CNS

PHARMACOLOGY
By:- Ephrem Ashenafi

1
Outline
 Introduction
 Anesthetics
 Sedative and Hypnotics
 Opioid Analgesics and Antagonists
 Anti-psychotics
 Depression, Anxiety and Mood Disorders
 Neurodegenerative disorders
 Antiepileptics Drugs
 Pharmacological and Toxicological Effects of Catha edulis F.
2
Introduction

 The CNS is composed of the brain and spinal cord

 It is responsible for integrating sensory information and generating

motor output

The brain is a complex assembly of interacting cells that regulate

many of life’s activities in a dynamic fashion.

3
Cont`d

 This occurs generally through the communication process of

chemical neurotransmission.

 The CNS is made up of several types of specialized cells that are

physiologically integrated to form complex functional brain tissue.

 The primary communicating cell is the neuron

4
Cont`d

 They are electrically excitable cells that process and transmit

information via an electrochemical process.

 And they are classified according to function, location and identity of

neurotransmitter synthesize and release.

5
Cont`d
The sites of interneuronal communication in the CNS are termed synapses.

Synapses contain array of specific proteins that are active zone of NT release and response

Types of synapses include

 Axodendritic

 Axosomatic

 Axoaxonic

 Dendrodendritic

 Dendrosomatic
6
Cont`d

 In addition to neurons, there are a large number of nonneuronal

support cells

 These include neuroglia, vascular elements, and the meninges

 Neuroglia are the most abundant support cells and classified as micro
and macroglia

7
Cont`d

 They are nonneuronal cells that maintain important brain functions,

such as
 Holding neurons in place

 Supplying oxygen and nutrients to neurons

 Insulating signaling between neurons and

 Destroying potential pathogens

8
Cont`d

 In the CNS, the macroglia consist of astrocytes, oligodendroglia, ependymal

cells, and radial glia.

 Astrocytes are the most abundant of these

 They play a variety of metabolic support roles, including

 Furnishing energy intermediates

 Anchoring neurons to their blood supply and

 Regulating the external environment of the neuron

9
Cont`d

 The oligodendroglia produce myelin, which permit non decremental

propagation of action potentials.

 Ependymal cells line the spinal cord and ventricular system and are
involved in the creation of CSF.

 Radial cells act as neuro progenitors and scaffolds

10
Cont`d

 Microglia consist of specialized immune cells found within the CNS.

 Located in a normal brain in a resting state

 Purported to become a very mobile, active macrophage during

disease

 The major effector cell in immune mediated damage in the CNS

11
Blood-Brain Barrier

 The blood-brain barrier (BBB) is a protective functional separation of

the circulating blood from the extracellular fluid of the CNS.

 This barrier consists of endothelial cells, astrocytes, and pericytes on

a noncellular basement membrane.

 It prevents or diminishes unencumbered access to the brain by

circulating blood components.
12
Cont`d

 However, the cells within the barrier also have the capacity to
actively transport molecules such as glucose and amino acids

 Clinical manifestations, such as cerebral ischemia and inflammation,

can modify the BBB.

13
Central Neurotransmitters

 Neurotransmitters are endogenous chemicals in the brain that act to

enable signaling across a chemical synapse.

 They carry, boost, and modulate signals between neurons or other cell
types and act on a variety of targets

 Neurotransmitters can be classified by chemical structure into various

categories

14
15
Amino Acids

 The CNS contains high concentrations of certain amino acids, notably

glutamate and GABA

 They are ubiquitously distributed within the brain and produce rapid and
readily reversible effects on neuron

 The dicarboxylic amino acid glutamate and aspartate produce excitation,

while the monocarboxylic amino acids GABA and glycine cause inhibition.

16
Gamma-Aminobutyric Acid

 GABA is the main inhibitory neurotransmitter in the CNS.

 It is synthesized in the brain from the Krebs cycle intermediate

α-ketoglutarate

 Which is transaminated to glutamate by GABA-T.

 GABA is subsequently formed from glutamate by the enzyme GAD

17
Cont`d

 GABA acts by binding to and activating specific receptors on both

pre- and postsynaptic membranes

 GABAA receptors (the most prominent GABA receptor subtype) are

ionotropic, ligand-gated Cl– channels.

 The GABAA receptors are the site of action of many neuroactive drugs
(e.g. benzodiazepines , barbiturates, ethanol, anesthetics and others)
18
Cont`d

 These drugs are used to treat various neuropsychiatric disorders, including

epilepsy, Huntington disease, addictions, sleep disorders, and more.

 The action of GABA is primarily terminated by reuptake of different GATs

present on both neurons and glia.

19
Glycine

 Glycine is an amino acid that can act as an inhibitory neurotransmitter,

particularly in the spinal cord and brainstem.

 It is synthesized primarily from serine by serine hydroxy methyl

transferase (SHMT)

 The action of glycine in the synaptic cleft is terminated by reuptake

through specific transporters (GLYT1 and GLYT2)

20
Cont`d

 Taurine and β-alanine are agonists of glycine receptors.

 Strychnine, which is a potent convulsant and has been used in some

rat poisons, selectively blocks glycine receptors

21
Glutamate
 Glutamate and aspartate are dicarboxylate amino acid
neurotransmitters with excitatory actions in the CNS.

 Both amino acids are found in high concentrations in the brain and
have powerful excitatory effects on neurons.

 Glutamate is the most abundant excitatory neurotransmitter and the

principal fast excitatory neurotransmitter.

22
Cont`d

 Glutamate transmission have long been hypothesized to be involved

in learning and memory.

 Glutamate acts through receptors that are classified as either ligand

gated ion channels (ionotropic) or metabotropic GPCRs.

 The ionotropic receptors are divided into three subtypes based on the
action of selective agonists AMPA, Kainate and NMDA.

23
Monoamines

 Monoamines include the catecholamines (dopamine, norepinephrine,

epinephrine), 5-hydroxytryptamine, histamine, and the trace amines.

 They regulate neurotransmission that underlies cognitive processes,

including emotion.

 These pathways are the site of action of many drugs; e.g. cocaine and
amphetamine appear to act primarily at catecholamine synapses.

24
Cont`d

 Drugs that affect monoamine receptors and signaling are used to treat
a variety of conditions, such as
 Depression,

 Schizophrenia, and

 Anxiety,

 Movement disorders like Parkinson disease.

25
Dopamine

Secreted by neurons of substantia nigra, medulla, hypothalamus and

chemoreceptor trigger zone

 DA signaling plays a role in motivation and reward, motor control,

and the release of various hormones.

 The major pathways containing dopamine are the projection linking

the substantia nigra to the neostriatum.

26
Cont`d

 And the other one is the projection linking the ventral tegmental
region to limbic structures, particularly the limbic cortex.

 In addition, dopamine-containing neurons in the ventral

hypothalamus play an important role in regulating pituitary function.

27
Norepinephrine

 NE is an endogenous neurotransmitter for the α and β adrenergic

receptor subtypes that are present in the CNS

 Most noradrenergic neurons are located in the locus coeruleus or the

lateral tegmental area of the reticular formation.

 It has Mostly excitatory effects through activation of α1 and β1

receptors which decrease K+ conductance
28
Cont`d

 It also has inhibitory effects through activation of α2 and β2 receptors which

will increase K+ conductance.

 NE is involved in regulation of:

 Mood

 Blood pressure

 Feeding center

 Learning and memory

 Sleep–wake cycle(alertness)

29
Epinephrine
 Most EPI in the brain is contained in vascular elements.

 EPI-containing neurons are found in the medullary reticular formation

and make restricted connections to pontine and diencephalic nuclei,

 They eventually course as far rostrally as the paraventricular nucleus of

the thalamus.

 But their physiological properties have not been unequivocally identified.

30
5-Hydroxytryptamine (Serotonin)

 5HT is almost entirely synthesized by cells located in the raphe nuclei in the
brainstem

Most 5-hydroxytryptamine (5-HT, serotonin) pathways originate from

neurons in the midline raphe nuclei of the pons and upper brain stem.

 In most areas of the CNS, 5-HT has a strong inhibitory action.

31
Cont`d

 This action is mediated by 5-HT1A receptors and is associated with

membrane hyperpolarization caused by an increase in potassium conductance.

 Serotonin signaling plays a role in modulating mood, depression, anxiety,

phobia, and GI effects.

 Reuptake of 5HT by the 5HT transporter is the primary mechanism for

termination of 5HT action
32
Cont`d
 Mood,
 It is involved in the regulation
 Sleep
 Appetite
 Cognition
 sexual behavior, and hormone
 Sensory perception
secretion
 Motor activity

 Temperature regulation

 Nociception

33
Histamine

In the CNS, histamine is exclusively made by neurons in the tuberomammillary

nucleus (TMN) in the posterior hypothalamus.

These neurons project widely throughout the brain and spinal cord where they

modulate
 Arousal

 Attention

 Feeding behavior

 Memory
34
Cont`d

 The H1 receptors are widely distributed in the brain, where high

densities are found in regions linked to
 Neuroendocrine

 Behavioral

 Nutritional state control

35
Acetylcholine

 Acetylcholine is present throughout the nervous system and functions

as a neurotransmitter.

 In the CNS, ACh is found primarily in interneurons.

The degeneration of particular cholinergic pathways is a hallmark of

Alzheimer disease.

36
Cont`d
 The effects of ACh result from interaction with ionotropic ligand-gated
ion channels termed nicotinic receptors

 It also interacts with metabotropic GPCRs called muscarinic receptors.

 Both nicotinic and muscarinic receptors are expressed in the brain.

 Eight major CNS nuclei of acetylcholine neurons have been

characterized with diffuse projections.

37
Cont`d

 These include neurons in the neostriatum, the medial septal nucleus,

and the reticular formation that appear to play an important role in
cognitive functions, especially memory.

38
CNS drugs

 This are agents that act on the brain and spinal cord

 They are used widely for medical and nonmedical purposes.

 Medical applications include

 Sedative-hypnotics & anxiolytics
 Treatment of psychiatric disorders
 Suppression of seizures
 Relief of pain
 Production of anesthesia, etc

39
Cont`d

 Nonmedical use of CNS drugs include

 Stimulant

 Depressant

 Euphoriant

 Other “mind-altering” abilities

40
Anesthesia

41
Introduction

 Anesthesia is the state of depressed CNS activity

 It is the condition of loss of responsiveness to sensory stimulation:

pain, touch, temp, taste, ..

 There is also muscle relaxation and state of insensibility

42
Cont`d

 Anesthetics are agents that depress CNS or consciousness

 There are two types of anesthetics

 Local anesthetics

 General anesthetics

43
Local Anesthetics

 Local anesthetics bind reversibly to a specific receptor site within the

pore of the Na+ channels in nerves and block ion movement.

 They act by reversibly blocking the action potentials responsible for

nerve conduction.

 Such blockade may bring with it other physiologic changes such as

muscle paralysis and suppression of somatic or visceral reflex.

44
Cont`d

 They Produces a state of local anesthesia without the loss of total

consciousness

 They have much low risk when compared to general ones

45
46
Pharmacological effects

 Small, non-myelinated neurons mediating pain are much more susceptible

than large, myelinated fibers mediating motor functions

 Functional consequences of Na+ channel blockade

 Nerves: decrease or abolition of conduction

 Vascular smooth muscle: vasodilatation

 Heart: decreased excitability (reduced pacemaker activity, prolongation of effective refractory

period)
 CNS: increased excitability, followed by generalized depression

47
Cont`d

 The vasodilation effect can be counter acted by concomitant

administration of epinephrine.

 Administration of epinephrine has also other benefits this include

 Prolongation of anesthetic action

 Decreased risk of toxicity

 Decrease in bleeding from surgical manipulations

48
Clinical use
 Topical Anesthesia

 For surface analgesia on skin & mucous membranes to relieve skin pain,
itching & soreness

 Tetracaine (2%), lidocaine (2%–10%), and cocaine (1%–4%) typically are

used.

 Cocaine is used only in the nose, nasopharynx, mouth, throat, and ear, where
it uniquely produces vasoconstriction as well as anesthesia.
49
Cont`d
 Infiltration Anesthesia

 Infiltration anesthesia is the injection of local anesthetic directly into tissue.

 Infiltration anesthesia can be so superficial as to include only the skin.

 It also can include deeper structures (including intra-abdominal organs).

 The local anesthetics most frequently used for infiltration anesthesia are lidocaine
(0.5%–1%) and bupivacaine (0.125%–0.25%).

50
Cont`d

The duration of infiltration anesthesia can be approximately doubled

by the addition of epinephrine (5 μg/mL) to the injection solution.

 The chief disadvantage of infiltration anesthesia is that relatively

large amounts of drug must be used to anesthetize relatively small
areas.

51
Cont`d

 Nerve block anesthesia

 Used for dental & minor surgery

 It is administered around the nerve supplying surgical field

 Lidocaine, mepivacaine or bupivacaine can be used

 Other clinical uses include IV regional anesthesia, Epidural anesthesia,

Spinal (Subarachnoid) anesthesia
52
Toxicity

 Local anesthetic toxicity derives from two distinct processes:

1. systemic effects following inadvertent intravascular injection or

absorption of the local anesthetic from the site of administration;

2. neurotoxicity resulting from local effects produced by direct contact

with neural elements

53
Cont`d

 CNS
 Excitation, convulsion, depression

 CVS
 Bradycardia, heart block, reduced contractile force, and even cardiac arrest & hypotension

 Allergic reactions
 From allergic dermatitis to anaphylaxis (Common with ester-type anesthetics)

 Prolong labor
 Depress uterine contractility and maternal expulsion effort

54
General anesthetics

 General anesthetics depress the CNS to a sufficient degree to permit

the performance of surgery and unpleasant procedures.

 Drugs that produce unconsciousness and a lack of responsiveness to

all painful stimuli

 They are used for surgical procedure

 They render the patient unaware / unresponsive to the painful stimuli

55
Cont`d
 An ideal anesthetic would produce
 Unconsciousness

 Amnesia

 Analgesia

 Muscle relaxation

 Brief & pleasant induction

 N.B: No single agent provide all these desirable effects—adjuncts to

anesthesia is needed
56
Some adjuncts to anesthesia and their functions

 Relief anxiety and facilitate amnesia —BZDs (midazolam, diazepam)

 Prevent gastric acid secretion—H2 blockers (Famotidine)

 Prevent allergic rxn—antihistamines (diphenhydramine)

 Prevention of aspiration of stomach contents and postsurgical NV—

Antiemetics (ondansetron)

57
Cont`d

 Prevention of bradycardia and respiratory secretions—anticholinergics

(glycopyrrolate, atropine)

 Provide analgesia—opioids (fentanyl)

 Facilitate intubation and S. muscle relaxation—NMJBs (pancuronium,

succinylcholine)

58
Stages of general anesthesia

 Stage I: Induction
 Depends on how fast effective conc. of the anesthetic drug reach the brain

 Adult—IV anesthetics (propofol—30-40sec unconsciousness)

 Children—non pungent inhalation GA(halothane/sevoflurane)

 Stage II: Maintenance of anesthesia

 Volatile anesthetics + opioids (fentanyl)

 Stage III: Recovery

 Reverse of induction—how fast drug diffuse out of brain

59
Depth of anesthesia

 Stage I- Analgesia
 Loss of sensibility to pain

 Mild CNS depression

 Increase in circulating endorphins

 Suitable for surgical procedure not requiring muscle relaxation

• Stage II- delirium or disinhibition

 Excitement, combative behavior – dangerous state

 Increase involuntary activity and hypersecretion

 Managed by anticholinergics 60
Cont`d

Stage III- Surgical anesthesia

 General loss of spinal reflexes and muscle tone

 Most surgical operations are performed at this stage

Stage IV- Medullary paralysis

 Respiratory and vasomotor control ceases

 Death rapidly ensue unless measure is taken to maintain circulation and respiratory system

 Manifestation of overdose

 Generally not desirable

61
Two classes of general anesthetics

 Inhalation anesthetics
 For maintenance

 Injectable (IV) anesthetics

 For induction

62
Inhalation Anesthetics

 They are given by inhalation

 Used for maintenance of anesthesia

 Have advantage of controlling the depth of anesthesia.

 Their metabolism is very minimal

 Excreted by exhalation

63
Molecular mechanism of action

 Their Molecular mechanism of action is unknown

 Postulations
 Nonspecific interactions with lipid components of neuronal cell membrane

 Suppress axonal conduction & synaptic transmission

 Enhancing transmission at inhibitory synapses & depressing transmission at

excitatory synapses

64
Cont`d

 All inhalation anesthetics enhance activation of receptors for GABA

 This action is mediated allosterically

Apart from that Nitrous oxide block-NMDA actions

65
Pharmacokinetics

 Uptake is determined by conc in inspired air

 Pulmonary ventilation

 Solubility in blood

 Pulmonary blood flow

 Distribution
 Determined by regional blood flow

 Brain, liver, kidney, heart---skin & skeletal muscles---fat, bone, ligaments & cartilage

66
Cont`d

 Elimination
 Redistribution [brain—blood—air]

 Metabolism
 toxic metabolites

67
Adverse effects

 Respiratory & cardiac depression

 Mechanical support for ventilation

 Sensitization of the heart to catecholamines

 Halothane

 Dysrhythmias

 Due to release of endogenous catecholamines

68
Cont`d

 Malignant hyperthermia
 All inhalation anesthetics except nitrous oxide

 Genetic predisposition

 Muscle rigidity & excessive elevation of body temp, 43 0C

 Increased risk with Succinylcholine

69
Cont`d

Aspiration of gastric contents

 Due to blockade of aspiration reflexes

 Bronchospasm & pneumonia

Hepatotoxicity

Toxicity to operating room personnel

 Headache, reduced alertness, and spontaneous abortion

70
Classification of inhalation anesthetics

 Gases
 Nitrous oxide

 Volatile liquids (Fluorinated halogenated hydrocarbons)

 Halothane
 Enflurane
 Isoflurane
 Desflurane

 Sevoflurane

71
Nitrous oxide

 It is the safest inhalational anesthetic

 Has no toxic effect on the heart, liver and kidney

 Might cause postoperative NV

 Caution about hypoxia, megaloblastic anemia

 Weak anesthetic but a good analgesic

 Supplement the analgesic effects of the primary anesthetic

72
Halothane
 Potent anesthetic but weak analgesic
 Co-administered with N2O, opioids

 Has GABAA potentiation effect

 Commonly used in children, due to lack hepatotoxicity in pediatrics
 Causes catecholamine sensitization of the heart
 Due to its broncho dilation effect it is preferred in asthmatics

73
Cont`d

Adverse effect
 Hypotension

 Respiratory depression

 Dysrhythmias

 Hepatitis

 Malignant hyperthermia

74
Isoflurane

 Has similar properties as halothane

 Commonly used with oxygen or nitrous oxide

 Does not sensitize the heart to catecholamines

 It irritates the respiratory system

 Causes respiratory depression & hypotension

 Has no hepatic or renal toxicity, myocardial depression

75
Enflurane

 Similar action as halothane

 Generally do not sensitizes the heart to catecholamines

 Seizures occurs at deeper levels –C/I in epileptics

 Caution in renal failure due to fluoride

76
Desflurane

 Delivered through special vaporizer

 Popular anesthetic for day care surgery

 Fast induction and recovery

 Irritates the air passages producing cough & laryngospasm

77
Sevoflurane

 Has fast induction and recovery

 Does not cause air way irritancy

 Have nephrotoxic effect

78
Anesthetic Features Notes
Halothane PLEASANT Arrhythmia
Hepatitis Hyperthermia

Enflurane PUNGENT Seizures Hyperthermia

Isoflurane PUNGENT Laryngospasm

Cough
Sevoflurane PLEASANT Ideal

Desflurane IRRITANT Rapid onset & recovery—least

blood solubility
Cough

Nitrous PLEASANT Anemia

79
Parenteral (IV) Anesthetics

 Used alone or to supplement the effects of inhalations

 Used for induction of anesthesia
• Rapid onset of action

 Recovery is mainly by redistribution

 Also reduce the amount of inhalation anesthetic for maintenance

80
Cont`d

 Has two benefits

 Reduction of inhalation anesthetic dosage

 Produce effects not produced by inhalations alone

1. Short-acting barbiturates, thiobarbiturates

 Thiopental

 Methohexital

 Used for induction of anesthesia

81
Cont`d

2. Benzodiazepines

 Provides unconsciousness and amnesia

Diazepam

Lorazepam

Midazolam
3. Propofol
 IV sedative-hypnotic
 For induction & maintenance of anesthesia
82
Cont`d

 Need addition of opioids

 Replaced thiopental

 Produce euphoria

 Does not cause postanesthetic NV

 Causes respiratory depression & hypotension

 Has GABAA potentiation effect

83
Cont`d
4. Etomidate
 Potent hypnotic agent

 Used for induction of surgical anesthesia

 Lack analgesic activity

 Less cardiovascular effects

 Usually only used for pts with angina, CV dysfunction such as shock

 Has GABAA potentiation effect

84
Cont`d

5. Ketamine
 Blocks NMDA receptors
 Good analgesia
 Produce dissociative anesthesia (Pt is unconscious & does not feel pain but appears
to be awake)
 Provide Sedation, immobility, analgesia, and amnesia
 Activate sympathetic outflow—increase CO
 Used when circulatory depression is undesirable
 Not used in HTN pts
 Unpleasant psychologic reactions
 Hallucinations, disturbing dreams, and delirium 85
Cont`d
6. Neuroleptic-opioid combination
 Droperidol + fentanyl

 Neurolept analgesia

 Latency, indifference to surroundings, and insensitivity to pain

 Used for diagnostic and minor surgical procedures

86
Anesthetic Duration Analgesia Muscle Others
I.V mins relaxation

Thiopental 5 - 10 --- --- Respiratory

depression

Propofol 5-10 --- --- Respiratory

depression

Ketamine 5-10 +++ --- Hallucinatio

ns

Midazolam 5-20 --- +++ Amnesia

Fentanyl 5-10 +++ --- Respiratory

depression
87
Preanesthetic medications (adjuvant agents)

 To complement the beneficial effects & counteract their adverse

effects

 Used before or after anesthesia

 Sedative-hypnotics
To relieve anxiety & promote amnesia

Midazolam, secobarbital, thiopental, diazepam

88
Cont`d

 Antihistamines
 To prevent allergic reactions

 Antiemetics
 Ondansetron, promethazine, droperidol

 To prevent nausea and vomiting

89
Cont`d

 Opioid analgesics
To provide analgesia, pre- & postoperative pain
Also suppress cough

Morphine, fentanyl, Sufentanil

 Anticholinergics
 To prevent bradycardia and secretion
 Atropine, scopolamine
90
Cont`d

 Neuromuscular blockers
 Succinylcholine, pancuronium

91
Sedatives and Hypnotics
Introduction
 A sedative drug decreases activity, moderates excitement, and calms the
recipient

 A hypnotic drug produces drowsiness and facilitates the onset and

maintenance of a state of sleep that resembles natural sleep.

 These properties usually reside on the same drug but the dosage differs
Cont`d

The drugs includes benzodiazepines, the Z compounds, barbiturates, as

well as several sedative hypnotic agents of diverse chemical structure.
Fig. 1 Dose-response curves for sedative-hypnotics
SEDATIVE-HYPNOTIC DRUGS
SEDATIVE-HYPNOTICS

Benzodiazepines Barbiturates Miscellaneous agents

Short Ultra short

action action
Intermediate Short
action action Chloral hydrate
Long Long Zaleplon
action action Zolpidem
Ramelteon

96
Benzodiazepines
Drugs available

Alprazolam Lorazepam
Chlordiazepoxide Midazolam
Clonazepam Oxazepam
Clorazepate Quazepam
Diazepam Temazepam
Estazolam Triazolam
Flurazepam
Benzodiazepines

 Benzodiazepines promote the binding of the major inhibitory

neurotransmitter GABA to the GABAA receptor.

 Benzodiazepines act at GABAA receptors by binding directly to a

specific site that is distinct from the GABA binding site.

 They are allosteric modulators of GABAA receptor function

100
Cont`d

 They increase the affinity of the GABAA receptor for GABA and thereby
enhance GABA-induced Cl– currents.

 They potentiate GABAergic inhibition at all levels of the neuraxis, including

 Spinal cord

 Hypothalamus

 Hippocampus

 Substantia nigra

 Cortex
Cont`d

 BZs increase the frequency of opening of the GABA A receptor Cl–

channel in the presence of GABA.

 This effect can be blocked by Flumazenil a BZ receptor antagonist.

 Although the benzodiazepines exert qualitatively similar clinical

effects, quantitative differences in their PD spectra & PK property exits.

 This have led to varying patterns of therapeutic application

Cont`d

The therapeutic effects of the benzodiazepines result from their actions on the CNS.

The most prominent of these effects are

 Sedation
 Hypnosis
 Decreased anxiety
 Muscle relaxation
 Anterograde amnesia
 Anticonvulsant activity
Antagonists & Inverse agonist

 Antagonists

 They are typified by the synthetic benzodiazepine derivative

flumazenil

 It blocks the actions of benzodiazepines, eszopiclone, zaleplon, and

zolpidem
Cont`d
 Inverse agonists

They act as negative allosteric modulators of GABA-receptor function.

Their interaction with BZ sites on the GABAA receptor can produce anxiety and
seizures

A typical example are carbolines, e.g. n-butyl-β-carboline-3 carboxylate (-CCB).

 In addition to their direct actions, these molecules can block the effects of
benzodiazepines.
Pharmacokinetics

 All benzodiazepines are absorbed completely except clorazepate.

 Clorazepate is decarboxylated rapidly in gastric juice to N-

desmethyldiazepam (nordazepam)

 It will then subsequently be absorbed completely.

Cont`d

 Benzodiazepines may be divided based on their elimination t1/2

 Short-acting agents (t1/2 < 6 h) including midazolam, triazolam

 Intermediate-acting agents (t1/2, 6–24 h), including estazolam and temazepam

 Long-acting agents (t1/2 > 24 h), including flurazepam, diazepam, and quazepam

 The benzodiazepines and their active metabolites bind to plasma proteins.

 The extent of binding ranges from about 70% for alprazolam to nearly 99%
for diazepam.
Cont`d

 These drugs cross the placental barrier and are also secreted into
breast milk
*Active metabolic product
Clinical uses

 Anxiety
 Alprazolam, chlordiazepoxide, clorazepate, diazepam, lorazepam, & oxazepam

 Insomnia
 Decrease latency time to falling asleep

 Reduce awakenings

 Increase total sleeping time

Cont`d

 Seizure disorders
 diazepam, clonazepam, lorazepam & clorazepate

 For induction of anesthesia

 diazepam, lorazepam & midazolam

 Muscle spasm
 diazepam

 Panic disorder
 Alprazolam, clonazepam & lorazepam
Adverse effects

Side-effects during therapeutic use

 Drowsiness, confusion, anterograde amnesia, impaired coordination.
 Main disadvantages are interaction with alcohol, long-lasting hangover and the development of
dependence
 Tolerance and dependence
 Fetal harm

Acute toxicity
 Cause prolonged sleep, without serious depression of respiration or cardiovascular.
 Reversed by an effective antagonist, flumazenil.
Drug-drug interactions
 Clinically important pharmacodynamic interactions between benzodiazepines and
other drugs have been infrequent.

 Additive effects with other sedative or hypnotic drugs is a major exception.

 Ethanol increases both the rate of absorption of benzodiazepines and the associated
CNS depression.

 Valproate and benzodiazepines used in combination may cause psychotic episodes.

Cont`d

 Additive effect with other CNS depressants

 Alcoholic beverages

 Antihistamines

 Antipsychotic drugs

 Opioid analgesics
Novel Benzodiazepine Receptor Agonists

 Agents in this class are commonly referred to as “Z compounds.”

 They include zolpidem, zaleplon, zopiclone and eszopiclone

 Z compounds are structurally unrelated to benzodiazepines, but they

have agonist effects at the benzodiazepine site of the GABAA receptor

 They are less effective as anticonvulsants or muscle relaxants than BZs

Cont`d

 They are preferred agents for insomnia

 They are not indicated for anxiety

 They have a low potential for tolerance, dependence, or abuse

Barbiturates
Introduction

 5,5- disubstituted derivatives of barbituric acid

 BTs depress the CNS at all level in a dose-dependent fashion

 They have been largely replaced by the much safer benzodiazepines

and Z compounds.

 Now they are mainly used in anesthesia and treatment of epilepsy

Cont`d

 The barbiturates reversibly depress the activity of all excitable tissues.

 The CNS is more sensitive than peripheral tissue even when given in
anesthetic concentration the effect appears to be weak.

However, serious deficits in cardiovascular and other peripheral functions

occur in acute barbiturate intoxication.
Cont`d

 They are no longer recommended to use as sedative-hypnotic agents

 Because they tend to:

 Have a narrow therapeutic index

 Develop tolerance relatively quickly

 Have a high potential for physical dependence and abuse

 Potent inducers of hepatic drug-metabolizing enzymes

Mechanism of action

 Barbiturates bind to a distinct allosteric site on the GABAA receptor.

 Binding leads to an increase in the mean open time of the GABA-

activated Cl– channel, with no effect on frequency.

 At higher concentrations, barbiturates directly activate channel

opening, even in the absence of GABA
Cont`d

 Barbiturates also reportedly inhibit excitatory AMPA/kainate receptors

and inhibit glutamate release

 These multiple actions may explain the potent CNS depressant effects
of barbiturates as compared to benzodiazepines
Classification

 Ultra-short-acting BTs
 Act within seconds, and duration of action is 30min.

 Thiopental which is used for induction of anesthesia

 Short-acting BTs
 Have a duration of action of about 2 hrs

 Secobarbital: sedative-hypnotics

 Works by depressing the reticular activating system

 They regulate the sleep-wakefulness cycle

Cont`d

 Intermediate-acting BTs
 Have an effect lasting 3-5hrs

 Amobarbital is as hypnotics

 Long-acting BTs
 Have a duration of action > 6hrs

 phenobarbital- antiepileptic agents

Pharmacokinetics

 Absorption
 Well absorbed due to its high lipophilicity

 Distribution
 High lipid solubility allows rapid transport across BBB and results in a rapid onset.

 Rapidly cross placenta

 Removal from the brain occurs via redistribution to the other tissues results in short
duration of action.
Cont`d

 Metabolism and Excretion

 liver microsomal enzymes

 BTs and their metabolites excreted via renal route.

 Alkalinization of the urine expedites the excretion of barbiturates. (Treatment of acute

over dosage)
Therapeutic use

 Seizure disorders- phenobarbital & mephobarbital

 Induction of anesthesia- Thiopental

 Acute manic states and delirium

 Excessive excitation from overdose with CNS stimulants

Adverse effect

 Respiratory depression

 CV depression

 Decreased myocardial contractility, vasodilation, hypotension

 Abuse

 Hangover-with long T1/2, cause residual effects: dizziness, drowsiness,

amnesia, impaired judgment, disorientation
Cont`d

 Fetal harm

 High degree of tolerance

 Dependence

 Skin eruptions and porphyria

Miscellaneous agents
Melatonin Congeners

 Melatonin is a circadian signaling molecule.

 It is the principal indoleamine in the pineal gland

 The synthesis of melatonin in the pineal gland is influenced by external

factors, including environmental light.

 Melatonin analogues have recently been approved for the treatment of

insomnia.
Mechanism of Action

 Two GPCRs for melatonin, MT1 and MT2, in the suprachiasmatic

nucleus, each play a different role in sleep.

 Binding of agonists such as melatonin to MT1 receptors promotes the

onset of sleep.

 Melatonin binding to MT2 receptors shifts the timing of the circadian

system.
Cont`d

 Ramelteon, synthetic melatonin analogue, binds to both MT1 and MT2

receptors with high affinity.

 Ramelteon is not known to bind to any other classes of receptors.\

Ramelteon is efficacious in combating both transient and chronic

insomnia
Pharmacokinetics

 Ramelteon is rapidly absorbed from the GI tract.

 Because of the significant first-pass metabolism that occurs after oral

administration, ramelteon bioavailability is less than 2%.

 M-II ramelteon's active metabolite acts as an agonist at MT1 and MT2

receptors and may contribute to the sleep-promoting effects of ramelteon.
Chloral Hydrate

 A general CNS depressant

 It has similar property as BTs

 It is a prodrug which will be reduced rapidly to the active compound

trichloroethanol

 Trichloroethanol, which can exert barbiturate-like effects on GABA A

receptor channels
Cont`d

 Used mainly to treat patients with paradoxical reactions to

benzodiazepines
Ethyl alcohol
 Ethyl alcohol is the chief constituent of all kinds of alcoholic beverages.

 Beside of its medical importance, it is of great social and economic value.

 It is the oldest recreational drug and likely contributes to more morbidity,

mortality, and public health costs than all illicit drugs combined.
Pharmacological actions
 On CNS

 Small doses lead to euphoria, relieve of anxiety, feeling of over

confidence, facilitation of motor activity and slurred uncontrolled speech.

 Moderate doses produce mild hypnosis & analgesia, antipyretic action,

depression of visual acuity etc.
Cont`d

 On CVS

 Dilatation of skin blood vessels leading to flushing and a sensation of

warmth

 Relieve of angina pain due to its analgesic action

Cont`d

 On body temperature

 Reduces body temperature through depression of heat regulating

center & depression of the vasomotor center

 Dilatation of blood vessels, increase of sweating and increased heat

loss.
Cont`d

 On GIT

 Low concentrations (1-10%) increase gastric secretion

 This results by exciting sensory nerves in the buccal and gastric

mucosa and promoting the release of gastrin and histamine

 But moderate concentrations (20 - 40 %) tend to decrease it.

Cont`d

 Heavy alcohol use can disrupt the gastric mucosal barrier and cause
acute and chronic gastritis.

 Beverages containing more than 40% alcohol also have a direct toxic
effect on gastric mucosa. (seen in chronic heavy drinkers)

 On kidney

 It has diuretic action due to inhibition of ADH

Therapeutic uses:

 As skin disinfectant against bacterial infections (70 %)

 To produce long lasting anesthesia by injection around nerves

 To improve appetite and digestion

 To relieve flatulence and distension by its carminative effect

 Insomnia (As a hypnotic)

Toxicity
 Acute alcoholism

The chief manifestation are

 Euphoria

 Slurred speech

 Vomiting

 Cold skin

 Hypothermia

 Tachycardia

 Slow respiration and coma

 Death may occur from respiratory failure

Cont`d

 Treatment

 Gastric lavage

 Artificial respiration

 Strong coffee orally or caffeine sodium benzoate 0.5 g. I.M. as a

cerebral stimulant
Chronic alcoholism

 Prolonged use of alcohols leads to addiction and liver cirrhosis as

well as atrophic gastritis

 Abrupt withdrawals of alcohol results in delirium, tremors and sever

excitation.

 Treatment of addiction

 Psychotherapy
Cont`d

 Drug therapy:- Disulfiram

 Act by inhibiting acetaldehyde dehydrogenase and accumulation of

acetaldehyde in the blood which produce unpleasant symptoms

 e.g. hypotension, dyspnea, headache, vomiting, sweating, thirst,

chest pain & blurred vision
Cont`d

 These unpleasant symptoms reinforce the will of the patient for treatment
of alcohol addiction

 Citrated calcium carbamide 50 - 100 mg / day orally may be used also. It

is similar to disulfiram but has a shorter duration of action (8 - 12h.).

On withdrawal of alcohol: Chlorpromazine or diazepam should be used to

avoid tremors and excitation.
Opioid Analgesics and
Antagonists

151
Introduction
 The term opioid describes all compounds that work at opioid receptors.

 Opiate specifically describes the naturally occurring alkaloids

 These includes morphine, codeine, thebaine, papaverine and many

semisynthetic derivatives.

 Endogenous opioids are naturally occurring ligands for opioid

receptors found in animals.

152
Cont`d

 Three principal families of endogenous opioid peptides have been

identified:
 Enkephalins

 Endorphins

 Dynorphins

 Endomorphin is another peptide that belong to a novel family of

endogenous opioids that include endomorphin 1 and endomorphin 2
153
Cont`d

 Endomorphins have an atypical structure and display selectivity

toward the MOR.

154
Opioid Receptors

 All opioid drugs act by binding to specific opioid receptors (μ, κ, & δ) in

CNS

Mu (μ) receptors mediate most analgesic effect and adverse effect
 Analgesia

 Respiratory depression

 Sedation

 Decrease GI motility

 Physical dependence and euphoria

155
Cont`d

 Delta (δ) receptors

 Analgesia

 Kappa (κ) receptors

 Analgesia

 Decrease GI motility

156
Classification of Opioid Drugs

 Based on opioid receptor actions, there are 3 groups:

1. Pure opioid agonists

2. Partial opioid agonists

3. Opioid antagonists

157
Cont`d

 Pure Opioid Agonists

They activate mu and kappa receptors and can produce:

 Analgesia

 Euphoria

 Sedation

 Respiratory depression

 Physical dependence

 Constipation, and other effects

158
Cont`d
 Partial Agonist

 When taken alone they produce analgesia

 But with pure agonists, antagonize analgesia produced by pure agonists.

 Pentazocine

 Nalbuphine

 Butorphanol

 Buprenorphine

159
Cont`d

 Pure Opioid Antagonists

 Act as antagonists at mu and kappa receptors

 They does not produce analgesia

 They reverse respiratory & CNS depression caused by overdose with

opioid agonists

 Naloxone and naltrexone are some examples

160
Basic Pharmacology of the Opioids

 Morphine
 Extracted from opium
 Strong opioid analgesics
 Multiple pharmacologic effect
 Analgesia- relief of pain [moderate- severe]
 Diarrhea
 Cough

161
Cont`d
 Adverse effects
• Respiratory depression • Physical & psychological dependence
• Constipation

• Orthostatic hypotension

• Cough suppression

• Emesis

• Euphoria/dysphoria

• Sedation

162
Cont`d

 Drug interactions
 CNS depressants

 Anticholinergic drugs

 Hypotensive drugs

 Monoamine oxidase inhibitors

 Meperidine/pethidine

 A synthetic opioid structurally unrelated to morphine.

 Used for acute pain 163
Cont`d
 Not clinically useful in treatment of diarrhea or cough

 Methadone
 A synthetic, orally effective opioid

 Equal in potency to morphine

 Induces less euphoria

 Longer duration of action

 Used as an analgesic & in controlled withdrawal of dependent abusers from heroin and
morphine

164
Cont`d

 Fentanyl
 Chemically related to meperidine

 100-fold the analgesic potency of morphine

 Used in anesthesia

 Highly lipophilic

 Rapid onset and short duration of action

165
Cont`d

 Sufentanil, Alfentanil, and Remifentanil

 Are related to fentanyl
 Codeine
 Prodrug of morphine

 Antitussive effects

 Much less potent analgesic than morphine

 But with a higher oral effectiveness

166
Cont`d

 Produces less abuse & euphoria than morphine

 Used in combination with aspirin or acetaminophen

 Oxycodone
 A semisynthetic derivative of morphine.

 Orally active

 Formulated with aspirin or acetaminophen

 Used to treat moderate to severe pain

167
Cont`d

 Agonist-Antagonist Opioids
 Pentazocine

 Promotes analgesia by activating receptors in the spinal cord

 Used to relieve moderate pain

 Administered either orally or parenterally

 Produces less euphoria compared to morphine.

 Buprenorphine, Nalbuphine, Butorphanol

168
Nonopioid Centrally Acting Analgesics
Clonidine

α2 agonist that blocks nerve traffic from periphery to brain in S. cord

Ziconotide

 n-type CCBs [nociceptive afferent neurons in s. cord]

Dexmedetomidine

 α2 agonist

This agents do not cause respiratory depression, physical dependence and lack abuse potential

169
Cont`d

 Tramadol
 A centrally acting analgesic

 Analogs of codeine

 Binds to the µ-opioid receptor

 Blocks reuptake of NE & 5-HT

 Activating mono-aminergic spinal inhibition of pain

 Used to manage moderate to moderately severe pain

170
Pure analgesic antagonists

 Naloxone
 Used to reverse coma and respiratory depression of opioid overdose
 Rapidly displaces all receptor-bound opioid molecules

 Able to reverse the effect of a heroin overdose

 Naltrexone
 Longer duration of action than naloxone
 Hepatotoxic
171
Cont`d

 Nalmefene
 A parenteral opioid antagonist

 Similar actions to naloxone and naltrexone

 A relatively pure MOR antagonist that is more potent than naloxone

 Longer duration of action

 Methylnaltrexone
 Have poor CNS bioavailability
 Used to manage opiate-induced constipation 172
Antipsychotics
Psychosis

 It is a symptom of mental illnesses characterized by a distorted or

nonexistent sense of reality.

 They are severe mental disorders with

 Impaired cognitive functioning

 Distortion of behaviour

 Impaired capacity of recognizing reality and perception (delusion &

hallucinations)
Cont`d

 Personality is severely altered and a person’s contact with reality is

impaired.
 The most common disorder is called schizophrenia

 Schizophrenia has a worldwide prevalence of 1% and is considered

the prototypic disorder.
 ~ 80 % of persons who develop SZ have a genetic basis
Cont`d

 Has more impact on urban people than rural people

 It has both positive and negative symptoms

 Positive symptoms - presence of inappropriate or exaggerated normal symptoms

include:
 Disorganized Thinking (fragmented, bizarre and distorted with false beliefs)

 Delusions (false belief)

 Hallucinations (false perception in absence of stimulus)

 Inappropriate Emotions and Actions

Cont`d

 Positive symptoms are usually associated with higher dopamine D2

receptor activity

 These symptoms respond to antipsychotic treatment

 In addition to positive symptoms, schizophrenia patients also suffer

from negative symptoms
Cont`d
 These symptoms includes
 Affective flattening – Poor emotional experience

 Anhedonia – Loss of capacity to experience pleasure

 Avolition - lack of desire, derive, or motivation to pursue goals

 Alogia (poverty of speech)

 Withdrawal from social contacts

 Cognitive deficits (The most disabling aspect of the disorder)

 More chronic and persistent and less responsive to some antipsychotic agents
Cont`d

 Negative symptoms might be difficult to evaluate because they are not as

grossly abnormal as positive symptoms.

 Cognitive symptoms include

 Impaired in:
• Thinking, attention,
• Learning & memory,
• Executive functions are the core element of cognitive symptoms
Clinical picture

 Socially disorganized behaviors

 Occasionally aggressive and violent aimlessly.

 Talking irrelevantly

 Suspiciousness

 Thoughts of being harmed or controlled by some external agencies.

 Laughing, smiling or crying without any obvious reason.

Cont`d

 Talking to self or imaginary figures

 Remaining quit and withdrawn,

 Neglecting personal care

 Disturbed sleep

 Lose the ability to get and keep friends …

Pathophysiology

 The Serotonin Hypothesis

 LSD (lysergic acid diethylamide ) is a nonselective 5-HT agonist and

causes psychotic symptoms; excess serotonin is the cause of Schizophrenia.

 The Dopamine Hypothesis

 Amphetamine and Cocaine causes increased dopamine that leads to

psychotic symptoms; excess dopamine is the cause of schizophrenia.
Cont`d
 The Glutamate Hypothesis

 Phencyclidine and ketamine are NMDA-antagonist and cause psychotic

symptoms; hypofunction of NMDA receptors contributed to schizophrenia .

 The Dysregulation hypothesis

 Overactivation of D2 in mesolimbic system causes +ve symptoms

 Hypostimulation of D1 in prefrontal cortex -ve & cognitive symptoms
Antipsychotic drugs
 They are also known as
1. Major tranquilizers because they tranquilize and sedate mitigate or
eliminate the symptoms of psychotic disorders but they do not cure
them.
2. Neuroleptics because they were found to cause neurolepsy, which is
an extreme slowness or absence of movement.
Classification of antipsychotic drugs
1. Typical Antipsychotics

A. Phenothiazine derivatives  Piperazine derivatives

 Aliphatic derivatives  Fluphenazine

 Chlorpromazine
B. Butyrophenone derivatives
 Piperidine derivatives  Haloperidol

 Thioridazine
C. Thioxanthene derivatives
 Thiothixene
Cont`d

2. Atypical Anti-psychotics
 Olanzapine

 Clozapine

 Risperidone

 Loxapine

 Quetiapine
Typical Antipsychotics

 First generation / Typical /old /conventional/ traditional antipsychotics

 Structurally heterogeneous

 Do not differ in efficacy

 Differ in clinical potency and side-effect profiles

 Primarily affect the positive symptoms

M.O.A

 Cause blockade of postsynaptic dopaminergic (D2) receptors and 5-HT2A receptors.

 They also have variable antagonist actions at muscarinic, α-adrenergic, and

histaminergic receptors in brain and peripheral tissue, mediate antipsychotics
adverse effects

 Therapeutic effect is primarily due to D2 blockade in mesolimbic area

 Effective against positive symptoms

Adverse effects

 Extrapyramidal effects: Blockade of the D2 receptors in the

nigrostriatal pathway is responsible
 Dystonia - involuntary muscle contractions
• Rx- centrally acting antimuscarinics: benztropine

Akathisia- inability to resist urge to move

• Rx- propranolol, BZDs
Cont`d

 Parkinson-like symptoms- evolve gradually over days to weeks

• Rx- central antimuscarinic agents, amantadine

 Tardive dyskinesia- involuntary mov’t of tongue, lips, neck, trunk, & limbs
(due to D2 receptor upregulation)
• Occur with chronic treatment, and thus, long term blocking of D2 in nigrostriatal
pathway, causing D2 super sensitivity phenomenon after D2 receptor upregulation
• May needs Discontinuation of the antipsychotic agent
Cont`d

 Neuroleptic malignant syndrome: due to DA antagonism

 Rare but serious reaction

 Marked by
• Hyperthermia or high fever (41Co)

• Sweating & autonomic instability

• Dysrhythmias & fluctuation in BP

• Seizure, coma & death

Cont`d

 Treatment
 Discontinuation of the antipsychotic agent

 Supportive treatment

 Cooling blankets

 Antipyretics: aspirin, paracetamol

 Rehydration

 BZDs

 Bromocriptine
Cont`d
 Anticholinergic effects
 Dry mouth, blurred vision, photophobia, urinary retention, constipation,
tachycardia

 α1-adrenergic blockade
 Orthostatic hypotension, reflex tachycardia, sedation

 H1 histaminergic blockade
 Weight gain, sedation
Cont`d

 Neuroendocrine effects
 Hyperprolactinemia: by blocking D2 receptors in pituitary and hypothalamus.

 Gynecomastia, galactorrhea, amenorrhea , infertility

 Sexual dysfunction
 increase libido (women), loss of libido (men), impotence (inhibit ejaculation)

 May be due to enhanced peripheral conversion of androgens to estrogens

Drug interaction

 The action of other CNS depressants may be enhanced , thus avoid sedatives,
hypnotics, anesthetics, and analgesics

 They interfere with the antihypertensive drugs: diuretics and others

 They augment the effect of antiarrhythmic drugs.

 They block the action of dopaminergic agonists e.g. levodopa used in Parkinson`s
and the condition may be aggravated.

 They induce the hepatic microsomal enzymes and decrease the effect of other drugs.
Second generation antipsychotics

 Atypical/newer antipsychotics

 They were developed in an attempt to minimize the side effects of typical

anti-psychotics

 Weakley block D2 receptors but strongly blocks 5-HT2A

 Fewer extrapyramidal adverse effects

 They act as partial agonists at the 5-HT1A receptor, which produces

synergistic effects with 5-HT2A receptor antagonism

Cont`d

 Effective against : +Ve, –Ve, and cognitive symptoms

 Indicated for patients refractory to typical one

 A potentially fatal metabolic effects : Glucose Metabolism Disorders

(hyperglycemia)
 Wt. gain, DM & dyslipidemia

 Cause CV events
Cont`d

 Clozapine & olanzapine are associated with greatest increases in LDL

cholesterol, triglycerides and with decreased HDL cholesterol

 The mechanism by which antipsychotic drugs disrupt glucose-insulin

homeostasis is not known
Cont`d

 Cariprazine is another second-generation agent.

 In addition to D2/5-HT2A antagonism, cariprazine is also a D3 partial

agonist with selectivity for the D3 receptor.

 Cariprazine’s selectivity for the D3 receptor may be associated with

greater effects on the negative symptoms of schizophrenia.
Cont`d

 Clozapine

 Block D2, 5-HT2A, α1, H1 & Ach receptors

 First atypical (1990)

 Most dangerous atypical: risk of agranulocytosis (severe decrease in

WBC count)

 Most effective in reducing EPSE, also in reducing negative symptoms

200
Cont`d

 Other adverse effects

 Sedation, wt. gain, orthostatic hypotension, dry mouth, blurred vision,

constipation, tachycardia

 Diabetes and dyslipidemia

 Seizures
Cont`d
 Olanzapine

 Similar structure & action as clozapine

 But does not cause agranulocytosis

 Blocks 5-HT, DA, histamine, ACh, and NE receptors

202
Cont`d

 Risperidone

 Has limited antimuscarinic properties

 Predominantly blocks D2, then 5-HT2A

 Block H1 & α1 receptors

 Increases prolactin levels (shouldn’t be given to people with breast

cancer)
Cont`d

 Paliperidone

 It is 9-hydroxyrisperidone, the active metabolite of risperidone.

 Same adverse and therapeutic effects as risperidone

 Ziprasidone

 Blocks D2, 5-HT2A, H1, and α1 receptors

 Blocks reuptake of 5-HT and NE

204
Depression, Anxiety and Mood
Disorders
Introduction

 Depression and anxiety disorders are the most common mental illnesses

 Both depression and anxiety can affect an individual patient simultaneously

 Some of the drugs used are effective in treating both types of disorders

 Suggesting common underlying mechanisms of pathophysiology and

response to pharmacotherapy
Cont`d

 Pathophysiological mechanisms underlying depression and anxiety has

been inferred from the MOA of psychopharmacological compounds

 Particularly their actions on neurotransmission involving 5-HT, NE,

and GABA
Depression

 Depression is classified as
 Major depression (i.e., unipolar depression)

 Persistent depressive disorder (dysthymia)

 Bipolar I and II disorders (i.e., manic-depressive illness)

 Lifetime risk of unipolar major depression is approximately 15%.

 Females are affected with major depression twice as frequently as males

Cont`d

 Depressive episodes are characterized by

 Sad mood, pessimistic worry

 Diminished interest in normal activities

 Mental slowing and poor concentration

 Insomnia or increased sleep

 Significant weight loss or gain due to altered eating and activity patterns

 Decreased energy and libido

 Feelings of guilt, worthlessness and suicidal ideation

Cont`d

 Depression is commonly associated with a variety of medical

conditions from chronic pain to coronary artery disease.

 Furthermore, it often complicates the management of other medical

conditions
Pathogenesis

 Biogenic amine theory of depression

 This hypothesis suggests that depression is related to a deficiency in the

amount or function of cortical and limbic 5-HT, NE, and DA

 Neurotrophic Hypothesis

 Nerve growth factors such as brain-derived neurotrophic factor (BDNF)are

critical in the regulation of neural plasticity, resilience, and neurogenesis.
Cont`d

 Depression is associated with the loss of neurotrophic support.

 And effective antidepressant therapies increase neurogenesis and

synaptic connectivity in cortical areas such as the hippocampus.
Antidepressants

 Typical antidepressants
TCAs

SSRIs

SNRIs

MAOIs (non-selective )

 Atypical antidepressants
Figure:- Sites of action of antidepressants at noradrenergic and serotonergic nerve terminals
Cont`d
 Tricyclic antidepressants (TCAs)
 Amitriptyline  Maprotiline

 Clomipramine  Nortriptyline

 Doxepin  Protriptyline

 Imipramine

 Trimipramine

 Desipramine
Cont`d

 The pharmacological action of TCAs is antagonism of SERT and

NET.

 Desipramine, nortriptyline, protriptyline, amoxapine inhibit NET

somewhat selectively

 Imipramine and amitriptyline inhibit both SERT and NET

Cont`d
 Clomipramine has relatively very little affinity for NET but potently binds
SERT.

 This selectivity for the serotonin transporter contributes to

clomipramine’s known benefits in the treatment of OCD.

 In addition to inhibiting SERT and NET these drugs block other receptors
(H1, 5HT2, α1 and muscarinic cholinergic receptors)
Cont`d
 Tertiary amine TCAs (e.g., doxepin, amitriptyline) are used in relatively
low doses for treating insomnia.

 Because of the roles of NE and 5HT in nociception, these drugs are

commonly used to treat a variety of pain conditions

 One TCA ,amoxapine, also is a DA receptor antagonist

 Its use poses some risk for the development of extrapyramidal side effects
Cont`d

 Common adverse effects of the TCAs

 Dry mouth and constipation, due to potent antimuscarinic effects

 Orthostatic hypotension, due to α1 antagonism

 Sedation, due to H1

 Cardiotoxicity

 Seizure

 Hypomania (mild mania)

 Suicide risk
Cont`d
 Drug interactions
MAOIs
 Hypertensive crisis
Anticholinergic agents
 Potentiation
 CNS depressants
 Additive
 Administration
 At bedtime
Cont`d

 Selective Serotonin Reuptake Inhibitors (SSRIs)

 Citalopram

 Escitalopram

 Fluoxetine

 Fluvoxamine

 Paroxetine

 Sertraline
Cont`d

 SSRIs allosterically inhibit the transporter by binding the SERT

 SSRIs used clinically are relatively selective for inhibition of SERT over NET

 SSRIs also are anxiolytics with demonstrated efficacy in the treatment of

 Generalized anxiety

 Panic attacks

 Social anxiety

 Obsessive-compulsive disorders
Cont`d

 SSRIs also are used for treatment of premenstrual dysphoric syndrome

and for preventing vasovagal symptoms in postmenopausal women

 Most commonly prescribed antidepressants

 Fewer side effects

 Less dangerous

 As effective as TCAs
Adverse Effects

 Increased serotonergic activity in the guts commonly associated with

nausea, gastrointestinal upset, diarrhea

 Increasing serotonergic tone at the level of the spinal cord and above
is associated with diminished sexual function and interest including
 Loss of libido

 Delayed orgasm

 Diminished arousal
Cont`d
 CNS stimulation
 Nervousness

 Insomnia

 Anxiety

 Headache

 Weight gain
 Insensitivity of 5-HTRs at feeding center

 Withdrawal syndrome
 characterized by dizziness, paresthesia
Cont`d

 5-HT/NE reuptake inhibitors (SNRIs)

 Venlafaxine

 Desvenlafaxine

 Duloxetine

 The SNRIs inhibit both SERT and NET and cause enhanced serotonergic
or noradrenergic neurotransmission.

 Does not block cholinergic, histaminergic, or α1-adrenergic receptors

Cont`d

 Monoamine Oxidase Inhibitors (MAOIs)

 Monoamine oxidases A and B are widely distributed mitochondrial enzymes

 MAO-A
 Brain- NE & 5-HT

 Intestine & liver- Dietary tyramine & other biologic amines in food

 MAO-B
 Brain- DA
Cont`d
 As effective as TCAs & SSRIs but more dangerous & reserved after
others
 Drugs of choice only for atypical depression
 Isocarboxazid

 Phenelzine

 Tranylcypromine

 Selegiline
 All MAOIs used for depression are nonselective
 Except selegiline which has specificity for MAOB at low doses
Adverse Effects

 CNS Stimulation-
 Anxiety
 Insomnia
 Agitation
 Hypomania, & mania

 Orthostatic hypotension

 Weight gain

 Hypertensive crisis
Atypical Antidepressants
 Bupropion

 It enhances both noradrenergic and dopaminergic neurotransmission via

inhibition of reuptake by NET and DAT

 It is indicated for the treatment of depression, prevention of seasonal

depressive disorder, and as a smoking cessation treatment

 Bupropion may improve symptoms of ADHD and has been used off label
for neuropathic pain and weight loss.
Serotonin Receptor Antagonists

 Trazodone and Nefazodone

 Block of 5-HT2 and α1 receptors

 Weak inhibitors of NE & 5-HT reuptake

 Mirtazapine and Mianserin

 Block of 5-HT2 and H1

Treatments of choice for some depressed patients with insomnia
Anxiety

 Anxiety is a normal human emotion that serves an adaptive function

from a psychobiological perspective.

 It is unpleasant emotional state or reaction

 i.e. distinguished from others, as anger or grief, by a unique combination of
experiential qualities and physiological changes.
 Overactive anxiety response leads to anxiety disorders
Types of Anxiety disorders
1. Generalized anxiety disorder- uncontrollable constant worrying, always imagine
horrible events will happen-

2. Panic attack- beyond worry, turns into fear reaction, fight/flight

3. Social phobias- social anxiety disorder- fear of something. e.g. speaking in front of
public

4. Post-traumatic stress disorder- fear after traumatic event

5. Obsessive-compulsive disorder- obsessions (intrusive thoughts), compulsions (repetitive

ritual to relieve anxiety)
Cont`d
 In general, symptoms of anxiety that lead to pharmacological treatment are those that
interfere significantly with normal function

 All of these conditions, with the exception of specific phobias, can be treated with
antidepressant medications, particularly SSRIs.

 Drug treatment includes acute drug administration to manage episodes of anxiety and
chronic treatment to manage unrelieved and continuing anxiety disorders
Bipolar Disorder

 Manic-depressive illness

 A chronic condition that requires treatment lifelong

 A severe biologic illness characterized by:

 Recurrent fluctuation in mood

 Abnormally elevated (mania) or depressed mood (dysphoria)

 Separated by periods of normal mood

Types of mood episodes

1. Pure manic episode (euphoric mania)

 Persistently heightened, expansive, or irritable mood

 Hyperactivity, excessive enthusiasm, & flight of ideas

 Overactivity at work, play, sexual

 Reduced need for sleep

 Excessive sociability & talkativeness

 Extreme self-confidence, grandiose ideas, & delusions of self-importance

236
Cont`d

 Engaged in high-risk activities w/o considering its bad consequences

 Severe, similar symptoms as psychosis

2. Hypomanic episode (Hypomania)

 A mild form of mania

 Persistently elevated, expansive, or irritable mood

 W/o marked impairment in social & occupational functioning

 No psychotic symptoms
Cont`d

3. Major depressive episode (Depression)

 Depressed mood

 Loss of pleasure or interest in usual activities

 Disruption of sleeping & eating patterns

 Difficulty concentrating

 Feelings of guilt, worthlessness, & helplessness

 Thoughts of death & suicide

238
Cont`d

4. Mixed episode
 Symptoms of both mania & depression simultaneously

 Significant risk of suicide

239
Drug therapy

 Four major groups of drugs:

1. Mood stabilizers
2. Antipsychotics
 Atypical antipsychotics
 Olanzapine & risperidone

3. Antidepressants
 Bupropion, venlafaxine & SSRIs

4. Benzodiazepines
 Lorazepam 240
 Drug Selection
Clinical Preferred strategy Preferred drugs
presentation Mood stabilizers Antipsychotics

Euphoric mania Mood stabilizer Valproic acid or

alone lithium
Dysphoric mania or Mood stabilizer Valproic acid or
true mixed mania alone lithium

Mania with Mood stabilizer Valproic acid or Olanzapine or

psychosis plus an lithium risperidone
antipsychotic
Rapid cycling Mood stabilizer Valproic acid
(currently manic) alone 241
Mood Stabilizers

 Relieve an acute manic or depressive episode

 Prevent symptoms from recurring

 All without aggravating mania or depression

 Without accelerating cycling

 The principal mood stabilizers

 Lithium

 Valproic acid

 Carbamazepine
242
Lithium

 A simple inorganic cation

 Controls acute manic episodes

 Long-term prevention of mania & depression recurrence

 Have a narrow therapeutic index

 Requires monitoring of its plasma levels

243
MOA

 Precise mechanism of action is unknown

 It both suppresses inositol signaling through depletion of intracellular

inositol and inhibits glycogen synthase kinase-3 (GSK-3)

 Lithium-induced inhibition of GSK-3 results in accumulation of β-catenin

 Accumulation of β-catenin via GSK-3 inhibition modulate energy

metabolism, provide neuroprotection, and increase neuroplasticity.
Pharmacokinetics

 Well oral absorption

 Even distribution to all tissues & body fluids

 Short half-life- rapid renal excretion

 Determined by serum levels of Na

 Reduced excretion when serum Na is low

245
Adverse effects
 At therapeutic levels

 GI effects

 Fatigue, muscle weakness, headache, confusion & memory impairment

 Tremor

 Polyuria/diabetes insipidus- antagonize ADH action

 Renal toxicity

246
Cont`d

 Goiter & hypothyroidism

 Teratogenesis- malformation of heart

 Leukocytosis

 Dermatologic rxns
Cont`d

 At excessive levels

 Persistent GI upset, tremor, confusion, hyperirritability of muscles,

sedation, incoordination

 Ataxia, polyuria, fasciculations, tinnitus, blurred vision, clonic

movements, seizures, stupor, severe hypotension

 Generalized convulsions, oliguria, and death

248
Neurodegenerative disorders

249
Introduction
 Neurodegenerative disorders are characterized by progressive and
irreversible loss of neurons from specific regions of the brain.

 The most common neurodegenerative disorders include Alzheimer disease,

amyotrophic lateral sclerosis, Parkinson disease & Huntington disease

 In PD and HD loss of neurons from structures of the basal ganglia results

in abnormalities in the control of movement

250
Cont`d

 Where as in AD loss of hippocampal and cortical neurons leads to

impairment of memory and cognitive ability

 ALS, where muscular weakness results from the degeneration of spinal,

bulbar, and cortical motor neurons.

 Currently available therapies for neurodegenerative disorders alleviate the

disease symptoms but do not alter the underlying neurodegenerative process.

251
Common Features of Neurodegenerative Disorders
 Proteinopathies

 Each of the major neurodegenerative disorders is characterized by

accumulation of particular proteins in cellular aggregates
 α-synuclein in PD

 Aβ and the microtubule-associated protein tau in AD

 TDP-43 in most cases of ALS

 Huntingtin in HD

252
Cont`d
 Selective Vulnerability

 A striking feature of neurodegenerative disorders is the exquisite specificity

of the disease processes for particular types of neurons.

 For example, in PD there is extensive destruction of the dopaminergic

neurons of the substantia nigra,

 Whereas neurons in the cortex and many other areas of the brain are
unaffected.
253
Cont`d

 In contrast, neural injury in AD is most severe in the hippocampus

and neocortex

 On the other hand within the cortex, the loss of neurons is not
uniform but varies dramatically in different brain networks.

254
Parkinson's Disease

255
Introduction

 Neurological disease affecting An estimated seven to 10 million

people worldwide.

 The clinical features of PD were adeptly described in 1817 by James

Parkinson

 Most common in the elderly

 The average age of onset is 55 years

256
Cont`d

 Parkinson’s is a progressive neurological disorder of muscle movement;

causing increasing disability of movement

 It is a clinical syndrome with four cardinal features:

 Bradykinesia (slowness and poverty of movement)

 Muscular rigidity

 Resting tremor (which usually abates during voluntary movement)

 Impairment of postural balance, leading to disturbances of gait and to falling

257
258
Pathophysiology

 The dopaminergic deficit in PD arises from a loss of the neurons in the

substantia nigra pars compacta that provide innervation to the striatum

 With the appearance of intracellular inclusions known as Lewy bodies.

 The principal component of the Lewy bodies is aggregated α-synuclein.

 A loss of 70%–80% of the DA-containing neurons accompanies

symptomatic PD

259
Cont`d

 It has been proposed that dopamine cell death is caused by reactive

free radicals produced by the catabolism of dopamine.

260
261
Glu
Glu
GABA

GABA GABA
Glu

Glu

GABA

262
263
Cont`d

Direct pathway

Dopamine ＋
→ D1 type medium spiny neuron －
→ internal portion of globus
pallidus → ventral anterior/ventral lateral region of thalamus
－ ＋
→ cortex

Indirect pathway

Dopamine －
→ D2 type medium spiny neuron －
→ external portion of globus
pallidus → subthalamic nucleus
－ ＋
→ internal portion of globus pallidus － →
ventral anterior/ventral lateral region of thalamus ＋
→ cortex

264
265
Treatment of PD

 Therapy is aimed at restoring dopamine in the basal ganglia and

antagonizing the excitatory effect of cholinergic neurons

 Thus reestablishing the correct dopamine/Ach balance.

266
Classification of PD drugs

 Drugs acting on dopaminergic system:

 Dopamine precursors

 Dopaminergic agonists

 MAO-B inhibitors

 COMT inhibitors

 Dopamine facilitator

 Drugs acting on cholinergic system

267
268
Dopaminergic treatment

 Levodopa, the metabolic precursor of DA, is the single most effective

agent in the treatment of PD.
 The effects of levodopa result from its decarboxylation to DA.

 Dopamine gets stored into secretory vesicles and released into corpus
striatum.

269
Pharmacokinetics

 L-Dopa is readily absorbed from GIT

 Food may delay absorption (tryptophan containing diet compete with L-
dopa for transport)- avoid protein food
 Levodopa is almost always administered in combination with a
peripherally acting inhibitor of LAAD, such as carbidopa

270
Cont`d
 Large first pass effect due to peripheral metabolism by LAAD & COMT
L-DOPA Dopa decarboxylase Dopamine

L-DOPA COMT 3-OMD

 Thus, large dose of levodopa are required because of its peripheral decarboxylation

 The effect of levodopa on the CNS can be greatly enhance by co-administering of

peripheral LAAD inhibitor

271
Cont`d

 Levodopa in combination with Carbidopa is a potent and efficacious

drug regimen
 Levodopa/Carbidopa treatment substantially reduces the severity of the
disease for the 1st few years of treatment.
 Patient then typically experience a decline in response during the third
to fifth year of therapy.

272
Cont`d

 This is b/c, as the disease progresses, more dopaminergic neurons are

lost
 This results in declining of the effectiveness of L-dopa as a replacement
therapy

273
"On/off" Effect

 Occurs after usually 2 yrs. on L-dopa

 In the later stages, patients may fluctuate rapidly between being "off,“

and being "on"

 May be adaptation process to variations in brain and plasma levodopa

levels

274
Cont`d

 Downregulation of DA receptor (due to too much striatal dopamine

receptor stimulation)

275
Side effects

 Nausea, vomiting, and anorexia

 Probably due to stimulation of CTZ in medulla
 Tolerance gradually develops and then the dose can be progressively increased.

 Cardiac arrhythmias
 cardiac stimulation due to beta adrenergic effect on heart
 Exacerbation of angina

 By increasing cardiac work

 Tolerance developed in few weeks

276
Cont`d

 CNS
 induce psychosis, confusion, hallucination, anxiety, delusion

 Abrupt withdrawal of levodopa or other dopaminergic medications may

precipitate the neuroleptic malignant syndrome of
 confusion,
 rigidity, and

 hyperthermia,

 It is a potentially lethal adverse effect.

277
Drug interaction

 Antipsychotic drugs – These drugs block DA receptor

 Reserpine - depletes dopamine storage

 Pyridoxine (Vit B6 )- facilitates peripheral conversion of levodopa

 Nonspecific MAOIs – can precipitate hypertensive crisis

278
Dopamine Receptor Agonists

 Directly bind and activate dopamine receptors in striatum.

 The DA receptor agonists in clinical use have durations of action
substantially longer than that of levodopa.
 They are often used in the management of dose-related fluctuations in
motor state
 They might also be helpful in preventing motor complications

279
Cont`d

 DA receptor agonists are proposed to have the potential to modify the

course of PD
 In the Presumed free radical hypothesis, may reduce endogenous
release of dopamine
 Do not compete with other substances for active transport into the blood
and across BBB

280
Cont`d

 Associated with a lower incidence of the response fluctuations and

dyskinesias

 There are two classes

 Ergot derivatives
 Non-ergot derivatives

281
Cont`d

 Ergot derivatives
 Bromocriptine—strong D2 agonist and a partial D1 agonist.
 Pergolide : an agonist of both classes
 Cabergoline

 Non-ergot derivatives
 Apomorphine (injectable )—acute mgt of hypomobility of “off “ phenomenon
 Pramipexole
 Ropinirole
 Rotigotine

282
Cont`d

 All equally effective for tremor, rigidity, and bradykinesia in PD

 Action largely via activation of striatal D2 receptors
 Long half-life = more “constant” levels = reduce motor fluctuations and
dyskinesias
 All are effective for advanced PD complicated by motor fluctuation and
dyskinesia
Cont`d

 More serious side effects-

 hallucinations
 daytime sleepiness
 postural hypotension

 But they are associated with less dyskinesia & motor fluctuation

284
Catechol-O-Methyltransferase Inhibitors

 COMT inhibitors block the peripheral conversion of levodopa to 3-O-

methyl DOPA

 Thus increasing both the plasma t1/2 of levodopa and the fraction of each
dose that reaches the CNS
 The COMT inhibitors tolcapone and entacapone reduce significantly the
“wearing off ” symptoms in patients treated with levodopa/carbidopa

285
Cont`d

 The two drugs differ in their pharmacokinetic properties and adverse

effects
 Tolcapone has a relatively long duration of action and appears to act by
inhibition of both central and peripheral COMT.
 Entacapone has a short duration of action and principally inhibits
peripheral COMT.

286
Adverse effect

 Common adverse effects of both agents include

 Nausea
 Orthostatic hypotension

 Vivid dreams
 Confusion

 Hallucinations

 An important adverse effect associated with tolcapone is hepatotoxicity.

287
Selective MAO-B Inhibitors

 Two isoenzymes of MAO oxidize catecholamines: MAO-A and MAO-B.

 MAO-B is the predominant form in the striatum and is responsible for
most of the oxidative metabolism of DA in the brain.
 Selective MAO-B inhibitors are used for the treatment of PD: Selegiline
and Rasagiline.
 These agents selectively and irreversibly inactivate MAO-B.

288
Cont`d

 Selective MAO-B inhibitors do not substantially inhibit the peripheral

metabolism of catecholamines
 Metabolites of selegiline include amphetamine and methamphetamine,
which may cause anxiety, insomnia, and other adverse symptoms.
 Unlike Selegiline, Rasagiline does not give rise to undesirable
amphetamine metabolites.

289
Cont`d

 Adjunctive therapy of levodopa with Rasagiline significantly reduces

wearing off symptoms in advanced PD
 Although selective MAO-B inhibitors are generally well tolerated, drug
interactions can be troublesome.
 Selegiline can lead to the development of stupor, rigidity, agitation, and
hyperthermia when administered with the analgesic meperidine.

290
Cont`d

 Tramadol, methadone, dextromethorphan are also contraindicated with

MAO-B inhibitors.
 Development of the serotonin syndrome has also been reported with
coadministration of MAO-B inhibitors and antidepressants.
 If concurrent treatment of MAO-B inhibitors with antidepressants is
undertaken, close monitoring is recommended.

291
Amantadine
 Amantadine, an antiviral agent used for the prophylaxis and treatment of
influenza A
 It appears to alter DA release in the striatum, has anticholinergic
properties, and blocks NMDA receptors.
 It is used as initial therapy of mild PD.
 It also may be helpful as an adjunct in patients on levodopa with dose-
related fluctuations and dyskinesias.
292
Cont`d

 Dizziness, lethargy, anticholinergic effects, and sleep disturbance, as

well as nausea and vomiting, side effects are mild and reversible

293
Alzheimer Disease(AD)

294
Introduction

 Alzheimer’s disease (AD) is the most common neurodegenerative

disorder.
 The cause of AD is not fully understood.
 There is neither cure nor therapy to slow the progress of the disease
 AD results in neuronal dysfunction and cell loss in the medial temporal
lobe, including entorhinal cortex and hippocampus.

295
Pathophysiology

 Amyloid plaques and neurofibrillary tangles (NFTs) are the pathologic

hallmarks of AD
 The plaques are composed of proteins called amyloid beta (Aβ)
 Hyperphosphorylated tau proteins are also accumulated in AD
 Amyloid plaques and neurofibrillary tangles (NFTs) are the pathologic
hallmarks of AD

296
Cont`d

 AD, however, is complex and also involves multiple neurotransmitter

systems, including glutamate, 5HT, and neuropeptides
 There is destruction of not only cholinergic neurons but also the cortical
and hippocampal targets that receive cholinergic input

297
Cont`d

 AD has three major stages:

 A “preclinical” stage during which accumulation of Aβ and tau begins, before any symptoms
appear.
 An MCI stage with episodic memory loss (repeated questions, misplaced items, etc.) that is
not severe enough to impair daily function.
 A dementia stage with progressive loss of functional abilities.

298
Cont`d

 Memory loss is gradual

 First short-term memory loss, then long-term distant memory loss

 In the advanced stages

 The individual may not recognize spouse or children
 impaired arousal and alertness
 reduced verbal fluency,
 naming deficits, and
 dysphasia (Impairment of speech)

299
Treatment of Alzheimer’s Disease

 At present, no disease-modifying therapy for AD is available;

 Current treatment is aimed at alleviating symptoms
 Augmentation of the cholinergic transmission is currently the mainstay
of AD treatment.
 Three drugs, donepezil, rivastigmine, and galantamine, are widely used
for this purpose

300
Cont`d

 All three are reversible antagonists of cholinesterase.

 They are the usual first-line therapy for symptomatic treatment of
cognitive impairments in mild or moderate AD.
 They are also widely used to treat other neurodegenerative diseases with
cholinergic deficits

301
Cont`d

 The drugs are usually well tolerated, with the most common side effects
being GI distress, muscle cramping, and abnormal dreams.
 They should be used with caution in patients with bradycardia or
syncope.

302
NMDA-Antagonists

 Memantine
 It is a noncompetitive antagonist of the NMDA type glutamate receptor.
 It blocks the receptor under conditions of excessive stimulation, with no
effect on normal neurotransmission.
 It is used as either an adjunct or an alternative to cholinesterase
inhibitors in AD

303
Cont`d

 Generally it is used in later stages of dementia, as there is less evidence

for its efficacy earlier.
 Memantine delays clinical deterioration in patients with moderate-to-
severe AD dementia.
 Adverse effects of memantine include mild headache or dizziness.

304
Treatment of Behavioral Symptoms

 In addition to cognitive decline, behavioral and psychiatric symptoms in

dementia are common,
 Particularly in middle stages of the disease.
 These symptoms include irritability and agitation, paranoia and
delusional thinking, wandering, anxiety, and depression.
 Generally nonpharmacological approaches should be first line.

305
Cont`d

 Both cholinesterase inhibitors and memantine reduce some BPSD, but

there effect is modest
 Citalopram, an SSRI, has shown efficacy for agitation.
 Atypical antipsychotics are more efficacious for agitation and psychosis
in AD, but their use is often limited by adverse effects
 Benzodiazepines can be used for occasional control of acute agitation

306
Cont`d

 The typical antipsychotics may be useful for aggression, but sedation and
extrapyramidal symptoms limit its use to control of acute episodes.

307
Antiepileptic Drugs

308
Introduction

 Epilepsy is a chronic disorder of brain function characterized by the

recurrent and unpredictable occurrence of seizures.

 Many cases of epilepsy are the result of damage to the brain, as occurs
in traumatic brain injury, stroke, or infections

 Seizure generation
 Initiated by synchronous, high-frequency discharge of hyperexcitable neurons

309
Types of seizures

 Partial (local) seizure

 Simple PS
 No loss of consciousness

 For 20-60 sec

 Complex PS
 Impaired consciousness

 Lack of responsiveness

 Lip smacking or hand wringing

 for 45-90 sec

310
Cont`d

Secondarily generalized seizure

 Loss of consciousness

 For 1-2 mins

 Involved into tonic-clonic seizures

 Generalized seizures

 Immediate loss of consciousness

 Convulsive or non-convulsive
311
Cont`d
 Tonic-clonic seizures, Grand mal
 Marked impairment in consciousness

 Muscle rigidity (tonic phase) followed by synchronous muscle jerks (clonic phase)

 For 90 sec

 Absence seizures, Petit mal

 Brief loss of consciousness

 Eye blinking

 Occurs in children

 For 10-30 sec

312
Cont`d

 Atonic seizure
 Sudden loss of muscle tone
• Neck muscles- head drop

• Limbs & trunk- drop attack, suddenly collapse

 Occurs in children

 Myoclonic seizures
 Sudden muscle contraction

 For 1 sec

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Cont`d

 Status epileptics
 Longer persisted seizure, ˃ 30 mins

 Life-threatening

 Loss of consciousness during entire attack

 Tachycardia, elevation of BP & hyperthermia

 Hypoglycemia & acidosis

 Permanent neurologic injury

 Cognitive impairment Memory loss

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Antiepileptic Drugs
 The mechanisms of action of ASDs fall into these major categories
 Modulation of cation channels (Na+, K+, Ca2+)
• Phenytoin, carbamazepine, valproic acid, ethosuximide

 Potentiation of GABA
• Benzodiazepines, barbiturates

 Antagonism of glutamate
• Felbamate & topiramate
 Modulation of synaptic release
• Gabapentin, Pregablin
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Drugs for Specific Types of Seizures
Seizure Traditional AEDs Newer AEDs
Type
Partial Carbamazepine, Oxcarbazepine, gabapentin,
phenytoin, valproic lamotrigine, levetiracetam,
acid, phenobarbital, pregabalin, topiramate,
primidone tiagabine, zonisamide

Tonic- The same as partial Lamotrigine, levetiracetam,

clonic seizure topiramate
Absence Ethosuximide, Lamotrigine
valproic acid
Myoclonic Valproic acid Lamotrigine, levetiracetam,
topiramate 316
Classifications of AEDs

 Two major categories

 Traditional
 Mostly used

 Less expensive
 High side effects

 Complex drug interactions

 Less safe in pregnancy
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Cont`d

 Newer
 Better tolerated

 Safer in pregnancy

 Both have equal efficacy

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Traditional AEDs

 Phenytoin
• Most widely used

• For treatment of PS, GT-CS, Status epilepticus

 MOA
• Selectively inhibit Na channels

• Hyperactive neurons

• Suppresses the activity of seizure-generating neurons

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Cont`d

 Pharmacokinetic
 Saturable kinetics

 Variable oral absorption

 Nonlinear hepatic metabolism

 Adverse effects
 CNS effects- sedation, nystagmus, ataxia, diplopia and cognitive impairment

 Gingival hyperplasia- oral hygiene

Teratogenic- cleft palate, heart malformations

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Cont`d

 Drug interactions

 Its level ↑ by- Diazepam, Cimetidine, valproate & acute alcohol

 Its level ↓ by- Carbamazepine, phenobarbital, and chronic alcohol

 Carbamazepine

 A cornerstone therapy

 used in PS, GT-CS, Bipolar disorder

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Cont`d

 Not used in treatment of absence seizure

 Increase risk of seizure

 Similar mechanism as phenytoin

 PK
 Delayed & variable oral absorption

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Adverse effects

 Hematologic effects- Suppresses bone marrow

 Birth defects- neural tube defects

 Hypo-osmolarity- ↑ADH

 Dermatological effects

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Valproic acid

Used for all major seizure types

 MOA
Block high firing Na channel

Blocks T-type Ca channel

Enhances GABA, inhibit GABA-T

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Adverse effects

 GI effects

 Hepatotoxicity

 Pancreatitis

 Teratogenic-neural tube defect or spina bifida

 Hyperammonemia

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Ethosuximide

 Only for absence seizures

 Blocks T-Ca channel on neurons in thalamus

 Adverse effects

 Drowsiness, dizziness & lethargy

 NV

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Phenobarbital

 Anticonvulsant barbiturate

 Potentiating effects of GABA

 the treatment of focal seizures and generalized tonic-clonic seizures.

 It is also used for status epilepticus

 The drug must be discontinued gradually over several weeks to avoid

the occurrence of severe seizures or status epilepticus.
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Adverse effects

 Neuropsychologic Effects

 Physical Dependence

 Exacerbation of Intermittent Porphyria

 Bleeding tendencies in newborns

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Cont`d

 Primidone

 Nearly identical in structure to phenobarbital

 For all major seizure disorders except absence seizures

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Newer Antiepileptic Drugs

 Better tolerated

 Smaller risk to the developing fetus

 Low interactions with other drugs

 Except oxcarbazepine
 Oxcarbazepine
 Derivative of carbamazepine

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Cont`d

 Blocks voltage-sensitive sodium channels

 It is used for the treatment PS in adults and children

 Lamotrigine
 Blocks of sodium & calcium channels

 Decrease glutamate release

 Used for PS, GS, & Absence seizure

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Gabapentin
 It is an analog of GABA
 It bind avidly to α2δ, a protein that serves as an auxiliary subunit of voltage-
gated calcium channels
 Effective in the treatment of focal seizures
 It is used in the treatment of neuropathic pain conditions, including
postherpetic neuralgia and painful diabetic neuropathy, and in the treatment
of anxiety disorders.
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Pregabalin

 Have the same mechanism of action with gabapentin

 Used for PS

 It is also used in the treatment neuropathic pain, restless legs syndrome,

and anxiety disorders.

 Pregabalin exhibits linear absorption within the therapeutic dose range.

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Felbamate

 It appears to have multiple mechanisms of action.

 Potentiation of GABA mediated inhibition

 Blocks voltage-dependent sodium channels, calcium channels and

NMDA glutamate receptors

 It is reserved for refractory epilepsy

• Due to risk of aplastic anemia and hepatic failure

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Zonisamide

 It is a Sulfonamide derivative

 Blocks neuronal sodium channels and calcium channels

 It is used for the management of PS

 Adverse effect

 Oligohydrosis

 Kidney stone
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Pharmacological and Toxicological
Effects of
Catha edulis F. (Khat)

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Introduction

 Khat, the edible part of Catha edulis Forsk, belongs to the score of vegetal
materials that humans ingest not for their nutritive value but to experience their
psychoactive effects

 In Ethiopia, khat covers about 0.2% of the total area and makes 10.5% of the
country’s export value.

During any one day, 3.6% of Ethiopia’s adult population chew khat, with a 5.3 kg
per capita annual consumption.

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CHEMICAL CONSTITUENTS OF KHAT

 Many different compounds are found in khat including alkaloids, terpenoids,

flavonoids, sterols, glycosides, tannins, amino acids, vitamins and minerals.

 The main phenylalkylamines are phenylpropylamines consisting of cathinone and

the two diastereoisomers, cathine and norephedrine.

 In addition, two oxazolidine derivatives, 2, 4-dimethyl-5-phenyloxazolidine and

4-methyl-2-(trans-1-pentenyl)-5-phenyloxazolidine have also been identified
Cont`d

 Cathinone is the main psychoactive alkaloid and mainly found in young shoots.

 It has structural and pharmacological similarity with amphetamine, thus called

natural amphetamine.

 High concentration of cathinone is detected in leaves as well as in green parts and

barks of stalks.

 In addition, a wave of new chemicals called substituted cathinones has emerged

in response to market trends and legislative controls
Cont`d

 Substituted cathinones are a large family of synthetic beta-keto phenethylamine

derivatives chemically related to the parent compound cathinone.

 Examples include methylcathinone, methylone and methedrone.

PHARMACKINETICS OF KHAT

 When khat leaves are chewed cathine and cathinone will be released.
 Which are then absorbed through the mucous membranes of the mouth and
subsequently the lining of the stomach.

 Maximal plasma concentrations of cathinone after a single oral dose of khat are
attained in about 2 h

 With terminal elimination half-life of about 4 h

Cont`d

 The major metabolite of cathinone is norephedrine, but small quantities of

norpseudoephedrine also form.

 Only less than 7% cathinone is excreted unchanged in the urine.

 In contrast, cathine and norephedrine are slowly absorbed and then excreted,
mainly in unchanged form, within about 24 h

 Cathine has also been shown to be found in breast milk of several lactating
women who chewed khat
Cont`d

 The enzymes involved in the metabolism have not been described.

 However, it was predicted from the metabolic pathways of amphetamines and

synthetic cathinones that major cytochrome P450 (CYPs) are involved.

 Khat exposure significantly inhibits CYP2D6 activity and has marginal inhibition
of CYP3A4.
PHARMACOLOGY AND TOXICOLOGY OF
KHAT

 Khat is known to produce a plethora of effects that could be either harmful or

beneficial.

 However, the effects cannot be totally ascribed to khat, as it is sprayed with

different growth promoters
Cont`d
 Central effect
 Khat chewing induces a state of euphoria and elation with feelings of increased
alertness and arousal.

 This is followed by stage of vivid discussions, loquacity and excited mood.

 This leads to inability to sleep at the end of the chewing session which is often
countered by drinking alcohol.
Cont`d

 Chewing large amounts of khat has been reported to be associated with manic
illness, psychosis, violent reactions as well as an apparent increase in suicidal
depression and an increased relative risk of hallucinations.

 It has been argued that khat chewing might exacerbate pre-existing psychiatric
disorders.

 It appears that age would play an important role in experiencing mental distress
with khat chewing.
Cont`d
 Studies done to assess verbal learning and memory demonstrated that khat use alone
did not affect immediate or delayed recall of previously learned words.

 However, concurrent use with tobacco smoking lowered verbal learning and delayed
recall.

 Regular khat chewing has also been linked with higher trait anger, more pronounced
negative responses during stress and less pronounced positive emotional states

 This indicates that khat chewing is associated with disturbances in emotion regulation
processes
Cont`d

 People chew khat believing that it improves memory, alertness and clear thinking.

 Although such beliefs are widely held, there are little or no reports assessing the effect
of khat on learning and memory as well as neural processes involved in these activities.

 A study conducted in mice subjected to acute, subacute and subchronic khat exposure
showed that Acute and subacute exposure had no effect on learning and memory.

 Subchronic exposure, however, produced a significant impairment in short-term

memory, without altering learning and long-term memory.
Cont`d
 Another area where khat central effects are manifested includes the motor system.

 Cathinone is shown to be capable of reversing haloperidol-induced catalepsy in rats.

 Likewise, khat extract is also demonstrated to reverse haloperidol induced but not
morphine-induced catalepsy in mice.

 These findings collectively indicate the antiparkinsonian potential of khat and/or

cathinone
Cont`d

 Currently, most of the deductions that are made about the central effects of khat
are based on amphetamine or its derivatives.

 Cathinone, like amphetamine, acts by releasing catecholamines, particularly

dopamine, from presynaptic storage sites and subsequently inhibiting their uptake

 Thereby it increases temporal and spatial presence of these neurotransmitters at

the postsynaptic receptors, in particular in the striatum
Cont`d

 The role of serotonergic, noradrenergic and opioid systems cannot be, however, ruled
out in the neuropharmacological actions of khat/cathinone.

 Although the reversal of haloperidol but not morphine-induced catalepsy strongly

contends that khat acts through the monoaminergic system

 There are several lines of suggesting that khat’s effect could be mediated via
interaction with other systems including the cannabinoid, opioid and GABAergic
system.
Cont`d

 To sum up, although other pathways could not be ruled out, there are reasonable
scientific data to suggest that khat/cathinone-induced psychostimulation is
mediated primarily via the meso-striato-cortico limbic dopaminergic pathway.
Thank you!

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