Drugs acting on the CNS

1
• Learning Objectives

 Able to describe the Anesthetic drugs

 Able to describe the sedative hypnotic drugs.

 Able to describe the drugs used in epilepsy.

 Illustrate the approaches in the management of parkinsonism.

 Explain the antipsychotic drugs.

 Able to describe the opioid analgesics.

2
Anesthetics

3
• Anesthetics are agents that bring about reversible loss of sensation and
consciousness.

• They are divided into two main groups:

1. general anesthetics

2. local anesthetics.

• Drugs are chosen to provide safe and efficient sedation based on

– the type and duration of the procedure and

– patient characteristics, such as

 organ function,

 medical conditions,

 concurrent medications 4
 For patients undergoing surgical and other medical procedures, anesthesia provides

these five important benefits:

1) Sedation and reduction of anxiety

2) Lack of awareness and amnesia

3) Skeletal muscle relaxation

4) Suppression of undesirable reflexes

5) Analgesia

5
General Anesthetics(GA)
 General anesthesia is a reversible state of CNS depression, resulting in loss of response to

and perception of external stimuli.

 GA depress the CNS to a sufficient degree to permit the performance of surgery and other
noxious or unpleasant procedures.

 GA have low therapeutic indices and thus require great care in administration.

 Because no single agent provides all desirable properties, several categories of drugs are

used in combination to produce optimal anesthesia.

 GA are classified into two on the basis of their route of administration as inhalation and

intravenous anesthetics.
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 Inhalation anesthetics
• Inhaled anesthetics are used primarily for maintenance of anesthesia after
administration of an IV drug.

• Inhalational agents have steep dose–response curves with very narrow therapeutic indices,

– so the difference in concentrations from eliciting general anesthesia to

cardiopulmonary collapse is small

• Inhaled anaesthetics

– Volatile liquid anaesthetics administered via calibrated vaporizers using carrier gas
(air, oxygen or nitrous oxygen mixture):

 halothane; isoflurane; sevoflurane; desflurane.

– Gaseous anaesthetic

 nitrous oxide.

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 Inhalation…

• MOA

– general anesthetics increase the sensitivity of the γ-aminobutyric acid (GABA-A)

receptors to the inhibitory neurotransmitter GABA.

– Receptors other than GABA that are affected by volatile anesthetics include the
inhibitory glycine receptors found in the spinal motor neurons.

– Unlike other anesthetics, nitrous oxide and ketamine do not have actions on GABA-A
receptors.

 their effects are mediated via inhibition of N-methyl-d-aspartate (NMDA)

receptors.

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Inhalation…

9
 Inhalation…
 Halothane
– is a potent inhalational anaesthetic but a relatively weak analgesic.
– It is a liquid at room temperature and it is administered with a special vaporizer.

– Induction and recovery are relatively fast

• Low as compared to newer inhalation anesthetics like desflurane and

sevoflurane.

– can easily produce respiratory and cardiovascular failure

• Need accurate control upon administration

– Has pleasant odor that makes it suitable in children.

– It causes arrhythmia, hangover and the risk of liver damage is high if used repeatedly.

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 Inhalation…

 Isoflurane
– is typically used for maintenance of anesthesia after induction with other agents
because of its pungent odor

 Its pungent odor stimulates respiratory reflexes (breath holding, salivation,

coughing, laryngospasm), so it is not used for inhalation induction.

– undergoes little metabolism and is not, therefore, toxic to the liver or kidney.

– precipitate myocardial ischemia in patients with coronary disease.

– Irritant to respiratory tract.

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 Inhalation…
 Desflurane
– provides very rapid onset and recovery due to low blood solubility.
 This makes it a popular anesthetic for short procedures.

– It has a low volatility, which requires administration via a special heated vaporizer.

– has significant respiratory irritation like isoflurane so it should not be used for
inhalation induction.

– Its degradation is minimal and tissue toxicity is rare.

 Sevoflurane
– has low pungency or respiratory irritation.
 This makes it useful for inhalation induction, especially with pediatric patients who do
not tolerate IV placement.

– It has a rapid onset and recovery due to low blood solubility. 12

 Inhalation…
 Nitrous oxide
– Odorless and colourless gas
– It is rapid in action and also an effective analgesic agent.
– Its potency is low,
 must be Combined with other more potent agents to attain pain free anesthesia
 Does not produce muscle relaxation

– It is a relatively free of serious unwanted effects

– Prolonged exposure (over 6 hours)

 causes inactivation of methionine synthase, enzyme required for DNA and
protein synthesis

 result in bone marrow depression

 cause anemia
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 Intravenous Anesthetics

• IV anesthetics cause rapid induction of anesthesia often occurring in 1 minute or less.

• It is the most common way to induce anesthesia before maintenance of anesthesia with an
inhalation agent.

• IV anesthetics may be used as single agents for short procedures or administered as

infusions to help maintain anesthesia during longer surgeries.

• The main induction agent in current use is: thiopentone, etomidate, propofol, ketamine
and short acting benzodiazepine (midazolam).

• the exact mode of action of IV anesthetics is unknown; however, GABA likely plays a large
role.

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 Intravenous …

– Their anesthetic effect is determined by

 Blood flow to the brain (poor CO → delayed effect)

 Amount of non-ionized drug (form of the drug that crosses BBB),

 Degree of protein binding of the drug (unbound drug is active).

 Lipid solubility of the drug.

 Distribution to other body tissues.

 Metabolism and excretion.

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Intravenous anesthetics…

 Thiopental
- It belongs to barbiturates with very high lipid solubility

- Short duration (about 5 minutes) because of redistribution, mainly to muscle.

- It has no analgesic effect

- There is risk of severe vasospasm if accidentally injected into artery.

 Thiopental is no longer available in many countries,

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Intravenous anesthetics…
 Ketamine
 a short-acting, non-barbiturate anesthetic
 MOA
- blockade of the membrane effects of the excitatory neurotransmitter glutamic acid
at the NMDA receptor subtype
 Highly lipophilic drug and is rapidly distributed into well-perfused organs (the brain, liver,
and kidney).
 The only IV anesthetic that possesses anesthetic and analgesic properties, as well as the ability to
produce dose-related cardiovascular stimulation.
 Adverse Effect
- postoperative disorientation
- sensory and perceptual illusions
- vivid dreams
- Increase intracrani00al pressure
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Intravenous anesthetics…
 Etomidate
 A hypnotic agent but lacks analgesic activity
 Poor water solubility, so is formulated in a propylene glycol solution.
 Rapid but short-acting
 Only used for patients with coronary artery disease or cardiovascular dysfunction,
such as shock.
 ADE
- Decrease in plasma cortisol and aldosterone levels

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Intravenous anesthetics…

 Propofol
 Used in the induction or maintenance of anesthesia

 Onset within 40 sec & replaced thiopental

 Narcotics are required for analgesia

 Doesn’t cause postanesthetic nausea and vomiting (antiemetic)

 Useful for spinal surgeries

 Potentiating the chloride current through the GABA-A receptor

 The most commonly used induction agent, because of its favorable recovery profile
and short elimination half-life.

 is a potent respiratory depressant and generally produces apnea after an induction dose

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 Preanesthetic medication:

 It is the use of drugs prior to the administration of anaesthetic agent with the
important objective of making anaesthesia safer and more agreeable to the patient.

 The drugs commonly used are,

 opioid analgesics,

 barbiturates (Benzodiazepines),

 anticholinergics, anti emetics and

 glucocorticoids.

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 Local Anesthetics
 Local anesthetics provide a reversible regional loss of sensation and motor activity.

 Abolish sensation in a limited area of the body without producing unconsciousness and
thereby facilitate surgical procedures.

 Generally applied locally and block nerve conduction of sensory impulses from the periphery to
the CNS

 Sodium ion channels are blocked to prevent the transient increase in permeability of the nerve
membrane to Na+ that is required for an action potential.

 When propagation of action potentials is prevented, sensation cannot be transmitted from the
source of stimulation to the brain.

 Based on duration of action

– Short: Procaine, chloroprocaine

– Intermediate: lidocaine, mepivicaine, prilocaine

– Long acting: Tetracaine, bupivacaine, etidocaine, ropivacaine, levobupivacaine 21

 Local Anesthetics…
 Based on the site & technique of application:

1. Topical or Surface anesthesia

• Applied to skin or mucous membrane

• Used to treat pain, itching & other stimuli on conjunctiva, larynx, throat, hemorrhoids,
damaged skin

eg. Benzocaine, pramoxine

2. Infiltration anesthesia
• Injected directly into or very close to the area to be anesthetized.

• Used during tooth extraction, surgical incision

eg. etidocaine, lidocaine, prilocaine & tetracaine

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 Local Anesthetics…

3. Nerve block anesthesia

• Injected as close as possible to the nerve trunk supplying the specific area to be
anesthetized.

• Enable minor operations on the limb.

eg. Lidocaine, mepivacaine, bupivacaine

4. Spinal anesthesia
• Injecting the anesthetics in to CSF, usually in the lumbar spine.

• The anesthetics blocks sensory impulses at the root of peripheral nerves as they enter the
spinal cord.

• Useful for surgery of lower abdomen & legs.

eg. Procaine, tetracaine

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 Local Anesthetics…

 Local anesthetics are used in minor surgery, dentistry, and painless childbirth.

Adverse effects
– Unwanted effects result mainly from escape of LAs into systemic circulation.

– Main unwanted effects are:

• CNS effects; agitation, confusion, tremors progressing to convulsions and respiratory

depression

• cardiovascular effects; myocardial depression and vasodilatation, leading to fall in blood

pressure (eg. Bupivacain)

• Occasional hypersensitivity reactions (eg. procaine).

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 Local Anesthetics…

 Addition of epinephrine (vasoconstrictors) to local anesthetic:

– decrease absorption  decrease metabolism & decrease toxicity

– Minimizes systemic toxicity

– Increases the duration of action

– Enhance neuronal uptake of the LA

– Vasoconstrictors are not given to fingers, toes, nose, ear & private part of males

• Due to the risk of tissue necrosis (gangrene)

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Drugs Used for Parkinson’s disease

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 Drugs for PD…

Parkinson’s Disease

 is a neurodegenerative disorder characterized by the chronic progressive loss of motor

function

 Most cases involve people over the age of 65 years.

 is due to the imbalance between the cholinergic and dopaminergic influences on the
basal ganglia.

– the normal inhibitory influence of dopamine on cholinergic neurons in the

neostriatum is significantly diminished,

– Thus, the aim of the treatment is either to increase dopaminergic activity or to

decrease cholinergic.

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 Drugs for PD…

• Two major categories of drug therapy

1. Dopaminergic agents :

 Promotion of dopamine synthesis

 Promotion of dopamine release

 Prevention of dopamine degradation

 Direct activation of dopamine receptors

2. Anticholinergic agents :

 Blockade of muscarinic cholinergic receptors in the striatum

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 Drugs for PD…
Levodopa+carbidopa

– is a potent and efficacious drug regimen to treat Parkinson's disease

– Levodopa is actively transported into the CNS and is converted to dopamine in the brain.

– Levodopa is extensively metabolized by peripheral dopa-decarboxylase, hence given in

combination with carbidopa, a peripheral dopa-decarboxylase inhibitor.

 prevent systemic adverse effects

 nausea, hypotension, and diaphoresis

– When levodopa is given without carbidopa it causes

 vomiting (which is due to stimulation of emetic center to dopamine) and

 CVS disorder (tachycardia, ventricular extrasystoles, atrial fibrillation and due to increased
catecholamine formation peripherally).

− Relief provided by levodopa is only symptomatic, and it lasts only while the drug is present in
the body.
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Drugs for PD…

30
 Drugs for PD…

Adverse effects
– Anorexia, nausea, and vomiting

– Tachycardia and cardiac arrhythmia

– Visual and auditory hallucinations

– mood changes, depression, psychosis, and anxiety.

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 Drugs for PD…

 Catechol-O-Methyltransferase Inhibitors (COMT-I)

– Tolcapone and entacapone selectively and reversibly inhibit COMT

– Inhibition of COMT by these agents leads to

 decreased plasma concentrations of 3-O-methyldopa (competent metabolites to levodopa
for active transport into the CNS),

 increased central uptake of levodopa, and greater concentrations of brain dopamine.

– Entacapone acts only in the periphery.

– Tolcapone acts in both the periphery and the brain by inhibiting the degradation of
dopamine.

– Most seriously, fulminating hepatic necrosis is associated with tolcapone use.

• it has been largely replaced by entacapone which lacks such effect

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Drugs for PD…

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 Drugs for PD…

Monoamine Oxidase-B Inhibitors

Selegiline, rasagiline, and safinamide

 Selegiline (deprenyl) selectively inhibits MAO type B, the enzyme that metabolizes
dopamine.
 By decreasing the metabolism of dopamine, selegiline increases dopamine levels in the
brain.

 loses selectivity at high doses, and there is a risk for severe hypertension.

 Rasagiline an irreversible and selective inhibitor of brain MAO type B, has five times the
potency of selegiline.

 Safinamide is also a selective inhibitor of MAO type B indicated for use as an adjunct to
levodopa–carbidopa.

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 Drugs for PD…

• Action of selegiline (deprenyl) in dopamine metabolism.

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 Drugs for PD…

 Dopamine Receptor Agonists

 Bromocriptine, Pergolide, Pramipexole and ropinirole

– have a longer duration of action than that of levodopa and are effective in patients exhibiting
fluctuations in response to levodopa.

– are effective in patients with Parkinson’s disease complicated by motor fluctuations and
dyskinesias.

– However, these drugs are ineffective in patients who have not responded to levodopa.

– Adverse effects severely limit the utility of the dopamine agonists.

Adverse effect

• Fatigue, sleep disorders, hypotension, psychosis, dyskinesias, and confusion

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 Drugs for PD…

 Amantadine
 Originally used as an antiviral agent- influenza
 Has several effects on a number of neurotransmitters implicated in parkinsonism,
including;
 increasing the release of dopamine,
 blocking cholinergic receptors, and
 inhibiting the N-methyl-d-aspartate (NMDA) type of glutamate receptors.

 Amantadine is less efficacious than levodopa, and tolerance develops more readily.
Adverse effects
• mental status changes
• lower extremity edema
• Restlessness, agitation, irritability (CNS)
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 Drugs for PD…

Anticholinergics

Trihexyphenidyl , benztropine, and procyclidine

 are much less efficacious than levodopa and play only an adjuvant role in
antiparkinsonism therapy.

 are often used in the tremor-predominant Parkinson’s disease.

 Blockade of cholinergic transmission produces effects similar to augmentation of

dopaminergic transmission,
 since it helps to correct the imbalance in the dopamine/acetylcholine activity

 Adverse effects

• blurred vision, dry mucus membranes including mouth, urinary retention, and
cognitive/mental status changes

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Sedative – hypnotic Drugs

39
 Introduction

 Disorders involving anxiety are among the most common mental disorders.

 Anxiety is an unpleasant state of tension, apprehension or uneasiness (a fear that arises

from either a known or an unknown source).

 The physical symptoms of severe anxiety are similar to those of fear (such as tachycardia,
sweating, trembling and palpitation) and involves sympathetic activation.

 Episodes of mild anxiety are common in life and do not need treatment

 However, the symptoms of severe, chronic, debilitating anxiety may be treated with anti-
anxiety drugs and/or some form of behavioral therapy or psychotherapy.

 Sedation is characterized by decreased anxiety, motor activity, and cognitive acuity.

 Hypnosis is characterized by drowsiness and an increased tendency to sleep.

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 Sedative & Hypnotic Drugs
• Anxiolytic drugs are used to treat the symptoms of anxiety.

• The main groups of the drugs are:

– Benzodiazepines

 are the most important sedative and hypnotic agents

– Barbiturates (phenobarbitone).

– 5- HT1A receptor agonist (e.g. buspirone).

– β -adrenoceptor antagonists (e.g. propranolol).

 They are used to treat some forms of anxiety, where physical symptoms
(sweating, tremor, and tachycardia), are troublesome.

– Miscellaneous drugs (chloral hydrate, paraldehyde, and diphenhydramine).

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 Sedative And Hypnotic…

Benzodiazepines
 Are among the most widely used drugs

 Based on their duration of action :

 Short acting (flurazepam, triazolam),

 Medium acting (alprazepam, lorazepam)

 Long acting (diazepam, chlordiazepoxide, clonazepam).

 Act by binding to a specific regulatory site on the GABA-A receptor,

 thus enhancing the inhibitory effects of GABA.

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Sedative And Hypnotic…

43
 Sedative And Hypnotic…
 Have three principal indications

– Anxiety

– Insomnia

– Seizure disorder

 Adverse effects

– Toxic effects due to acute over-dosage causes prolonged sleep.

– Unwanted effects occurring during normal therapeutic use includes:

 drowsiness, confusion, amnesia, and impaired motor coordination.

 Sedative effects can be reversed with flumazenil

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 Sedative And Hypnotic…

 Benzodiazepine – like drugs

– (zolpidem, zaleplon, and eszopiclone), often referred to as “Z-drugs,”

– are similar to benzodiazepine in nature though they are unrelated to benzodiazepines

on a molecular level.

– the pharmacodynamics of Z-drugs is almost entirely the same as that of

benzodiazepine.

 therefore employs similar benefits, adverse effects, and risks.

– Like the benzodiazepines, exert their effects by binding to and activating the
benzodiazepine site of the receptor complex.

– Their actions are blocked and reversed by the benzodiazepine antagonist flumazenil.

45
 Sedative And Hypnotic…

 Barbiturates
– Include: Amobarbital, Phenobarbital, Pentobarbital, Secobarbital, Thiopental.
– were formerly the mainstay of treatment to sedate patients or to induce and maintain
sleep.
– They have been largely replaced by the benzodiazepines, primarily because
barbiturates
 induce tolerance and physical dependence,
 are lethal in overdose, and
 are associated with severe withdrawal symptoms.

– The sedative–hypnotic action of the barbiturates is due to their interaction with

GABA-A receptors, which enhances GABAergic transmission.
– The binding site of barbiturates on the GABA receptor is distinct from
that of the benzodiazepines. 46
 Sedative And Hypnotic…
– Classification
• can be grouped in to three classes based on duration of action

• The duration of action influences, the clinical application of barbiturates.

Characteristics of barbiturate subgroups

Subgroup Drug Lipid Onset Duratio Applications
solubility (min) n (hr)
Ultra short-acting Thiopental High 0.5 0.2 Induction of
anesthesia, treatment
of seizures

Short to Secobarbital Moderate 10-15 3–4 Treatment of insomnia

intermediate-acting
Long-acting Phenobarbital Low 60 10-12 Treatment of seizure

47
 Sedative And Hypnotic…

– Adverse effects

 respiratory depression (over dosage resulting in death)

 should not be used in pregnancy

 potential for abuse.

– Drug interactions

 since it stimulates hepatic drug – metabolizing enzymes, some medications need

increased dosages (warfarin, oral contraceptives, phenytoin).

48
 Sedative And Hypnotic…

 5 - HT1A receptor agonist

– Buspirone is a potent partial agonist of 5 - HT1A receptors.

– Anxiolytic effects take days to weeks to develop.

– its mode of action differs from that of the benzodiazepines.

– is useful for the chronic treatment of generalized anxiety disorder (GAD)

– It has a slow onset of action and is not effective for short-term or “as-needed”
treatment of acute anxiety.

– usually requires therapy of 3 to 6 weeks to demonstrate efficacy.

– It does not cause sedation, motor incoordination and withdrawal effects.

– The main side effects are nausea, dizziness, headache, and restlessness.

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50
OPIOID ANALGESICS

51
 What is analgesic?

 Medications that relieve pain without causing loss of consciousness.

 Alleviation of pain depends on the specific type of pain (nociceptive or neuropathic pain).

 For example, with mild-to-moderate arthritic pain (nociceptive pain),

o Non-opioid analgesics such as NSAIDs are often effective.

 for severe acute pain or chronic malignant or nonmalignant pain,

o opioids can be considered as part of the treatment plan in select patients.

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Opioid analgesics (narcotic analgesics)

– Opioids are natural, semisynthetic, or synthetic compounds.

– Opioids interact with receptors (Mu (the most important), kappa, and delta) on the
membranes of certain cells like CNS, PNS, GIT.
53
• Therapeutic Use of opioids.

– Analgesia
• Opioids are used for pain in trauma, cancer, and other types of severe pain.

– Treatment of diarrhea
• Opioids decrease the motility and increase the tone of intestinal circular smooth muscle.

– Agents commonly used include diphenoxylate and loperamide

– Relief of cough
• codeine and dextromethorphan are more commonly used

– Treatment of acute pulmonary edema

• Intravenous morphine dramatically relieves dyspnea caused by pulmonary edema associated with left
ventricular failure, possibly via the vasodilatory effect.

– Anesthesia
• Opioids are used as preanesthetic medications, for systemic and spinal anesthesia, and for
postoperative analgesia 54
• Side effects of opioid analgesics:

– Acute toxicity: classic triad

 Pinpoint pupils

 Respiratory depression

 Coma

– Management of acute toxicity:

 Supportive

 IV naloxone

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56
Antiepileptic Drugs

57
 Introduction
Seizure

 finite episodes of brain dysfunction resulting from abnormal discharge of cerebral

neurons.

Epilepsy

 a disease characterized by spontaneous recurrent seizures

 Seizure may be partial or generalized depending on the location and the spread of the
abnormal neuronal discharge.

 The attack mainly involves motor, sensory or behavioral phenomena.

58
Introduction…

59
 Antiepileptic drugs

• Antiepileptic drugs suppress but do not cure seizures

• Mechanism of Action

 Anticonvulsant drugs act by two mechanisms:

 by reducing electrical excitability of cell membrane and

o inhibition of sodium channel -phenytoin, carbamazepine

 by enhancing GABA mediated synaptic transmission.

 The main drugs used in the treatment of epilepsy are phenytoin, carbamazepine,
valproate, ethosuximide and phenobarbitone.

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Phenytoin
 It is commonly used antiepileptic drug.

 It is effective against different forms of partial and generalized seizures;

 however it is not effective in absence seizures.

 Well absorbed when given orally.

 It is metabolized by the liver.

 It is liver enzyme inducer and therefore, increases the rate of metabolism of other
drugs.

 Main side effects are sedation, confusion, gum hyperplasia, skin rash, anemia,
nystagmus, and diplopia.

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Carbamazepine

 It is derived from tricyclic antidepressant.

 Its pharmacological action resembles those of phenytoin, however, it is chiefly

effective in the treatment of partial seizure.

 It is also used in the treatment of trigeminal neuralgia and manic-depressive illness.

 It is powerful inducer of liver enzymes, thus accelerates the metabolism of phenytoin,

warfarin, oral contraceptives and corticosteroids.

 Carbamazepine causes sedation, mental disturbances and water retention.

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Phenobarbitone
 The clinical use of phenobarbitone is nearly the same as that of phenytoin.

 It is well absorbed after oral administration and widely distributed.

 Renal excretion is enhanced by acidification of the urine.

 Phenobarbitone is liver enzyme inducer and hence accelerates the

metabolism of many drugs like oral contraceptives and warfarin.

Adverse effect

 Very strong sedation; Cognitive impairment; Behavioral changes

 Tolerance may arise; Risk of dependence

 now seldom used in initial therapy, owing to side-effects

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Benzodiazepine

 Clonazepam and related compounds, clobazam are claimed to be relatively

selective as antiepileptic drugs.

 Diazepam is also available for rectal administration to avoid or interrupt prolonged

generalized tonic–clonic seizures or clusters when oral administration is not possible.

 Sedation is the main side effect of these compounds.

64
Valproic Acid

 Valproate is chemically unrelated to the other antiepileptic drugs.

 The mechanism of action is unknown.

 It is used in grand mal, partial, petit mal and myoclonic seizure.

 Relatively has few side effects, however, it is potentially hepatotoxic.

 It is non sedating.

Ethosuximide

 used in the treatment of absence seizures.

 Has fewer side effects.

 Less sedating than other AEDs

65
Newer Antiepileptic Drugs( Second- Generation )
1. Vigabatrin
2. Gabapentin
3. amotrigine
4. Topiramate
5. Tiagabine
6. levetiracetam
7. Oxcarbazepine
8. Zonisamide
Newer Agents Differ From Older Drugs
 Relatively lack of drug-drug interaction (simple pharmacokinetic profile)
 Improved tolerability
 But they are costly with limited clinical experience
66
Antidepressant Drugs

67
 Depression

 “psychic disorder characterized by loss of interest or pleasure in almost all a person’s

usual activities or pastimes.”

 Antidepressants are the drugs which are mainly used in the management of

depression.

68
Antidepressant Classes

1. Selective Serotonin Reuptake Inhibitor (SSRI)

• Sertraline, Fluoxetine, Paroxetine

2. Tricyclic Antidepressant (TCA)

• Amitriptyline, Nortriptyline, Imipramine, Desipramine

3. Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)

• Venlafexine, Desvenlafaxin, Duloxetine

4. MAO Inhibitors

• Phenelzine, Tranylcypromine

5. Atypical Antidepressants

• Bupropion, Trazodone, Mirtazepine

69
 Pharmacokinetics

 Most tricyclic are incompletely absorbed and undergo significant first-pass metabolism.

 Highly protein bound and relatively high lipid solubility.

 Fluoxetine (SSRIs)) is well absorbed.

 The MAO inhibitors are readily absorbed from the GI tract.

 MOA

 Almost all antidepressant drugs result in a potentiating of the neurotransmitter actions

of NE, serotonin (5-HT) or both.

 However buspirone has unknown mechanism of action

70
• Adverse Effects:

– Postural hypotension, dry mouth, blurred vision, constipation, urine retention,

sedation, are the most important side effects of TCAs.

– MAOI cause postural hypotension, atropine-like effects, weight gain, and CNS

stimulation causing restlessness, tremor, and insomnia.

71
Antipsychotic Drugs

72
Psychosis

 Psychosis is a thought disorder characterized by disturbances of reality and perception,

impaired cognitive functioning, and inappropriate or diminished affect (mood).

 Schizophrenia is a particular kind of psychosis characterized mainly by a clear

sensorium but a marked thinking disturbance.

 characterized by a divorcement from reality in the mind of the person (psychosis).

 may involve visual and auditory hallucinations, delusions, intense suspicion, feelings
of persecution or control by external forces (paranoia), depersonalization, and there
is attachment of excessive personal significance to daily events, called “ideas of
reference”.

73
Classification of Antipsychotic drugs

 Main categories are:

 Typical antipsychotics

 Phenothiazines (chlorpromazine, perphenazine, fluphenazine, thioridazine)

 Thioxanthenes (flupenthixol, clopenthixol)

 Butyrophenones (haloperidol, droperidol)

 Atypical antipsychotics

 e.g. clozapine, risperidone, quetiapine, olanzapine)

74
• Most antipsychotic drugs are readily but incompletely absorbed.

• Many of these drugs undergo significant first-pass metabolism.

• Very little of any of these drugs is excreted unchanged, as they are almost completely
metabolized to more polar substances.

• The phenothiazine antipsychotic drugs have a wide variety of CNS, autonomic, and
endocrine effects. It blocks receptors including;

– dopamine and alpha-adrenoceptor,

– muscarinic,

– H1 histaminic, and

– serotonin (5-HT2) receptors.

 Of these, the dopamine receptor effects quickly became the major focus of interest.

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• Clinical uses
– Schizophrenia

– Mania

– Vomiting

• Adverse Reactions
– Extrapyramidal reactions

– Seizures

– Autonomic nervous system effects (antimuscarinic effects, orthostatic hypotension)

– Metabolic and Endocrine Effects (weight gain, hyperprolactinemia, infertility, loss of

libido and impotence)

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Antidepressants…

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THANK YOU

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