DRUGS ACTING ON CNS
By
Mahmoud Mahmoud, MD, PhD
State of well being
MAO enz
Characteristics of CNS transmitters
The transmitter has to:
a- Present in a high concentration at locations
b- Release by electrochemical potential and calcium
dependent
c- Having the same effect of physiological response
Sites of action of drugs
Direct binding to affect the
membrane potential
Affecting synthesis of
neurotransmitter
Affecting storage
Affecting metabolism
Affecting release of
transmitter
Affecting re-uptake
Affecting postsynaptic
Affecting extracellular
disposition
Affecting postsynaptic
receptor activation
Transmitter - Receptor: Antagonist Mechanism
(found in different Agonist
neurons
Ach Muscarinic (CNS), Atropine Excitatory, decreases K+
M1 muscarine conductance
Muscarinic, M2 Atropine Inhibitory, increases K+
muscarine (heart + conductance
also CNS)
Nicotinic, nicotine Dihydro Beta- Excitatory, increases Na+
erythroidine) conductance
Dopamine(anti- D1 Phenothiazines Inhibitory, increases cAMP
Parkinson's basal (antipsychotics)
ganglia)
D2 Phenothiazines Inhibitory, é K+ conductance, ê
Ca++, decreases cAMP
D1 - also in kidney - decreases afferent resistance - via increasing cAMP
GABA (neutral amino GABAA Picrotoxin (convulsant- Inhibitory, increases Cl- (this
acid) hyperexcitability) is excitatory in newborns -
thus susceptible to seizure)
GABAB saclofen Inhibitory presynaptic
decreases Ca++ postsynaptic
Transmitter - Receptor: Antagonist Mechanism
(found in different Agonist
neurons
Glutamate, aspartate-- Excitatory, increases Na+
acidic amino acids or Ca++conductance
Glycine-neutral amino Strychnine(rat Inhibitory, increases Cl-
acid poison) (convulsant) conductance
5-Hydroxy- tryptamine 5-HT1, LSD Inhibitory, increases K+
(Serotonin)
5-HT2, LSD Excitatory, decrease K+
NE a1 Phenylephrine Prazosin Excitatory, decreases K+
a2 clonidine Yohimbine Inhibitory, increases K+
b1 isoproterenol, propranolol Excitatory, decrease K+
dobutamine mediated by cAMP
b2 terbutaline propranolol inhibitory, increase Na+/K+
pump -- membrane
becomes more
hyperpolarized
Postsyna
Name Type ptic Location(s) Function(s)
Effect
Brain, smooth
Dopamine Amine Excitatory Control arousal levels
muscle
Brain, smooth Effects on mood, sleep, pain,
Serotonin Amine Excitatory
muscle appetite
Brain, smooth Induce arousal, heighten
Noradrenaline Amine Excitatory
muscle mood
Excitatory Parasymathetic
Acetylcholine Acetic
& nervous system, Role in memory, vasodilation
(ACh) acid
Inhibitory brainstem
amino
GABA§ Inhibitory Brain Control anxiety level
acid
Enkephalin Neurope Reduce stress, promote calm,
Inhibitory Brain, spinal cord
(opiate) ptide natural painkiller
Neurotransmitter in the Brain
Acetycholine (M1 e.g AC esterase inhibitors)
Dopamine (D1…5)
Norepinephrine (alpha 1 and beta 2)
Serotonin
Glutamic acid (NMDA, AMPA receptors)
GABA and Glycine (Cl channel opener)
Peptide transmitters (endorphin and encephalen.. Etc )
Endocanabinoids
AMPA: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
Monoamies: catecholamine (dopamine and norepinephrine) + serotonin
Neuropeptides
Encephalin and endorphin
Neurotensin
Substance P
Somatostatin
Cholecystokinin
VIP (vasoactive intestinal peptide)
ANTIPSYCHOTIC DRUGS
Indications
1- Psychiatric
Schizophrenia
Manic phase of Bipolar Disorder
Disturbance behavior in Alzheimer
Tourette syndrome
2- Non-Psychiatric
Vomiting
(itching)
Pruritis
Anesthesia with opoid and fentanyl
Mechanism of Action of Anti-Psychotics
- It blocks the D2 receptors
- Super sensitivity of the receptors
Classification
1- Typical (1st generation): to block D2 receptors at
mesolimbic and mesocortical
High risk of EPS
Low potency: see table in red
High Potency: see table
2- Atypical (2nd generation): low affinity to D2 and
high affinity to serotonin receptors?
Typical Anti-psychotic
BRAND NAME GENERIC NAME COMMENTS
(additional uses)
Haldol Haloperidol Bipolar Disorder, Schizophrenia, Tuberous Sclerosis.
and Tourette Syndrome
Largactil Chlorpromazine Schizophrenia, and Tuberous Sclerosis
Loxtane Loxapine Bipolar Disorder
Mellaril Thioridazine Bipolar Disorder and Schizophrenia
Moban Mlindone Bipolar Disorder and Schizophrenia
Navane Thiothixene Schizophrenia
Orap Pimozide Tourette Syndrome, Schizophrenia, and Tuberous
Sclerosis
Permitil Fluphenazine Bipolar Disorder, Schizophrenia, and Tourette
Syndrome
Prolixin Fluphenazine Bipolar Disorder, Schizophrenia, and Tourette
Syndrome
Serenace Haloperidol Bipolar Disorder, Schizophrenia, Tuberous Sclerosis.
and Tourette Syndrome
Serentil Mesoridazine Schizophrenia
Stelazine Trifluoperazine Bipolar Disorder and Schizophrenia
Thorazine Chlorpromazine Schizophrenia, Severe Nausea and Vomiting, and
Severe Hiccups
Trilafon Perphenazine Schizophrenia, Severe Nausea and Vomiti
Atypical Anti-psychotic
BRAND NAME GENERIC NAME COMMENTS
(additional uses)
Clozaril Clozapine Schizophrenia especially resistant
Geodon Zirasidone Bipolar Disorder and Schizophrenia
Risperdal Risperidone Bipolar Disorder , Schizophrenia,
and Psychosis
Serpquel Quetiapine Bipolar Disorder and Schizophrenia
Zyprexa Olanzapine Bipolar Disorder and Schizophrenia
Pharmacokinetics
Metabolized in liver, first pass
Excreted in urine
High Volume of distribution
Rule:
All the drugs which block dopamine receptors and
any dopamine stimulant drugs exacerbate the
schizophrenia.
EPS: extra-pyramidal side effects
Extrapyramidal Side Effect (EPS)
A condition characterized by a range of findings–e.g:
rigidity, tremors, drooling, shuffling gait–parkinsonism,
akathisia–restlessness, dystonia–odd involuntary postures,
akinesia–motor inactivity, and other neurologic
disturbances
Extrapyramidal dysfunction, often a reversible side
effect of certain sychotropics eg, e.g phenothiazines
Side effect of Chlorpromazine
1- Dry mouth
2- Difficulty in sleeping (insomnia)
3- A drop in blood pressure (orthostatic hypotension)
4- Drowsiness
5- Agitation
6- Nasal congestion
7- Skin rashes
8- Weight gain
9- Abnormal heart beats (arrhythmias)
10- Abnormal reaction of the skin to light, usually a rash (photosensitivity)
11- Abnormal movements of the hands, legs, face, neck and tongue, eg tremor,
twitching, rigidity (extrapyramidal effects)
12- Decrease in the number of white blood cells in the blood (leucopenia)
13- High blood prolactin (milk producing hormone) level (hyperprolactinaemia).
Sometimes this can lead to symptoms such as breast enlargement, production of milk
and stopping of menstrual periods.
14- Rhythmical involuntary movement of the tongue, face, mouth and jaw, which may
sometimes be accompanied by involuntary movements of the arms and legs (tardive
dyskinesia)
15- High temperature combined with falling levels of consciousness, paleness,
sweating and a fast heart beat (neuroleptic malignant syndrome).
16- Anxiety, restlessness and agitation (akathisia)
Adverse Pharmacological Effect
The effect Manifestation Mechanism
Autonomic Nervous - Loss of accommodation, dry Atropine like effect
System mouth, retention of urine,
constipation
-Orthostatic hypotension, failed Alpha blocking effect
ejaculation
-EKG: abnormal QT and T wave
CNS Parkinsonism Dopamine (D2) blocker
Tardive dyskinesia Super sensitivity
Toxic confusion state Muscarinic blocker
Endocrinal system Amenorrhea, glactorrhea, Hyperprolactinemia
impotence, gynecomastia
Others Weight gain Antihistaminic effect (H1)
Serotonin (5HT2) blocker
Eye Corneal and lens deposits
Side Effects of Typical Neurolpetic Drugs
Acute neurological side-effects:
Acute EPS on first day of treatment
The extrapyramidal system is composed of two pathways, dopamine and
acetylcholine. When the dopamine pathway is blocked by the antipsychotic the
balance in the system is disrupted, resulting in spasm.
- Acute treatment is oral or intramuscular injection of an anticholinergic – such
as benztropine (2 mg). The response is immediate and pleasing.
Medium-term neurological side-effects
Akathisia
Parkinsonism
Chronic neurological side-effects (also known as chronic or late
EPS) usually occur after months or years of continuous D2 blockade.
- Tardive dyskinesia (TD) supersensitivity of D2 receptors
- Neuroendocrine effects result from blockade of dopamine transmission in the
infundibular tract. Prolactin levels rise, producing galactorrhea, amenorrhoea
and infertility.
- Neuroleptic malignant syndrome (NMS) is probably due to disruption of
dopaminergic function, but the mechanism is not understood. Untreated the
mortality rate is 20%, so immediate medical attention is mandatory. The symptoms
include muscle rigidity, hyperthermia, autonomic instability and fluctuating
consciousness.
Renal failure secondary to rhabdomyolysis is a major complication and the cause
of mortality.
- Anticholinergic side-effects include dry mouth, difficulty with micturition,
constipation, blurred vision and ejaculatory failure. Anticholinergic effects can
contribute to a toxic confusional state.
- Histamine blockade may produce severe sedation.
- Alpha adrenergic blockade may produce postural hypotension, cardiac
arrhythmias and impotence.
- Dermatological side-effects include skin rash and photosensitivity
- Weight gain is common with most typical antipsychotics.
Side Effects of Atypical Anti-psychotic
Weight gain is problem in schizophrenia and other mental disorders,
in part because of poor eating habits and lack of exercise.
Type 2 diabetes is twice as high in people with schizophrenia
compared to the general population.
Hyperlipidemia (raised cholesterol and triglycerides) appears to be
associated with the dibenzodiazepine-derived antipsychotics
(clozapine, olanzapine and quetiapine).
QTc interval prolongation has been a matter of concern.
Myocarditis and cardiomyopathy are rare
Mood Stabilizer
Aim: to prevent mood swinging in patients with bipolar
disorder (manic depression)
Medication Used:
1- Lithium: element
2- Valproate (antiepileptic)
3- Carbamazepin (antiepileptic)
4- Olanzapine (atypical antipsychotic)
Causes of mood changes: unknown, Catecholamine dominate
activity, genetic element
Lithium (Li +)
Monovalent element
Mechanism of action: unclear
Electrolyteion transport (substitute Na+ ions)
Affecting neurotransmitter (enhance serotonin, block
Dopamine sensitivity, increase Acetylcholine synthesis)
Affecting second messenger
Pharmacokinetics
Absorption:
Complete, peak after ½-2hr
Distribution:
Total body water (0.5 L/Kg)
Metabolism:
None
Excretion:
Urine
T1/2 = 20 hr
Target plasma conc.: 0.6-1.4 mEq/L
Therapeutic drug monitor to determine the steady state
level after 5 days of treatment. (0.6-0.9 mEq/L) over 2
mEq/l is toxic need dialysis
Side effects:
Neurologica;L tremors, ataxia, choreoasthetossis
Decrease thyroid function
Diabetes insipidus (ADH loss of response)
Edema
Sick sinus syndrome, ECG changes
ANTI-DEPRESSANTS
Theory:
Amine hypothesis of the mood where NE and
serotonin pathways are responsible.
This theory is weak due to:
No postmortem changes is detected in the amine
levels
The effect is not spontaneous
Down regulation of the receptors
Some medications have very small effect on the
amines
Depression
According to : Statistical Manual of Mental Disorders (DSM-IV,
to be considered depressed, you have at least five of the following
symptoms and they represent a change in your life:
1- Depressed mood most of the day, nearly every day
2- Markedly diminished interest or pleasure in all, or almost all, activities
3- Significant weight loss when not dieting or weight gain, or decrease or
increase in appetite nearly every day
4- Insomnia or sleeping too much (hypersomnia) nearly every day
5- Psychomotor agitation or retardation nearly every day
6- Fatigue or loss of energy nearly every day
7- Feelings of worthlessness or excessive or inappropriate guilt
8- Diminished ability to think or concentrate, or indecisiveness
9- Recurrent thoughts of death, recurrent suicidal ideation, or a suicide
attempt or a specific plan for committing suicide
The five D's of depression symptoms in the elderly
are:
disability
decline
diminished quality of life
demand on caregivers
dementia.
Types of depression:
Reactive depression: a response to external event
Bipolar affective (manic depression)
Major depression with no obvious causes
Drugs:
MAO inhibitors
Amine reuptake blockers: e.g. tricyclines and
heterocyclines
5HT selective reuptake blocker
alpha 2 blocker
Annual Lost Workdays and Associated
Costs Due to Behavioral Disorders
Total Lost
Total Cost
Disorder Workdays
($ billions)
(millions)
Major depressive disorder 136.9 9.9
Dysthymia 47.3 4.1
Bipolar disorder 31.0 2.5
Generalized anxiety disorder
61.2 5.4
General Effect
Pharmacological actions:
Amine reuptake inhibition
Sedation
Muscarinic blocker (atropine like effect)
CVS
Seizures with over dosage
Antihistaminics
Clinical Uses: depression, acute panic attacks, attention
deficit disorder (ADT), neuropathic pain, bulimia,
phobia, OCD
Off label: insomnia
Resistant patients: 5Ds: diagnosis, drug, dose,
duration and different treatment
Antidepressants
1- Selective serotonin re-uptake inhibitors (SSRIs)
Citalopram (Celexa)
Escitalopram (Lexapro)
Fluoxetine (Prozac)
paroxetine (Paxil, Pexeva)
sertraline ( Zoloft)
These medicines tend to have fewer side effects than other
antidepressants. Some of the side effects that can be caused
by SSRIs include dry mouth, nausea, nervousness, insomnia,
sexual problems and headache
2- Tricyclics
Affecting norepinephrine and serotonin
First generation:
amitriptyline (brand name: Elavil) I.M
desipramine (brand name: Norpramin)
imipramine (brand name: Tofranil)
nortriptyline (brand name: Aventyl, Pamelor)
Common side effects caused by these medicines include dry
mouth, blurred vision, constipation, difficulty urinating,
worsening of glaucoma, impaired thinking and tiredness. These
antidepressants can also affect a person's blood pressure and
heart rate.
3- Norepinephrine and dopamine reuptake
inhibitors (NDRIs)
second generation
Bupropion (brand name: Wellbutrin)
Amoxapine
Maprotiline
Trazodone
Some of the common side effects in people taking NDRIs
include agitation, nausea, headache, loss of appetite and
insomnia. It can also cause increase blood pressure in some
people.
Psychosis????
4- Serotonin and norepinephrine reuptake
inhibitors (SNRIs)
Third generation:
venlafaxine (brand name: Effexor)
duloxetine (brand name: Cymbalta)
Some common side effects caused by these medicines
include nausea and loss of appetite, anxiety and
nervousness, headache, insomnia and tiredness. Dry
mouth, constipation, weight loss, sexual problems,
increased heart rate and increased cholesterol levels
can also occur.
5- Combined reuptake inhibitors and
receptor blockers
trazodone (brand name: Desyrel)
nefazodone (brand name: Serzone)
maprotiline
mirtazpine (brand name: Remeron)
Common side effects of these medicines are
drowsiness, dry mouth, nausea and dizziness.
Liver problems, No nefazodone.
Seizures, No maprotiline.
6- Monamine oxidase inhibitors (MAOIs)
isocarboxazid (brand name: Marplan)
phenelzine (brand name: Nardil)
tranlcypromine (brand name: Parnate)
MAOIs are used less commonly than the other antidepressants.
They can have serious side effects, including weakness, dizziness,
headaches and trembling. Taking an MAOI antidepressant with
another antidepressant or certain over-the-counter medicines for
colds and flu can cause a dangerous reaction. Food containing
tyramine and alcoholic beverages should be avoided. You should
not take an MAOI unless you clearly understand what
medications and foods to avoid. MAOI must be washed out
before starting a new regimen