Antidepressant

Drugs

Ali Mohammed Alalawi, PhD.

Assistant Professor,
Department of Pharmacology & Toxicology,
Faculty of Pharmacy, Taibah University, KSA
 Mood Disorders
 The most common psychiatric disorders that has increased risk of
suffering and suicide
More than 264 million people worldwide

 Mood disorder shows signs (affect) of:

o Depression and/or
o Mania for a significant period of time

 Occurs in the absence of clearly identifiable trigger

 Severe enough to impair normal functioning
Extended state of sadness and helplessness, more in women
 Pathophysiology of depression

• Genetics: about 4 genes were identified

• Monoamine and receptor theory

• Neurotrophic hypothesis (molecular and cellular theory):

For example: decrease in expression of brain-derived neurotrophic factor (BDNF) in hippocampus.
 Types of depression

• Unipolar Depression (Major depressive disorder)

Bipolar Mania

Depression

• Bipolar Depression (Manic depressive disorder)

 Symptoms of depression

• Emotional Symptoms

Serotonin

• Biological symptoms
Norepinephrine
Treatment of depression
Mechanism of Action of Antidepressants
Classification of Antidepressants

Monoamine Oxidase Inhibitors (MAOIs)

Tricyclic Antidepressants (TCAs)

Selective Serotonin Reuptake Inibitors (SSRIs)

Atypical Antidepressants
• Selective Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)
• Selective Noradrenaline Reuptake Inhibitors (NaRIs)
• Monoamine receptor antagonists
• Melatonin receptor agonists
 Monoamine oxidase inhibitors (MAOIs)
Examples and Mechanism of action:
Phenelzine, tranylcypromine, moclobemide and Selegiline (MAOI-B)

Mechanism of action: Monoamine oxidase inhibitors

 Monoamine oxidase inhibitors (MAOIs)

Important side effects:

 Postural hypotension (α-adrenoceptor block)
 Sexual dysfunction (Delay orgasm)
Serotonin Syndrome (hyperthermia, muscle rigidity, cardiovascular collapse) if combined with
TCA and SSRIs)
 CNS stimulation (restlessness, insomnia and sometimes convulsions)
 Cheese Reaction (severe hypertensive response to tyramine-containing foods (e.g.
cheese, beer, wine, yeast or soy extracts)

 Interaction with other sympathomimetic amines (e.g. ephedrine in over-the-counter

decongestants), other TCAs and serotonin-enhancing drugs (SSRIs,….) and some other
drugs (e.g. the opioid pethidine) are also potentially lethal.
 Tricyclic antidepressants (TCAs)
Examples:
Amitryptiline, Imipramine, Clomipramine, Desipramine.
Most are long acting, and they are often converted to active metabolites

Mechanism of action:
Inhibition of 5-HT and/or NA reuptake. Also block different receptors (histaminic, adrenergic, 5-
HT and muscarinic).
 Tricyclic antidepressants (TCAs)

Important side effects:

 Postural hypotension (α-adrenoceptor block)
 Sexual dysfunction (impotence)
Serotonin Syndrome (hyperthermia, muscle rigidity, cardiovascular collapse) if combined with
MAOIs and SSRIs)
 CNS Sedation (antihistaminic due to H1 block) and
 Atropine like effects: dry mouth, blurred vision, constipation (anticholinergic due to
muscarinic block)
cardiac dysrhythmias. Dangerous in acute overdose: confusion and mania, cardiac
dysrhythmias.

 Interact with other drugs (e.g. alcohol, anaesthetics, hypotensive drugs and NSAIDs; should
not be given with MAOIs).
 Selective Serotonin Reuptake Inhibitors (SSRIs)

Examples:
Fluoxetine (long-acting), Paroxetine (can show withdrwal effects), Citalopram, Escitalopram,
Sertraline, Fluvoxamine

Mechanism of action:
Inhibition of 5-HT and reuptake.
 Selective Serotonin Reuptake Inhibitors (SSRIs)

Important side effects:

 Postural hypotension
 Sexual dysfunction (delayed orgaism)
 Serotonin Syndrome (if combined with MAOIs and TCA)
 CNS Sedation or insomnia at the start of therapy

 GIT irritation (common)

 Cardiac dysrhythmias. less than that of MAOIs or TCAs

Used for some other psychiatric indications, e.g. anxiety.

 Selective Serotonin and Noradrenaline Reuptake
Inhibitors (SNRIs)
Examples:
Venlafaxine and Duloxetine

Mechanism of action:
Selective Serotonin and Noradrenaline Reuptake Inhibitors

Side effects:
Similar to SSRIs (Sedation, dizziness, nausea, Sexual dysfunction )
Hypertension (with high doses of Venlafaxine)
 Selective Noradrenaline Reuptake Inhibitors (NaRIs)

Examples:
Bupropion and Atomoxetine
Mechanism of action:
Selective Noradrenaline Reuptake Inhibitors

Side effects:
Similar to TCAs (Sedation, dizziness, nausea, Sexual dysfunction )
  Mood Stabilizers (for bipolar disorders)
Lithium:

 An inorganic ion, taken orally as lithium carbonate. Unknown mechanism.

 Used in prophylaxis and treatment of mania, and in the prophylaxis of bipolar or unipolar disorder
(manic depression or recurrent depression).

 Narrow therapeutic window and long duration of action. Dose must be adjusted according to the
plasma concentration

 Acute toxic effects include cerebellar effects, nephrogenic diabetes insipidus and renal failure.
Diuretics increase the toxicity of Lithium

 Thyroid disorders and mild cognitive impairment occur during chronic use

Antiepileptic drugs (e.g. carbamazepine, valproate, lamotrogine):

 Better side effect and safety profile.

Atypical antipsychotic drugs (e.g. olanzapine, risperidone, quetiapine, aripiprazole).

 Anxiolytic
Drugs

Ali Mohammed Alalawi, PhD.

Assistant Professor,
Department of Pharmacology & Toxicology,
Faculty of Pharmacy, Taibah University
 Anxiety symptoms includes:
 psychological symptoms: (tension, fear lack of concentration,…….)
 sympathetic and somatic symptoms: (tachycardia, sweating, tremors,
GI distress,…..)
Anxiolytics
Agents
Anxiolytics, Sedatives and Hypnotics
Anxiolysis

Normal

Sedation

Hypnosis

Anesthesia

Medullary depression, Coma

Death
 Anxiolytics, Sedatives and Hypnotics

Anxiolysis Sedation Hypnosis Anesthesia

Medullary depression, Coma Death

 Anxiolytics are drugs used to reduce anxiety and calm

the patient

 Sedatives are drugs that decrease activity and calm the

patient without inducing sleep

 Hypnotics are drugs that induce sleep resembling normal

sleep. They are used for insomnia
 Classification of Anxiolytics and Hypnotic

Barbiturates

Anxiolytics and
Hypnotic
Benzodiazepines

Other Anxiolytics

Other Hypnotics
Z-drugs or Non Benzodiazepines

 Older anxiolytics cause also some degree of sedation and drowsiness.

 Newer anxiolytic drugs show much less sedative effect
 Other hypnotics drugs have been introduced that lack specific anxiolytic effects.
 Anxiolytics and GABA Receptors

Cl
Hyperpolarization Lead to anxiolytic and sedation effect
 Barbiturates

 Were used as sedative-hypnotics, but now replaced by BDZs.

 Barbiturates have higher risk of CNS depression compared to BDZs

 Also they are hepatic enzyme inducers, increasing metabolism of

their own (increased tolerance) and of other drugs

 Currently, only Thiopental (for ultra-short anesthesia) and

Phenobarbital (for some cases of seizures) are used.
  Benzodiazepines (BDZs)

 Mechanism: enhancing the inhibitory effect of GABA

 Pharmacological effects:
 Anxiolytic (e.g. alprazolam …..)
 Hypnotic (e.g. Oxazepam……; mainly short-acting)
 Anticonvulsant and myorelaxant (e.g. diazepam)
 Anaesthetic (e.g. midazolam)
 Adverse effects:
 morning sedation and drowsiness
 confusion, poor motor coordination,
 amnesia.
 Tolerance and risk of drug dependence:
 Treatment should not exceed 4 weeks (Use Lowest effective
dose for the shortest possible time) ……….ALWAYS taper
gradually!!!
 Withdrawal syndrome: anxiety, sleep disturbances, tremor,
restlessness, memory impairment, convulsions….
 Buspirone

 Partial agonist at the serotonin 1A (5-HT 1A) receptor.

 No physical dependence/ withdrawal

 No abuse potential

 Less sedation and psychomotor impairment

 Lack of interaction with alcohol

 Slow onset of action (1-2 weeks)

 Short t1/2 (~2.5h) ® b.d./ t.d.s. administration

 Used for chronic anxiety states.

 Treatment of
Parkinson’s
Disease

Ali M Alalawi, PhD

Assistant Professor,
Department of Pharmacology & Toxicology,
Pharmacy college, Taibah University
 Parkinson's Disease
Parkinson’s disease is the second most
common age-related
neurodegenerative disorder after
Alzheimer’s disease.

10 million
people worldwide have Parkinson’s disease
(affects about 1% of population).

60 years Men are 1.5 times

more likely to have Parkinson’s
Average age of onset than women.
 Parkinson’s disease
 Degenerative disease of the basal ganglia characterized by:
Dopamine in the brain

Pituitary gland
(Prolactin)
Dopamine in the brain

Vomiting center
CRTZ

Pituitary gland
(Prolactin)
Pathophysiology of PD
Treatment of Parkinson’s disease

Pharmacologic Classes 6
al treatment

Surgical High-frequency deep brain

stimulation of the subthalamic

Procedures nucleus or globus pallidus by

an implanted electrode

Glutamic acid decarboxylase

(GAD), to facilitate synthesis of
GABA

Infusion into the striatum of

Gene Therapy
adeno-associated virus type 2
:as the vector for the gene
Aromatic acid decarboxylase
(AADC), to increase metabolism
of levodopa to dopamine
Neurturin (a growth factor that
may enhance the survival of
dopaminergic neurons)
Pharmacological Treatment of PD
DDC: DOPA decarboxylase
COMT: Catechol-O-MethylTransferase
MAO-B: Monoamine oxidase B

COMT

DDC

MAO-B
DOPAC
 Levodopa
 A first line treatment of motor symptoms of PD.
 It is converted by dopa decarboxylase (DDC) to dopamine, both in periphery and in CNS. Levodopa
crosses the BBB but dopamine does not.
 Has plasma half-life of 1-2 h. Absorbed from small intestine.
 Combined with DDC inhibitor (such as carbidopa, benserazide), and/or COMT inhibitor (such as
entacapone and tolcapone) to reduce the metabolism of Levodopa both peripherally and centrally
(reduces the dose by about 10-fold and diminishes the peripheral side effects).
 Levodopa
Short-term adverse effects:
o Nausea, vomiting and anorexia.
Domperidone, a dopamine antagonist that works in the
chemoreceptor trigger zone (where the blood–brain
barrier is leaky) but does not gain access to the basal
ganglia, may be useful as antiemetic.

o Postural hypotension:
may be a problem in some patients

o Psychological effects
a schizophrenia-like syndrome with delusions and
hallucinations, and more commonly, confusion,
disorientation, insomnia or nightmares. It may be
necessary to reduce or withdraw the medication.
• Several atypical antipsychotic agents that have
low affinity for dopamine D2 receptors (clozapine,
olanzapine, quetiapine, and risperidone) may be
helpful in counteracting such behavioral
complications.
 Levodopa
Long-term adverse effects: (not with other drugs for PD)
Involuntary movements (dyskinesia),
which do not appear initially but develop in the majority of
patients within 2 years of starting levodopa therapy

Response fluctuation (on/off and wearing effects),

where bradykinesia and rigidity may suddenly worsen
for anything from a few minutes to a few hours, and
then improve again. Can occur within 3-10 years after
using levodopa

These long-term adverse effects may be caused by the fluctuating plasma

concentration of levodopa (as it is short-acting) , down-regulation of dopaminergic
receptors and progression of neurodegeneration where neurons are not able to
store dopamine and requires continuous extra neural formation of dopamine

Decreasing levodopa dose, increasing dose frequencies, the use of sustained-

release preparations, or co-administration dopamine agonists and/or MAO-B
inhibitors may be used to counteract these long-term effects
 Levodopa
Drug and food Interactions:
 Pyridoxine (vitamin B6) enhance the
extracerebral metabolism of levodopa
especially if used without a DDCI

 Levodopa should not be given to patients

taking MAO-A inhibitors or within 2 weeks of
their discontinuance because such a
combination can lead to hypertensive crises.

 Iron, some amino acids, antacids and

anticholinergics can delay levodopa
absorption

Contraindications:
 Psychotic patients, angle-closure glaucoma,
active peptic ulcer and patients with a history
of melanoma or with suspicious undiagnosed
skin lesions
 Dopamine agonists
Examples: rotigotine, apomorphine
Advantages:
 No response fluctuations and dyskinesias that occur
with long-term levodopa therapy.

Disdvantages:
 Can cause nausea, vomiting, sleepiness, headache,
nasal congestion, postural hypotension (at beginning
of treatment),

 Sometimes hallucinations, and may predispose to

compulsive behaviours, such as excessive gambling,
shopping, betting, over-eating and sexual excess,
related to the ‘reward’ functions of dopamine.

 Short plasma half-life (6–8 h), requiring three-times

daily dosage, though slow-release once-daily
formulations and transdermal patches (rotigotine) are
now available.

 Contraindicated in patients with a history of psychotic

illness or recent myocardial infarction, or with active
peptic ulceration.
 Dopamine agonists
 Their dose should be built up gradually over weeks

Examples:
 Rotigotine
 Current choice for use in PD
 They are D2/3 selective and better tolerated

 Apomorphine
 As monotherapy or used SC as a rescue drug
to rapidly control the intermittent hypomobility
‘off effect’ with levodopa. (onset 10 min,
duration 2 hours)
 Powerful emetic action, must be combined with
an oral antiemetic drug
 It has other serious adverse effects (mood and
behavioural changes, cardiac dysrhythmias,
hypotension)
 MAO-B inhibitors
 MAO-A metabolizes NE, 5-HT and
dopamine
 MAO-B metabolizes dopamine
selectively

Examples: Selegiline and Rasagiline

 Enhance actions of levodopa (and

dopamine) by preventing its metabolism
 Neuroprotective (mainly rasagiline)

 Rasagiline may somewhat retard

disease progression, as well alleviating
symptoms especially in young patients
or mild conditions.
 Muscarinic ACh receptor antagonists

 Examples: biperiden

 These agents may improve the tremor and rigidity of

parkinsonism but have little effect on bradykinesia.

 The side effects of muscarinic antagonists – dry

mouth, constipation, impaired vision, urinary
retention – are troublesome especially in elderly

 They are now rarely used, except to treat

parkinsonian symptoms in patients receiving
antipsychotic drugs (which are dopamine
antagonists and thus nullify the effect of levodopa)
 Clinical use of drugs for PD
 Start with low dose and gradually increase till
benefit/adverse effect

 Never stop an antiparkinsonian drug suddenly.

 When symptomatic treatment becomes necessary, a

trial of rasagiline, amantadine, or an antimuscarinic
drug (in young patients) may be worthwhile.

 With disease progression, dopaminergic therapy

becomes necessary. This can conveniently be
initiated with a dopamine agonist (omit in elderly),
either alone or in combination with low-dose
levodopa/carbidopa

 In patients with severe parkinsonism, and long-term

complications of levodopa therapy such as the on-off
phenomenon, a trial of treatment with a COMT
inhibitor or rasagiline may be helpful.

 Try to save the use of levodopa/carbidopa for as late

as possible. This will avoid or delay motor
complications
 Ali M Alalawi, PhD

Assistant Professor,
Department of Pharmacology & Toxicology,
Pharmacy college, Taibah University
  Opioid Analgesics

 Opioid: endogenous or synthetic substances that produces

morphine-like effects
 Opiate: natural compounds from opium poppy such as
morphine and codeine

 Narcotic analgesic: old term for opioids

Mechanism of action:

 Bind to CNS opioid receptors on inhibitory fibers.

Stimulation of these receptors reduces neuronal excitability
and inhibits the release of pain neurotransmitters, including
substance P.

 Specific opioid receptors, mainly µ(mu), δ (delta) or Κ

(kappa), are located at several spinal and multiple
supraspinal sites in the CNS.

 There are endogenous peptides (such as endorphins) that

can bind these opioid receptors
  Classification of Opioids

1. Pure agonist: has high efficacy (strong) e.g. Morphine,

Methadone , Heroin , Fentanyl

2. Partial agonists: has low efficacy e.g. Codeine

3. Mixed agonist-antagonist: has medium to high efficacy ex.

Nalbuphine and Buprenorphine

4. Pure antagonist: ex. Naloxone (IV) and Naltrexone (oral)

5. Miscellaneous: ex. Tramadol is a centrally acting oral analgesic

that acts as weak opioid receptor agonist.
  Actions of morphine

The main pharmacological effects are:

– analgesia (for moderate to severe pain)
– euphoria and sedation
– respiratory depression
– suppression of cough
– nausea and vomiting
– pupillary constriction (miosis)
– reduced gastrointestinal motility, causing constipation
– histamine release, causing itch, bronchoconstriction
and hypotension.
– antidiuresis (decrease ADH release)
  Clinical uses of opioids

1- Strong analgesic (for moderate to severe pain, acute or

chronic), Ex. morphine, buprenorphine or fentanyl.

2- Suppression of cough: Ex. codeine and dextromethorphane

3- Treatment of diarrhea of any cause (Ex. loperamide) (Note: if

infection is present must be treated)

4- Preanestheic medication: Ex. Morphine for systemic and spinal

anesthesia.

5- Treatment of acute pulmonary edema: Only Morphine, which

decreases anxiety, and relieves dyspnea by its vasodilating
effects (thus decrease cardiac pre and after load)
 Adverse effects of opioids
  Tolerance to opioids

 A high degree of tolerance (decreased effect by

repeated use) may develop to the analgesic,
sedating, and respiratory depressant effects of
opioid agonists.

 Tolerance begins with the first dose of an opioid

but may not become clinically manifest until
after 2–3 weeks of frequent therapeutic doses.

 Tolerance also develops to the antidiuretic,

emetic, and hypotensive effects but NOT to the
miotic, convulsant, and constipating actions
  Opioid Dependence

 Repeated administration of opioids is

accompanied with development of
tolerance, psychological and physical
dependence (more with strong
agonists of μ receptors).

 Failure to continue administering

opioids results in a characteristic
withdrawal or abstinence syndrome
(exaggerated rebound from the acute
pharmacologic effects of the opioid).
 Opioid withdrawal or abstinence syndrome
  Treatment of Opioid Dependence
 Take the history If the patient is disclosing dependent use of opiates
(whether prescribed or otherwise obtained)

 If withdrawals are mild-moderate, prescribe symptomatic relief :

 Loperamide (for diarrhoea)
 Metoclopramide (for nausea/vomiting)
 Mebeverine (for stomach cramps)
 Diazepam (for agitation/anxiety)
 NSAIDs, Paracetamol (for muscular pains/ headaches)

 Lofexidine (a central adrenergic alpha-2 agonist) may be used

 If withdrawal symptoms are not being effectively managed

symptomatically or severe, a long-acting opioid (eg, methadone) is
given in a planned supervised prescription for about 4 weeks.

 Naltrexone oral is usually used for 6 months to prevent relapse

Thank you