emergence
phenomena).



It is considered useful for poor-risk geriatric
patients and in cardiogenic or septic shock.



It is also used in children undergoing painful
procedures (eg, dressing changes for burns).
PHARMACY FACULTY






Remifentanil (opioid) has an extremely short
duration of action
Fentanyl and droperidol together produce
analgesia and amnesia and are used with
nitrous oxide to provide
neuroleptanesthesia.
Midazolam is frequently given intravenously
before induction of general anesthesia
because it causes amnesia (> 50%)
PHARMACY FACULTY

Twalumba!

PHARMACY FACULTY

CNS Pharmacology
5. Antidepressant Drugs







PHARMACY FACULTY

Psychopharmacology

L MWEETWA-Pharmacologist

PHARMACY FACULTY

Drugs affecting the cns psychopharmacology by pharmacologist l mweetwa

Drugs affecting the cns psychopharmacology by pharmacologist l mweetwa

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