Sedative Anxiolytic &

Hypnotics
Prof. Mahran S. Abdel-Rahman
Sphinx University
2024-2025
• Anxiety ( ‫( القلق‬: Physical and
emotional distress which interfere
with normal life.
• Insomnia (‫)األرق‬: Chronic inability to
fall sleep or remain sleep for an
adequate length of time.
What are the symptoms anxiety ?
1. Irritability
2. Restlessness
3. Insomnia
4. Feeling tense
5. Tachycardia
6. Excessive fear and worry
 Terminology
• Anxiolytics: are drugs that calm the patient, reduce tension &
anxiety with little or no effect on motor or mental function.

• Sedatives: are drugs that quite the patients but produce

drowsiness & decrease reaction time (i.e., affect motor
function).

• Hypnotics: are drugs that induce sleep & can be achieved by

most sedative/ anxiolytic drugs just by increasing the dose.
Anxiety or Normal Degree of CNS depression

ANXIOLYSIS (Relief from Anxiety)
_________  _________________
SEDATION
(Drowsiness/decrease reaction time)

HYPNOSIS (Induction of sleep)

Confusion, Delirium, Ataxia

SURGICAL ANAESTHESIA

Depression of respiratory and vasomotor center
in the brainstem
COMA

DEATH
 “Classification based on their mode of action”
1. Benzodiazepines receptor agonists:
– Benzodiazepines (BDZs): e.g., Alprazolam, diazepam, etc.
– Z- Compounds: e.g., Zolpidem & zaleplon.
2. 5-HT1A receptor agonists: e.g., buspirone & Ipsapirone
3. SSRIs: e.g., Sertraline, fluxetine (used in depression)
4. Old drugs:(rarely used now due to many disadvantages.......)
– Barbiturates (BARBs) : e.g., Pentobarbital, phenobarbital
– Chloral hydrate
5. Drugs produce sedative action as side effect: rarely used EXCEPT
– H1- blockers: 1st generation (used in children with insomnia, URTI).
– Antidepressant drugs: amitryptyline (used in depression).
– -blockers: e.g., propranolol (used in tachycardia and angina).
– Clonidine (used during narcotic withdrawal)
– Antipsychotic drugs: e.g., chloropromazine (used in psychotics)
 Physiology of sleep
• All anxiolytics induce sleep at high dose.
• Normal sleep consists of two phases,
based on: electroencephalogram and
electromyogram.

1) Non-rapid eye movement (NREM): 70-75% of

total sleep. 4 stages. Most sleep  stage 2.
2) Rapid eye movement (REM): Recalled dreams.
 1- Benzodiazepines:
A-Pharmacological Classification
1. Short acting: ( t1/2: 3-5 hours):
Triazolam Oxazepam

1. Intermediate acting: (t1/2: 6-24 hours):

Alprazolam Lorazepam
Oxazepam Temazepam

3. Long acting: (t1/2:  24 hours):

Clonazepam Diazepam
Flurazepam Quazepam
 Benzodiazepines:
B- Therapeutic Classifications:
a) Drugs used for anxiety:
– Diazepam (has active metabolites)
– Clorazepate (has active metabolites)
– Lorazepam (has inactive metabolites)
– Oxazepam (has inactive metabolites)
– Alprazolam (has active metabolites)
(b) Drugs used for insomnia:
– Triazolam (has active metabolites), short acting
– Flurazepam (has active metabolites), long acting
– Temazepam (has inactive metabolites), long acting
– Nitrazepam (has inactive metabolites), long acting
 Advantages of BDZs over BARBs
• BDZs more safe compared to BARBs-why?
Because BDZs:
a) Wider margin of safety (for short periods).
b) Not Enzyme inducer (few drug interactions).
c) Less respiratory depressant effect.
d) Lower abuse and dependence potential (short
period).
e) Little disturbance of REM sleep.
f) No or little hangover.
• So, BDZs are currently used and preferred as sedative,
hypnotics and anxiolytics compared to barbiturates
Give reasons???
 Mechanism of action of Benzodiazepines

• GABA Action:
BDZs bind to specific benzodiazepine binding
sites on GABA receptors → allosterically
enhances the binding of GABA to its GABAA
receptors (i.e., Increasing affinity of GABA to
GABA receptors) → Increasing the frequency of
openings of the GABA-Cl- channel → increase Cl-
influx → hyperpolarization → inhibitory post
synaptic response → Anxiolytic effect.
 Types of Drugs Acting on Benzodiazepine Receptors
1. Agonists:
– e.g., BDZs and Z compounds facilitate GABA actions and
used as anxiolytics (Bind to BDZ receptors type A) .
2. Inverse agonists:
– e.g., -carboline produces anxiety and convulsions.
– Bind to BDZ receptors type B
3. Antagonists:
– e.g., Flumazenil: used I.V. (1st pass hepatic metabolic effect)
in the treatment of poisoning by:
a) Benzodiazepine
b) -carboline
c) Z- compounds.
 Pharmacological actions of Benzodiazepines
A) CNS:
i- Dose-dependent CNS depression:
 Anxiolytics  sedative  hypnotics  coma.
 However, BDZs are not true general anesthetic (not produce loss of
consciousness nor loss of sensation).
 Anxiolytics:
– Small doses of BDZs reduce tension, anxiety and aggressive behavior.
 Hypnotics:
• Larger doses of BDZs induce hypnosis with the following properties:
–  the latency of sleep onset (time taken to fall in sleep) stage 0 (stage of wakefulness).
–  the time spent in stage 1 of NREM sleep (descending drowsiness)
–  the duration of stage 2 NREM sleep (prolong total deep sleep time).
–  stages 3 and 4 of NREM sleep (i.e., decrease sleep with nightmares and tremors).
–  the time spent in in REM sleep (stage of nightmare dreaming, irregular respiration and
rapid unstable pulse)
 Cont CNS effects of BDZs:
ii- Central Skeletal muscle relaxant:
– Useful in patients with cerebral palsy why?
• Because they can decrease muscle rigidity as a result of central muscle
relaxant action.

iii- Preanesthetic effect: BDZ produce amnesia at preanesthetic dose.

iv- Anticonvulsant:
– Useful in status epilepticus (Diazepam 1st choice).
– Their chronic use is limited by tolerance & dependence.
– Their anticonvulsant is mediated by GABA system.
 Pharmacological actions of Benzodiazepines (Cont.)

B) Respiratory depression:
– Only with high doses (preanesthetic dose).
– At high doses, BDZs depress ventilation and may cause respiratory
acidosis especially in chronic COPD or those used CNS depressants
as morphine.

C) CVS:
– Hypotension , negative inotropic and reflex tachycardia with high
doses (preanesthetic doses).

D) GIT:
BZDs improves stress and anxiety related ulcer and other GI disorders.
Pharmacokinetics of Benzodiazepines
1. Absorption & Distribution:
 Taken orally or parenterally.
 High lipid solubility  high rate of entry into CNS 
rapid onset and undergoes redistribution into adipose
tissues.

 All BDZs cross the placenta & detectable in breast milk

 may exert depressant effects on the CNS of the
lactating infant (sedated, sleepy, with weak suckling
capacity) .
 2. Elimination of Benzodiazepines

 Hepatic metabolism:
 Almost all BDZs undergo:
 Phase I metabolic reactions (Microsomal oxidation; N-
dealkylation and aliphatic hydroxylation; (active metabolites).
 Phase II Conjugation reaction: forming inactive glucoronides.
 Many have active metabolites with half-lives greater than the parent
drugs:
 e.g., Diazepam (Valium), has active metabolites (nordiazepam and oxazepam)
and so diazepam is long acting (t½ = 20-80 hr).
 Some have no active metabolites:
 e.g., Oxazepam and lorazepam: directly metabolized to glucoronides have the
least residual (drowsiness) effects(Give reasons) .
 Benzodiazepines and metabolites are excreted in urine.
Biotransformation of Benzodiazepines

From Katzung, 1998

 Therapeutic Uses of BDZs
1. Anxiolytic BDZs 2. Hypnotic BDZs
• Clorazepate (Tranxene) • Flurazepam (Dalmane)
• Diazepam (Valium) • Triazolam (Halcion)
• Alprazolam (Xanax) • Temazepam (Restoril)
• Lorazepam (Ativan) • Nitrazepam (Mogadon)
3. Anticonvulsant: Diazepam (status epilepticus) and clonazepam (absence seizure).
4. Preanesthetic medication:
• Diazepam, Lorazepam and midazolam: to produce amnesia and
sedation when given before anesthesia..
5. For induction of anesthesia:
• Diazepam, lorazepam or midazolam are used I.V for induction of anesthesia.
• I.V. may be used in endoscopy, cardioversion, cardiac catheterization and in ICU
6. Skeletal muscle relaxants: to control certain spastic conditions as cerebral palsy or
spinal cord lesions.
7. Alcoholism: to control ethanol withdrawal symptoms.
 Benzodiazepines are preferred over barbiturates Why?

because of the following advantages:

• Better therapeutic index.
• There is available antagonist for benzodiazepines (flumazenil).
• Low risk for abuse and dependence.
• They cause less drug interactions, as they are non-enzyme
enzyme inducers.
• They cause fewer disturbances in the rapid eye movement
sleep (REM).
• Less depressant effect on respiration.
 Benzodiazepine uses in insomnia
• Short acting BDZs e.g., triazolam (t1/2 ≈ 3h) is preferred for
patients with prolonged sleep latency i.e., difficult to enter in
sleep (initial insomnia).
• Intermediate acting BDZs (e.g., Temazepam) & long acting
BDZs (e.g., Flurazepam) are preferred for patients who suffer
from early morning awakening (latent insomnia) or frequent
awakening.
• If BDZs used regularly for more than 2 weeks, should be
withdrawn gradually.
Benzodiazepines uses in anxiety
• Long acting drugs (e.g., diazepam & lorazepam) are
preferred for long-term treatment of anxiety disorders .
 Adverse Effects of Benzodiazepines
1. Residual CNS depressant effects:
– Drowsiness, hangover, vertigo, amnesia (memory loss), motor
incoordination → impair driving, and other psychomotor skills.
2. Tolerance and dependence development:
– Tolerance is developed after prolonged use (of pharmacodynamic
type).
– Cross tolerance between BDZs and others as barbiturates &
alcohol.
– Dependence develops with these drugs after prolonged or chronic
use.
• Serious withdrawal syndrome can include anxiety, convulsions
and irritability if BDZs suddenly stopped.
• The abuse potential of BDZs are much less than other sedatives.
 Adverse Effects (Cont.)
3. Rare paradoxical bizarre effects:
– insomnia, anxiety, irritability and nightmares (sometimes and
dose-dependent).
4. Alcohol interactions:
– Alcohol increases absorption of BDZs and also the CNS
depressant effects (PK & PD interactions).
– It is the common cause of death due to benzodiazepines.
5. Overdosage toxicity:
– Cardiovascular and respiratory depression.
6. Other common side effects:
– Dry mouth, bitter taste, nausea, vomiting and diarrhea.
– Blurring of vision, weakness, headache, joint and chest pain.
Precautions and contraindications
• Alcohol users.
• Driving and machinery users.
• Respiratory insufficiency.
• Pregnancy and lactation.
Disadvantages of benzodiazepines:
• Some sedation and drowsiness.
• They potentiate the action of CNS depressants.
• Liability for dependence, tolerance and withdrawal
symptoms.
• Formation of active metabolites which cause residual
effects.
Novel Benzodiazepin receptor
agonists (Z- compounds)
 3. Novel Benzodiazepin receptor agonists (Z- compounds)
• e.g., Zolpidem and Zaleplon
• Structurally unrelated to BDZ but produce hypnotic effect. BUT
• Act as agonist on benzodiazepine binding sites on GABA receptors.
• Have some selectivity over BDZs since they bind only to  subunits;
while BDZ bind non-selectively to all subunits (,  and ) of BDZs
binding sites. Therefore, Z compounds with less muscle relaxant and
anticonvulsive action (Give reasons?????).
• Both drugs (Zolpidem and zaleplon) are used in sleep onset insomnia
(initial insomnia) i.e., used in patients who are difficulty falling a
sleep.
• Toxicity of Z-compounds can be treated by Flumazenil.
Advantages over BDZs:
– No tolerance development
– No rebound insomnia on abrupt withdrawal.
 BUSPIRONE
1. Acts as 5-HT1A receptor agonist in the brain (partial agonist).
2. Not acts on BDZ receptors & nor GABA action.
3. Most selective anxiolytic currently available.
4. The anxiolytic effect is of delayed onset (takes 1-2 weeks) =>
not useful in acute severe anxiety but used only for chronic
anxiety (Give reasons).
5. Relatively high margin of safety
6. Rapidly absorbed orally.
Few side effects including:
A. Restlessness
B. Dysphoria
C. Elevated BP if used with MAO inhibitors,
D. Slow onset of action (delayed effect)
 Buspirone (Cont.)
Only anxiolytic in chronic anxiety
• No sedative effect.
• No hypnotic effect.
• No muscle relaxant effect.
• No anticonvulsant effect.
• No or little abuse potential and no tolerance.
No withdrawal syndrome on sudden stop
• No potentiation of other CNS depressants.
• No impair of driving skills.
• No rebound anxiety or signs of withdrawal when discontinued.
• No interaction with CNS depressants.
• Minimal psychomotor and cognitive dysfunctions.
 D) Barbiturates
Members:
A. Ultrashort barbiturates: e.g., thiopental (15-30
min).
B. Short acting: e.g., pentobarbital (less than 3 h).
C. Intermediate acting: e.g., amobarbital (4-6 h).
D. Long acting: e.g., phenobarbital (6-8 h).
 Mechanism of action
• As benzodiazepines, they act by
facilitation of the inhibitory action of
GABA but differ from benzodiazepines in:
A. They prolong the duration of opening of
chloride channels not increase the
frequency of opening.
B. GABA is not essential for their action as
in absence of GABA and in high
concentration they can directly activate
chloride channels.
C. Their action is less selective than
benzodiazepines.
D. Due to multiplicity of the action of
barbiturates, they cause more CNS
depression than benzodiazepines.
 Current Uses of Barbiturates
• Phenobarbitone:
– Antiepileptic: it is used in grand mal, partial and status
epilepticus. Although low cost, high efficacy, and less
toxicity, it causes sedation so not widely used as first line.
– In hyperbilirubinemia and kernicterus in neonate:
as it increases the hepatic glucuronyl transferase and
bilirubin binding proteins, so it enhances conjugation of free
bilirubin (active) to the glucuronide conjugate form
(inactive).
• Thiopental:
– Induction of anesthesia and minor short operation.
 Side effects
• After effects: drowsiness and hangover.
• Paradoxical effect (idiosyncrasy): as anxiety and
excitement
• Tolerance: of both pharmacokinetic & pharmacodynamic
types (c.f. benzodiazepine dynamic only).
• Physical dependence: if used in high doses.
• Withdrawal manifestations: if suddenly stopped.
• Drug interactions: Induction of liver microsomal enzymes,
so they decrease the effect of other drugs.
33
 Opioid Analgesics

by
Prof. Mahran. S. Abdel-Rahman
Sphinx University
Clinical Pharmacy Batch
2022
 Analgesics (pain killers)
Commonly used pain killers are:

1) Opioids
2) NSAIDs
3) Local anesthetics

1) Some antiepileptics
2) Some antidepressants
 OpioidsTerminology
Opiates: ‫المستحضر األفيوني‬
- Agents derived from NATURAL opium poppy
either: Natural alkaloids e.g., morphine, codeine, or
Semisynthetic derivatives e.g., heroin.
Opioids: ‫أَ ْفيُو ِنيَّاتُ ال َمفْ ُعول‬
– Any substance with morphine-like actions and their
effects blocked by antagonist such as naloxone.
– Natural, semisynthetic and synthetic compounds (e.g.,
morphine, heroin , fentanyl, tramadol, etc).
Opioid analgesics:
- Drugs which relieve pain, however produce drowsiness,
change mood and mental clouding.
Opiopeptides:
– Naturally endogenous ligands acting on opioid
receptors e.g., Endorphins, Dynorphins, Enkephalins.
 Classification of Opioids
According to their action on opioid receptors
• Pure opioid agonists:
– Drugs acting as agonist on opioid receptors and produce morphine-like
effects (e.g., Morphine and Fentanyl).
a) Morphine and its analogs: e.g., morphine, codeine, tramadol & heroin
b) Meperidine and its analogs: e.g., Meperidine, fentanyl, sufentanyl
c) Methadone and its analogs: e.g., methadone and propoxyphen
• Pure opioid antagonists:
– Drugs acting as antagonists on opioid receptors and prevent the effects
of opioid agonists (e.g., Naloxone & Naltrexone).
• Mixed agonists/antagonists:
– Act as agonists at some opioid receptors and as antagonists at other
opioid receptors (e.g., Nalbuphine, Pentazocine & Buprenorphine).
Classifications-based on analgesic
efficacy.
Mechanism of action of opioids
-Opioids act by binding to endogenous
opioid receptors (Mu: µ, Kappa;  and
Delta;  receptors) in the CNS and extra-
cerebral tissues.
-These receptors are G-protein coupled
receptors that act by:
a- Inhibition of adenyl cyclase with  in cAMP.

b- Opening of potassium channels increasing K+ efflux.

c- Blocking of voltage-sensitive Ca++ channels.

a- Block of voltage-sensitive
Ca++ channels.

Opioid receptors are

G-protein coupled
receptors
b- Increases K+ efflux.

+ c-
decrease cAMP
Decrease in cAMP
 Opioid Receptors

μ1: supraspinal analgesia.

μ μ2: spinal analgesia, respiratory .depression,

sedation, euphoria, miosis and decreased GIT
motility (constipation).

• spinal analgesia,

κ
• dysphoria,
• Sedation & respiratory depression (less than
Mu).

• analgesia at both spinal and supraspinal

δ analgesia.
 Endogenous Opiopeptides

• They are Endogenous peptides interact with

opioid receptors so called opiopeptides to
cause analgesia and modification of pain
sensation.
• They are very strong analgesics and widely
distributed in the CNS and in the GIT.
• They can’t cross the BBB and if used I.V they
are ineffective.
• They include endorphine, enkephaline,
dynorphine & noceciptin.
 I- Morphine
* Pharmacological actions:
Central Nervous System

Cardiovascular Effects

Gastrointestinal tract

Other smooth muscles

Metabolism
 I- Morphine and its congeners
1. Morphine (prototypical opioid)

2. Codeine

3. Tramadol
Collecting resin
of opium poppy
 1. Morphine
Pharmacological actions of morphine
1. CNS effects
a) Analgesic
b) Sedation, hypnosis and clouding
c) Euphoria
d) Miosis
e) Respiratory depression
f) Antitussive.
g) Nausea & Vomiting
 a) Analgesia & Euphoria
• Morphine relieve severe types of pain “both visceral and
somatic pain” without affecting consciousness.
Mechanism of analgesia:
• The analgesic effect of morphine may be related to:
a) Interference with pain perception: by inhibiting pain
impulse transfer to the brain (anti-nociceptive effect)
b) Euphoriatic action: modify emotional reactions to pain
through euphoria.
Euphoria:
• False sensation of well-being especially in presence of pain,
anxiety or addiction.
• This effect may be due to inhibition of inhibitory effect on the locus
ceruleus (LC) activity which contains dopaminergic neurons and
high conc of opioid receptors (i.e., mediated by increased
dopamine).
 b) Sedationa, hypnosis and mental clouding
• Morphine causes sedation, hypnosis and
mental clouding (drowsiness, decrease physical
activity, decrease ability to concentrate and
mental apathy). These effects are due to CNS
depression by morphine.

c) Respiratory depression
• Morphine causes depression of all phases of
respiratory activity by suppressing respiratory
center.
 d- Antitussive, e) Miosis & f) Vomiting
• Antitussive: (non-productive dry cough)
– It depresses the cough center
– It is the most useful drug in treatment of dry non-
productive cough, but it is not used due to its addicting
properties.
• Miosis (Pin-point pupils): (in toxic doses).
– Due to activation of occulmotor nucleus in the brain (i.e., of
central origin).
– The pinpoint pupil is the characteristic of morphine addict or user
with little tolerance.
• Emesis: morphine causes nausea & vomiting by
stimulating the CTZ (in the medulla.
 2. GIT Effects
i. Antimotility & constipating effects:
• Morphine increases smooth muscles tone of intestine & anal
sphincters, decreases motility → Constipation (no tolerance)

• Decreases gastric emptying & all GI secretions (saliva, gastric,

intestinal and pancreatic).

ii. Biliary spasm:

• Morphine increases pressure in the biliary tract by producing spasm in the
sphincter of Oddi & increases biliary colics. This spasmogenic effect could be
overcome by Concurrent use of atropine or nitrates as nitroglycerin (more
acceptable than atropine).
 3. Effects on other smooth muscles
• Ureter and urinary bladder:
– Urinary retention due to  tone of urinary sphincter.
• Postoperative urinary retention is
frequently encountered. Treated by
catheterization.
• Bronchial muscles:
– In asthmatics, morphine is contraindicated because
of bronchoconstrictor effect due to histamine
release.
 4. Effect of Morphine on CVS
• Morphine → VD → Orthostatic hypotension
(fainted on standing up).
• Morphine → VD → relieve pulmonary veins
congestion.

5. Neuroendocrine Effect of Morphine

– ADH release → Urinary retention.
– Block the release of testosterone → Impotence
– Block the release of gonadotrophines from pituitary →
hypogonadism & infertility.
– Release of ACTH → Hyperglycemia
 6. Effect of morphine on histamine release

• Histamine release is stimulated by

morphine 
– Hypotension.
– Itching
– Bronchospasm (so, morphine should
never be given to asthmatics).
 I- Morphine
* Pharmacokinetics:
Absorption From Oral, Parenteral and rectal

Distribution To all including CNS & Placenta

Metabolism

Excretion
 Metabolism of morphine
Metabolism:
– Glucuronide conjugation in the liver:
• Morphine 6-glucuronide: is more active as an
analgesic than morphine (produces long-lasting
effect of morphine with chronic dosing). The half-life
of morphine-6-glucuronide is much longer than
morphine.
• Morphine-3-glucuronide: with little or no analgesic
activity (no affinity to opioid receptors).
– Because of low conjugation capacity in neonates,
morphine and its congeners should not be used in the
neonatal period and the dose should be reduced in
elderly.
Excretion: Via Bile and kidneys as conjugated
metabolites
Metabolic pathways of morphine and codeine

Active analgesic
Excreted by
kidneys

No analgesic activity
* Therapeutic uses of Morphine

1- Pain killer in severe pain

2- Cardiac asthma with
pulmonary edema (LSHF)

3- In preanesthetic medication if
there is preoperative pain.

4- Antitussive in dry cough

5- to check severe diarrhea
 Therapeutic uses of morphine
1. Analgesic: in severe acute constant pain;
– Burns, postoperative pain, fracture pain, pain due to biliary
and renal colics (with spasmolytics), acute MI & cancer pain.
– Given IV or S.C. BUT!
– In shock: repeated SC injections of morphine must
be avoided why? because absorption is improved
after termination of shock → toxicity. So, it is not
recommended to be used SC in shocked patients.
– Excessive use postoperatively must be avoided→
urinary retention, respiratory depression,
constipation.
– In gall stone biliary colics → biliary spasm (worsen
pain) # with atropine or nitroglycerin spasmolytics.
Q: Why atropine must be given with morphine to
patients with biliary colics.
 Cont. therapeutic uses of morphine
2. Cardiac asthma (LSHF with pulmonary edema):
– Reduces anxiety & fear, reduce both preload and afterload
(VD effects) → relieving dyspnoea due to pulmonary
oedema.

3. Antitussive:
– Morphine is effective in dry non-productive cough.
However, non-addicting drug dextromethorphan is
preferred to be used for this purpose.

4. To check severe diarrhea:

– In the past, crude opium has been used to check severe
diarrhea.
– Now, non-addicting meperidine analogues are used in
severe diarrhea e.g., Loperamide and Diphenoxylate.
 Therapeutic uses of morphine cont
5. Preanesthetic medication:

• Due to sedative, anxiolytic, and analgesic properties.

• Systemically with local anesthetics (epidural

anesthesia) for 48 h duration.

• Used as supplement with general anesthesia.

• Caution: respiratory suppression & urinary retention in

elderly.
 Precautions of Morphine
shocked / epileptic Acute abdomen
During labour/ patients
pregnancy
Asthma

Precautions &
relative
contraindications
Hepatic or
Renal
Head Injury Impairement
Extreme ages
 Precautions and relative contraindications
1. Asthmatic patients why?
– Depress respiratory centre.
– Depress cough reflex.
– Histamine releasing agent (bronchoconstriction)
– Dry respiratory secretions
2. During labour:
– It is not given to the mother if labor is expected within 4-5 h as it crosses
placental barrier causing depression of the respiratory center of newborn and
causing asphyxia neonatorum.
3. Head injuries:
– Morphine depress respiration →  CO2 retention and
subsequent VD→  intracranial pressure (ICP).
4. Old people and infants:
• More susceptible to respiratory depressant effect of
morphine.
5. Acute abdomen: e.g., appendicitis and ectopic pregnancy.
– Morphine mask diagnosis and hence rupture may
happen.
 Precautions and contraindications of morphine use
6. Hypovolumia due to hemorrhage:
• Hypotensive + hypovolumia + hemorrhage = circulatory
collapse.
7. Patients with severe hepatic / renal dysfunctions:
– Inadequate metabolism/ excretion → drug
accumulation and toxicity.
8. Patients with epilepsy: as morphine may increase the
epilepsy.
9. Chronic alcohol users: cross tolerance.
10. Alone in Biliary colic: spasm of Oddi exaggerates pain.
11. SC in shocked patients: to avoid toxicity after circulation
improvement.
 Acute Toxicity of Morphine

Manifestations:
• Respiratory depression.
• Postural hypotension.
• Constipation.
• Nausea & Vomiting.
• Urinary retention (with BPH in elderly).
• Increased intracranial pressure
• Itching and urticaria
* Triad Symptoms of Acute
Morphine Poisoning:

Coma Normal versus pinpoint

pupil

Depressed respiration

Pin point pupils

 Treatments of Acute morphine poisoning
• In Non- Addict Patients:
– I.V. Naloxone (pure opioid antagonist): reverse respiratory depression in
magic way. In case of newly born baby, naloxone is injected into
umbilical cord if poisoned during delivery.
– Oral naltrexone is useful in mild conscious cases .
– ABC (airway-Breathing and Circulatory )support.
– Gastric lavage & emesis are indicated immediately after poisoning
ingestion (patient must be conscious).
• In Addict Patients:
– Naltrexone orally or Naloxone (I.V) very cautiously because may
precipitate withdrawal syndrome in dependent subjects and cause
undesirable cardiovascular side effects + ABC + Gastric lavage
and/or emesis.
 Chronic toxicity (ADRs)
Due to repeated exposure of morphine (opioids):
1. Morphine Dependence (both physical and psychic):
– Definition: compulsory use of drug as a result of
habitual control on physiological or psychological
properties. The patient become a slave to the drug.
– Reinforcement factor: euphoria.
– Manifestation:
• Warm flushing skin - Euphoria
• Sensation in the lower abdomen described by the addict as
similar to sexual orgasm known as rush, kick or thrill.
– Tolerance and withdrawal syndrome: are characteristics
of opioid dependence
– Outcomes of dependence: social problems as divorcing +
impotence.
 ADRs Cont
2. Morphine Tolerance:
– Decrease in response to the drug # by increasing doses
– Not develop to all morphine actions.
• Developed to analgesia, respiratory depression, sedative
and euphoria.
• Not developed to constipation and miosis.
3.Withdrawal syndrome due to:
a) Sudden withdrawal of morphine
b) The use of antagonist as naloxone
• Manifestations: opposite to the action of morphine
– Autonomic hyperactivity: lacrimation, rhinorrhea,
sweating, dilated pupils, hypertension and tachycardia.
– Psychological hyper-excitability: anxiety, restlessness,
yawning, tremors and insomnia.
– Motor hyperactivity: Muscle and joint pain, tremors.
 TTT of morphine dependence
1. Gradual morphine withdrawal
2. Methadone orally: Replacement of morphine by another
agents with lower abuse potential as methadone orally.
– Methadone has a cross dependence with morphine but
with low abuse potential.
3. Use of clonidine (2-agonists) to control autonomic
hyperactivity.
4. Using of partial opioid agonist: as buprenorphine (SL)
(has lower abuse potential, suppress withdrawal
symptoms and decrease craving for opioid).
5. Methylnaltrexone: has important role in the management
of constipation in patient undergoing chronic opioid
therapy or addict patients.
• Psychotherapy is essential.
 Morphine derivatives
a) Codeine
• It is Methyl morphine and acts as weak µ-agonist.
• Weak Analgesic potency
– Of 1/12 of morphine (140 mg codeine is equipotent to 10 mg
morphine),
– Used in mild pain not responding to NSAIDs.
– It is usually combined with aspirin or paracetamol to control pain.
• Highly effective orally: little first pass metabolic effect.
• Powerful Antitussive.
• Lower addiction liability and lower withdrawal effects than morphine.
• Frequently in the past (1950-1990), codeine was prescribed and dispensed in
antitussive and cold preparations (e.g., Tussivan, Paracodeine, and others) using
normal non-narcotic prescriptions. However, now it is scheduled drug and used by
narcotic prescription.
 Morphine derivatives Cont.
b) Tramadol.
- Synthetic codeine analogue with weak  agonist activity.
- It also inhibits the reuptake of norepinephrine and
serotonin in the CNS.
- Has active metabolite (O-demethylated) -2-4 times more
potent than the tramadol and may be responsible for part
of the analgesic effect.
- Naloxone is partially prevent the analgesic effect of
tramadol.
- Tramadol is effective in treatment of mild to moderate
pain as morphine but less effective in chronic and severe.
- It does not depress the respiration or CVS but may cause
convulsions.
- The abuse and dependence is less than morphine.
Morphine derivatives Cont.

c) Heroin (diacetylmorphine).
• It has high addiction potential, so it
is not used clinically.
• The analgesic effect is 2 times as
morphine.
 II- Meperidine (Pethidine)
Disadvantages:
– 1/10th in analgesic potency (10 mg morphia = 100 mg pethidine)
– Tachycardia (due to antimuscarinic action)- harmful in
tachyarrhythmias.
– It was believed to provides short-lasting analgesia and has little or no
addiction because of its shortened duration; however, this belief proved
false.
– Not used I.V. (cause severe reaction) and not used S.C. (causes local
irritation and tissue induration),BUT Used I.M
Advantages:
a) Spasmodic action on smooth muscles is much less than morphine
BUT may be spasmolytic (so, non-harmful in Gallstone colics).
b) Safer in asthmatics than morphine (less histamine release).
c) Not produce respiratory depression like morphine. So, preferred
opioid analgesic during labour (less neonatal respiratory depression).
d) It can be used in treatment of postanesthetic shievering
 Side effects of Meperidine

1- Similar to that of morphine (but less

constipation and urinary retention).
2- CNS excitation (tremors, hyperreflexia and
convulsions) due to the formation of
normeperidine metabolite.
3-Physical dependence: is common and
withdrawal syndrome has rapid onset and short
duration (it disappears within 24 h.) with less
autonomic manifestations.
 Meperidine derivatives
a) Fentanyl, alfentanil, remifentanil & sufentanil
Fentanyl:
- μ (mu) receptor agonist
- Very high potency (100 times or more than morphine).
- Used as I.V. anesthetic with droperidol to produce
neuroleptanalgesia.
- High dose of fentanyl can cause muscle rigidity.
- Fentanyl Transdermal Patch (Durogesic; 25, 50, 75, 100
μg) is available for use in cancer pain giving long-lasting
analgesic effect (48h).
Fentanyl derivatives: - e.g., sufentanil and alfentanil
- Used in:
a) General anesthesia,
b) Acute post-operative analgesia
c) Treatment of chronic pain.
 Meperidine derivatives

b) Diphenoxylate & Loperamide.

- Non addicting opioids (in therapeutic dose) used in
diarrhea
- Diphenoxylate may combined with atropine (Lomotil).
- They act by decreasing intestinal motility and secretion.
However,
- They are contraindicated in acute diarrhea in children
(due to the risk of paralytic ileus and respiratory
depression)
- Also, Contraindicated in amebic and bacillary dysentery
(as they increase the ulceration and may cause toxic
megacolon).
 III- Methadone
- μ (mu) agonist.
- Methadone is Used in the treatment of morphine
addiction –Why?
a) More effective orally
b) Longer in duration
c) Lower potential for addiction and less euphoric effect.
d) Tolerance and physical dependence develop slowly.
e) Symptoms of withdrawal are milder than morphine.
f) Sedative effects are less intense than
morphine.
g) Use as substitute therapy for opioid
dependence (1 mg methadone replace 4 mg
morphine).
IV- Mixed agonist-antagonist
a) Pentazocine
- It is agonist on κ-receptor, but weak antagonist (partial
agonist) on μ receptor.
- It has 1/5 of the analgesic effect of morphine.
- It causes tolerance, dependence and respiratory
depression but less than morphine.
- It is not used in addicts to μ-agonist, as it can
precipitate withdrawal syndrome.
- In patients with coronary artery disease I.V.
pentazocine increases pulmonary artery pressure and
cardiac work.
- It is used as analgesic in chronic severe pain but due to
its cardiac effects, it is not used in patients with CHF or
myocardial infarction.
IV- Mixed agonist-antagonist

b) Butorphanol
- It is agonist on κ-receptor, but weak antagonist (partial
agonist) on μ receptor.
- Unlike pentazocine,it precipitates withdrawal syndrome
in methadone addicts but not in morphine addicts.
- It is used I.V. or I.M. to control acute pain.
IV- Mixed agonist-antagonist

c) Nalbuphine.
-It is agonist on κ-receptor, but weak antagonist (partial
agonist) on μ receptor.
-As pentazocine, but does not affect CVS, so can be used
as analgesic in cardiac patients.
IV- Mixed agonist-antagonist
d) Buprenorphine
- Its potency is 25-50 times as morphine.
- The addiction liability is lower with less withdrawal
syndrome than morphine.
- It acts as partial agonist on μ-receptors with no action
on κ-receptors.
- Uses:
1-It can be used as analgesic.
2-It can be used as alternative to methadone for opioid
detoxification and as a maintenance treatment for
opioid dependence as it can prevent the withdrawal
syndrome.
V- Pure opioid antagonists

Naloxone
-It is a competitive pure antagonist.
-It has high affinity to block μ-receptors, less affinity to
block κ-receptors
-It is very weak in blocking δ-receptors.
-It is used only by I.V. injection due to extensive first pass
metabolism, with duration of action l-4 h.
Uses
1- Treatment of acute opioid poisoning in non-addicts (it is
not used in addicts as can precipitate fatal withdrawal
syndrome).
2- Treatment of neonatal asphyxia induced by morphine.
3- Diagnosis of the cases of opioid addiction.
V- Pure opioid antagonists
Naltrexone

- It differs from naloxone in:

1-It is used only orally (more bioavailable).
2-It has longer duration of action (24 h).
3-It is more potent than naloxone.
Uses:
1- as maintenance treatment for acute opioid poisoning.
2- in ex-abusers to opioids to prevent readdiction by blocking the
effect of self-administered opioids.
3- given to physicians, nurses and pharmacists who contact with
opioids to protect them from the risk of addiction.
4- Treatment of alcoholism.

Nalmefene

- It is a new agent, which is a derivative of naltrexone but used I.V. with

duration 8-10 h.
 NON-STEROIDAL
ANTI-INFLAMMATORY DRUGs
(NSAIDs)
Lecture 5
By
Prof . Mahran S. Abdel-Rahman
Professor of Pharmacology & Toxicology
Faculty of Pharmacy
Sphinx University
New Assiut City

24-25
 Anti-inflammatory Drugs
Steroids Non-steroids (NSAIDs)
• e.g., Hydrocortisone, • e.g., Ibuprofen-
betamethasone, • Diclofenac
Dexamethasone Indomethacin
• Most effective anti- • Less effective anti-
inflammatory inflammatory
• More side effects • Less side effects
• Anti-inflammatory- • Analgesic- antipyretic, anti-
immunosuppressant and inflammatory, antiplatelet
anti-allergic actions actions.
• Block both Prostaglandins • Blocks only PGs formation but
(PGs) and leukotrienes accumulate LTs
• Treat acute bronchospasm & • Induce bronchospasm and
anaphylaxis precipitate BA & intolerance
Common Properties of Most NSAIDs
All NSAIDs Share the following:
1. Analgesics action: relief mild-moderate pain.
2. Antipyretic aaction : normalize elevated body temperature.
3. Anti-inflammatory action: suppression of inflamm. (not all).
4. Mechanism of action: cyclooxygenase inhibitors.
5. Therapeutic uses: analgesic, antipyretic and antiinflammatory.
6. GI adverse effects: gastritis, GI upset and ulcer (Most)
7. Induce bronchospasm in some asthmatics (due to LTs
accumulation).
 A- Pharmacological Classification
I- Non-selctive COX inhibitors (tNSAIDs):
1. Salicylate acid derivatives: Acetyl salicylic acid (Aspirin)
2. Para-aminophenol dérivatives:
Acetaminophen (Paracetamol , Paramol, Pyral, Adol, Panadol) (no antiinflammatory)
3. Acetic acid derivatives:
Indomethacin (indocid) Diclofenac (Voltaren)
4. Oxicam derivatives:
Piroxicam (Felden),
5. Propionic acid derivatives:
Ibuprofen (Brufen) Ketoprofen (ketofan) Fenoprofen (Nalfon)
6. Fenamic acid derivatives:
Mefenamic acid (Ponstan)
II) Preferential Cox II inhibitors:
Meloxicam (Mobic) Nabumeton
Sulindac Etodolac
III) Selective COX 2 inhibitors: (Coxib derivatives):
Celecoxib (Celebrex) Rofecoxib (Vioxx-withdrawn) Prohibited
Etoricoxib (Arcoxia) Valdecoxib (Bextra)
B- Therapeutic Classification of NSAIDs
 Mechanism of action of NSAIDs
➢ NSAIDs act by inhibition of cyclooxygenase enzymes (COX):
1) Inhibition of PGs synthesis (mediate inflammation,
pain and fever). So, NSAIDs have analgesic, antipyretic and
antiinflammatory actions.
2) Inhibition of thromboxane A2 synthesis by low dose
aspirin (mediate platelet aggregation & VC). So, used as antiplatelet.
➢ All NSAIDs cause non-selective reversible inhibition of COX
enzymes EXCEPT:
1. Aspirin produces irreversible inhibition (10 days duration
in platelets).
2. Selective COX-2 inhibitors which selectively inhibit only
COX-2.
 Types of COX enzymes (OUT)
➢ There are 2 type of COX enzymes (COX-1 and COX-2):
1. COX-1 (constitutive): responsible for
physiological PG synthesis (PGs mediate
protection of gastric mucosa, normal function
of kidney and platelets aggregation).
– Inhibition of COX-1 in platelets give antiplatelet
effect (desirable) but other NSAIDs effects on
GIT and Kidney are undesirable
1. COX-2 (inducible): induced in inflammation
by cytokines as IL 1 & TNF); plays role in
inflammation, fever and pain.
 A) Salicylates e.g., Aspirin
Pharmacological Actions of Salicylates
1. Analgesic effect:
• Somatic pain “muscles, joints
and bones’’ but less effective
in visceral pain.
• Effective in mild - moderate
pain.
• Acts peripherally
and centrally.
• Acts as analgesic by inhibiting
PG That sensitizes pain
receptor in nerve endings to
pain stimuli by PGS
2- Antipyretics & Hyperpyrexia of Salicylates

• Therapeutic doses of salicylates → Antipyretic:

– by inhibiting PGs synthesis.
– resetting the thermostat point of Hypothalamic
Thermoregulatory Center (HTC) into normal
temp (37 C).
– salicylates increased heat lost via sweating.
• Toxic doses of salicylates → Hyperpyrexia:
– Salicylates uncouples oxidative phosphorylation
reactions responsible for ATP formation and the
energy is lost as heat.
 3. Anti-inflammatory effect
➢ PGs cause vasodilatation (capillary permeability),
oedema and pain i.e, participates in pathogenesis
of inflammation.
➢ NSAIDs cause inhibition of PGs synthesis in the
peripheral tissues and so reduce inflammation and
produce anti-inflammatory effects.

➢ NSAIDs reduces:
➢ Edema
➢ VDs Anti-inflammatory effect
➢ Pain
 4- Antiplatelet Effect of Salicylates
• Small dose of aspirin (75-150 mgday) → Antiplatelet:
– Irreversible inhibition of platelet cyclooxygenase 1
(thromboxan A2 synthase) →  thromboxane A2
formation.
– Inhibition of thromboxane A2 synthesis allow large
amount of Prostcycline accumulation with
antiplatelets effects.
– The effect lasts for up to 8 days till synthesis of
new platelets as platelets have no ability for
synthesis of new enzymes (non-nucleated cells).
• Large doses inhibit both thromboxane A2 and
Prostacycline (no benefit).
 5. Acid-Base Balance & Electrolytes
Compensated Respiratory Alkalosis:
➢ Large dose stimulates respiration centrally (rate &
depth)→ wash out CO2 and decreased CO2 level in the
blood → respiratory alkalosis.

➢ This respiratory alkalosis is compensatory in adults

(compensated by enhanced excretion of NaHCO3).
 Cont. Acid-Base Balance
• Toxic doses: non-compensated
respiratory & metabolic acidosis in
children why?
➢Toxic doses → respiratory depression →
CO2 retention → Respiratory acidosis.

➢Toxic doses → accumulation of acidic

metabolites → Metabolic acidosis.
 6. Effects of Salicylates on GIT
– Hyperacidity (heart burns)
– Gastritis & epigastric distresses (nausea, vomiting)
– Peptic ulcer complicated by hematemesis, melena and
even perforation (in severe cases).

Mechanisms of GI upset -induced by salicylates:

– Direct irritant effect (if used orally).
– Central stimulation of CTZ by both oral &
parenteral salicylates.
– Inhibition of cytoprotective PGs (PGI2 & PGE2)
synthesis by salicylates in stomach.
 Management Approaches of GI - ADRs of NSAIDs
– Use NSAIDs after meal with plenty of water or milk & use
one of the following with NSAIDs:
• Prostaglandin analogues e.g., Misoprostol. (cytoprotective
on GIT)
OR
• H2-blockers. e..g., Ranitidine
OR
• PPIs: e.g., Omeprazole.
OR
• Selective COX-2 inhibitors e.g., celecoxib

N.B. Both selective COX-2 inhibitors and Paracetamol lack GIT

adverse effects.
7. Effect of Salicylates on Urate Excretion
 8. Analgesic Nephropathy by NSAIDs
• PGs are renal vasodilators which maintain renal blood
flow against angiotensin II & NEP ‘’renal
vasoconstrictors’’.

• Aspirin & other NSAIDs→PGs → renal VD →renal VC

(unopposed Angio II & NEP) → GF & consequently
increase sodium and water retention → edema and
hyperkalemia in some patients.

• Nephropathy (Interstitial nephritis) can occur with all of

the NSAIDs especially in mixture forms for long time.
 PKs of Salicylates
Absorption:
• Orally ingested: salicylates are absorbed from GIT (stomach &
small intestine).
• Rectal absorption: slow and unreliable, but it is useful in vomiting
children.
Distribution:
• Distributed to almost all body tissues but:
– High amount: Liver, Heart and Muscles.
– Significant amount: in CSF, milk, saliva, synovial fluid, and
others.
– Low amount: in the brain
– Significant interactions with warfarin
 Cont. PK
Elimination:
• Low dose (600 mg/day), aspirin is hydrolyzed
to salicylate and acetic acid by estrases (First-
order kinetics) t1/2 =3.5 hours.
• Large doses (4 g/day), Zero-order kinetics
t1/2 = 15 hrs or more.
• Alkalization of urine by NaHCO3 →
ionization of salicylates →  re-absorption
from renal tubules →  excretion.
 General Therapeutic Uses of Aspirin
1. Analgesic:
– headache, OA, dysmenorrhoea, neuralgia and
myalgia.
– Dose: 0.3-1 g4h.
– N.B. The use of aspirin in dental extraction is not
recommended to avoid bleeding
2. Antipyretics:
– Dose (0.3-1 g/4h)
– AS symptomatic relief of fever.
– Paracetamol is preferred..
3. Anti-inflammatory:
– in both acute rheumatic fever and rheumatoid
arthritis but in large dose (6 g) of aspirin.
 Therapeutic uses of Aspirin Cont.
4. Antiplatelet:
– Low dose aspirin (75-150 mg; once daily dose.
– Small dose decreases thromboxane A2 and
does not affect PGI2 (desirable).
– Large dose as it decreases PGI2 (prostacyclin)
which has antiplatelet effect (unwanted).
– It reduces MI, cerebral thrombosis &
postoperative DVT especially in bedridden
patients.
5) Reduces the risk of cancer colon and rectum:
– Aspirin is used why? (PG mediated
carcinogenesis).
 Uses of Aspirin in pregnancy & Labour
1. Frequent miscarriage in anti-phospholipid
syndrome:
➢This autoimmune disease produces
antibodies enhancing clotting factors
causing DVT, arterial thrombosis or
placental thrombosis.
➢The Placental thrombosis may lead to
miscarriage and abortion.
➢This miscarriage can be treated by aspirin
low dose 81 mg+ Enoxaparin (during the
entire pregnancy)
 ADVERSE EFFECTS of SALICYLATE$
1. Aspirin-induced bronchoconstriction due to
accumulation of LTs (Aspirin intolerance)
2. Aspirin- induced vasoconstriction of renal artery
(NSAIDs nephropathy)
3. Aspirin-induced Ulcer and Gastric upset due to
inhibition of cytoprotective PG in stomach.
4. Aspirin – induced Reye’s syndrome in children
(less than 16 years) with viral infections
(Hepatoencephalopathy with aspirin only).
5. Aspirin-induced hyperuricemia
1
2-
3-
4-
 Unwanted Effects of Salicylates Cont.
5.  Bleeding tendency:
– Due to Antiplatelet action of aspirin.
– Aspirin should not be taken for at least 1 week before
surgery.
– When salicylates are administered, anticoagulants
may have to be given in reduced dosage (PK & PD
interactions).
– Contraindicated in events with bleeding tendency e.g.,
haemophilia and haemorrhage.
 6- Salicylate Toxicity
1. Chronic toxicity “ Salicylism ”:
– With chronic use of large doses of salicylates as that taken in
rheumatic fever.
– Mild chronic intoxication.
– Manifested by nausea, vomiting, headache, mental
confusions, dizziness, and tinnitus.
2. Acute toxicity (toxic dose):
• Acid-base and electrolyte imbalance: respiratory and
metabolic acidosis especially in children.
• CNS: restlessness, delirium, hallucinations, convulsions,
and coma.
• Dehydration, hyperthermia and death from respiratory
failure.
 Treatment of acute salicylate toxicity
1. Hospitalization: is necessary
2. Supportive treatment: artificial respiration to treat
respiratory disorders
3. Symptomatic treatment: hyperpyrexia (cold fomentation
not antipyretic), dehydration (I.V. fluids), acid-base
imbalance (Na bicarbonate & electrolytes).
4. Increasing the pH of the urine and correct acidosis: by
I.V. sodium bicarbonate & fluids.
5. Decontamination: by gastric lavage or induction of
vomiting.
6. Vitamin K: in case of bleeding.
7. Hemodialysis in severe cases as aspirin has low Vd (10 L).
The use of aspirin in pregnancy: not
recommended- why?
Causes prolongation of gestation due to inhibition of PG
which plays a role in the onset of delivery.
- May cause early closure of ductus arteriosus as PG maintains
its patency.
- The use of aspirin late in pregnancy may increase the risk of
postpartum hemorrhage.
BUT recommended in frequent abortion and miscarriage
 Contraindications of Aspirin and Other NSAIDs

• C/I Adverse Effects of Aspirin

• Ulcer: Internal bleeding, possible haemorrhage
• Asthma: Asthmatic attack similar to allergic reaction
• Diabetes: High doses may cause hyper/hypoglycemia
• Gout: Low doses increase plasma urate
• Influenza: Reye’s syndrome in children
• Hypo-coagulation states: Excessive bleeding
• During delivery: to avoid blood loss and closure of
patent ductus arteriosus
 B) PARAAMINOPHENOL DERIVATIVES
ACETAMINOPHEN (Paracetamol)
Paracetamol unlikes aspirin in the following:
1. No Reye´s syndrome (safe drug).
2. No GIT adverse effects (not ulcerogenic).
3. No uricosuric effect.
4. Not produce acid-base imbalance.
5. No anti-inflammatory activity (drawbacks).
Actions:
1. Has analgesic-antipyretic action.
2. Acts mainly centrally and so has no peripheral action.
3. Recent evidence suggests that paracetamol may act as “
(COX3 inhibitor) which is a new discovered COX isozyme
in the CNS. It appears to be a product of COX-1 gene.
Indications of paracetamol:
– Analgesic and antipyretic for all ages.
– 15 mg/kg/day for children.
– 500-1000mg/6h for adults.
Advantages of paracetamol over aspirin:
1. No GIT adverse effects → useful in patients
with ulcer.
2. No antiplatelet effect → useful before surgery
3. No intolerance → useful in asthmatics
4. No Reye’s syndrome → useful in children with
viral infections
 Paracetamol is preferable over aspirin in
the following conditions:
1. Hypersensitivity to aspirin.
2. GIT bleeding.
3. Children with febrile viral infection.
4. Gout.
5. Bleeding tendency.
6. Pregnancy as analgesic.
7. Bronchial asthma
8. Patients use oral anticoagulant
Metabolism of Paracetamol & Its Role in Poisoning
– The main part (about 95 %) is inactivated by conjugation
with glucuronic & sulphoric acids.
– The minor part (5%) is hydroxylated into N-acetyl-p-
benzoquinone imine (highly reactive metabolites). It reacts
with SH group of glutathione causing it harmless.
– Toxic doses (> 5 g) cause nausea and vomiting, then, after
24-48 h, potentially fatal liver damage by saturating normal
conjugating enzymes causing the drug to be converted by
mixed function oxidases to N-acetyl-p-benzoquinone imine.
– This reactive metabolite reacts with SH group of hepatic
proteins (SH containing proteins) → hepatic cell necrosis.
– This hepatic toxicity can be treated by using of N-acetyl
cysteine which provides the liver by glutathione.

N.B. Glutathione is not used as it poorly penetrates liver cells.

 Ac-glucuronide Ac Ac-sulfate

Cytochrome P450
(mixed function oxidase)
Reactive N-acetyl-p-benzoquinone imine (Ac*)

Ac: Acetaminophen (Ther. doses)

Ac* reactive metabolite
GSH (toxic doses)
GSH Glutathione
Cell macromolecules (protein)
Gs-Ac* Ac*-protein

Ac-mercapturate Hepatic cell death

Harmless Harmful

Mechanism of hepatotoxicity-induced by toxic doses of paracetamol

 ADRs of paracetamol
– Well tolerated at therapeutic dose.
1. Allergic reactions (rash): very rare
2. Fatal hepatic cell necrosis: with overdosage
manifested by nausea and vomiting, right
upper quadrant pain, jaundice &
encephalopathy in severe cases.
3. Analgesic nephropathy: if used chronically
in mixture with other NSAIDs.
– Notes: total daily dose must not exceed 4 gm
 C) Other NSAIDs
1. Indomethacin (Indocid)
➢ Potent analgesic antipyretic and anti-inflammatory agent.
➢ The most toxic NSAIDs (limits its usefulness).
Uses:
– Antipyretics: Malignancy-induced fever (systemic) when
refractory to other conventional agents.
– Anti-inflammatory: in acute gouty arthritis, ankylosing
spondylytis, RA and OA of the hip & gingival
inflammation (mouth wash).
- Premature labour and dysmenorrhea: because it
suppresses uterine contraction.
- Patent ductus arteriosus: before birth, the ductus is
kept patent by the effect of PGs. Patent ductus can be
closed by I.V. indomethacin (0.2 mgkg).
 Adverse effects of indomethacin
- Indomethacin is the NSAID with great toxicity:
- Toxicity occurs in up to 50 % of patients (20 % discontinue the
use of it). Toxic manifestations include:
- Hematopoietic disturbances: thrombocytopenia & aplastic
anemia
- Hypersensitivity reactions: rash, urticaria, itching, and acute
asthmatic attacks especially in asthmatics (cross reactivity
with aspirin).
- Acute pancreatitis and fatal hepatitis rarely to occur.
- CNS disturbances: headache, dizziness, vertigo, mental
confusion and psychosis.
- GIT disturbances: nausea, vomiting, diarrhea and peptic
ulceration.
- So, Indomethacin is not widely used.
 2. Diclofenac (Voltaren)
• More Hepatotoxic than other NSAIDs (liver function test needed).
• Potent analgesic, antipyretic & anti-inflammatory.
• Readily absorbed from GIT and achieve high synovial
concentrations after oral uses.
Uses:
- Anti-inflammatory: in OA, RA and ankylosing spondylitis.
- Analgesic: in myalgia, postoperative pain and dysmenorrhea.
- Antipyretic: suppositories for children and tab or injection for adults.
Adverse effects:
– Common in about 20 % of patients.
– GIT manifestations (hyperacidity & ulceration).
–  hepatic transaminase enzyme.
– CNS effects: insomnia and visual disturbances.
– Allergic reactions.
– Fluid retention.
 3. IBUPROFEN (Brufen)
• Ibuprofen is the least toxic NSAIDs (similar aspirin & Cox-
2 ino hibitors)
• Has anti-inflammatory, analgesic and antipyretic
activities.
• Better tolerated than aspirin and so recommended in
dental pain.

-Indications:
1. Analgesic: Short-term analgesia e.g., toothache,
myalgia, acute tendinitis & primary
dysmenorrhea.
2. Anti-inflammatory: in RA, OA, ankylosing
spondylitis and acute gouty arthritis.
 6. MEFENAMIC ACID (Ponstan)
• Has marked analgesic activity with mild
antiinflammatory action.
• It is not superior to other analgesics and has
serious toxicity. So, not recommended.
• Most frequent side effects include: severe
diarrhoea & haemolytic anaemia.
• If diarrhea developed, the drug should be
stopped and must not be used again.
• Used only for one week as an analgesic.
 7. Oxicam derivatives
i. Piroxicam (Feldene):
Actions:
- Has anti-inflammatory activity comparable to aspirin.
- Possesses analgesic-antipyretic activity.
PK:
- It is completely absorbed from GIT
- Long half life (50 h) partly due enterohepatic recyclization and so
administered once daily dosage.
ADRs:
- GIT: hyperacidity and gastric ulceration
- CNS: dizziness, drowsiness.
Uses:
- TTT of acute gout
- Rheumatoid arthritis, osteoarthritis & ankylosing spondylitis.
- Postoperative pain and dysmenorrhea.
 ii. Meloxicam (Mobic)

• Relatively selective COX-2 inhibitors (not pure).

• Has little GIT adverse effects.
• Has long half life and used once daily.
• Used in TTT of OA & RA.
 8. Selective COX-2 inhibitors
• Members:
– Celecoxib (Celebrex 100 & 200 mg) tablets.
– Etoricoxib (Arcoxia 60, 90 and 120 mg) tablets.
• Actions:
– Exhibit analgesic, antipyretic and antiinflammatory actions
comparable to non-selective NSAIDs.
• Advantages:
– Free or with little GIT disturbance.
• Disadvantages:
– They do not inhibit platelet aggregation.
– They may produce more cardiovascular risk (heart attacks)
than non-selective NSAIDs.
– Rofecoxib (Vioox) has been withdrawn from the market
because of increased cardiovascular mortality.
– These cardiovascular risks may be attributed to inability to
inhibit platelet aggregations.
 Very Important Drug interactions of NSAIDs
• With antihypertensives & diuretics:
– They reduce the hypotensive action because NSAIDs
decrease renal PGs which may play role in increase
salt & water excretion.
– So, when given together salt and water retention
results and decrease the effectiveness of
antihypertensives & diuretics.
• With warfarin oral anticoagulant:
– NSAIDs by their antiplatelet effects and displacement
effect of warfarin from plasma protein binding sites
→ the anticoagulant effect of warfarin.
– So, the dose of warfarin must be reduced when given
with NSAIDs.
 The Best NSAIDs
1. The best antiplatelet NSAID: Aspirin 75-325 (only
Irreversible)
2. Acute rheumatic fever: Aspirin
3. Orthopedic pain & inflammation: Piroxicam and meloxicam
(long duration and accumulated in bone in joints)
4. To Close Ductus Arteriosus and tocolytic: Indomethacin
5. Tocolytic: Indomethacin
6. In Gout: All EXCEPT Aspirin
7. Dental disease: Ibuprofen
8. Least ulcerogenic in stomach: Cox 2 inhibitors or
paracetamol
9. Least CVS effects: Naproxyn
10. Dysmenorrhea: Ibuprofen, mefenamic acid or indomethacin
 Lecture 6:
Neurodegenerative diseases
1- Parkinson’s Disease
2- Alzheimer’s Disease
by

Prof. Mahran S. Abdel-Rahman

Prof. Of Pharmacology
Sphinx University
2024-2025
 Introduction
• Neurodegenerative disease is a range of neurological
conditions which affect the neurons in the human brain.
• Neurons are the building blocks of the CNS Which
includes the brain and spinal cord .
• Neurons normally don’t reproduce or replace themselves.
– So, damaged or dead neurons can’t be replaced by the
body.
• Neurodegenerative diseases are incurable diseases
mostly that result in progressive degeneration or death of
nerve cells.
• This causes problems with movement, or mental
functioning (called dementias)
 Examples of neurodegenerative
disorders
–Parkinson's disease
–Alzheimer disease and Dementia
–Huntington's disease
–Multiple sclerosis.
 Parkinsonism
• Parkinsonism: is a slowly progressive
neurodegenerative disorder of basal
ganglia with abnormalities in fine
movement and behaviors;
characterized by tremors, muscular
rigidity, bradykinesia or akinesia, and
postural and gait abnormalities.
 1- Parkinson’s Disease
Physiological background:
• Fine motor control dependent upon balance
between excitatory and inhibitory NT (dopamine
and Ach):
• In Parkinsonism: imbalance between DA and Ach
in basal ganglia occurs.
 
Pathophysiology of Parkinsonism
 Symptoms of Parkinsonism
1. Tremor: at rest, in hands or limbs
2. Muscular rigidity: Disorganized coordination.
3. Bradykinesia or akinesia: slow or absence of movement
4. Speech disturbances: Hypophonia (Heavy tongue),
dysphonia (difficult speech).
5. Mood changes: anxiety or apathy.
6. Drooling (‫)سيالن اللعاب‬: most likely caused by a weak,
infrequent swallow and stooped posture.
7. Dysphagia: inability to swallow  Aspiration, pneumonia.
8. Masked faces: no face expression.
9. Sleep disturbances: sleeping during day time, early
awakening, nightmares, or restless sleep.
10. Cognitive disturbances: amnesia, confusion, dementia, etc
Patient with Parkinsonism
 Etiology of Parkinsonism
• Idiopathic……. Most

• Head trauma and cerebral anoxia: Destruction of

dopaminergic neurons in the basal ganglia by head trauma
(Mohamed Ali –Int. Boxer Championship) with a consequent
reduction of dopamine actions in brain's basal ganglia that are
involved in motor control.

• Genetic factors may play a role in the etiology of Parkinson's

disease (not dominant).

• Environmental factor or toxins may play a role in the loss of

dopaminergic neurons.

• Drug-induced PD….. Some

Mohamed Ali From Champion Boxer into Parkinsonism
 Types of Parkinsonism
1. PRIMARY (IDIOPATHIC) PARKINSON DISEASE: Classic
Parkinsonism Disease Or Paralysis Agitans. The disease is
incurable.
2. SECONDARY PARKINSONISM: These disease are curable.
– DOPAMINE ANTAGONISTS:
• Phenothiazines (e.g., chlorpromazine, perphenazine)
• Butyrophenones (e.g., haloperidol)
• Reserpine & alpha methyl dopa
• Metoclopramide.
• Physostigmine & pilocarpine.
– POISONING BY CHEMICALS OR TOXINS:
• Carbon monoxide poisoning
• Heavy-metal poisoning, manganese or mercury
• MPTP (methyl-phenyl-tetrahydropyridine), a commercial
compound used in organic synthesis
– INFECTIOUS CAUSES
• Viral Encephalitis & Syphilis
 Laboratory Diagnosis
• Diagnosis is based on medical history and
neurological examination.

• No lab diagnosis is available

• MRI and CT are usually normal.

 Objective of Clinical Management
• Incurable disease, unfortunately.
• The goals of treatment are to:
– Control symptoms.
– Improve patient's ability to carry out daily
performance.
– Prevent further neuronal degeneration.
– Minimize disability.
– Reduce the possible side effects of drug therapy.
– Maintain the highest possible quality of life
– Restore dopaminergic/cholinergic balance.
 Treatment of Parkinsonism
• Drug therapy: to improve symptoms even
temporary.
• Physiotherapy Reduces rigidity & corrects
abnormal posture.
• Speech therapy to improve dysphonia and speech
disturbances.
• Neuropsychiatric therapy: For depression
• Gene Therapy
• Surgical & Radiofrequency pallidotomies
 Drug Treatment Strategy
1.Enhancement of dopaminergic activity by:
a) Levodopa: which is its natural precursor of dopamine.
b) Dopamine receptor agonists: Bromocriptine,
Pergolide, Cabergoline, Apomorphine;
c) Prolong the action of dopamine: through selective
inhibition of its metabolism (Selegiline),
d) Release dopamine from stores and inhibit reuptake
(Amantadine)
2.Reduction of cholinergic activity by central
antimuscarinic drugs:
a) Benztropine, Trihexephenidyl
b) Antihistaminics
c) Phenothiazine
 A) Dopaminergic drugs
1- L-Dopa
 Levodopa is a metabolic precursor of dopamine.
 Mechanism of action:
Pass BBB → in presence of DOPA decarboxylase → dopamine.

 L-dopa + carbidopa:
Inhibits peripheral conversion of L-dopa to dopamine.
 L-dopa + entacapone:
 ↓ L-dopa peripheral metabolism by COMT.

Both drugs: ↑ t½ of L-dopa, ↓ dose & ↓ its side effects.

Levodopa Mechanism
• Levodopa + Carbidopa (Cinemet)

Can`t pass BBB.•

Passes BBB
Inhibits peripheral
decarboxylation of levodopa
to dopamine

Can`t pass BBB.

Dopamine
Synthesis of dopamine from levodopa in the absence and presence of carbidopa, an
inhibitor of dopamine decarboxylase in the peripheral tissues. GI = gastrointestinal.
 Therapeutic effects:
 ↓ Tremors & rigidity.
 Tolerance may develop (3-5 years).

 Adverse effects:
1. Response fluctuation:
 “Wearing off“ or end of dose akinesia: related to the timing of
dose, symptoms appear before next dose; overcome by adding
MAO inhibitors or COMT inhibitors or dopamine agonist.
 On-off phenomena: not related to the dose (3-5 years); related to
fluctuation in responses (on: symptoms disappear, Off: akinesis
appear.
2. GIT: Anorexia, nausea & vomiting, & bleeding peptic ulcer.
3. CVS: Postural hypotension (vascular DA receptors), Tachycardia &
dysrhythmias (α & β effects).
4. CNS: Psychosis, hallucinations & mood changes (↑ mesolimbic
dopaminergic activity).
5. Dyskinesia (after 3-5 years; due to adaptive alterations
in expression of dopamine receptors.
Side effects could be minimized by using of:
– Levodopa + Carbidopa
N.B.
• Don’t use phenothiazine, or metoclopramide to
stop vomiting –why? Because they block dopamine
receptors) and exacerbate Parkinsonism. However,
vomiting could be stopped by cyclizine
(antihistamine) or by domperidone (hardly passes
the BBB).

Prof. Mohamed Adel

 On-off phenomena
• Related to fluctuation in plasma level)
• Clinical responses fluctuate from improving of
dyskinesia (On) to akinesia (Off) within few hours.
• TTT of on-off Phenomena:
– Uses of frequent doses every 2 hours.
– Drug holidays (stop drug for few days).
– Using a combination of levodopa, bromocriptine or
better levodopa and selegiline.
  Interactions of L-dopa
Carbidopa:  L-dopa effects and ↓ peripheral side effects.
Vitamin B6→↓ L-dopa effects (↑ peripheral breakdown of
L-dopa & decrease central effects).
↑ Protein meal → ↓ L-dopa absorption.
MAO inhibitors → hypertensive crisis (due to increased
catecholamines levels).
Antipsychotic drugs (dopaminergic antagonists)→↓ L-dopa
effects (block dopamine receptors).

 Precautions:
Cardiac & psychotic patients.
Some drug interactions observed
with levodopa.
 2- Bromocriptine:
Mechanism of action: dopamine receptor agonist.
Therapeutic effects: similar to L-dopa.
Adverse effects:
↑ Hallucinations, confusion & postural hypotension.

 Contraindications:
Psychotic patients.
Peripheral vascular disease.
 3- Amantadine:
Antiviral

 Mechanism of action:
↑ synthesis & release of dopamine.
 Therapeutic effects:
Less effective than L-dopa.
No effect on tremors.
Tolerance develop quickly.
Antiviral activity

 Adverse effects: similar to L-dopa.

 4- Selegiline
 Mechanism of action: ↓ MAOB →↓ dopamine breakdown →↑
dopamine level.
 Selegiline + L-dopa: ↑ effects of L-dopa.

 Selegiline is metabolized to methamphetamine and

amphetamine (may cause insomnia if administered
midafternoon)

5- Rasagiline
• It is an irreversible and selective (MAO-B) inhibitor of brain, has
five times the potency of selegiline.
• Unlike selegiline, it is not metabolized to an amphetamine-like
substance.
Effect of entacapone on dopa concentration in the central nervous system
(CNS).
COMT = catechol-O-methyltransferase.
 B) Anticholinergic Drugs
1. Atropine
2. Atropine substitutes are better than Atropine (good
CNS effect).
1. Benztropine.
2. Trihexyphenidyl.
Clinical uses:
• Mainly for tremor, rigidity & salivation.
• Used in conjunction with L-dopa.
• If one fails use another.
• i.m or i.v in acute drug-induced dystonia.
Side effects & contraindications:
Dry mouth, blurred vision, glaucoma, retention
of urine, hallucination, memory defect &
psychosis
 Benztropine:
 Mechanism of action: block muscarinic receptor in
basal ganglia.
 Therapeutic effects: less effective than L-dopa.
 Adverse effects:
Visual disturbances.
Dry mouth, constipation & urinary retention,  IOP.
 Contraindications:
Glaucoma (close angle type).
Prostatic hypertrophy.
 Alzheimer’s disease is an irreversible,
progressive brain disease characterized by
memory loss (Dementia- early symptoms) &
thinking skills (cognitive impairement)
followed by changes in personality or
behavior.
 Alzheimer's advances in stages,
progressing from mild forgetfulness and
cognitive impairment to widespread loss of
mental abilities.
 The time course of the disease varies by
individual, ranging from 5 - 20 years
 Alzheimer's disease causes loss of brain cells in
areas of the brain (Marked atrophy of the cerebral
cortex and subcortex)
 Some of the deterioration may be related to a loss
of neurotransmitters in the brain that allow nerve
cells in the brain to communicate properly.
 People with Alzheimer's disease have two things in
the brain that are not normal: amyloid plaques
and neurofibrillary tangles
 Beta Amyloid plaques are clumps of a protein
builds up around the cells in the brain that
communicate with each other.
 Twisting and tangles of tau protein.
1. Genetical and biological factors.

2. Lifestyle factors: dietary habits,

high blood pressure and high
cholesterol).

3. Stress factors.
Pathology Of AD
 Patient history, collateral history from relatives, and clinical
observations, based on the presence of characteristic neurological and
neuropsychological defects.
 Advanced imaging with CT (Computer tomography) or MRI (magnetic
resonance imaging), single photon emission computer tomography
(SPECT) or positron emission tomography (PET) is generally used to
help to diagnose the subtype of dementia and exclude other cerebral
pathology.
 Neuropsychological evaluation including memory testing and
assessment of intellectual functioning can characterize the
dementia.
 Diagnostic criteria that may be impaired in AD: memory, language,
attention, orientation, problem solving and functional abilities.
 Recent markers of the disease: as analysis of cerebrospinal fluid
for β-amyloid or tau proteins.
.

PET scan of the brain of a person with AD showing a loss

of function in the temporal lobe.
Microscopy image of a neurofibrillary tangle, conformed by
hyperphosphorylated tau protein.
 The main symptoms of Alzheimer's:
1. Memory loss and confusion are the main symptoms .
2. Cognitive: mental decline:
 Difficulty thinking and understanding

 Confusion in the evening hours

 Delusion, disorientation, forgetfulness, making

things up
 Mental confusion, difficulty concentrating

 Inability to create new memories

 Inability to do simple maths

 Inability to recognize common things

3. Behavioural symptoms:
 Aggression • Agitation • Difficulty with self care
 Irritability •
 Meaningless repetition of own words
 Personality changes, lack of restraint •
 Wandering and getting lost •
4. Mood symptoms:
 anger • Apathy • General discontent •
5. Psychological: depression, hallucination, or paranoia •
6. Whole body: loss of appetite or restlessness
In advanced Alzheimer's, people become dependent on others
for every aspect of their care.
 About 40 million people worldwide
have Alzheimer’s
 Alzheimer's is the fifth leading
cause of death in people 65 and
older
 I-AChE-inhibitors: control moderate symptoms but do
not alter the course of the underlying dementing
process.
 Members: donepezil, galantamine and rivastigmine.
 donepezil, galantamine: Taken orally.
 Rivastigmine used once-daily as transdermal patch.

II- Novel N-methyl-D-aspartate (NMDA) receptor

antagonist: e.g., Memantine has been shown to be
moderately clinically efficacious.
 Derivative of amantadine
 NMDA receptor antagonist and so protect neurons from
excitotoxic (degenerative) actions of excessive glutamate).
 IIII- Vaccines or immunotherapy:
 Unlike typical vaccines, immunotherapy would be
used to treat diagnosed patients not disease
prevention.
 Training efforts based on the immune system to
recognize and attack beta-amyloid, the immune
system might reverse deposition of amyloid and thus
stop the disease.
 IV- Simvastatin: a statin, stimulates brain
vascular endothelial cells to create a beta-
amyloid ejector. The use of this statin may be
having a causal relationship to decreased
development of the disease
 Aducanumab Lowers Amyloid Plaque
Associated with Alzheimer’s, Extension
Trial Shows

VI- Other drugs:

 NSAIDs (anti-inflammatory),
 Selegiline (MAO-B inhibitor)
 Vitamins E & C (antioxidants).
 Fruit
and vegetables, wheat and other cereals,
olive oil and fish “the components of a
Mediterranean diet”, may all individually or
together reduce the risk of Alzheimer's disease.

 Vitamins E, B, and C, or folic acid have

appeared to be related to a reduced risk of
Alzheimer.
2016- 2017
 Lecture 8:
Antipsychotics /
Schizophrenia
By
Prof. Mahran S. Abdel-Rahman
I- Pathophysiology of Psychosis.
II- Pharmacology of Antipsychotic Drugs.
2025
Schizophrenia
1. Definition
major psychological disorder (brain disorder)
means an abnormal condition of the mind
described as “ loss of contact with reality".
Schizophrenia Psychosis

Split Mind mind abnormal

Split-mind Abnormal mind

Loss of reality
 2. Pathophysiology
# Genetics: strong genetic component
1. Dopamine Theory:
The disease arises from increased dopaminergic
activity in the mesocortical-mesolimbic system
It was found that drugs which increase
dopaminergic activity (amphetamine that
increases release and amantadine that inhibits
turnover) worsen the condition
Drugs that block dopamine D2 receptors
decrease symptoms and can be used as
antipsychotics.
2. Serotonin theory
• It was found that brain of psychotic patients characterized by up-
regulation of 5HTA2 receptors and increase in serotonin activity in
mesocorticalsystem
3. Glutamate theory
• It is thought that glutamate deficiency causes similar
effects to that of dopamine hyperactivity.

• Abnormally low levels of glutamate receptors found in

pos-tmortem brains

• Discovery that the glutamate blocking drugs such as

phencyclidine and ketamine can mimic the symptoms
and cognitive problems associated with the condition.
3. Symptoms
 Treatment of
Psychosis/Schizophrenia
Adverse effects Cont.
Adverse effects Cont.
 Pharmacology of
Drugs in Patients with
Bronchial Asthma
By
Prof. Mahran S. Abdel-Rahman
Prof. of Pharmacology,
Dept. of Pharmacology,
Faculty of Pharmacy
Sphinx University
 What is Bronchial Asthma?
• Def: Asthma, is a chronic inflammatory disorder
of the airways “mostly in genetically
susceptible individuals” characterized by
Airway hyperresponsiveness & Reversible
airway obstruction.
• Symptoms:
• Cough
• Wheezing
• Airway obstruction
• Chest tightness & Dyspnea
 Inflammation & Asthma
• Inflammation in asthmatic patients can be
present during symptoms-free periods.

• If the inflammation is not controlled,

symptoms are likely to reoccur.

• Inflammation can be detected by eosinophilia

and treated by inhaler steroids.
 Aims of Asthma Treatment
• Although asthma can’t be cured- but can be controllable.
• Control is so effective & resembles to a cure.
• Complete control of asthma can be achieved as:
1. No daytime symptoms.
2. No night-time awakening due to asthma.
3. No need for rescue medication.
4. No asthma attacks.
5. No limitations on activity including exercise.
6. Normal lung function.
7. Minimal side effects from medication.
 Which is preferred inhaler or oral Albuterol Syrup?

• Albuterol syrup used in the past decades but

now the better targeted, inhaler delivery
systems are commonly used.
Why?
• American Academy of Allergy, Asthma &
Immunology (AAAAI) Guidelines (2004, p88)
prefer inhaled beta2-agonists to oral because
higher concentrations are delivered more
effectively to the airways, with faster onset of
action and minimum systemic side effects.
Regular or Increasing
Use of SABA
 Good asthma control = Little SABA Need

• Good asthma control is associated with little

or no need for short-acting β2 agonist.

• Anyone prescribed more than one short

acting bronchodilator inhaler device a month
should be identified and have their asthma
assessed urgently and measures taken to
improve asthma control if this is poor.
 FACTS
• Inhaled corticosteroids are recommended as
the most effective preventer drug for adults
and children with asthma, for achieving
overall treatment goals.

• There is an increasing evidences

demonstrating that, at recommended doses,
ICS are also safe and effective in children
under five with asthma.
 Frequency of Dosing of Inhaled steroids
• Most current ICS are slightly more
effective when taken twice rather than
once daily. However, may be used once
daily in some patients with mild asthma.

• Little evidence of benefits for dosage

frequency more than twice daily.

• So, it is recommended for most inhaled

steroids to be given initially twice daily
(EXCEPT Ciclesonide which is given once
daily).
 Risk of High Doses of ICS.
• Medium - high doses ICS (at or above 400
micrograms BDP a day or equivalent) may be
associated with systemic side effects (e.g
growth failure and adrenal suppression) .
 Local Side Effects of ICS
1. Oropharyngeal candidiasis
2. Hoarseness
3. Coughing
4. May slow bone growth in Children but similar
adult height.

• To reduce the potential for adverse affects:

a) Use the lowest possible dose necessary to maintain
control.
b) Administer with spacers/holding chambers.
c) Advise patients to (Rinse with water , gargle and spit
out) after inhalation.
Proper Use of ICS
Which Particles Can Pass Into Airway??

Only 1-5  size can pass into airway

 How Children Use Inhaler Drugs??
• MDI and spacer are the preferred method of
delivery of β2 agonists or inhaled
corticosteroids.

• A face mask is required until the child can

breathe reproducibly using the spacer
mouthpiece.

• Where this is ineffective a nebuliser may be

required
Inhaler with spacer
Spacer Concentrate the Optimum Particles in the Lungs
 Stepping Down Therapy
• Stepping down therapy once asthma is
controlled is recommended, but often not
implemented leaving some patients over-
treated.
• Patients should be maintained at the lowest
possible dose of inhaled corticosteroid.
• Gradual Dose Reduction of inhaled
corticosteroid is recommended as rapid
reduction may deteriorate Asthma.
• Reductions should be considered every three
months, decreasing the dose by approximately
25–50% each time.
 FDA Warning Messages of Inhaler LABA
• FDA reported a possible increased risk of
asthma- related death in patients using LABA
alone in a small group of individuals.
• So, LABA should not be used as monotherapy
in asthma & must only be used in combination
with an appropriate dose of ICS.
• LABA should only be started in patients who
are already on inhaled corticosteroids, and the
inhaled corticosteroid should be continued.
 LABA-ICS Fixed-Dose Combinations
• In clinical practice, it is generally acceptable
that fixed-dose combination of inhalers (ICS
and LABA) aid adherence and also have the
advantage of guaranteeing that the LABA is
not taken without the ICS.
Seretide = Fluticasone + Salmeterol
Fostair= Beclomethasone + Formoterol
Flutiform = Fluticasone + Formoterol
 Benefits of LABA/ICS Combination
• The addition of LABA (e.g., salmeterol or
formoterol) to the treatment of patients who
require more than low dose ICS alone to:
a) Control asthma,
b) Improves lung function,
c) Decrease symptoms,
d) Decrease exacerbations

– But use SABA only for quick relief in most patients.

Leukotriene Modifiers
 Efficacy vs Toxicity of Methylxanthines
• Efficacy:
– Effective bronchodilator through accumulation of cAMP
by inhibiting phosphodiesterase enzymes.
• Hazards:
– Has narrow margin of safety (5-12 g/ml)
– Above maximal concentration, SE are dose dependent:
• Tremors, vomiting and palpitations (15 g/ml).
• Agitations, tachypnea and hypotension (20 g/ml).
• Increased muscle tone and flashes of light seen (25 g/ml).
• Delirium and worsening CVS disorders (30 g/ml).
• Convulsion, shock and arrhythmias (35 g/ml)
• Death may be observed at higher concentrations (  35 g/ml)
Oral Theophyline
 ANTI-IgE MONOCLONAL ANTIBODY
• Omalizumab is a humanized monoclonal
antibody which binds to circulating IgE,
reducing levels of free serum IgE.
• In adults and children over 6 years of age
• It is licensed in the UK with the following
indication:
– Patients on high-dose ICS and long-acting β2
agonists who have impaired lung function,
– Patients who are symptomatic with frequent
asthma attacks, and have allergy as an important
cause of their asthma.
 Dosages and Administration
• Omalizumab is given as a subcutaneous injection
every two or four weeks depending on IgE level
and weight.

• The total IgE must be <1,300 international units

(IU)/ml for children over 6 years of age.

• In adults and children >12 years, the licensed

indication is a IgE up to 1,500 IU/ml but there is
no published data to support its efficacy and
safety above 700 IU/ml.
 Hazards of Omalizumab
• Local skin reactions may occur.
• Anaphylaxis, presenting as bronchospasm,
hypotension, syncope, urticaria, and/or
angioedema of the throat or tongue has been
reported to occur after administration of
omalizumab.
– Anaphylaxis has occurred as early as the first dose,
but has also occurred after one year.
• Due to risk of anaphylaxis, omalizumab should
only be administered to patients in a healthcare
setting under direct medical supervision.
When Omalizumab is Given to Asthma patients?

• Omalizumab given by subcutaneous injection

may be considered in patients with a high
steroid burden to reduce the steroid burden
for the patient.

• Omalizumab treatment should only be

initiated in specialist centers with experience
of evaluation and management of patients
with severe and difficult asthma.
MEDICATIONS TRIGGERING ASTHMA
 1- Aspirin Triggers asthma
• Approximately 10% - 20% of adults with asthma
have sensitivity to aspirin or a group NSAIDs
(NSAIDs intolerance)-- such as ibuprofen,
diclofenac, naproxen, Indomethacin, piroxicam, ----
etc. frequently used as analgesics, antipyretics and
anti-inflammatory.
• Asthma attacks caused by NSAIDs can be severe
and even fatal, so these drugs must be completely
avoided in people who have known aspirin -
sensitive asthma.
• Only paracetamol of this group, which acts
centrally, is a safer alternative for people known to
have aspirin-sensitive asthma. However, some
studies have linked asthma to the use of
paracetamol in some people.
 Smater’s Triad
• Some people with asthma can’t take aspirin or NSAIDs
because of what’s known as Samter’s triad -- a
combination of asthma, aspirin sensitivity, and nasal
polyps.

• Aspirin sensitivity occurs in about 30% to 40% of those

who have asthma and nasal polyps.

• Patients with Samter's triad have: nasal symptoms, such

as running nose, postnasal discharge, and congestion,
along with asthma symptoms, such as wheezing, cough,
and shortness of breath.
• If patient with Smater’s triad, He/She should talk to his
doctor about alternative options other than aspirin and
NSAIDs whenever required.
 NSAIDs Triggers Asthma in Asthmatic Children
• The rate of asthma exacerbation was higher in the asthmatic children
using NSAIDs + Antiasthma , resulting in asthma-related
hospitalizations more compared to those using antiasthma alone.

• Short-term aspirin, ibuprofen, and diclofenac use probably correlated

with asthma exacerbation in children with asthma.

• Conclusion: NSAIDs and antiasthmatic agents are generally co-

prescribed, and a certain proportion of children with asthma are
allergic to aspirin/NSAIDs and those children must avoid NSAIDs in
general EXCEPT Paracetamol.

Ref: Pei-Chia Lo et al., (2016): Risk of asthma exacerbation associated

with nonsteroidal anti-inflammatory drugs in childhood asthma. This
study was done retrospectively using the data of one million children in
Taiwan between 1997-2012.
 2- Beta-blockers Trigger Asthma.
• Beta-blockers are commonly prescribed drugs used
systemically in various CVS disorders as HTN, CHF,
Stable angina, Arrhythmias, migraine headache,
and topically as eye drops in glaucoma.
• Not all BBs are hazardous, but mainly non-
selective BBs (first generation). However, second
and third generation BBs should be used cautiously
and tested in asthma patients. Only minimal doses
could be used because they loose selectivity at
high doses.
• Taking disease history and drug history by a
physician including ophthalmologists, or
pharmacists is very important to avoid asthma
attacks.
 3- ACE inhibitors & Asthma
• Examples: Captopril, Enalapril, lisinopril, Quinapril,
perindopril, etc.
• These types of medications used in HF, HTN and
diabetic nephropathy mainly.
• These medicines appear to be safe for people who have
asthma. BUT:
• These drugs can cause persistent dry coughs in about
10% of the patients who use them as a side effects.
• This cough may be confused with asthma or, trigger
asthma in case of unstable airways.
• If a persistent dry cough developed, patient should
inform the doctor at once.
• In this case, ACE inhibitor may be replaced by ARBs
(losartan, Valsartn, candesartan, Telmisartan, etc).
 4- Can antihistaminic worse asthma?
• Antihistamines are usually safe for people who
have asthma to use, but they can cause side
effects.
• Dryness of secretion may be hazardous and
cause sticky sputum in asthma (i.e., worse
asthma).
5- What about contrast dye for X-rays?
• Sometimes, before X-ray, a patient should
drink or get an injection of contrast dye to
make the X-ray picture show up.
• Some contrast dyes may trigger an asthma
attack.
• It’s very important that asthma patient should
tell the doctor or the X-ray technician that
He/she has asthma.
• Sometimes, X-ray specialist give the patient
steroids before the contrast dye, to avoid the
asthma triggering.
 6- Anesthetics may triggers asthma
• PATIENTS with asthma who require general anesthesia
and tracheal intubation are at increased risk for the
development of bronchospasm during anesthesia.
• Avoidance of endotracheal tubes and the use of
inhalational anesthetics are a solution. BUT
• It is not always possible to avoid the use of endotracheal
tubes or to anesthetize the patient with inhalational
anesthetics before intubating the trachea. Thus,
induction of anesthesia with intravenous agents,
followed by rapid tracheal intubation, is sometimes
necessary in patients with asthma.
• Some anesthetics may irritate the tracheobronchial tree
especially in intubated patients. Therefore,
bronchodilator anesthetics should be used in asthma
patients as sevoflurane
 8- Opioids Worsen Asthma
• San Francisco: A new abstract presented at the 2019 Annual
Meeting of the American Academy of Allergy, Asthma &
Immunology (AAAAI) has found the prevalence of asthma in
opioid dependent patients is greater than the national
prevalence of asthma.
• AAAAI in 2019 reported that opioid dependent patients seeking
emergency care for asthma. Opioids such as morphine and
heroin worsen asthma.
• Explanation: Opioid drugs such as morphine can directly activate
the release of histamine from cells, specifically mast cells, in the
body.
• CONCLUSION: ASTHMA APPEARS MORE COMMON IN OPIOID
DEPENDENT PATIENTS
 9- Common Allergens Trigger Asthma
a) House dust mites,
b) Animal dander,
c) Molds,
d) Pollen and cockroach droppings.

• Identifying the type of allergens which trigger

asthma is important allergic asthma

• Patients is recommend to avoid exposure to

these allergen triggers.
PHARMACOLOGY OF PEPTIC ULCER
by
Prof. Mahran S. Abdel-Rahman

2024-2025

DE PARTME NT O F PHARMACO LOGY AND TOX I COLOGY

SPHI NX UNI VE RSITY
Peptic ulcer are open sores that develop in the gastric or duodenal
mucosa.
• Peptic ulcers: formed
when cells on the surface
of the lining epithelium
become inflamed and die
(sores ‫)قروح‬
• PU: develops in the lining
of the stomach, lower
esophagus, or small
intestine.
• Inflammation caused by
the bacteria H. pylori, &
from erosion from
stomach acids.
Etiology:
There are 4 main causes of peptic ulcer disease:
a- NSAIDs.
b- Chronic H pylori infection.
c- Acid hypersecretory states as Zollinger-Ellison syndrome.
d. Emotional or mental stress

Peptic ulcer is caused by an imbalance between gastric

mucosal defense factors (e.g. bicarbonate, mucin,
prostaglandin and nitric oxide) and injurious factors (e.g.
acid and pepsin).
Helicobacter pylori (H. pylori) are Gram negative bacteria that infect
stomach or duodenum and damage the mucosa that protects the lining
of the mucosa allowing stomach acid to burn.
NSAID-induced ulcers Inhibition of COX-1 in the
gastrointestinal tract leads to a reduction of prostaglandin
secretion and its cytoprotective effects in gastric mucosa.
Zollinger–Ellison syndrome (ZES) is a rare disease in which tumors
cause the stomach to produce too much acid, resulting in peptic
ulcers.
I-GASTRIC ANTISECRETORY DRUGS

1- Proton pumps inhibitors.

2- H2-receptor antagonists.

3- Antimuscarinic drugs.
 1- Proton pump inhibitors, PPIs (Inhibitors of H+, K+-ATPase)
Examples: Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole

Mechanism of Action
• PPI are prodrug, require activation by acid forming sulphenamides.
• PPI covalently irreversibly bind to sulfhydryl group of H+,K+-ATPase enzyme and inhibit the
gastric proton pump on the luminal surface of the parietal cell membrane, inhibiting gastric
acid secretion into lumen (almost 100 %) .
• Due to the property of covalent bonds, the inhibitory activity lasts longer
(long duration).

• Most potent suppressor of gastric acid secretion, a single daily dose can
inhibit about 95-100% of the HCL.
Therapeutic Uses of PPIs
1- Healing of gastric and duodenal ulcers (1st line drugs).

2- Treat gastroesophageal reflux disease that is either complicated or

unresponsive to therapy with H2-antagonists.

3- Healing of NSAIDs-induced peptic ulcer.

4- Zollinger-Ellison syndrome (drugs of choice).

Adverse Effects of PPIs
1- GIT: Nausea, constipation, flatulence.
2- Skin rashes and arthralgia.
3- Hypergastrinemia: rebound gastric acid hypersecretion
upon discontinuation or promote growth of GIT tumors
4- Drug Interactions: Omeprazole inhibits the hepatic
microsomal metabolism of diazepam by about 50% and has
minor effect on the elimination of phenytoin.
5- Bacterial overgrowth: with local GIT infection.

Warning Notes: PPI particularly omeprazole and esmoprazole

produced by Astrazenca have nephrotoxic potentials and the
Company paid more than 280 million dollars to the victims.
 2- H2-Histamine receptors antagonists
Examples: Cimetidine, Ranitidine, Famotidine and
Nizatidine.

Mechanism of action: competitively block the action of histamine on H2 receptors

located on the basolateral membrane of gastric parietal cells, leading to decrease of
intracellular cAMP concentration (c-AMP is necessary for activation of protein kinases
required for activation of proton pump system and acid secretion) and so .

• suppress up to 70% of 24 hours gastric acid secretion, but still less potent than PPI
Uses:
1- Treatment of duodenal and gastric ulcers: control symptoms during acute
episodes and promote healing.

2- Treatment of gastroesophageal reflux disease.

3- Prophylaxis of stress-induced ulcers: during the major illness or trauma.

4- Preanesthetic medication.
Adverse Effects:
Most of this group are well tolerated, and serious adverse effects are rare, serious adverse
effects are related to enzyme inhibiting activity of cimetidine.

Cimetidine: Mostly due to enzyme inhibiting activity

a) Antiandrogenic effects in men.

b) Increases serum prolactin: due to prolonged use at high doses of
cimetidine  (galactorrhea in females and loss of libido, impotence
and gynecomastia in males).

c) Cytochrome P-450 inhibition  inhibits the hepatic microsomal

biotransformation of certain drugs as warfarin, theophylline,
diazepam and phenytoin.
d- Headache, dizziness, myalgia, nausea, skin rashes and itching.
 3- Anticholinergic: Selective M1 blockers
Examples: Pirenzepine & Telenzepine
MOA:
 Inhibit acetylcholine action on muscarinic receptor- Decreases HCl secretion
(Selective M1 receptor blocker)- No healing effect.
SE:
 Have anticholinergic side effects (dry mouth-constipation,
urinary retention, Tachycardia and arrhythmias) .
II- MUCOSAL PROTECTIVE AGENTS:
1- Misoprostol (Cytotec)

MOA:
• Misoprostol is a synthetic; PGE1 analogue that stimulates prostaglandin
E1 receptors on parietal cells in the stomach  inhibit gastric acid secretion.
•  mucus and bicarbonate secretion are also increased leading to thickening of
the mucosal bilayer so the mucosa can generate new cells (Predominant effect).
Uses:
1. Misoprostol is as effective as H2-antagonists in promoting the healing of
duodenal ulcers.
2. Preventing gastric and duodenal ulcers in patients using large doses of
ulcerogenic NSAIDs-
Dose: 200 ug /four times daily with food.
Adverse Effects OF :
1. Diarrhea, nausea and abdominal cramps.
2. It is abortifacient and should not be used during pregnancy.

Contraindications: PGs are contraindicated during pregnancy because

it can increase uterine contractility and may cause abortion.
2- COLLOIDAL BISMUTH compounds
Mechanism of action:
• Bismuth subcitrate is a mucosal protective agent, inhibits the activity of pepsin
and increase secretion of mucus and interact with proteins in the necrotic ulcer
forming a barrier to the diffusion of acid.
• Antibacterial action against H. Pylori.

Adverse Effects
• Encephalopathy and osteodystrophy: with Long-term use of high concentration.
• Darkening of the oral cavity.
3- SUCRALFATE
Chemistry: Consists of the octasulfate of sucrose with aluminum hydroxide.
MOA:
• In an acid environment (pH < 4), sucralfate polymerizes to form a viscous, sticky
gel that adheres strongly to epithelial cells and to the base of ulcer: preventing
mucosal injury, reducing inflammation, and healing existing ulcers (acting as
a barrier to acid & pepsin).
• In addition, sucralfate stimulates the local production of prostaglandins by the
gastric mucosa which produces an additional cytoprotective effect.
Adverse effects: Constipation, dryness of mouth & abdominal discomfort
Precautions:
• Sucralfate should be taken on an empty stomach, one hour before meals.
• Should not be administered simultaneously with antacids, H2-receptor
antagonists or proton pump inhibitors why? Because the drug is active only in
acidic mdium.
III- ACID NEUTRALIZING DRUGS (ANTACIDS)
(Systemic: sod. Bicarbonate, Sod. Citrate) • (Non- systemic: Al(OH)3, Mg(OH)2
MOA: Antacids are weak bases that react & neutralize gastric acid forming
water and a salt, thereby diminishing gastric acidity. A single dose of antacid
(taken 1 hour after meal) can neutralize the acid for 2 hours.
1- Sodium bicarbonate (NaHCO3)
This preparation is highly soluble and rapidly absorbed from the gut
and so has rapid onset but short acting. Used in acidosis.
Side-Effects:
1- Metabolic alkalosis.
2- Worsening of heart failure or hypertension.
3- Evolution of CO2 may lead to eructation, gastric distension.
4- Milk-alkali syndrome.
Note: See Aluminum hydroxide, Calcium carbonate (CaCO3),
Magnesium hydroxide (milk of magnesia) and Magnesium trisilicate in
lab session
V-ANTIBACTERIAL AGENTS
EX: Clarithromycin, Amoxicillin, Metronidazole and bismuth.
• In patients positive for H. Pylori, eradication of this microorganism
with antibacterial agents promotes healing and reduces the
possibility of recurrence.

MOA: The antimicrobial agents acts on bacterial cell wall synthesis (amoxicillin)
and bacterial protein synthesis (Clarithromycin).

Adverse effects: Epigastric pain & Hypersensitivity reactions,

Resistance:
• Single agent therapy of H. Pylori infection has proven relatively ineffective and
has led to the emergence of resistant strains. The use of multiple drugs is, thus,
advocated
• • Resistance to metronidazole occurs rapidly but not with amoxicillin.
Course of antibiotic therapy:
a) Initial antibiotic therapy is designed for 14 days; includes one of the PPIs
e.g. omeprazole plus clarithromycin and amoxicillin (called "Triple antibiotic
therapy).
- In case of patient allergic to penicillin, metronidazole replaces amoxicillin.

b) In patients whose infection persists after an initial course of antibiotic

therapy including clarithromycin, "quadruple therapy" is indicated which
consists of a PPI plus bismuth, tetracycline and metronidazole.
 Clinical Cases
Mr. Hassan Ali is a 56 years-old man who complained from frequent
epigastric pain especially after any emotional stress. The pain used
to appear frequently before meals. Mr. H. A. was diagnosed using
Endoscopy to have duodenal ulcer.

1) Which One of the following measures should be undertaken for

the management of this case:

A- Taking diet with salt restriction.

B- Long-term hospitalization.

C- Avoiding nervousness and irritability*.

D- Avoiding taking small frequent meals.

2) This patient was advised to completely avoid taking all the
following EXCEPT:

A- Pickles.
B- Strong tea.
C- Meat*.
D- Spicy and fatty diet.

3) This patient was advised to avoid administration of all of the

following drugs Except:

A- Hydrocortisone.
B- Aminophylline.
C- Diazepam*.
D- Aspirin
4) One of the following drugs was prescribed to Mr. H.A.:

A- Mepyramine.
B- Codeine.
C- Ranitidine*.
D- Neostigmine.

5) Your answer to the last question was based on that this drug acts through One of
the following mechanisms:

A- Neutralization of HCl secretion.

B- Blocking of muscarinic receptors.

C- Blocking of H2 receptors in parietal cells*.

D- Mucosal protection.
6) After sometimes of treatment with H 2 antagonists; the condition of Mr. H.A. was not very much
improved. A decision was made to treat his case with the following drug:

A- Omeprazole*.
B- Famotidine.
C- Pirenzepine.
D- Reserpine.

7) The drug you selected in the last question has all the following pharmacological
properties EXCEPT:
A- It is a prodrug which is administered orally.
B- Single daily dose of this drug can inhibit 95%- 100% of the gastric HCl.
C- It inhibit hepatic microsomal enzymes rendering drug-drug interactions
D- It is cleared unchanged by the kidneys*.
8) Which is not correct regarding treatment of peptic ulcer disease:

A- Proton pump inhibitors show more rapid healing and pain relief over 2-4 weeks
compared to H2 antagonists.

B- Colloidal bismuth will suppress H.pylori and chelate with the base of the ulcer to aid
healing.

C- H.pylori eradication with omeprazole, Amoxicillin and metronidazole requires only one
week of treatment*.

D- Misoprostal is indicated for prevention of NSAID induced ulcers, when treatment

necessary with NSAID’s