Components of PHL419 part II:
• Toxcicity of Commonly Used Drugs ( CNS-acting drugs & cardiac
glycosides).
• Environmental Toxicity (Heavy metals , Pesticides & gaseous air
pollutants)
References
- Casarett & Doull’s Toxicolology . The Basic Science of Poisons. 7th edition,
2008 by Curtis Klaassen
- Classroom materials and lectures.
1. CNS-acting drugs
- Most of CNS- acting drugs have potential risk of toxicity due to chronic
uses, accedintal overdosage and /or drug misuse or abuse.
- Most of CNS-acting drugs carry the risk of happening of tolerance, drug
dependence and withdrawal syndrome once abruptly stop.
- Tolerance: means decrease responsiveness to a drug following repeated
exposure. This needs escalation of the drug dose to maintain the desired
effect.
- Drug dependence: The consequence of prolonged use of drugs that lead
to recipient's dependence on the drug in both psychologic and
physiologic (or physical) terms.
Psychologic dependence includes neurotic behavior pattern of relapsing
drug use. Users lose their control on their feeling of craving or
tendency for the drug use (addiction).
Physiologic (or physical) dependence can be described as an altered
physiologic state that require continuous drug administration to
prevent happening of withdrawal or abstinence syndrome.
Withdrawal syndrome: are signs of physical debility and illness associated
with abrupt stopping of drug use. Each CNS-acting drug has its own
spectrum of withdrawal symptoms, but in most cases it will be the
reverse of physiological effects.
- For examples withdrawal symptoms of most of CNS depressant drugs
involve signs of CNS excitability (increased anxiety, insomnia, tremors
that may progress to convulsion).
CNS-acting drugs include the following categories:
I. Anixiolytic and hypnotic drugs:
e.g. Barbiturates and benzdizipines
II. Opiates and narcotic analgesics:
e.g. Morphine, Codiene, Percoset, Percodan ….etc
III. Drugs used to treat psychological disorders
e.g. Antipsychotics (antischizophrenic drugs), and Antidepressants.
IV. Stimulants:
e.g. Cocaine, Amphetamines and Methamphetamines
V. Hallucinogens and psychedelics
( recreational drugs or drugs of abuse e.g. Cannabis , LSD and
Mescaline
Drug Scheduelling
Drugs are classified into one of five lists (schedules) based on the
substance's medical utility, potential for abuse, and dependence
liability.
SCHEDULE I:
•
Drug has no current accepted medical use and has a high potential for
abuse.
•
•
Class examples: Heroin,
Cannabis.
LSD, GHB, Cathinone, marijuana and
Pharmacies do not sell Schedule I drugs, and they are not available
with a prescription by physician.
SCHEDULE II:
•
•
•
•
Drug has current accepted medical use and has high potential for
abuse.
Class examples: Cocaine, Morphine, Fentanyl, Codeine, methadone,
meperidine, Amphetamine, Methamphetamines, amobarbital,
secobarbital and pentobarbital.
Schedule II drugs may be available with a prescription by a physician
without refill, but not all pharmacies may carry them.
These drugs require more stringent records and storage procedures
than drugs in Schedules III and IV.
SCHEDULE III
•
•
•
Drug has current accepted medical use and has moderately high
potential for abuse.
Class examples: Anabolic steroids, Ketamine, Hydrocodone with
Aspirin, and Hydrocodone with Acetaminophen (Lortap).
Schedule III drugs may be available with a prescription , most of
pharmacies may carry them upon written or phone prescriptions with
or without refill.
SCHEDULE IV
•
•
•
Drugs have current accepted medical use and have moderate potential
for abuse.
Class examples: Chloral, benzodiazepines, meprobamates and
Phenobarbital.
These drugs may be available with a prescription with refill, all
pharmacies may carry them.
SCHEDULE V:
•
•
Drug has accepted medical use and has lowest potential for abuse.
Class examples: Lomotil (diphenoxylate and atropne),
dextromethorphane and cough suppressants with codeine like
Robitussin.
Schedule V drugs are regulated but generally prescription is unnecessary.
Schedule
Schedule
I
Abuse
Liability
High
Approved
Medical
Use
No
Availability
investigational
use only
Examples





Schedule
II
High
Yes
written
prescription
with no refills


Schedule
III
Moderately
High
Yes
written or
telephone
prescription
with refills





Schedule
IV
Moderate
Yes
written or
telephone
prescription
with refills



Schedule
V
Low
Yes
prescription
not necessary
marijuana, THC
LSD, mescaline,
peyote
heroin
amphetamine,
methamphetamine,
cocaine
codeine, levorphanol,
meperidine
methadone, morphine,
opium
amobarbital,
pentobarbital,
secobarbital
phencyclidine
Tylenol with codeine,
paregoric
chlorphentermine
anabolic steroids
chloral hydrate
chlordiazepoxide,
diazepam,
flunitrazepam
meprobamate
methohexital,
phenobarbital
Robitussin A-C
(contains less than
100 mg codeine per
100 ml)
Toxicity of Barbiturates
• Barbiturates are a group of CNS depressants, class of drugs known as
anixiolytics and hypnotics which generally describes their sleepinducing and anxiety-decreasing effects.
• Barbiturates are big family (of over 2500 members), all are derived
from barbituric acid, of which about 50 have been marketed.
•
•
•
Barbiturates act by potentiate the ability of the inhibitory
neurotransmitter, GABA, to activate its specific type of receptors
known as GABAA receptors.
Barbiturates increase the effectiveness of GABA by altering the
receptor so that GABA can bind more easily, an effect known as
allosteric activation.
Barbiturates in large doses, may be agonists at GABAA receptors, thus
barbiturates produce potent CNS depressant effect.
• Barbiturates are now little used as anxiolytic and hypnotic agents due
to the narrow therapeutic margin and excessive side effects
(sometime lethal).
• Barbiturates are also addictive, produce physical dependence, and
can cause a life-threatening withdrawal syndrome upon abrupt
discontinuation of therapy.
• Barbiturates also induce a high degree of tolerance that they strongly
induce the synthesis of hepatic CYP450 and conjugating enzymes,
and thus increase the rate of metabolic degradation of its own and
many other drugs, giving rise to a number of potentially troublesome
drug interactions.
• Barbiturate toxicity:
-
Barbiturates users usually suffer from depressant side effects like
drowsiness, sluggishness, some staggers, slurred speech, ataxia,
nystagmus, headache and impaired concentration.
- These CNS depressant effects of barbiturates may intensify with uses
of other CNS depressants like opiates or ethanol (alcoholic beverages).
-
Barbiturates hangover: Hypnotic doses of barbiturates produce a
feeling of tiredness and lack of concentration well after the patient
wakes. This drug hangover may lead to impaired ability to function
normally for many hours after waking. Occasionally, nausea and
dizziness occur. Patients under barbiturate therapy are contraindicated
to drive or operate dangerous machinery.
- Physical dependence: Abrupt withdrawal from barbiturates therapy
may cause abstinence symptoms that include tremors, anxiety,
weakness, restlessness, nausea and vomiting, seizures, delirium, and
cardiac arrest. Withdrawal is much more severe than other CNS
depressants and can result in death.
- Precautions: As noted previously, barbiturates induce the liver P450
system and, therefore, may decrease the duration of action and
therapeutic efficacy of drugs that are metabolized by these hepatic
enzymes
(oral
contraceptives,
hypoglycemic
drugs,
anticoagulants,……etc)
- barbiturates are also dangerous to patients suffering from the
metabolic disease porphyria .
- Poisoning: Barbiturate poisoning has been a leading cause of death
resulting from drug overdoses due to severe depression of respirator
and CV centers in brain stem.
-
This results in a shock-like condition with shallow, infrequent
breathing.
- Treatment includes only symptomatic interventions (no specific
barbiturate antagonist is available) which include artificial respiration
and purging the stomach of its contents if the drug has been recently
taken. Hemodialysis may be necessary if large quantities have been
taken. Alkalinization of the urine often aids in the elimination of
barbiturates . Administration of pharmacologic antidote like
respiratory stimulants like doxapram.
Toxicity of Benzodiazepines
•
•
•
Benzodiazepines are the most widely used anxiolytic-hypnotic drugs.
They have largely replaced barbiturates and meprobamate in the
treatment of anxiety disorders and insomnia, because they are
considered safer (high TI) and more effective.
The basic chemical structure of benzodiazepines consists of a sevenmembered ring fused to an aromatic ring, with four main substituent
groups that can be modified without loss of activity. Thousands of
compounds have been made and tested, and about 20 are available for
clinical use
Like barbiturates, the targets for benzodiazepine actions are the GABAA
receptors . Benzodiazepines enhance the response to GABA by
facilitating the opening of GABA-activated chloride channels. They bind
specifically to a regulatory site of the receptor, distinct from the GABA-
binding site (and from barbiturates site), and act allosterically to
increase the affinity of GABA for the receptor.
•
Major uses of benzodiazepines include:
- Anixiolytics (reduction of anxiety and aggression ) e.g. Clonazepam,
Lorazepam, Alprazolam and Diazepam
- Hypnotics (induce sedation and induction of sleep leading to
improvement of symptoms of insomnia ) e.g. Flurazepam,
Temazepam, and Triazolam
- Muscle relaxant (induce
muscle relaxation through central
mechanism totally not related to its anixiolytic–hypnotic action,
spasmolytics, and excessivly used in treatment of muscle spasm like
that happen with muscle strain, and in treating spasticity from
degenerative disorders, such as multiple sclerosis and cerebral palsy.
e.g. Diazepam
- Anticonvulsant (suppression of convulsions (antiepileptic effect)
used the treatment of epilepsy. e.g. Clonazepam, Diazepam, and
Lorazepam.
- Induce amnesia: Benzodiazepines obliterate memory of events
experienced while under their influence .They utilized as
premedication for minor surgical procedures such as endoscopic,
bronchoscopic, and certain dental procedures can thus be performed
without leaving unpleasant memories. They also cause a form of
conscious sedation, allowing the person to be receptive to instructions
during these procedures. e.g. Midazolam
Benzodiazepines toxicity:
•
The main side effects associated with benzodiazepines therapy are
drowsiness, confusion, amnesia and impaired coordination (ataxia),
which considerably affects job performance daily skills such as driving.
•
Cognitive impairment (decreased long-term recall and acquisition of
new knowledge) can also occur with use of benzodiazepines.
•
-
-
Tolerance is less marked with benzodiazepines with some exceptions,
Triazolam, one of the most potent oral benzodiazepines with the most
rapid elimination, often shows a rapid development of tolerance, early
morning insomnia, and daytime anxiety, along with amnesia and
confusion.
Benzodiazepines are relatively safe in overdose than other
anxiolytic/hypnotic drugs.
In overdose, benzodiazepines cause prolonged sleep, without serious
depression of respiration or cardiovascular function.
Alcohol and other CNS depressants (like barbiturates, phenytoins,
phenothizines,..etc) enhance the sedative-hypnotic effects of the
benzodiazepines and may cause severe, life-threatening, respiratory
depression upon overdosage.
Benzodiazepines should be avoided in patients with liver disease and
acute narrow-angle glaucoma (benzodiazepines increase IOP).
- Flumazenil is a specific benzodiazepines antagonist . It is used as an
antidote in the treatment of benzodiazepine overdose.
- It reverses the effects of benzodiazepines by competitive inhibition at
the benzodiazepine binding site on the GABAA receptor benzodiazepines.
- The drug is available for IV administration only. Onset is rapid but
duration is short, with a half-life of about 1 hour. Frequent
administration may be necessary to maintain reversal of a long-acting
benzodiazepine.
Toxicity of Opiates
•
•
•
•
Opiates, sometimes referred to as narcotic analgesics, are a group of
drugs which are used medically as strong pain killers to relieve
moderate to severe types of pains which exert their effects mainly
through central actions.
Some opiates originally isolated from a resin taken from the seeded
pod (poppy capsule) of hemp plant (Papaver somniferum), while
other opiates are semisynthesized or chemically manufactured
(opoids).
Opiates exert their actions through binding to different types of opiate
receptors (μ, δ, and κ), which are found principally in the central
nervous system and some peripheral areas (e.g. GIT and immune
cells).
Opiate receptors are a group of Gi-protein coupled receptors with
endogenous opioids as ligands. The other opiates act as agonists with
different affinity and efficacy to these receptors.
•
•
Pure agonists:
These opoids have high affinity for receptor binding plus high efficacy
used in management of sever pains. They all have high affinity for μ
receptors and generally lower affinity for δ and κ sites. They always
cause both physical and psychological dependence.
e.g. Morphine, methadone, hydromorphone,
fentanyl, oxymorphone, and heroin.
Weak aagonists:
These drugs have high affinity for receptor binding but low efficacy. They
are used mainly in management of moderate pain in addition to other
therapeutic uses . both analgesic and unwanted effects, are less than
those of morphine, and they have lower tendency to cause
dependence.
e.g. Propoxyphene, codeine, hydrocodone,
oxycodone, dihydrocodone, methadone,
dexropropoxyphene and pethedine.
•
•
Partial agonists and mixed agonist-antagonists:
These drugs may produce agonist effects at some opiate receptors and
antagonist effects at another opiate receptors
e.g Pentazocine, Nalbuphine, Nalorphine, and
Dezocine.
Nalbuphine is agonist on -receptor and potent anatagonist at receptor but weak antagonist at -receptors.
Pentazocine is antagonist at μ-receptors but partial agonists on - and
-receptors.
Full Antagonists:
These opiate drugs have affinity for binding with opiate receptors but no
efficacy and block action of both endogenous and exogenous opiates.
e.g. naloxone, nalmefene and naltrexone.
- In addition to their strong analgesic effects they also have many other
effects like cough supression and antidiarrheal effects.
- Opiates are strong CNS depressant and produce narcosis (tranquil,
sedating and euphoric effect). Both physical and psychological
dependence are probable with continued use of opiates (addictive and
strong tolerance).
- Opiates have many legal medicinal uses in addition to high potential of
abuses.
- Members of opiates family are listed in different drug schedules.
Therapeutic uses of Opiates :
i. Pain management:
- Relief of moderate to severe acute pain (Like postoperative pain, pain
associated with orthopedic manipulations, myocardial infarction pain,
cancer pain, renal colic)
- To induce brief tranqulling effect with analgesia in serious and frightening
conditions accompanied by pain (e.g. multiple traumas )
ii. Preanesthetic medication to reduce pain sensation and anxiety ( e.g
Fentany, Pethidine)
iii. Cough Suppression (e.g. codeine, dextromethorphan)
iv. Symptomatic treatment of sever diarrhea and dysentery (e.g.
Diphenoxylate, Loperamide)
Narcotic Drug
Most Common Uses
Narcotic
Schedule
Heroin
Abuse
Heroin
I
Morphine
Analgesia
Morphine
II,III
Methadone
Methadone
II
Meperidine
Treat narcotic
dependence
Analgesia
Fentanyl
II
Oxycodone
Analgesia
Hydromorphone
II
Propoxyphene
Analgesia
Meperidine
II
Codeine
Analgesia, antitussive
Codeine and its
combinations
II, III, V
Loperamide
Antidiarrheal
Pentazocine
IV
Diphenoxylate
Antidiarrheal
Propoxyphene
IV
Opium tincture
Antidiarrheal
Opiates toxicity:
• The main side effects associated with use of opiates include:
1- Apathy, lethargy drowsiness, mood disturbance and coordination
impairment.
2- Constricted eye pupils, nystagmus with photophobia
3- Slow Shallow breathing, and slow heart rate.
4- Difficulty in breathing and itching (histamine-releasing)
5- Constipation, nausea and GIT upset.
6- Opiates depress appetite and thirst.
7-Loss of libido and impotence in men; amenorrhea and infertility in
women.
8- The body's tolerance to pain is increased that delays awareness of
serious medical conditions (abusers).
Most of CNS depressant side effects of opiates are enhanced by concurrent
administration of many CNS depressants like alcohol, barbiturates,
benzodiazepines, phenothiazines, MAOIs, and TCAs.
-
Administration of overdose of morphine or other opiates (acute toxicity)
usually associated with the following symptoms:
Loss of conciousness
Cyanosis, Low pulse and bradycardia
Pinpoint pupils
Anurea and constipation
Hypothermia
Flaccid muscles
Death may be a result from either respiratory depression or acute
pulmonary edema or both.
Treatment of acute opiate toxicity include
- Ventilation (carbogen; 95% O2 + 5% CO2)
- Administeration of opiate antagonist
(e.g. naloxone or naltrexone).
Tolerance and physical dependence are manifestations of opiates chronic
toxicity.
•
Tolerance to opiates develops rapidly, accompanied by physical
withdrawal syndrome. It may result in the need for an escalation of
the dose to maintain symptomatic improvement.
• The mechanism of tolerance may involve the inhibitory effect on
endogenous opiates, and opiates’ receptor internalization,
desensitization (uncopling from Gproteins or downregulation
(decrease receptor density which would reduce the response to the
normal dose of the drug) all have been proposed as potential
mechanisms of tolerance development.
• Tolerance to opiates is develops rapidly to Analgesia, Euphoria,
Sedation and Nausea, while tolerance occurs slowly to other effects
like itching, urinary retention, and respiratory depression. However,
tolerance does not develop to constipation or miosis.
-
• Tolerance does not become clinically manifested until after 2-3 weeks
of frequent exposure to ordinary therapeutic doses.
• It develops most readily when large doses are given at short intervals.
• Cross-tolerance is developed between opioids
• Some strategies are now developed (still within pre-clinical research)
trying to actively reduce/prevent opiate tolerance trying to make
patients get much analgesic benefits by concurrent administration of:
CaM KII inhibitor e.g. KN-93
CCK inhibitors e.g. Proglumide
NMDA glutamate receptor antagonist e.g. d-methadone
CYP 450 inhibitor e.g. Cimetidine
Withdrawal symptoms appear 4-6 hours following the last dose. Symptoms
include:
- Sever bone aches and muscle pain (back and extremities), irritability and
fearfulness
- Hyperventilation (increased respiratory rate)
- Dysphoria, depression and generalized weakness
- Restlessness, and insomnia
- Increased blood pressure and hyperglycemia
- Diarrhea, abdominal pain, nausea and vomiting.
- Pupillary dilation (mydriasis)
- Hyperthermia, excessive sweating and yawing.
- Lacrimation, runny nose and piloerection
- Spontaneous tremors.
- Alternating episoded of chilliness and flushing with kicking movements
of the legs (goose bumps).
•
•
•
The intensity of these symptoms depends on how much of the drug
was taken, how often and for how long. These symptoms are usually
strongest 24 to 72 hours after onset and can persist for seven to 10
days.
Successful treatment of narcotic drug withdrawal symptoms is based
on the idea that it is best slowly withdraw (tapering off), and give the
patient enough drugs to get rid of withdrawal symptoms without
causing mental clouding.
Treatment with medicines: (14-21 days)
(1) Detoxification: Detoxification: Opiate dependence is satisfied by μreceptor agonists, weak, long-acting μ-receptor agonists such as
methadone, bupereonrphine,and diamorphine may be used
(2) Supportive treatment: Symptomatic treatment of withdrawal signs
(irritability, GIT effects, sever aching,…… etc). Clonidine can help by
reducing the intensity of withdrawal symptoms by 50 – 75%. Clonidine
is especially effective at reducing anxiety, cramping, muscle aches,
restlessness, sweating, tears, and runny nose. Acetaminophen, or
ibuprofen could help in pain and hyperthermia, loperamide can help
with diarrhea, and hydroxyzine may ease nausea. Plenty of fluids and
rest are important.
•
•
Psychological Treatment: this may take few month, it is considered
more important step in treatment of psychologic dependence or
addiction.
Precautions: Opiates should be avoided to be used in patients with
the following pathologic disorders:
i. Decreased impaired respiratory functions e.g. emphysema, asthma and
CPOD.
ii. Biliary colic
iii. Head injury (increase in ICP)
iv. Reduced blood volume
v. Hepatic and renal insufficiency
vi. During pregnancy and labour
Toxicity of Antidepressants
Depression
•
•
•
•
It is the most common mood and affective disorders that defined as
“ A mood disturbance characterized by feelings of sadness, despair, and loss of
interest or pleasure in activities. These feelings may be accompanied by somatic
complaints, such as changes in appetite, sleep disturbances (insomnia or
oversleeping), restlessness or lethargy, and decreased concentration. Thoughts of
injuring one's self, death, or suicide may also occur”.
Depression strikes 10% - 15% of adults population, affecting all racial, ethnic, age,
and socioeconomic groups. It's twice as common in women as in men and is
especially prevalent among adolescents.
Many theories have been postulated to illustrate mechanisms of depression
development, but the most acceptable one is the monoamine theory which states
that “monoamine neurotransmitters (NE, 5-HT) function in the expression of
mood”.
Depression is caused by a functionally deficit monoaminergic transmission in
certain sites of the CNS (like cerebral cortex, hippocampus and amygdla), while
mania results from a functional excess.
Antidepressants
•
•
•
•
•
•
•
Tricyclic antidepressants: e.g. amitriptylline (Tryptazol), clomipramine (Anafranil),
imipramine (Tofranil)
Tetracyclic antidepressants: e.g. Mianserin (Lumin)
Selective serotonin reuptake inhibtors (SSRIs): e.g. citalopram (Celapram),
fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Aropax), sertraline (Zoloft)
Selective noradrenaline reuptake inhibitor (SNaRIs ): e.g. reboxetine (solvex),
maprotiline (lodumil)
Irreversible MAO A inhibitors: e.g. Phenelzine (Nardil), Tranylcypromine (Parnate)
Reversible MAO A inhibitors: e.g
(manirex)
moclobemide (Clobemix), modobemide
Atypical antidepressants: e.g. Venlafaxine (Effexor ), Duloxetine (Cymbalta),
Trazodone (Trazorel) , Miratazapine (Remeron), and Bupropion (Zyban).
Tricyclic antidepressants:
The mechanism of action of tricyclic antidepressants is mainly related to their
ability to inhibit the transmitter-uptake mechanism of monoaminergic neurons.
Therapeutic uses:
1. Antidepressant
2. Treatment of neuropathic pain
3. In migraine prophylaxis
4. Treatment of nucternal enuresis
5. Antianxiety ( OCD, Phobias…etc)
6. ADHD
Tricyclic antidepressants toxicity:
I.
II.
III.
IV.
V.
VI.
VII.
Drowsness, slurred speech, sedation and weight gain (H1 block);
Postural hypotension (α-adrenoceptor block)
Flushing, dry mouth, blurred vision, excessive perspiration mydriasis, increase
IOP, urine retention and constipation (muscarinic block). TCAs are
contraindicated to be used in patients with glaucoma, patients with urinary
pathology )
occasionally seizures (Contraindicated to be used in patients with convulsive
disorders )
Tachycardia, disturbances in cardiac conduction with risk of ventricular
dysrhythmias, congestive heart failure, myocardial infarction, heart block,
asystole. ECG changes (prolong QT interval, inversion of T wave or widened QRS),
mainly due to decrease the sodium influx through the fast Na+-channels. TCAs
are contraindicated in patients with heart diseases, especially those who have a
history of conduction disorders and in patients with thyrotoxicosis or those use
thyroid drugs
Dangerous in acute overdose: Convulsion, confusion, decrease mental alertness,
palpitation , respiratory depression, cardiac dysrhythmias, and coma.
TCAs should be avoided to administered simultaneously with many drugs like:
a. CNS depressants; alcohol, anaesthetics, Barbiturates, Opioids,
Benzodiazepinesand
b. Hypotensive drugs like guanethidine, and resirpine (reverse their action
and blocking its transport into sympathetic nerve endings)
c. Anticholinergic agents or antiparkinsons (e.g., atropine, hyoscine,
levodopa), neuroleptics with an anticholinergic action (e.g.
Chlorpromazine) , exaggerate symptoms of anticholinergic especially
urine retention and paralytic ileus with hyperexcitation states or delirium
may occur, as well as attacks of glaucoma.
d. Anti-arrhythmic agents of the quinidine type.
e. MAOIs: TCAs should not be administered for a period of at least 14 days
after the discontinuation of treatment with MAO inhibitors .The same
caution should also be observed when administering an MAO inhibitor
after previous treatment with TCAs. To avoid happening of Hypertensive
episodes with excitement and hyperactivity.
f. The plasma concentration of Imipramine may increase when the drug is
given concomitantly with hepatic enzyme inhibitors (e.g., cimetidine,
fluoxetine) and decrease by concomitant administration with hepatic
enzyme inducers (e.g., barbiturates, phenytoin), and adjustment of the
dosage of Imipramine may therefore be necessary.
g. Avoid the use of preparations, such as decongestants and local
anesthetics, that contain any sympathomimetic amine (e.g. epinephrine,
norepinephrine), since it has been reported that tricyclic antidepressants
can potentiate the cardiovascular effects of catecholamines.
Selective serotonin reuptake inhibitors (SSRIs)
SSRIs are believed to increase the extracellular level of 5-HT by inhibiting its
reuptake into the presynaptic cell, increasing its level in the synaptic cleft available
to bind to the 5-HT postsynaptic receptor.
1.
2.
3.
4.
5.
Therapeutic uses:
Most widely prescribed drugs in treatment of major depressive disorders
Anorexigenic agents in treatment of obesity
Management of panic attack
Anixiolytic (OCD, phobias, GAD)
Treatment of alcohol dependence
Toxicity:
•
•
•
•
•
•
SSRIs are considered to have fewer adverse (less non-specific mechanisms)
effects and less severe in toxicity and overdosage than other antidepressants.
SSRIs administration is associated with headache,
sweating, anxiety and agitation, nausea, vomiting, diarrhea, aneroxia,
weakness and fatigue, sexual dysfunction, weight loss, insomnia.
Overdoses: may be associated with seizures (much less cardiotoxicity)
SSRIs act as inhibitors of hepatic cytochrome P450 isozymes (e.g CYP1A2,
CYP2C19) that inhibit the liver metabolic rate and increase the risk of toxicity
with concurrently administered drugs like like warfarin, digoxin, propafenone,
propranolol, amitriptyline , sumatriptan, diazepam , carbamazepine, clozapine,
and cyclosporine.
Combination of SSRIs and other antidepressants like TCAs and MAOIs should
avoided to avoid happening of “serotonin syndrome” that include hyperthermia,
muscle rigidity, sweating, shivering, dilated pupils, confusion, restlessness
myoclonus (clonic muscle twitching), or loss of muscle coordination and changes
in mental status and vital signs. Death may occur from cardiovascular collapse.
Therefore, extended periods of washout for each drug class should occur prior to
the administration of the other class of drugs. Management of serotonin
syndrome could be attributed by symptomatic treatment using of antiseizure
drugs (lorazepam), Muscle relaxants (balcofen) and 5-HT blocker
(cyproheptadine)
•
•
SSRIs should be used for treating depression with great caution in children and
adolescent under age of 18 due to adverse effects, including excitement,
insomnia and aggression in the first few weeks of treatment . In addition to
increased suicidal ideation.
SSRIs have the potential for causing mild physical dependence and abstinence
syndrome after their abrupt withdrawal. Possible include headache, malaise
and flu-like symptoms, agitation and irritability, nervousness, and changes in
sleep pattern. Depletion of serotonin stores may stands behind these symptoms.
Gradual withdrawal is preferred.
Monoamine oxidase inhibitors(MAOIs)
•
•
•
•
•
•
•
MAOIs are used much less than other antidepressants because of their adverse
effects and serious interactions with other drugs and foods. They are indicated as
last line for treatment of major depression in patients who have not responded to
other drugs.
MAOIs act by inhibiting the activity of monoamine oxidase, thus preventing the
breakdown of monoamine neurotransmitters and thereby increasing their
availability. There are two isoforms of monoamine oxidase, MAO-A and MAO-B.
MAO-A preferentially deaminates serotonin, melatonin, epinephrine and
norepinephrine. MAO-B preferentially deaminates phenylethylamine. Dopamine is
equally deaminated by both types.
Some MAOIs inhibited monoamine oxidase irreversibly. (e.g. Phenelzine &
Tranylcypromine ) that permanently t, deactivate MAO and the enzyme cannot
function until it has been replaced by the body, which can take about two weeks. A
few newer MAOIs (e.g. moclobemide & modobemide) are reversible
In normal human subjects, MAOIs cause an immediate increase in motor activity,
and euphoria and excitement develop over the course of a few days.
Main side effects: postural hypotension (sympathetic block); atropine-like effects (as
with TCA); weight gain; CNS stimulation, causing restlessness and insomnia.
headache, anxiety, flushing of the skin, and cardiovascular complications including
hypertension and tachycardia are the most common symptoms of acute overdosage
toxicity.
MAOIs are CYP 450 inhibitors and should be used with great caution with other
drugs. For example: Pethidine, concurrent adminsteration with MAOIs cause severe
hyperpyrexia, with restlessness, coma and hypotension. Due it abnormal pethidine
metabolite is produced because of inhibition of demethylation.
MAOIs are also liable to interact with food elements especially those riche in indirect
sympathomimetic “tyramine” like cheese, beer, yeast or soy cotaining food and othe
indirectly-acting sympathomimetics like ephedrine , amphetamine to cause
hypertensive crisis or Cheese reaction. Symptoms include severe hypertension with
severe throbbing headache, high body temperature, seizures and occasionally even
to intracranial haemorrhage. Such reactions can occur up to 2 weeks after treatment
is discontinued.
Atypical Antidepressants
Atypical antidepressants, are a lot with variable mechanism of actions. In general
they are more specific with less toxicity. such as ;
•
•
•
•
Venlafaxine: it is a potent inhibitor of serotonin reuptake and, at medium to higher
doses, is an inhibitor of norepinephrine re-uptake. It is also a mild inhibitor of
dopamine reuptake at high doses. The most common side effects of venlafaxine
are nausea, headache, sexual dysfunction, dizziness, insomnia, somnolence , and
constipation.
Duloxetine: is another atypical antidepressant that inhibits serotonin and
norepinephrine reuptake at all doses GI side effects are common with
duloxetine, including nausea, dry mouth, and constipation and CNS side effects
including Insomnia, dizziness, somnolence, and sweating are also seen. Sexual
dysfunction also occurs along with the possible risk for an increase in either
blood pressure or heart rate.
Bupropion: acts as a weak dopamine and norepinephrine reuptake inhibitor to
alleviate the symptoms of depression. Also, it assists in decreasing the craving and
attenuating the withdrawal symptoms for nicotine in tobacco users trying to quit
smoking. Side effects may include dry mouth, sweating, nervousness, tremor, a very
low incidence of sexual dysfunction, and an increased risk for seizures at high doses.
Mirtazapine: Enhances serotonin and norepinephrine neurotransmission via
mechanisms related to its ability to block presynaptic α-2 receptors. Additionally, it
may owe at least some of its antidepressant activity to its ability to block 5-HT2
receptors. It is a sedative because of its potent antihistaminic activity, but it does not
cause the antimuscarinic side effects of TCAsor interfere with sexual functioning, as
do the SSRIs. Increased appetite and weight gain frequently occur. Mirtazapine is
markedly sedating, which may be used to advantage in depressed patients having
difficulty sleeping.