DEPRESSION

Symptoms: extreme feelings of sadness, despair, hopelessness, anhedonia,

loss of energy, change in sleep pattern and appetite, suicidal thoughts

Monoamine Hypothesis of Depression Due to: deficiency in neurotransmitter

Norepinephrine (NE)
Serotonin (5HT)
Dopamine (DA)
Neurotrophic Hypothesis of Depression Due to deficiency in Brain-derived Neurotrophic Factor (BDNF) which
regulates resilience and neurogenesis
Neuroendocrine Factors Abnormalities in the Hypothalamic-Pituitary-Adrenal Axis → causes
elevated corticotropin-releasing hormone and cortisol levels due to Non-
suppression of Adrenocorticotropic Hormone (ACTH)

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRI)

FLUOXETINE Therapeutic Uses: Obsessive-Compulsive Disorder (also Fluvoxamine)
PAROXETINE Generalized anxiety
SERTRALINE Social anxiety
CITALOPRAM Premenstrual Dysphoric Disorder
ESCITALOPRAM Post-traumatic Stress Disorder
Panic Disorder
Bulimia nervosa (only Fluoxetine)

PhKinetics: Fluoxetine differs from the others:

it has an active metabolite (s-norfluoxetine)
it has a much longer half-life (50 hrs)
suspended-release (SR) formulation allows 1 week dosing
Fluoxetine + Paroxetine → enzyme inhibitors

AE: 1. Sedation – Paroxetine & Fluvoxamine

Insomnia – Fluoxetine & Sertraline
2. Headache, NV, drowsiness, diarrhea
3. Sexual dysfunction
4. Anxiety and suicidal thinking (teenagers)
5. Discontinuance Syndrome

HA, malaise, agitation, irritability, nervousness, change in sleep pattern

SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS (SNRI)

Use: for patients where SSRI is ineffective and for relieving pain symptoms (back/muscle pain)

VENLAFAXINE
AE: >BP HR insomnia HA, NV, diarrhea, constipation, sexual dysfunction, D/C syndrome
PhKinetics: enzyme inhibitor

DULOXETINE (less vomiting and diarrhea)

PhKinetics: food delays absorption
CI: Hepatic insufficiency and End-stage renal disease
TRICYCLIC ANTIDEPRESSANTS (TCAs)
 DESIPRAMINE, IMIPRAMINE, CLOMIPRAMINE, AMITRIPTYLINE, DOXEPIN
MOA : Serotonin-Norepinephrine Reuptake Inhibitors
Most common antidepressants before discovery of SSRI
Use : only when unresponsive to SSRI/SNRI
AE : Weight gain
Thrombocytopenia
Cardiac effect (tachycardia, arrhythmia dur to orthostatic hypotension)
Antimuscarinic effects
Seizures/Sedation/Sexual dysfunction
DI : MAOi → mutual enhancement >BP temp + convulsions
Adrenergic agonists → potentiates effect
Ethanol → toxic sedation

MONOAMINE OXIDASE INHIBITORS (MAOi)

MECLOBEMIDE, PHENELZINE, ISOCARBOXAZID, TRANYLCYPROMINE, SELEGELINE (transdermal)
Use : only when unresponsive or allergic to TCAs
MOA : * irreversible inactivation of monoamine oxidase enzyme
which lasts for 2 weeks before enzyme regeneration
* increase in NE, DA, 5HT
Food Interaction : Tyramine-containing foods (cheese, meat, red wine) except Selegeline TD
Causes Hypertensive crisis >BP HR HA nausea stiff neck, seizures, stroke
Tx: PHENTOLAMINE and PRAZOSIN
AE : orthostatic hypotension, drowsiness, antimuscarinic

ATYPICAL ANTIDEPRESSANTS
BUPROPION
MOA : DA/NE reuptake inhibitor (DNRI)
Use : decreases craving and attenuate withdrawal symptoms of nicotine
SE : dry mouth, sweating, nervousness, tremor, low incidence of sexual dysfunction,
seizures at high dose

MIRTAZAPINE
MOA : block ɑ2 receptor → enhance NE-5HT transmission
SE : sedation (antihistamine activity)
increase appetite and weight gain

NEFAZODONE and TRAZODONE

MOA : weak 5HT reuptake inhibitor and with chronic use may increase 5HT release
SE : sedation (antihistamine activity)
Trazodone → priapism

Nefazodone → hepatotoxic

Note:
onset of therapeutic effects: 2-12 weeks
change in medication should be done after “wash-out” of previous
drug these drugs do not produce mood elevation in normal
individuals
 SEDATIVE-HYPNOTICS

Anxiety – unpleasant state of tension, uneasiness and fear

Symptoms: tachycardia, sweating, trembling, palpitations
Sedative (anxiolytic) – should reduce anxiety by exerting a calming effect; has minimal CNS effects
Hypnotic – should produce drowsiness and encourage onset of sleep; has pronounced CNS
depression

Effects as dose increases: Sedative → Hypnotic → Anesthetic (Gen)→ Respiratory depressioon → Coma & Death

BENZODIAZEPINES
Long-Acting (1-3 days) Intermediate (10-20 hr) Short-acting (3-8 hr)
CLONAZEPAM (Klonopin) ALPRAZOLAM (Xanax) MIDAZOLAM
DIAZEPAM (Valium) ESTAZOLAM OXAZEPAM
FLURAZEPAM (Dalmane) LORAZEPAM (Ativan) TRIAZOLAM
TEMAZEPAM (Restoril)

MOA : Targets the GABAA receptor

enhancing binding of GABA neurotransmitter
increasing the frequency of Cl- channel opening
causing hyperpolarization of cells making it harder to depolarize

Therapeutic Uses:
Sleep disorder – not all benzodiazepines are hypnotic
Flurazepam (long) – reduces time of sleep induction and awakenings
– increases duration of sleep
SE: little rebound insomnia but causes daytime sedation
Temazepam (int) – decrease awakenings in insomnia
D/A: late peak effect (give 1-2 hrs before bedtime)
Triazolam (short) – for inducing sleep
SE: rebound insomnia and
tolerance
short-term use only (2-4 wks)

Anxiety – Generalized anxiety PTSD

Panic disorder (ALPRAZOLAM) OCD
Social anxiety disorder Schizophrenia
Performance anxiety
Note : Antianxiety effect has lesser tolerance than hypnotic effect
CLONAZEPAM (long)
LORAZEPAM (int)
DIAZEPAM (long)

Convulsions – LORAZEPAM and DIAZEPAM → grand mal seizures and status

epilepticus DIAZEPAM and OXAZEPAM → alcohol w/d related seizures

Amnesia – for anxiety provoking procedures (endoscopy, bronchoscopy, angioplasty)

MIDAZOLAM (short) for induction of anesthesia
Muscular disorder – DIAZEPAM
– for muscle spasms in musle strain multiple sclerosis, cerebral palsy
AE : drowsiness and confusion
cognitive impairment
Dependence → W/D symptoms: confusion, anxiety, agitation, restlessness, insomnia, tension
Prec : Alcohol
CNS Depressants
CI : Glaucoma
Liver disease (except Lorazepam and Temazepam – no phase II metabolism)
Antidote : FLUMAZENIL (IV)
MOA : GABA receptor antagonist
reverses Benzodiazepine effects
AE : dizziness, agitation, NV
seizures if BZD is used as antiseizure
withdrawal symptoms for BZD dependent Px
BARBITURATES – former mainstay sedative-hypnotic drugs
Long-acting (1-2 days) Short-acting (3-8 hrs)
PHENOBARBITAL (Luminal) PENTOBARBITAL Ultra-short (20 m)
SECOBARBITAL THIOPENTAL
AMOBARBITAL

MOA : 1. Targets the GABAA receptor

enhancing binding of GABA neurotransmitter
to prolong duration of Cl- channel opening
causing hyperpolarization of cell
2. Blocks glutamate receptors
Therapeutic Uses:

Anxiety – has mild sedative action to relieve anxiety
nervous tension and insomnia
but now replaced by BZD
Anesthesia – Thiopental for induction of anesthesia
Anticonvulsant – Phenobarbital → grand mal & status epilepticus + eclampsia
DOC for recurrent febrile seizures in children
AE: may depress cognitive function
PhKinetics:
readily crosses BBB but easily distributed to muscles and fats resulting in short duration of action
readily crosses the placenta and depresses the fetus
enzyme inducer
AE:
drowsiness, vertigo, impaired concentration; mental and physical sluggishness, tremors
Drug Hangover – tiredness, drowsiness, nausea upon awakening, impaired ability to function
Tolerance and Potential for addiction
Dependence → w/d symp.: Tremor, anxiety, weakness, restlessness, NV, seizures, delirium, cardiac arrest
DI : Ethanol
Enzyme induction of other drugs
CI : Acute porphyria
Poisoning : Artificial respiration
Purging of stomach contents (if recent)
Hemodialysis
Urine alkalinization
OTHER ANXIOLYTICS
Buspirone Use : chronic generalized anxiety
AE : hypothermia and increased prolactin and growth hormone secretion
DI : enzyme inducer : Rifampin
enzyme inhibitor : Erythromycin
D/A : no anticonvulsant and muscle relaxant activity
slow onset of action
Hydroxyzine(antihistami Use : sedative in dental procedures and surgery
ne – H1)
Antidepressants Use : long-term anxiety disorder
SSRI (PAROXETINE, FLUVOXAMINE) TCAs MAOi

OTHER HYPNOTICS
Zolpidem MOA : acts on the benzodiazepine receptor
D/A : no anticonvulsant and muscle relaxant activity
Adv : minimum withdrawal, tolerance, rebound insomnia
AE : nightmares, agitation, HA, dizziness, daytime sedation, GI upset
Zaleplon MOA : same as above
Adv : fewer AE than Zolpidem
Eszopiclone MOA : same as above
D/A : effective only for 6 months
AE : anxiety, HA, somnolence, peripheral edema, dry mouth, unpleasant taste
Ramelteon MOA : Melatonin (MT1and MT2) agonists
Use : induction of sleep
Adv : no tolerance and dependence allowing long-term use
AE : dizziness, fatigue, inc. prolactin levels
Chloral Hydrate – induces sleep in 30 min
(prodrug) → – with sleep duration of 6 hours
Trichloroethanol AE : GI irritation and unusual taste
DI : ethanol
Antihistamine Use : for mild types of insomnia
SE : anticholinergic effects
Ethanol PhKinetics: • Zero-order kinetics
has sedative- •Metabolized in the liver (Ethanol → Acetaldehyde → Acetate)
hypnotic effects •A fraction is excreted through the lungs
but its toxicity DI : BZD, Barbiturates, Antihistamine
outweighs AE : Liver diseases, gastritis, and nutritional deficiencies
benefits Cardiomyopathy in heavy drinking
Tx for w/d:
1. Benzodiazepines DOC
2. Carbamazepine for convulsion
3. Naltrexone (long-acting opiate antagonist) → no hangover effect
4. Disulfiram → blocks oxidation of acetaldehyde to acetate → hangover effect
→ flushing, tachycardia, hyperventilation, nausea
5. Acamprosate – should be used w/ supportive psychotherapy like Naltrexone
 OPIOIDS
Pain - unpleasant sensation that can be acute or
chronic - Subjective (only patient can
perceive/describe)

Pallative - medicine used to relieve pain

MOA: Bind to specific opioid receptors to mimic endogenous peptides ENKEPHALINS, ENDORPHINS,
DYNORPHINS

Opioid Receptors Effect

Mu( µ) Major analgesic receptor, Sedation, Respiration, Motility, Hormone release
Kappa (Κ) Psychomimetic effects, motility
Delta(δ) Hormone release

STRONG AGONISTS
MORPHINE – from Papaver somniferum
Uses : Diarrhea, Analgesia, Cough, Pulmonary edema
PhKinetics:
Administration Extended release to maintain constant concentration
Morphine pump for self-administration
IV, IM, SC to surpass 1stpass metabolism
Distribution Crosses the placenta and may cause physical dependence on fetus
Metabolism Metabolite is active (Morphine-6-glucoronide)
- lower dose in elderly
- not used on infants

Actions:
1. Analgesia Relieve pain without loss of consciousness
2. Miosis “Pinpoint pupil” – characteristic of Morphine Overdose
3. Euphoria Sense of contentment and well-being
4. Respiratory depressionDecrease sensitivity to CO2- common cause of death in Opioid
overdose
5. Emesis Stimulates chemoreceptor trigger zone
6. Cough Reflex depression Antitussive property
7. GI tract Decrease in motility &sphincter constriction
Antidiarrheal property
8. Cardiovascular Hypotension &bradycardia due to respiratory depression
&vasodilation
9. Histamine release Urticaria and bronchoconstriction
CI: asthmatic patients
10. Hormonal actions Decrease gonadotropin-releasing hormone and corticotropin-
releasing hormone (low cortisol and testosterone)
Increase growth and antidiuretic hormone
Increase prolactin secretion
11. Labor Decrease uterine contraction and prolongs labor
Adverse effects Severe Respiratory depression
Hypotension
Urinary retention and constipation
Vomiting
Allergies
Tolerance and dependence : Withdrawal symptoms may lead to death
Detoxification meds : METHADONE . BUPRENORPHINE . CLONIDINE
Contraindications : Asthma, Labor, Liver failure
 Meperidine (Demerol) Use : Commonly used in Labor
AE : Respiratory depression
Antimuscarinic (Mydriasis and dry mouth)
Anxiety → Psychosis due to toxic metabolite
Tremors &Convulsions Normeperidine
Tolerance &Dependence
DI : MAOi – convulsions and hyperthermia
Neuroleptics – enhanced depression
Cross tolerance w/ opioids
Methadone Use : Analgesia
Withdrawal of heroin and morphine abuse
Oxycodone Formulated with Aspirin or acetaminophen
&Hydrocodone(Morphine Ingestion of crushed tablet may lead to death
derivatives)
Fentanyl Use : Analgesia &Anesthesia
(Meperidine derivative) Ph Kinetics : Oral
100x more potent than Transmucosal (cancer)
morphine IV (Cardiac surgery)
Epidural (Post op &labor analgesia
AE : Muscle rigidity of abdomen and chest
Respiratory Depression and Miosis
Derivatives : SUFENTANIL ALFENTANIL RAMIFENTANIL
Heroin Produced by diacylation of morphine
(converted to morphine in Crosses the Blood brain barrier more rapidly
body; 3x more potent) Increased Euphoria

MODERATE AGONISTS
Codeine Action : Cough Suppression
(Synthesized from and Low analgesia
converted to Morphine) Euphoria
Sedation
Use : Antitussive &Analgesia
Adv : Lower abuse potential than morphine and less euphoria
Propoxyphene(Methadone AE : Nausea, Anorexia, Constipation
derivative) High doses: Respiratory depression, hallucination, convulsion
d isomer → Analgesic DI : synergism with acetaminophen
Lisomer → Antitussive alcohol &sedatives – severe CNS &respiratory depress.
&cardiotoxicity
Antidote: NALOXONE for sedation and respiratory depression
PARTIAL AGONISTS (MIXED AGONIST-ANTAGONIST)
Act as antagonist in the presence of strong agonists | Use: OPIOD DEPENDENCE
Act as agonist in the absence of antagonist | Use: ANALGESIC

Pentazocine AE (High dose) : Respiratory Depression

Constipation
Tachycardia
Dizziness
 Nightmares
Hallucination
Tolerance and dependence
CI : Angina – Increase work of heart
Kidney disease – Decrease renal plasma flow
Buprenorphine Major use : Opioid detoxification
Preferred than Methodone due to less Respiratory depression,
Hypotension, Sedation
(IV) analgesia
(Sublingual) Opioid dependence
Nalbuphine &Butorphanol Use : limited role as analgesic
Adv : Less psychomimetic &CV effects than Pentazocine

Other Drugs:
Tramadol MOA : Binds to Opioid receptor &weakly inhibits reuptake of NE and 5HT
Use : Moderate to moderately severe pain
Adv : Less respiratory depression
DI : Antidepressants → Seizures

ANTAGONISTS
MOA : Blockade of Opioid receptors
Use : Reverse effects of agonists (for OD)
Precipitate w/d symptoms (dependence)

Naloxone Short duration but rapid (1 hour)

- Reverses respiratory depression without analgesia
Nalmefene Intermediate (16-20 hrs)
Naltrexone Long acting (48 hrs)
Used in combination with Clonidine &Buprenorphine
Also used for Chronic Alcoholism
AE: Hepatotoxic

Stages of Withdrawal
STAGE 1 (8 hours) STAGE 2 (8-24 hours) STAGE 3 (UP to 3 days)
Anxiety GI disturbance Hypertension
Drug craving Rhinorrhea Tachycardia
Anxiety Fever
Insomnia Chills
Mydriasis Tremors
Diaphoresis Seizures
Muscle pain
 Diarrhoea

Degrees of Tolerance to Opioid Effects

High Moderate Minimal/None
Cough suppression Bradycardia Miosis
Urinary retention Constipation
Respiratory depression Convulsion
NV
Sedation
Analgesia
Mental clouding
Euphoria