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

A gap between two neurons



Mostly chemical



Rarely electrical
 Mostly present in lower animals
 Gap junctions

...
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY


Presynaptic membrane
 Contains neurotransmitter

vesicles


Synaptic cleft



Postsynaptic membrane
 Contains recep...
Action potential passes from the presynaptic
neuron to the postsynaptic neuron
Although an axon conducts both ways, conduc...


Chemicals that facilitate signal transmission across a synapse



Neurotransmitters are released on the presynaptic si...


“At rest”, the synapse contains numerous synaptic vesicles filled
with neurotransmitter



Intracellular calcium level...
Ca2+

Ca2+

L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
Once released, the neurotransmitter molecules diffuse across the
synaptic cleft
 When they “arrive” at the postsynaptic m...


Excitation
 1. Na+ influx cause accumulation of positive

charges causing excitation
 2. Decreased K+ efflux or Cl- i...


Inhibition
 1. Efflux of K+
 2. Influx of Cl 3. activation of receptor enzymes to inhibit

metabolic functions or to...


Excitatory effects of neurotransmitters
 EPSP: excitatory post synaptic potential



Inhibitory effects of neurotrans...


Synaptic integration

 On average, each neuron in the brain receives about

10,000 synaptic connections from other neu...
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
 First neurotransmitter discovered in 1921
 secreted by motor neurons, autonomic nerves, large

pyramidal cells of the m...
 present in the autonomic nerves, brain stem,

hypothalamus, locus ceruleus of the pons
 Mostly it causes excitation but...
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present in the cerebral cortex, hypothalamus
secreted by neurons in the basal ganglia
Mainly inhibitory
Invol...

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Present in the basal ganglia
Also present in the spinal cord, cerebellum &
many other areas of the Cortex
Major i...



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Present in the synapses of the spinal cord,
interneurons
also present in the retina
Inhibitory (increase Cl influ...


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

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and other ...
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secreted by the nuclei originating in the
median raphe of the brain stem and
terminate in dorsal horn of the...


histamine:
 present in pathways from hypothalamus to

cortical areas & spinal cord
 receptors: H1, H2, H3 (all presen...


synthesized by ribosomes in the cell body



ER and Golgi apparatus enzymatically split the large
molecule into smalle...


however vesicle is autolysed and not reused



quantity of neuropeptides released is smaller than that of
other neurot...


Removal of neurotransmitter:
by diffusion into the surrounding fluids
enzymatic destruction (Ach)
active transport re-u...


Endorphin

 present in pituitary, earliest discovered opioid peptide



enkephalins: met-enkephalin, leu-enkephalin

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

– GH
– Gast...


nitrous oxide (NO)
 present in brain
 probably involved in memory

L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SC...


Neurotransmitters transmit an impulse from
one neuron to another



Neuromodulator modulate regions or
circuits of the...
This is a modified
synapse
 Consists of


 Presynaptic membrane

(nerve terminal)
 Synaptic cleft
 Postsynaptic membr...
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
Terminal has synaptic vesicles and mitochondria
Mitochondria (ATP) are present inside the presynaptic
terminal

Vesicles c...
Presynaptic membrane contain voltage-gated
Ca channels
The quantity of neurotransmitter released is
proportional to the nu...
Ca2+

Ca2+

L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY



Postsynaptic membrane contain receptors for the
neurotransmitter released
eg: Acetylcholine receptor
Na+

Ach

•This ...


Na+ influx causes depolarisation of the
membrane
 End Plate Potential (EPP)
▪ This is a graded potential
▪ Once this r...


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



Each nerve impulse release 60 Ach vesicles



Each...


Even at rest small quanta are released



Which creates a minute depolarising spike
called Miniature End Plate Potenti...


After the Ach binding is over



Cholinesterase present in the synaptic cleft
will hydrolyse Ach into choline and acet...


A cellular process responsible for movement of
mitochondria, lipids, synaptic vesicles, proteins, and other
organelles ...


NMJ not well developed



Smooth muscle does not depend on motor neurons to be stimulated



However, motor neurons (...
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA
SCHOOL OF MEDICINE , PHARMACY FACULTY
CNS Pharmacology
L.Mweetwa-Pharmacologist

University of Zambia
Dept of Pharmacy
Faculty of Medicine

L Mweetwa-Pharmacolo...


Parkinsonism is a progressive degenerative,
extrapyramidal disorder of muscle movement, due
to dysfunction in basal gan...


It is slowness in initiating and carrying out
voluntary movements. It is called poverty and
suppression of voluntary mo...


Rigidity is due to increased muscle tone. The
rigidity affects the opposing muscles equally,
flexors and extensors. Rig...


Tremors are defined as rhythmic oscillatory
movements caused by the opposing muscles
around a joint. Tremors of Parkins...
Dyskinesia: Abnormal involuntary movements
Chorea: It consists of irregular, unpredictable, involuntary
muscle jerks that ...


The degeneration of neurons occurs in substantia nigra pars
compacta and the nigrostriatal tract that are dopaminergic
...


Substantia Nigra:
 The substantia nigra pars compacta is the source



dopaminergic neurons that travel through nigro...


In Parkinson’s disease dopaminergic
inhibitory activity is reduced and cholinergic
excitatory activity is increased. Th...


Drug therapy is aimed at restoring the
balance between the dopaminergic and
cholinergic components, which is achieved
b...
Idiopathic Parkinson's disease
 Idiopathic Parkinson's disease - or Parkinson's - is
the most common type of parkinsonism...
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Vascular parkinsonism is one of the atypical forms of
parkinsonism.
The most likely causes of vascular parkinso...
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A small number (around 7%) of people diagnosed with parkinsonism
have developed their symptoms following t...
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Dementia with Lewy bodies is similar, in some ways, to
Parkinson's and Alzheimer's.
Symptoms differ slightly fr...
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


There is no conclusive evidence that Parkinson's is a
hereditary condition that can be passed on within fami...


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

L Mweetwa-Pharmacologist - ...
Causes of parkinsonism:
Idiopathic PD:
- Due to loss of dopaminergic neurons of the
substantia nigra
- Progressive loss of...


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

L Mweetwa-Pharmacologi...
-Amantadine
-Antimuscarinic agents e.g
benztropine,biperiden,trihexyphenidyl
 Bromocriptine
 Carbidopa
 Deprenyl (seleg...
Levodopa is (the most effective drug used in the treatment of parkinsonism)
Chemistry:
• It is the metabolic precursor of ...




If levodopa is administered alone, the drug is
largely decarboxylated by enzymes in the
peripheral sites so that lit...
•

In practice, levodopa is administered in combination
with a peripherally acting inhibitor of aromatic Lamino acid decar...
Adverse effects:
A) Central:
1)
long-term therapy leads to "wearing off" phenomenon: each
dose of levodopa improves mobili...
2) Mental effects
Depression, anxiety, agitation, insomnia,
delusions, hallucinations, euphoria
3) Dyskinesias (excessive ...
Peripheral:
Due to formation of dopamine peripherally
1. The most common peripheral side effects are
anorexia, nausea, and...
Drug Interactions:
1. Pharmacologic doses of pyridoxine (vitamin B6)
enhance the extracerebral metabolism of
levodopa and ...
Contraindications
1. Psychotic patients
2. Angle-closure glaucoma
3. Cardiac disease
4. Peptic ulcer
5. Melanoma

L Mweetw...
•
1)

Four orally administered dopamine-receptor
agonists are available for treatment of PD:
Ergot derivatives: as bromocr...


Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a
number of pharmacologic effects. Five ...


The dopamine D2 receptor is a 7-transmembrane G-protein coupled
receptor associated with Gi proteins. In lactotrophs, s...
E.g ropinirole
Mechanism of action
Ropinirole binds the dopamine receptors D3 and D2.
Although the precise mechanism of ac...
Adverse effects:
I. Central:
•
Dyskinesias , mental Disturbances
Peripheral:
A) Gastrointestinal Effects:
• Anorexia and n...
Contraindications
1. Psychotic patients
2. Angle-closure glaucoma
3. Cardiac disease
4. Peptic ulcer
5. Peripheral vascula...
Two types of monoamine oxidase (MAO) have been distinguished. Monoamine oxidase (A)
metabolizes norepinephrine and seroton...
COMT inhibitors
Periphery

CNS (striatum)

3-O-Methyldopa
tolcapone

x

COMT

L-DOPA
carbidopa

x

AAD

Dopamine

DOPAC
se...
Tolcapone
• Mechanism of action:
1.
Inhibit catechol O methyl transferase (COMT) which is
responsible for the conversion o...
Amantadine, an antiviral agent. Its mode of action in parkinsonism is unclear
Clinical Use
• Amantadine is less potent tha...
Benztropine
Mechanism of Action
Benztropine is a selective M1 muscarinic acetylcholine
receptor antagonist. It is able to ...
Adverse Effects
1) Central nervous system effects, including drowsiness,
restlessness, confusion, agitation, hallucination...
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
CNS Pharmacology
2.Anxiolytic and Hypnotic Drugs
 L.Mweetwa-Pharmacologist


University of Zambia
 Dept of Pharmacy
 F...



Def:
Anxiety is an unpleasant state of tension,
apprehension or uneasiness arising from
unknown source. Anxiety is th...
SEDATION
 Reduction of anxiety
 Calming effect
ANXIOLYTIC
 Drug that reduces anxiety
 Sedative
HYPNOSIS
 Induction of...





Verbal complaints. The patient says he/she
is anxious, nervous, edgy.
Somatic and autonomic effects. The
patient i...
Generalized anxiety disorder (GAD): People
suffering from GAD have general symptoms of
motor tension, autonomic hyperactiv...
1). Medical:
a) Respiratory
b) Endocrine
c) Cardiovascular
d) Metabolic
e) Neurologic.
L Mweetwa-Pharmacologist - UNIVERSI...
2). Drug-Induced:
 Stimulants

▪ Amphetamines, cocaine, TCAs, caffeine.
 Sympathomimetics
▪ Ephedrine, epinephrine, pseu...
 Miscellaneous:

▪ Baclofen, cycloserine, hallucinogens,
indomethacin.

3). Drug Withdrawal:
▪ BDZs, narcotics, BARBs, ot...
Strategy for treatment
Reduce anxiety without causing sedation.

L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF...
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
1) Benzodiazepines (BZDs):

2)
3)

4)

5)

Alprazolam, diazepam, oxacepam, triazolam
Barbiturates:
Pentobarbital, phenobar...
6) Propanediol carbamates:
Meprobamate

7) Piperidinediones
Glutethimide

8) Azaspirodecanedione
Buspirone

9) -Blockers**...
Others:
11) Antyipsychotics **
Ziprasidone
12) Antidepressants **
TCAs, SSRIs

13) Antihistaminic drugs **
Dephenhydramine...
The benzodiazepines are the most
important sedative hypnotics.

Developed to avoid undesirable
effects of barbiturates (ab...


Benzodiazepines (BDZs) bind to the gamma
sub-unit of the GABA-A receptor. Their
binding causes an allosteric (structura...
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY





BDZ have no antipsychotic activity nor any
analgesic action and do not affect the
autonomic nervous system.
Action...




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2. Sedative and Hypnotic action: All BDZ have
sedative action and some produce hypnosis at
higher doses.
3. Antic...
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Pharmacokinetic variation and duration of
action influence the choice of BDZ
1. Anxiety disorders associated with
...




3. Seizures: Clonazepam is useful in chronic
treatment of epilepsy, whereas diazepam is
the drug of choice in termin...


4. Sleep disorders: Not all BDZ have
hypnotic action although all have sedative or
calming action. Drugs of choice for ...


Psychological and Physical dependence BDZ
can develop due to prolonged high dosage
use over a prolonged period and abru...
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
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Drowsiness and Confusion
Cognitive impairment
Early morning insomnia
Tolerance

L Mweetwa-Pharmacologist - UNIVER...
Flumazenil
Mechanism of action
Flumazenil, an imidazobenzodiazepine derivative,
antagonizes the actions of benzodiazepines...
Although BDZs are highly protein bound
(60-95%),
few
clinically
significant
interactions.*
High lipid solubility  high ra...
Hepatic metabolism. Almost all BDZs
undergo
microsomal
oxidation
(Ndealkylation and aliphatic hydroxylation)
and conjugati...
Many have active metabolites with halflives greater than the parent drug.
Prototype drug is diazepam (Valium),
which has a...
From Katzung, 1998
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY






Keep in mind that with formation of active
metabolites, the kinetics of the parent drug
may not reflect the time ...






BDZs have a wide margin of safety if used
for short periods. Prolonged use may cause
dependence.
BDZs have little...


Drug overdose is treated with flumazenil (a BDZ
receptor antagonist, short half-life), but respiratory
function should ...



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BDZ's have additive effects with other CNS
depressants (narcotics), alcohol => have a
greatly reduced margin ...

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Mechanism of action
Barbiturates act on GABAA receptors, increasing
synaptic inhibition. This has the effect of
eleva...

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1. Depression of CNS: is dose dependant
2. Respiratory Depression: barbiturates
suppress the hypoxic and chemorece...


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1. Anaesthesia: e.g short acting drugs like
thiopental.
2. Anticonvulsant : e.g Phenobarbital
3. Anxiety : used as ...
Rapid absorption following oral
administration.
 Rapid onset of central effects.
 Extensively metabolized in liver (exce...
In the elderly and in those with limited
hepatic function, dosages should be
reduced.
 Phenobarbital and meprobamate caus...
Strong physiological dependence may
develop upon long-term use.
 Depression of the medullary respiratory
centers is the u...





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Withdrawal is characterized by increase
anxiety, insomnia, CNS excitability and
convulsions.
Drugs with long-...
Buspirone
 Chloral hydrate
 Hydroxyzine
 Meprobamate (Similar to BARBS)
 Zolpidem (BZ1 selective)
 Zaleplon (BZ1 sele...



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

Most selective anxiolytic currently available.
The anxiolytic effect of this drug takes
several weeks to devel...
Side effects:
• Tachycardia, palpitations,
nervousness, GI distress and
paresthesias may occur.
• Causes a dose-dependent ...
Mechanism of Action:
• Buspirone binds to 5-HT type 1A serotonin receptors on

presynaptic neurons in the dorsal raphe and...
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Not effective in panic disorders.
Rapidly absorbed orally.
Undergoes extensive hepatic metabolism
(hydroxylat...

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
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Structurally unrelated but as effective as
BDZs.
Minimal muscle relaxing and anticonvulsant
effect.
Rapidly meta...
Mechanism of Action:
• Zolpidem

modulates the alpha-subunit,
known as the benzodiazepine receptor, within
the GABAA recep...



Mechanism of action
Hydroxyzine competes with histamine for
binding at H1-receptor sites on the effector
cell surface...





Chloral hydrate
Is used in institutionalized patients. It
displaces warfarin (anti-coagulant) from
plasma proteins...
2-Adrenoreceptor Agonists (eg. Clonidine)
• Antihypertensive.
• Has been used for the treatment of panic
attacks.
• Has be...
-Adrenoreceptor Antagonists
(eg. Propranolol)
• Use to treat some forms of anxiety,

particularly when physical (autonomic...
1. Generalized Anxiety Disorder
Diazepam, lorazepam, alprazolam, buspirone
2. Phobic Anxiety
a. Simple phobia. BDZs
b. Soc...


THANK You End

L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
CNS Pharmacology
3. CNS Stimulants
L.Mweetwa-Pharmacologist




University of Zambia
 Dept of Pharmacy
 Faculty of Med...


We will look at two groups of drugs that act
primarily to stimulate the central nervous
system, i.e Psychomotor stimula...
L MWEETWA-Pharmacologist
UNIVERSITY OF ZAMBIA
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMAC...
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
Few clinical uses, Important as drugs of abuse.
Factors that limit the therapeutic usefulness include:
1.
Dependence: Psyc...
1. Psychomotor stimulants
cause: Excitement, Euphoria, Decrease feeling of fatigue &
Increase motor activity
Ex., Methylxa...
Q. What are Stimulants?
Answer. Chemical stracture are similar to monoamine
neurotransmitters. All are indirect-acting
sym...
3.

Drugs with stimulant effects; however, they are marketed
as antidepressants include:
Atomoxetine– a relatively selecti...
Obesity (anorectic agents).
Attention Deficit Hyperactivity Disorder (ADHD); lack the
ability to be involved in any one ac...
A. methylxanthines
1.
Theophylline (found in tea) : long-acting, prescribed for
night-time asthma
2.
Theobromine: found in...
several mechanism have been proposed
Mechanism of action of methylxanthine
1-It inhibits phosphodiesterase enz. → ↑ cAMP

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

of coffees
 Anxiety & tremors- 1....
Pharmacokinetics





The methylxanthines are well absorbed orally.
Caffeine distributes throughout the body, including...





Nicotine is the active ingredient in tobacco.
Used in smoking cessation therapy,
Nicotine remains important, becau...
I. CNS:
1. Low dose: euphoria, arousal, relaxation, improves attention,
learning, problem solving and reaction time.
2. Hi...
highly lipid soluble absorbed everywhere (oral mucosa, lung,
GIT, skin).
 Crosses the placental membrane, secreted with m...
CNS; irritability and tremors
Intestinal cramps, diarrhea
↑HR & BP
Withdrawal syndrome: nicotine is
addictive substance,
...





partial agonist at Nn receptor in CNS.
It produces less euphoric effects than
those produced by nicotine itself
(n...
1. Mechanism of action: blockade
of reuptake of the monoamines
(NE, serotonin and dopamine)
Thus, potentiates and prolongs...




Initially produces the intense
euphoria by prolongation of
dopaminergic effects in the brain’s
pleasure system (limb...
a. CNS-behavioral effects result from powerful stimulation of
cortex and brain stem.
 Cocaine acutely increase mental awa...
b. Sympathetic NS: peripherally potentiate the action of NE→
fight or flight
c. Hyperthermia:
 impair sweating & cutaneou...


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

Because of the irritability, many u...
Is a non catecholamine, (shows neurologic and clinical
effects quite similar to those of cocaine),
 dextroamphetamine is ...
Amphetamine, act by
 releasing intracellular

stores of catecholamines.
 also inhibits MAO, high
level CAOs are readily
...
a. CNS: the major behavioral effects of amphetamine result
from a combination of its dopamine and NE release
enhancing pro...





Amphetamine, methylphenidate.
Recently, a new drug, modafinil and its R-enantiomer
derivative, armodafinil, have b...
The amphetamines may cause addiction, dependence,
tolerance, and drug seeking behavior.
a. CNS: insomnia, irritability, we...
Overdoses are treated with chlorpromazine or haloperidol,
which relieve the CNS symptoms as well as the HTN because
of the...




approved for ADHD in children and adults.
It is a NE reuptake inhibitor (should not be taken by
individual on MAOI)...
It has CNS stimulant properties similar to those of
amphetamine and may also lead to abuse, although its
addictive potenti...




Methylphenidate has been used for several decades in the
treatment of ADHD in children aged 6 to 16.
It is also eff...
GIT effects are the most common; abdominal pain and nausea.
Other reactions include anorexia, insomnia, nervousness, and
f...
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY




A few drugs have the ability to induce altered perceptual
states reminiscent of dreams, are accompanied by bright,
c...





Multiple sites in the CNS are affected by lysergic acid
diethylamide (LSD).
The drug shows serotonin (5-HT) agonis...




include hyperreflexia, nausea, and muscular weakness.
High doses may produce long-lasting psychotic changes in
susc...
The main psychoactive alkaloid contained in marijuana is
tetrahydrocannabinol (THC), which is available as
dronabinol.
 T...
THC receptors, designated CB1 receptors, have been found
on inhibitory presynaptic nerve terminals. CB1 is coupled to
a G ...
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY








The effects of THC appear immediately after the drug is
smoked, but maximum effects take about 20 minutes. By...
as an appetite stimulant for patients with acquired
immunodeficiency syndrome who are losing weight.
2. It is also sometim...
Rimonabant: The CB1-receptor antagonist,
1. Obesity (decrease appetite and body weight in humans).
2. induce psychiatric d...






Phencyclidine (also known as PCP, or “angel dust”)
inhibits the reuptake of dopamine, 5-HT, and
norepinephrine.
...




Phencyclidine, an analog of ketamine, causes dissociative
anesthesia (insensitivity to pain, without loss of
conscio...
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
CNS Pharmacology
4. Anesthetics
L.Mweetwa-Pharmacologist




University of Zambia
 Dept of Pharmacy
 Faculty of Medici...
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General anesthesia (GA) is the state produced
when a patient receives medications for
amnesia, analgesia, muscle paraly...
The combination of anesthetic agents used for
general anesthesia often leaves a patient with
the following clinical conste...
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General anesthesia uses intravenous and inhaled agents to allow
adequate surgical access to the opera...
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Disadvantages Requires increased complexity of care and
associated costs
Requires some degree of preoperative ...
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
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1. Relieve anxiety- Benzodiazepines
2. Relax Muscles- Muscle relaxants
3. Prevention of fluids into the respira...
Ether Operation 1846

L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
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General anesthesia includes:
 Analgesia
 Amnesia

 Loss of consciousness
 Inhibition of sensory and autonomic refle...
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Anesthetics depress activity of neurons in
many regions of the brain.

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A primary target of many anesthetics is the
G...
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Ketamine does not affect GABAA it
antagonizes glutamic acid on NMDA
receptor.

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Inhaled anesthetics also cause membra...
1.

Analgesia: first analgesia, later analgesia
and amnesia.

2.

Excitement: delirium, excitement, irregular
respiration,...
3.

Surgical Anesthesia: the recurrence of
regular respiration.
The most reliable indication is loss of the
eyelash reflex...
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
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MAC stands for: Minimum Alveolar
Anesthetic Concentration

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In steady state, the partial pressure of an
inhaled anest...
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MAC values decrease in elderly patients and
with hypothermia, but are not affected by
sex, height, and weight.
Pre...
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The rate at which a given concentration of
anesthetic in the brain is reached depends on:
 Solubility properties

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

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

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Compounds that are not ...
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It is directly proportionate to the rate of
induction of anesthesia by increasing the rate
of transfer into the blood.
...
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The rise of gas tension in arterial blood is
directly dependent on both the rate and
depth of ventilation.

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

L Mweetwa-Phar...
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Pulmonary veins contain less anesthetic than
arteries. The greater this difference, the more
has been taken up by the b...
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One of the most important factors governing
rate of recovery is the blood:gas partition
coefficient

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

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The duration of exposure to the anest...
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Despite their solubilities, the elimination of
halothane is more rapid than enflurane
because 40% of halothane versu...
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In terms of the extent of metabolism of
inhaled anesthetics, the rank order is:
Methoxyflurane > Halothane > Enflurane ...


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

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Halothane and enflurane ...
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Nitrous oxide in combination with potent
gases produces sympathetic stimulation that
minimizes cardiac depressant effec...
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All gases are respiratory depressants but it is
lessened by surgical stimulation.
Isoflurane and enflurane are t...
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Inhaled anesthetics are bronchodilators.



Halothane and sevoflurane the anesthetics of
choice in patients with airwa...
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Most volatile agents decrease cerebral
vascular resistance, increase cerebral blood
flow and ICP.
It is prudent no...
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Kidney
 All gases decrease GFR and renal plasma flow in spite of

well-maintained or even increased perfusion pressure...
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Hepatotoxicity
 Hepatotoxicity due to halothane is one in 20,000–

35,000. Obese patients having several exposures
to ...
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Malignant hyperthermia
 It is an autosomal dominant genetic disorder of

skeletal muscle occurs by inhaled agents and ...
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Reproduction
 Female operating room personnel have a higher

than expected incidence of miscarriages but the
evidence ...
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Intravenous anesthetics have an onset of
action faster than the fastest of the gaseous
agents so they are used for i...
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Thiopental can produce loss of consciousness
(hypnosis) in one circulation time.

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Because of its rapid removal from ...
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Its onset of action is similar to thiopental but
recovery is more rapid (similar to the shortestacting inhaled anesthet...
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Etomidate causes minimal cardiovascular and
respiratory depression.

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Etomidate produces a rapid loss of consciousnes...
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Ketamine produces dissociative anesthesia,
characterized by: catatonia, amnesia, and
analgesia, with or without l...


Ketamine may produce postoperative
sensory and perceptual illusions,
disorientation and vivid dreams (emergence
phenome...
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Remifentanil (opioid) has an extremely short
duration of action
Fentanyl and droperidol together produce
analgesia...
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
Twalumba!

L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMACY FACULTY
CNS Pharmacology
5. Antidepressant Drugs
L.Mweetwa-Pharmacologist
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University of Zambia
 Dept of Pharmacy
 Faculty ...
Psychopharmacology

L MWEETWA-Pharmacologist

L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE ,
PHARMAC...
Drugs affecting the cns  psychopharmacology by pharmacologist l mweetwa
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Drugs affecting the cns  psychopharmacology by pharmacologist l mweetwa
Drugs affecting the cns  psychopharmacology by pharmacologist l mweetwa
Drugs affecting the cns  psychopharmacology by pharmacologist l mweetwa
Drugs affecting the cns  psychopharmacology by pharmacologist l mweetwa
Drugs affecting the cns  psychopharmacology by pharmacologist l mweetwa
Drugs affecting the cns  psychopharmacology by pharmacologist l mweetwa
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Drugs affecting the cns psychopharmacology by pharmacologist l mweetwa

  1. 1. 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
  2. 2. L.Mweetwa-Pharmacologist University of Zambia L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , Dept of Pharmacy PHARMACY FACULTY Faculty of Medicine
  3. 3.  A gap between two neurons  Mostly chemical  Rarely electrical  Mostly present in lower animals  Gap junctions  Synapses could be  Axo-dendritic  Axo-somatic  Axo-axonic L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  4. 4. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  5. 5.  Presynaptic membrane  Contains neurotransmitter vesicles  Synaptic cleft  Postsynaptic membrane  Contains receptors for the neurotransmitter L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  6. 6. 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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  7. 7.  Chemicals that facilitate signal transmission across a synapse  Neurotransmitters are released on the presynaptic side and bind to receptors on the postsynaptic side  Earliest neurotransmitter discovered was acetylcholine  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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  8. 8.  “At rest”, the synapse contains numerous synaptic vesicles filled with neurotransmitter  Intracellular calcium levels are very low  Arrival of an action potential causes opening of voltage-gated calcium channels  Calcium enters the synapse  Calcium triggers exocytosis and release of neurotransmitter  Vesicles are recycled by endocytosis L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  9. 9. Ca2+ Ca2+ L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  10. 10. 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:   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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  11. 11.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  12. 12.  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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  13. 13.  Excitatory effects of neurotransmitters  EPSP: excitatory post synaptic potential  Inhibitory effects of neurotransmitters  IPSP: inhibitory post synaptic potential L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  14. 14.  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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  15. 15. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  16. 16.  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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  17. 17.  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  1, 2, 1, 2, 3  second messenger: cAMP L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  18. 18.       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  Increased levels associates with schizophrenia, low levels are associated with Parkinsonism L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  19. 19.     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  Low GABA levels are associated with anxiety and epilepsy L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  20. 20.     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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  21. 21.  Excitatory amino acids  glutamate is present in presynaptic terminals in the sensory pathways       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  Increased levels are associated with certain neurological diseases L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  22. 22.       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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  23. 23.  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  Substance P  found in primary nerve ending in the spinal cord  mediator of pain in the spinal cord L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  24. 24.  synthesized by ribosomes in the cell body  ER and Golgi apparatus enzymatically split the large molecule into smaller precursor or active molecules  Golgi apparatus makes vesicles  these vesicles are transported through the axoplasm slowly  remain in the terminal  release by a process similar to the other neurotransmitter L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  25. 25.  however vesicle is autolysed and not reused  quantity of neuropeptides released is smaller than that of other neurotransmitters  but the neuropeptides are thousand times more potent  they also cause much more prolonged action  generally only one type of small molecule neurotransmitter is released by a neuron  several neuropeptides could be released L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  26. 26.  Removal of neurotransmitter: by diffusion into the surrounding fluids enzymatic destruction (Ach) active transport re-uptake into the presynaptic terminal  Actions     prolonged closure of Ca pores prolonged changes in cell metabolism deactivation of specific genes prolonged changes in excitatory or inhibitory receptors L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  27. 27.  Endorphin  present in pituitary, earliest discovered opioid peptide  enkephalins: met-enkephalin, leu-enkephalin  present at substantia gelatinosa in the spinal cord & brain stem reticular nuclei  widely distributed  dynorphin  recently discovered  opioid peptides are involved in the descending pain inhibitory pathway  receptors: , , L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  28. 28.           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) L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  29. 29.  nitrous oxide (NO)  present in brain  probably involved in memory L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  30. 30.  Neurotransmitters transmit an impulse from one neuron to another  Neuromodulator modulate regions or circuits of the brain  They affect a group of neurons, causing a modulation of that group  Neuromodulators alter neuronal activity by amplifying or dampening synaptic activity  eg. dopamine, serotonin, acetylcholine, histamine, glutamate L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  31. 31. This is a modified synapse  Consists of   Presynaptic membrane (nerve terminal)  Synaptic cleft  Postsynaptic membrane (motor end plate) L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  32. 32. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  33. 33. Terminal has synaptic vesicles and mitochondria Mitochondria (ATP) are present inside the presynaptic terminal Vesicles containing neurotransmitter (Ach) L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  34. 34. 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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  35. 35. Ca2+ Ca2+ L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  36. 36.   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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  37. 37.  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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  38. 38.  An average human end plate contains 15-40 million Ach receptors  Each nerve impulse release 60 Ach vesicles  Each vesicle contains about 10,000 molecules of Ach  Ach is released in quanta (small packets) L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  39. 39.  Even at rest small quanta are released  Which creates a minute depolarising spike called Miniature End Plate Potential (MEPP)  When an impulse arrives at the NMJ quanta released are increased in several times causing EPP L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  40. 40.  After the Ach binding is over  Cholinesterase present in the synaptic cleft will hydrolyse Ach into choline and acetate  Choline is reuptaken to the presynaptic terminal  AchE is also found in RBC membranes L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  41. 41.  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  anterograde transport  movement toward the synapse is called  retrograde transport  Movement toward the cell body L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  42. 42.  NMJ not well developed  Smooth muscle does not depend on motor neurons to be stimulated  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))  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.   The contraction of smooth muscle tends to be slower than that of striated muscle  It also is often sustained for long periods L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  43. 43. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  44. 44. 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
  45. 45.  Parkinsonism is a progressive degenerative, extrapyramidal disorder of muscle movement, due to dysfunction in basal ganglia, comprising four cardinal features:    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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  46. 46.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  47. 47.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  48. 48.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  49. 49. 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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  50. 50.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  51. 51.  Substantia Nigra:  The substantia nigra pars compacta is the source  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  52. 52.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  53. 53.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  54. 54. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  55. 55.     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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  56. 56.       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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  57. 57.     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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  58. 58.      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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  59. 59.  Juvenile Parkinson's is a term used when the condition affects people under the age of 20. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  60. 60. 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 , PHARMACY FACULTY 1)
  61. 61.  Aim of treatment is to enhance dopaminergic pathway or inhibit cholinergic pathway in the brain L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  62. 62. -Amantadine -Antimuscarinic agents e.g benztropine,biperiden,trihexyphenidyl  Bromocriptine  Carbidopa  Deprenyl (selegilline)  Levodopa  Pramipexole  Ropinirole  Tolcapone   L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  63. 63. 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) . L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  64. 64.   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, L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  65. 65. • 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  66. 66. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  67. 67. 2) Mental effects Depression, anxiety, agitation, insomnia, delusions, hallucinations, euphoria 3) Dyskinesias (excessive and abnormal involuntary movements) as chorea and tremor L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  68. 68. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  69. 69. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  70. 70. Contraindications 1. Psychotic patients 2. Angle-closure glaucoma 3. Cardiac disease 4. Peptic ulcer 5. Melanoma L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  71. 71. • 1) Four orally administered dopamine-receptor agonists are available for treatment of PD: Ergot derivatives: as bromocriptine or pergolide L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  72. 72.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  73. 73.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  74. 74. 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.   L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  75. 75. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  76. 76. Contraindications 1. Psychotic patients 2. Angle-closure glaucoma 3. Cardiac disease 4. Peptic ulcer 5. Peripheral vascular disease (ergot derivatives). L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  77. 77. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  78. 78. 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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  79. 79. 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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  80. 80. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  81. 81. 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.    L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  82. 82. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  83. 83. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  84. 84. CNS Pharmacology 2.Anxiolytic and Hypnotic Drugs  L.Mweetwa-Pharmacologist  University of Zambia  Dept of Pharmacy  Faculty of Medicine  L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  85. 85.   Def: Anxiety is an unpleasant state of tension, apprehension or uneasiness arising from unknown source. Anxiety is the most common mental disorder. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  86. 86. SEDATION  Reduction of anxiety  Calming effect ANXIOLYTIC  Drug that reduces anxiety  Sedative HYPNOSIS  Induction of sleep L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  87. 87.    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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  88. 88. 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). L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  89. 89. 1). Medical: a) Respiratory b) Endocrine c) Cardiovascular d) Metabolic e) Neurologic. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  90. 90. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  91. 91.  Miscellaneous: ▪ Baclofen, cycloserine, hallucinogens, indomethacin. 3). Drug Withdrawal: ▪ BDZs, narcotics, BARBs, other sedatives, alcohol. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  92. 92. Strategy for treatment Reduce anxiety without causing sedation. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  93. 93. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  94. 94. 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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  95. 95. 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
  96. 96. Others: 11) Antyipsychotics ** Ziprasidone 12) Antidepressants ** TCAs, SSRIs 13) Antihistaminic drugs ** Dephenhydramine L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  97. 97. The benzodiazepines are the most important sedative hypnotics. Developed to avoid undesirable effects of barbiturates (abuse liability). L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  98. 98.  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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  99. 99. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  100. 100.    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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  101. 101.    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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  102. 102.    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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  103. 103.   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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  104. 104.  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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  105. 105.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  106. 106.     Drowsiness and Confusion Cognitive impairment Early morning insomnia Tolerance L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  107. 107. 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.   L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  108. 108. 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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  109. 109. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  110. 110. 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). L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  111. 111. From Katzung, 1998 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  112. 112.    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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  113. 113.    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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  114. 114.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  115. 115.      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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  116. 116.   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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  117. 117.    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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  118. 118.    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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  119. 119. 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.  L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  120. 120. In the elderly and in those with limited hepatic function, dosages should be reduced.  Phenobarbital and meprobamate cause autometabolism by induction of liver enzymes.  L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  121. 121. 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.  L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  122. 122.      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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  123. 123. Buspirone  Chloral hydrate  Hydroxyzine  Meprobamate (Similar to BARBS)  Zolpidem (BZ1 selective)  Zaleplon (BZ1 selective)  L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  124. 124.      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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  125. 125. Side effects: • Tachycardia, palpitations, nervousness, GI distress and paresthesias may occur. • Causes a dose-dependent pupillary constriction. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  126. 126. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  127. 127.      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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  128. 128.     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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  129. 129. 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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  130. 130.   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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  131. 131.    Chloral hydrate Is used in institutionalized patients. It displaces warfarin (anti-coagulant) from plasma proteins. Extensive biotransformation. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  132. 132. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  133. 133. -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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  134. 134. 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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  135. 135.  THANK You End L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  136. 136. CNS Pharmacology 3. CNS Stimulants L.Mweetwa-Pharmacologist   University of Zambia  Dept of Pharmacy  Faculty of Medicine  L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  137. 137.  We will look at two groups of drugs that act primarily to stimulate the central nervous system, i.e Psychomotor stimulants and Psychotomimetic drugs. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  138. 138. L MWEETWA-Pharmacologist UNIVERSITY OF ZAMBIA L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  139. 139. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  140. 140. 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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  141. 141. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  142. 142. 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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  143. 143. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  144. 144. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  145. 145. 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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  146. 146. 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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  147. 147. 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.  L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  148. 148. 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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  149. 149.    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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  150. 150. 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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  151. 151. 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.  L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  152. 152. 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    L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  153. 153.    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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  154. 154. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  155. 155.   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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  156. 156. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  157. 157. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  158. 158.  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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  159. 159. 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.  L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  160. 160. Amphetamine, act by  releasing intracellular stores of catecholamines.  also inhibits MAO, high level CAOs are readily released into synaptic spaces. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  161. 161. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  162. 162.    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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  163. 163. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  164. 164. 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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  165. 165.    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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  166. 166. 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.  L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  167. 167.    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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  168. 168. 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.   L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  169. 169. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  170. 170. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  171. 171.   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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  172. 172.    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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  173. 173.    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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  174. 174. 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  L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  175. 175. 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.  L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  176. 176. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  177. 177.      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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  178. 178. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  179. 179. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  180. 180.     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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  181. 181.   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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  182. 182. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  183. 183. CNS Pharmacology 4. Anesthetics L.Mweetwa-Pharmacologist   University of Zambia  Dept of Pharmacy  Faculty of Medicine  L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  184. 184.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  185. 185. 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  L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  186. 186.          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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  187. 187.      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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  188. 188. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  189. 189.      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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  190. 190. Ether Operation 1846 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  191. 191. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  192. 192. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  193. 193.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  194. 194.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  195. 195.  Ketamine does not affect GABAA it antagonizes glutamic acid on NMDA receptor.  Inhaled anesthetics also cause membrane hyperpolarization via activation of potassium channels. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  196. 196. 1. Analgesia: first analgesia, later analgesia and amnesia. 2. Excitement: delirium, excitement, irregular respiration, vomiting & incontinency. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  197. 197. 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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  198. 198. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  199. 199.  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). L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  200. 200.    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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  201. 201.  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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  202. 202.  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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  203. 203.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  204. 204.  It is directly proportionate to the rate of induction of anesthesia by increasing the rate of transfer into the blood. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  205. 205.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  206. 206.  Increase in pulmonary blood flow (increased cardiac output) slows the rate of rise in arterial tension. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  207. 207.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  208. 208.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  209. 209.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  210. 210.   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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  211. 211.  In terms of the extent of metabolism of inhaled anesthetics, the rank order is: Methoxyflurane > Halothane > Enflurane > Sevoflurane > Isoflurane > Desflurane > Nitrous Oxide L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  212. 212.  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). L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  213. 213.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  214. 214.     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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  215. 215.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  216. 216.    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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  217. 217.  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). L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  218. 218.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  219. 219.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  220. 220.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  221. 221.   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 L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  222. 222.  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) L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  223. 223.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  224. 224.  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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  225. 225.    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. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  226. 226.  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). L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  227. 227.    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%) L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  228. 228. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  229. 229. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  230. 230. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  231. 231. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  232. 232. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  233. 233. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  234. 234. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  235. 235. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  236. 236. L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  237. 237. Twalumba! L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  238. 238. CNS Pharmacology 5. Antidepressant Drugs L.Mweetwa-Pharmacologist   University of Zambia  Dept of Pharmacy  Faculty of Medicine  L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY
  239. 239. Psychopharmacology L MWEETWA-Pharmacologist L Mweetwa-Pharmacologist - UNIVERSITY OF ZAMBIA SCHOOL OF MEDICINE , PHARMACY FACULTY

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