DRUGS FOR ALZHEIMERS

CHOLINERGIC HYPOTHESIS
CNS PHARMACOLOGY
DRUGS FOR ALZHEIMERS
AMYLOID HYPOTHESIS
DRUGS FOR ALZHEIMERS
TAU HYPOTHESIS
NOTE:TAU lengthens and support microtubules and microtubules will transport
information and nutrients
DRUGS FOR ALZHEIMERS
MANAGEMENT:Cholinesterase
inhibitors
Treatment of Alzheimer’s Disease
CHOLINESTERASE INHIBITORS
■ Tacrine, Donecipil (Aricept), Rivastigmine
(Excelon), Galanthamine (Reminyl)
DRUGS FOR ALZHEIMERS
MANAGEMENT

NMDA RECEPTOR ANTAGONISTS

Treatment of Alzheimer’s Disease
NMDA RECEPTOR ANTAGONISTS
Memantine, Selfotel, Eliprodil,
Dextromethorphan
GLUTAMATE INHIBITORS
Adenosiine, Lobeluzole
NEURONAL NICOTINIC RECEPTORS
(NNRs)
Targecept
Treatment of Alzheimer’s Disease
GLUTAMATE INHIBITORS
Adenosiine, Lobeluzole
NEURONAL NICOTINIC RECEPTORS
(NNRs)
Targecept
NEURONAL NICOTINIC RECEPTORS (NNRs) -
TARGACEPT
Neuronal nicotinic receptors (NNRs), serve as
key regulators of nervous system function.

Binds to an NNR → normalizes chemical

signaling → allowing neurons to communicate
properly (neuromodulation)

Results in increased signaling when the nervous

system is understimulated and decreased
signaling when the nervous system is
overstimulated → Nervous system's "volume
knob”
Anti-Parkinsonism
Parkinsonism
__ dopamine, __ ACh, damage to
the basal ganglia
Anti-PD
Levodopa-Carbidopa (Sinemet)
DOC for PD
Which combination is good?
Levodopa + MAOI
Levodopa + Carbidopa
Levodopa + Vitamin B6
Levodopa + Antipsychotics
SUMMARY OF ANTIPARKINSONS
DRUGS
Dopamine Agonists
Bromocriptine
Pergolide
Pramipexole
Ropinirole
(1)
(2)
Selegiline
irreversible inhibitor of MAO-B
Selegiline + Sinemet
(1)
(2)
Catechol-O-Methyl Transferase Inhibitors

“-capone”
__ t50 of levodopa
Drugs
Tolcapone
■Acts in the
Entacapone
(+) with Sinemet
Amantadine
MOA: ___ DA release
in the brain
S/E: livedo reticularis
Anticholinergic Drugs
(1) Trihexyphenidyl
(2)
(3)
(4) Procyclidine
(5) Diphenhydramine
(for __________)
MOA: block muscarinic receptors in the
striatum
NOTE!
Other Movement Disorders
Disorder Description Management
Huntington’s
disease
Wilson’s disease
Tourette syndrome
Restless leg
syndrome
Anxiolytics/Sedatives/Hypnotics

Anxiety
Hypnotics
GABA
GABA-A RECEPTOR
MOA:
BENZODIAZEPINE BARBITURATES NON-BZ
 GABA
-
CL

++++
Na Channel

Na Channel

GABA
Receptor

- - - -

Intra cellular - - - -
Benzodiazepines
Most widely use anxiolytic
(1) _______ GABA
(2) ↑ the _______ of Cl− channel
opening
Have __ GABA mimetic activity
Act through BZ receptors
BZs vs Barbs
Barbiturates
______ GABA activity
↑ ______ of Cl− channel opening
Have GABA mimetic activity at high
doses
Do ___ act through BZ receptors
BZs vs Barbs
Therapeutic Uses
Short-term treatment of anxiety
_____: Long-term treatment of
anxiety
Generalized anxiety disorder
Situational anxiety disorder
Panic disorders
Social phobia
Therapeutic Uses
Short-Acting BDZs
Duration: 2-8hrs
Drugs
(1)C
(2)O
(3)M
(4)T
Intermediate-Acting BDZs
Duration: 10-20hrs
Drugs
(1)L
(2)A
(3)T
(4)E
Long-Acting BDZs
Duration: 1-3 days
Drugs: Charlie Chaplein
DIed From Q-fever
(1)
(2)
(3)
(4)
Benzodiazepine poisoning: ________
Zolpidem, Zaleplon, Eszopiclone
Short-term treatment of insomnia
Antidote:
Buspirone
Treatment of generalized anxiety
disorder
Adv:
The BENZODIAZEPINES
Special uses
Diazepam Status epilepticus
(Valium)
Chlordiazepoxide Alcohol
(Librium) withdrawal
Alprazolam Panic attack
(Xanax)
MOST COMMON SIDE EFFECT:

ANTIDOTE:

CI:
Barbiturates
______ GABA activity
↑ ______ of Cl− channel opening
Have GABA mimetic activity at high
doses
Do ___ act through BZ receptors
Barbiturates: Duration of Action
Long-acting (>6 hrs)
(1)Ph
(2)Me
Intermediate-acting (3-5 hrs)
(1)B
(2)A
(3)V
Barbiturates: Duration of Action
Short-acting (2 hrs)
(1)Seco
(2)hexo
(3)pento
Ultra short-acting (30 mins):
(1)thio
(2)thia
(3)metho
Adverse Drug Reaction
cytochrome P450 induction
ALA synthase induction
Antipsychotics / Neuroleptics
Schizophrenia / Psychosis
DA Hypothesis: __ dopamine
Symptoms:
 4 major parts of brain affected by
dopamine
MESOLIMBIC MESOCORTICAL NIGROSTRIATAL TUBROINFUNDIBULAR
Positive and negative symptoms of schizophrenia

Hallucinations Affective flattening

Delusions Alogia
Thought disorders Apathy
Disorganized speech Amotivation
Bizarre behavior Anhedonia
insomnia Asocial behavior
Combativeness Inattentiveness
 TYPICAL vs ATYPICAL
TYPICAL ATYPICAL
Haloperidol, chlorpromazine, Risperidone
thioridazine Clozapine
Thiothixene Olanzapine
Fluphenazine Quietiapine
Prochloroperazine Ziprasidone
Aripiprazole
Blocks D2 receptors Blocks D2 and 5-HT2 (risperidone)
Blocks D1 and
5-HT2 (clozapine)
Treats positive symptoms only Treats both positive and
negative symptoms
Causes movement disorders Little or no movement
disorders
Anti-psychotic Agents
MOA: block the following
receptors:
dopamine
cholinergic
adrenergic (a1)
Histamine
Take several weeks to give
beneficial effect
Typical vs Atypical
Typical Atypical
Receptor blockade
Positive symptoms
Negative symptoms
EPS
Tardive dyskinesia
Antipsychotic-induced Motor Disturbances

Acute dystonia
■Sustained muscle spasm anywhere in the body
■Tx:
Diphenhydramine,benztropine,trihexyphenidyl,
amantadine
Parkinsonism
■Resting tremor
■Tx: benztropine ,anticholinergic
Tardive dyskinesia
■Involuntary movement of lips, head limbs
tongue and trunk
■Typically irreversible once sets in
Antipsychotic-induced Motor Disturbances

Akathisia
■Restlessness, getting up and sitting
down
■Tx: lower medication dose,BB,BZ,
anticholinergics
Neuroleptic Malignant Syndrome
■Life-threatening muscle rigidity,
fever
■Tx: cool patient, hydrate with IV
fluids
■Dantrolene,bromocriptine,
amantadine
Important Uses
Drug Use
Prochlorperazine
Chlorpromazine
Promethazine
Clozapine
Aripiprazole &
olanzapine
Molindone
TOXICITY
Toxicity Drug Involved Management
EPS (Parkinson-like) Haloperidol, Antimuscarinic
fluphenazine
Tardive dyskinesia Typical antipsychotics Switch to
Atropine-like effect Thioridazine -
Hyperprolactinemia
Neuroleptic malignant Typical antipsychotics (1)
syndrome (2)
(3)
(4)
Sedation Phenothiazines
Other uses of antipsychotics
Antiemetic (blocks dopamine
receptors)-prochlorperazine
Intractable hiccups- chlorpromazine
Pruritus (antihistamine)-
promethazine (Zinmet, Thaprozine)
Other toxicity
Clozapine
(1)
(2)
(3)
Thioridazine
(1)
(2)
Ziprasidone & Quetiapine
(1)
CHEMICAL CLASSES
Phenothiazines
Aliphatic- chlorpromazine
Piperazine- fluphenazine
Piperidine- thioridazine
Thioxanthenes- thiothixene
Butyrophenones- haloperidol
Dihydroindolines- molindone
Diphenylbutylpiperidines-
pimozide
Antidepressants
ANTIDEPPRESSANT CLASSIFICATION
ANTIDEPPRESSANT CLASSIFICATION
Selective Serotonin RIs
“first line of choice”
Adv:
lesser lethality with overdoses
(1) __________
(2)
(3) __________
(4) Paroxetine
(5) __________
(6) Escitalopram
MOA: Allosteric inhibition of 5-HT reuptake
Serotonin Norepinephrine RIs
Venlafaxine
Desvenlafaxine
Duloxetine
Serotonin Receptor Antagonists
Nefazodone
Trazodone
MOA: block of the 5-HT2A receptor
Monoamine Oxidase Inhibitors
Non-selective
(1)
(2)
(3)
Clorgyline
MAO-A Inhibitor
(1)
MAO-B Inhibitor
(1)
MOA: inhibit the enzyme MAO which
metabolizes NE, 5-HT & dopamine
TCA
Ami/nor/protryptiline
Clomi/desi/imipramine
Maprotiline
Doxepin
amoxapine
ATYPICAL ANTIDEPRESSANTS
BUPROPION
ATYPICAL ANTIDEPRESSANTS
MIRTAZAPINE
ATYPICAL ANTIDEPRESSANTS
VILAZODONE
VORTIOXETINE
ATYPICAL ANTIDEPRESSANTS
TRAZODONE
NEFAZODONE
Drug Interactions
MAOI + TCA
MAOI + SSRI

serotonin syndrome: mental status

changes, myoclonus and
restlessness
Mood Stabilizers

Bipolar disorder
Mania
BIPOLAR AFFECTIVE DISORDER
LITHIUM CARBONATE is the
universally preferred treatment
esp. in manic phase
80% overall success rate for
achieving remission
MOA
Lithium Carbonate (Lithase)
First line agent for the treatment and
prevention of bipolar disorders
MOA:
___NE release
___NE metabolism
___NE reuptake
___NE & 5-HT receptor sensitivity
Lithium vs Na
Pregnant:
 LITHIUM
Baseline labs Adverse effects
Thyroid hypothyroidism
function
BUN/Crea Renal
insufficiency
Electrolytes Dec. Na
(esp.sodium)
CBC leukocytosis
Anticonvulsants
Partial Seizures
involve a single hemisphere of the brain
Simple Partial
motor (Jacksonian march)
sensory (tingling, paresthesia)
no loss of consciousness (LOC)
Complex Partial
LOC
during LOC: hallucinations, chewing, rubbing
Generalized Seizures
affect both hemispheres
Tonic-Clonic / Grand mal
most dramatic
LOC
tonic (10s) - stiffening
clonic (1-2mins) - muscle contractions
alternating with relaxation
Generalized Seizures
affect both hemispheres
Absence / Petit mal
children
alterations of consciousness lasting 10-
30s
blank stare, blinking, LOC
Generalized Seizures
Myoclonic
involuntary jerking of the facial, limb, or
trunk muscles
no LOC
Atonic
sudden loss of postural tone
Generalized Seizures
Febrile
children
Status epilepticus
series of grand mal seizures with no
recovery of consciousness in between
attacks or episodes
Main problem:
Mechanism of Drug Action
↑ GABA activity
↓ ionic activity (e.g. closes Na
channels)
SUMMARY
Drug of Choice
Type of Seizure Drug of Choice
Simple Partial Carbamazepine
Complex Partial
Tonic-Clonic Valproic acid

Absence Ethosuximide
Myoclonic Valproic acid
Atonic Valproic acid
Febrile Phenobarbital
Diazepam
Status Epilepticus Lorazepam, Diazepam
Phenobarbital
Phenytoin (cardiotoxic due to
propylene glycol)
OPIOIDS & OPIATES
aka narcotics
alkaloid: juice of opium poppy seed
mu, kappa, delta receptors in CNS
Receptors
Μ receptor
supraspinal and spinal analgesia; euphoria;
sedation; respiratory depression; decreased GI
motility; tolerance and physical dependence
κ
supraspinal and spinal analgesia; sedation;
decreased GI motility
σ
psychomimetic effects; hallucinations;
dysphoria
δ: unknown
Agonists

Analgesics HECk
a. histamine release - urticaria /
1. Morphine pruritus, bronchoconstriction
b. emesis
■prototype c. cardiovascular - hypotension

■HECk of a DREAM
DREAM a. analgesia
b. euphoria
c. respiratory depression
d. depression of cough reflex /
antitussive, ↓ GI motility / antidiarrheal,
CNS depression / sedative
e. miosis
Analgesics cont…
Uses:
1. Analgesia - DOC for moderate to severe
pain
2. Diarrhea - paregoric (camphorated
tincture of opium)

S/E: tolerance, dependence, addiction

Poisoning triad: coma, pinpoint pupils,
respiratory depression
Agonists
Heroin
diacetylmorphine
hydrolyzed to morphine
crosses BBB more quickly
Agonists
2. Meperidine (Demerol)
3. Fentanyl (Sublimaze)
 80 times more potent than morphine
+ Droperidol (Innovar) - dissociative
anesthesia
4. Nalbuphine (Nubain)
classification
FULL AGONIST

PARTIAL AGONIST
classification
MIXED AGONIST/ANTAGONIST

FULL ANTAGONIST
NATURAL
Morphine
Codeine
Thebaine – precursor
substrate for the synthesis of
naloxone
SEMI - SYNTHETIC
Heroin – diacetylmorphine,
diamorphine
Apomorphine –emetic
Hydrocodone – antitussive
Oxycodone
Hydromorphone –analgesis
Oxymorphone
PURELY SYNTHETIC
Methadone
Loperamide,diphenoxylate
Meperidine
Fentanyl
Tramadol
pentazocine
End…