Common medical emergencies - PowerPoint Presentation

Slide1

Common medical emergenciesand drug toxicity

By

Dr. Mohamed Abdel

Moneim

Attia

Slide2

PARASYMPATHOMIMETICS (

Cholinomimetics

)

This group of drugs produces pharmacological effects similar to that produced by parasympathetic stimulation

 

Classification

1- DIRECTLY ACTING PARASYMPATHOMIMETICS

They directly stimulate the cholinergic receptors.

Choline esters:

Acetylcholine.

Carbachol

.

Bethanechol

Methacholine

B

.

Alkaloids:

Pilocarpine

.

Muscarine

.

Slide3

2- INDIRECTLY ACTING PARASYMPATHOMIMETICS (CHOLINE ESTERASE INHIBITORS)

They inhibit

cholineesterase

enzymes leading to accumulation of A.ch at the receptor sites which in turn produces the cholinergic effects on (CNS, NMJ, Ganglia, wall of blood vessels... etc

.).

A. Reversible

cholineesterase

inhibitors

.

Physostigmine

Neostigmine and its substitutes.

Tacrine

Donepezil

 

B. Irreversible

cholineesterase

inhibitors.

Organophosphorous

compounds.

Slide4

ACETYLCHOLINE (A.Ch) Pharmacokinetics A.ch is inactive orally because it is poorly absorbed being a quaternary ammonium compound. I.V. it has very short duration of action because it is rapidly metabolized by choline esterase enzymes.

True cholinesterase enzyme

Pseudocholinesterase

enzyme

Site

Cholinergic nerve - CNS – RBCs

Plasma – liver – intestine

Synthesis

3 months

2-3 weeks

Specificity

specific

Not specific

Slide5

►Pharmacodynamics

 



Mechanism of Action: act via:

Stimulation of the muscarinic receptors.

Stimulation of the nicotinic receptors.

Cholinoceptors

They are broadly subdivided into muscarinic and nicotinic receptors.

Slide6

A. Muscarinic receptors (peripheral, M receptors)

Types:

M1 receptors:

Are present in autonomic ganglia, CNS and parietal cells of the stomach

M2 receptors:

Are present

in

heart.

also present

presynaptically

on the cholinergic fibers to inhibit acetylcholine release (feedback)

M3 receptors:

are present in

smooth muscle fibers

and

secretory glands.

M4 and M5 receptors:

in the C.N.S.

B. Nicotinic receptors (central, N receptors)

►Types:

Nn

(Neuronal nicotinic receptors):

present in autonomic ganglia and suprarenal medulla.

Nm (Muscle nicotinic receptors):

present in the

neuromuscular junction.

Slide7



Pharmacological Effects

*C.V.S

Heart:

Decreases all cardiac properties, except the conduction in the atria, which is increased.

Blood vessels:

generalized vasodilatation.

Blood

pressure:

blood

pressure is

decreased.

*G.I.T

:

A.ch increases gastric and intestinal peristalsis and relax the sphincters. It also stimulates salivary and gastric secretions.

*Lung

:

bronchoconstriction and increased bronchial secretion.

 

*

Urinary

tract:

A.ch contracts the detrusor muscle and relaxes the sphincter of the urinary bladder.

 

*

Eye

:

A.ch produces

meiosis.

►Skeletal muscles:

stimulate motor end plate.

Slide8

►Therapeutic Uses

It has limited use because of its short duration and non-selectivity.

 

►

Untoward Effects

All effects produced by A.ch are untoward

effect.

 

►INDIRECTLY ACTING PARASYMPATHOMIMETICS

(

Cholinesterase Inhibitors)

 

►

Mechanism of action

By inhibiting cholinesterase, the indirect – acting agonists “amplify” the action of endogenous acetylcholine. Therefore, the indirect agents have muscarinic or nicotinic.

Slide9

A- REVERSIBLE CHOLINESTERASE INHIBITORS

 

1- PHYSOSTIGMINE

 

►

Chemistry

It is a tertiary amine

 

►

Pharmacokinetics

Being a tertiary amine, it can diffuse readily through the mucous membranes.

It can cross blood brain barrier.

 

►Pharmacodynamics

 



Mechanism of Action

Physostigmine

binds to both

esteratic

and anionic sites of cholinesterase enzymes.

The attraction between this drug and the enzyme is 10,000 times that of Ach, but this binding is loose and the drug would dissociate gradually leaving the enzyme free.

Binding of

physostigmine

to cholinesterase leads to accumulation of Ach in the effector organs (CNS, NMJ, Ganglia, blood vessels and opposite the parasympathetic nerve endings).

Slide10

Pharmacological Effects

Muscarinic effects. (See above)

, Nicotinic

effects. (See above)

CNS effects: headache, restlessness, insomnia, nightmares, tremors and convulsions.

 

►Therapeutic Uses

1-Treatment

of glaucoma (locally in the eye)

2-To

counteract the

mydriatic

effect and

cycloplegia

produced by atropine.

4-Treatment

of atropine poisoning and tricyclic antidepressant toxicity.

5-Alzheimer disease.

Donepezil

,

Tacrine

and

Rivastigmine

Are new, centrally acting, reversible cholinesterase inhibitors that readily cross the blood–brain barrier and act to increase the concentration of acetylcholine at central cholinergic synapses. These drugs are used in the treatment of Alzheimer’s disease

.

►

Untoward Effects

All the muscarinic effects. (See above)

All the nicotinic effects. (See above)

All the CNS effects. (See above)

Slide11

2- NEOSTIGMINE (

Prostigmine

)

 

►

Chemistry:

It is a synthetic quaternary ammonium compound.

►Pharmacokinetics

Being a quaternary ammonium compound, it is irregularly absorbed from GIT and it cannot cross the B.B.B.

►Pharmacodynamics

 



Mechanism of Action

*Reversible

inhibition of cholinesterase

enzymes (

Muscarinic

effects and Nicotinic effects ).

*Direct

stimulant action on neuromuscular junctions.

 

*It

has no CNS effects.

Slide12

►Therapeutic Uses

1-Treatment

and diagnosis of myasthenia gravis:

*S.C

for diagnosis

*Oral

for treatment.

2-Antidote

to D-

tubocurarine

.

3-Treatment

of postoperative retention of urine.

4-Treatment

of paralytic ileus.

 

►Untoward Effects

All the muscarinic and nicotinic effects except that intended for therapeutic purposes.

Slide13

3- NEOSTIGMINE SUBSTITUTES

Neostigmine substitutes have been introduced with the advantage of being more selective on the neuromuscular junction or having a longer duration of action to be more convenient for the treatment of myasthenia gravis and other clinical purpose.

a-

Pyridostigmine

 

b-

Ambenonium

:

Similar to

pyridostigmine

.

Slide14

c-

Edrophonium

More selective on NMJ than neostigmine.

Very short acting (5 min.)

 

►Uses

Diagnosis of myasthenia gravis.

Treatment of

myasthenic

crisis.

Differentiation between

myasthenic

crisis and cholinergic crisis (Weakness due to over treatment with anticholinesterase). It aggravates cholinergic crisis, but improves

myasthenic

crisis.

Antidote for D-

tubocurarine

.

Slide15

Myasthenia Gravis

►Definition

Myasthenia gravis is a disease characterized by impaired transmission at N.M.J.

Aetiology

:

Autoimmune disease due to formation of antibodies that attack the nicotinic receptors in N.M.J.

 

►Clinical picture

Marked weakness of skeletal muscles.

 

►

Diagnosis

Edrophonium

:

it improves the contraction of skeletal muscles in patient with myasthenia gravis.

neostgmine

but atropine is given before neostigmine because atropine produced initial bradycardia followed by tachycardia. This initial bradycardia potentiates bradycardia caused by neostigmine → cardiac arrest.

Slide16

►

Treatment

Choline

estrase

inhibitors:

Ambenonium

or

pyridostigmine

.

Neostigmine + atropine ( If

ambenonium

or

pyridostigmine

are unavailable).

Ephedrine: Facilitates transmission at N.M.J.

Immunosuppressives

, corticosteroids, ACTH or cyclosporine.

Thymectomy

.

Kcl

& Spironolactone

Slide17

Myasthenic

crisis

Cholinergic crisis

Cause

Deficient cholinergic transmission

Excessive cholinergic transmission e.g.

ch.

E inhibitor

overdosage

.

Nicotinic manifestations

Muscarinic

manifestations

Flaccid paralysis.

No

Spastic paralysis. Weakness in cholinergic crisis is due to permanent depolarization of nicotinic receptors at motor end plate.

↓ H.R. – ↓ B.P. –

Miosis

– Colic – sweating.

Edrophonium

test

Improves

Aggrevates

.

Treatment

*

Edrophonium

or neostigmine

+

atropine.

*Artificial respiration

1-PAM (

pralidoxime

)+ Atropine

2.

Artificial respiration

3.

Stop causative drug

Slide18

B- IRREVERSIBLE CHOLINESTERASE

INHIBITORS (

 

ORGANOPHOSPHOROUS COMPOUNDS)

 

Nerve gases:

Sarin

,

Soman

.

Insect

killers: Malathion, Parathion, TEPP (

tetraethylpyrophosphate

)

Drugs used clinically: DFP (

Diisopropyl

flurophosphate

)

►

Mechanism of Action

Organophosphorous

compounds bind covalently (irreversibly) to cholinesterase enzymes. In this situation the body has to replace the inactivated enzymes. This replacement takes two weeks for

pseudocholine

-esterase and three months for true cholinesterase. A.ch. will accumulate at the effector sites in large amounts producing

parasympathomimetic

effects.

Irreversible inhibition of the enzyme takes about 1-12

hrs

after exposure until the complex (enzyme and

organophosphorous

) loses some alkyl and

alkoxyl

groups, a process known as aging of the enzyme (i.e. the enzyme is no more suitable for functioning). During the first 12

hrs

after exposure the enzyme could be reactivated.

Slide19

►Pharmacological Effects

(All are toxic

effects)

 

►

Toxicity

 

The

signs and symptoms of

over dosage

are readily predicted from the general pharmacology of acetylcholine.



Muscarinic Toxicity

These include CNS stimulation

,

meiosis, spasm of accommodation, bronchoconstriction, increased gastrointestinal and genitourinary smooth muscle activity, increased secretory activity (sweat glands, airway, gastrointestinal tract), vasodilatation, and

bradycardia.



Nicotinic Toxicity

These include CNS stimulation, ganglionic stimulation, and neuromuscular endplate depolarization leading to fasciculation and paralysis.

Muscarinic effects. (See above)

Nicotinic effects. (See above)

CNS effects. (See above)

Slide20

►Untoward Effects and Toxicity

The indirect acting agents have toxicological importance because of potential accidental exposures to toxic amounts of pesticides. The most toxic of these drugs, (e.g., parathion) is rapidly fatal if exposure is not immediately recognized and treated.

Generally

the

clinical picture

could be summarized as follows:

Slide21

Respiratory:

Bronchospasm, respiratory distress, and paralysis of respiratory muscles.

Cardiovascular:

Bradycardia, hypotension and excessive cold sweating.

Gastrointestinal:

Excessive secretions, abdominal colic, diarrhea, vomiting,

C.N.S:

Severe meiosis, headache, irritability, skeletal muscle fasciculation.

Convulsions and coma are terminal manifestations.

The usual cause of death is

respiratory failure

(Bronchospasm, excessive secretions, inhibition of R.C. and contraction of the intercostal muscles and diaphragm)

Slide22

►Treatment of the Untoward Effects

 

Protection

Farmers who spray the insecticides should wear gloves and masks.

Thorough washing of vegetables.

Glasses containing domestic insecticides should be kept away from children.

Treatment

Stomach wash.

Wash the skin, if contaminated by sodium bicarbonate or ethyl alcohol.

Maintain the air passage open by sucking secretion and start artificial respiration if needed.

Atropine

in high doses:

2 mg I.V. or I.M. every 5 -10 minutes until the patient is put on the merge of atropine toxicity (dilated pupil, dry mouth, and tachycardia).

The patient should be kept

atropinized

for 24 hours.

Slide23

The intoxicated patient may need up to 100 mg for full

atropinization

.

Atropine eye drops may relieve the headache caused by

miosis

.

Atropine will antagonize the peripheral and central effects of

organophosphorous

compounds, but not the action of N.M.J. and the ganglia.

The patient should be maintained on atropine until the enzymes are recovered.

*

Convulsions

may be controlled by anticonvulsants (diazepam).

Slide24

Cholinesterase re-activators (

oximes

):

They should be given within 1/2 to 1

hr

after exposure maximum 12 hrs. i.e. before aging of the enzyme.

During this period they are life saving because they react directly with the

alkylphosphorylated

enzyme to free the active unit (de-phosphorylation) of the enzyme.

Moreover

oximes

compete with the enzyme for the organophosphate i.e. (phosphorylated very easily so, they divert the poison from cholinesterase to

oximes

.

 

Preparations

Pralidoxime

(PAM,

Protopam

): 2.5 gm in 100 ml I.V. infusion (within 30 min.), 1 gm I.M. every 1

hr

until recovery. 20 mg /kg for infants and children.

Diacetylmonoximes

(DAM)

Bisquaternary

oxime

.

Slide25

PARASYMPATHOLYTICS (Muscarinic antagonists)

 

Definition

These are drugs, which block the muscarinic receptors.

 

Classification

A- Natural Alkaloids

Examples:

Atropine

: extracted from

Atropa

belladonna plant or

Datura

stramonium

plant.

Scopolamine

(L –Hyoscine).

B- SYNTHETIC ESTERS

These are either tertiary amines (lipid soluble and cross the blood brain barrier or quaternary amines (lipid insoluble) and cannot cross the blood brain barrier).

They are classified according to their clinical uses into:

Slide26

-

Drugs mainly used to treat the manifestations of

parkinson’s

disease:

Benzatropine

,

Trihexyphenidyl

,

Biperiden

.

2-

Drugs mainly used to produce

mydriasis

and

cycloplegia

:

Atropine,

Homatropine

,

Eucatropine

,

Cyclopentolate

,

Tropicamide

.

3-

Drugs mainly used to produce bronchodilation

:

Ipratropium,

tiotropium

4-

Drugs mainly used as

antisecretory

and antispasmodic on the GIT

:

Hyoscine

butylbromid

e

,

Homatropine

methyl bromide

,

Propantheline

5-

Drugs mainly used for its effect on the genitourinary system

:

Oxybutynin,

Glycopyrrolate

,

Emepronium

.

Slide27

►Pharmacokinetics of Atropine

Because it is a tertiary amine, atropine is relatively lipid soluble and readily crosses membrane barriers. The drug is well distributed into the CNS and other organs

The duration of action of normal doses is 4-8 hours except in the eye, where effects last for 72 hours longer

 



Pharmacological Effects

The peripheral actions of muscarinic blockers are mostly predictable effects derived from

cholinoceptor

blockade . These include the ocular, GI, genitourinary, and secretory effects.

The CNS effects are less predictable. Those seen at therapeutic concentrations include sedation, reduction of motion sickness, and,

reduction of some of the signs of parkinsonism.

Cardiovascular effects at therapeutic doses include an initial slowing of heart rate caused by stimulation of the central vagal nucleus, followed by the tachycardia and decreased atrioventricular conduction time that would be predicted from peripheral vagal blockade.

Slide28

►Clinical Uses

The muscarinic blockers have several useful therapeutic applications in the central nervous system, eye, bronchi, gut, and the urinary bladder.

 

Cardiovascular

:

Bradycardias and heart

blook

Treatment of bradycardia caused by excessive beta-blockers

Treatment of reflex bradycardia caused by alpha stimulants e.g. noradrenaline

 

Neurological:

Motion Sickness:

scopolamine is a standard therapy for motion sickness; this drug is one of the most effective agents available for this condition.

A transdermal patch formulation is available.

Treatment of parkinsonism:

benztropine

,

biperiden

, and

trihexyphenidyle

are representative of several

antimuscarinic

agents used in parkinsonism.

Slide29

Eye (Local drops)

Fundus examination:

Antimuscarinic

drugs (Substitutes are better) are used to dilate the pupil and to paralyze accommodation.

To

counteract the effect of

miotics

.

Iritis

and

iridocyclitis

:

Alternatively with

miotics

to cut recent mild adhesions between the iris and anterior surface of the lens.

 

Bronchi:

Ipratropium is a quaternary

antimuscarinic

agent used by inhalation to reduce bronchoconstriction in asthma and chronic obstructive pulmonary disease (COPD). Although not as effective as beta

gonists

, ipratropium is less likely to cause cardiac arrhythmias. It has very few

antimuscarinic

effects outside the lungs because it is poorly absorbed and rapidly metabolized.

Slide30

Gastrointestinal:

To relieve spasm in the G.I.T (intestinal colic, spastic colon and biliary colic)

Muscarinic blockers can also be used to reduce cramping and

hypermotility

in transient diarrheas.

Bladder:

Cystitis:

Glycopyrrolate

, and similar agents may be used to reduce urgency in mild cystitis and to reduce bladder spasms following urologic surgery.

Nocturnal enuresis:

emepronium

could be used for treatment of nocturnal enuresis and urinary incontinence

To

releive

ureteric spasm in renal

colics

Slide31

In Pre-

Anaesthetic

Medication

Atropine is given half an hour before the administration of the general

anaesthetic

to produce the following:

Decrease salivary and bronchial secretion:

This prevents or minimizes the possibility of inhalation of the salivary secretions preventing the postoperative lung infection.

The inhibition of the mucus secretion in the bronchial tree prevents the possibility of blockage of a main bronchus, which could lead to lung collapse.

Atropine protects the heart from excessive vagal tone, which sometimes occur at the beginning of the first plane of the surgical stage of anesthesia (Stage III).

Counteracts the inhibitory effect of morphine and the

anaesthetic

on the respiratory center.

Slide32

►Side Effects

Mild side effects may develop after the use of therapeutic doses for example:

Dryness of the mouth.

Skin flushing:

Children are more susceptible to develop coetaneous V.D which makes the child flushed and this is usually accompanied by slight elevation of body temperature (Due to reduction of sweating) especially in hot environments.

Retention of urine especially in patients with enlarged prostate.

Acute attack of glaucoma in patients who have or susceptible to glaucoma.

 

►Toxicity

A traditional mnemonic for atropine toxicity is “

Dry as a bone, red as a beet, mad as a hatter

“. This description reflects both predictable

antimuscarinic

effects and some unpredictable actions.

Slide33

In young children

Blockade of thermoregulatory sweating may result in hyperthermia or “ atropine fever”. This is the most dangerous effect of the

antimuscarinic

drugs and is potentially lethal in infants.

 

In adults

Dryness of secretions:

The condition is described by “dry as a bone “ because sweating, salivation, and lacrimation are all significantly reduced or stopped in the elderly.

Acute angle – closure glaucoma may occur

Urinary retention is possible.

Constipation.

Blurred vision is common adverse effects in all age groups.

Full dilatation of the pupil and lost light reflex.

 

Slide34

Other Toxicity

Toxicity not predictable from peripheral autonomic actions include the

following: , Dry as bone, Blind as bat, red as beet, mad as hatter.

 

CNS effects:

CNS toxicity includes:

sedation, amnesia, and delirium or hallucinations (“mad as a hatter”)

convulsions and excitation may develop and later this excitation is followed by depression in the form of coma and the cause of death is respiratory failure.

 

Cardiovascular effects:

At toxic doses,

intraventricualr

conduction may be blocked; this action is probably not mediated by muscarinic blockade and is difficult to treat.

Dilation of the cutaneous vessels of the arms, head, neck and trunk also occurs at these doses; the resulting “atropine flush“ (“red as a beet”) may be diagnostic of overdose with these drugs.

 

Slide35

Treatment of

Toxicity (symptomatic)

Control of environmental temperature and application of cold baths and sponges.

Cathetrization

if necessary.

Protection of the respiratory system.

Avoidance of over treatment of convulsions by barbiturates.

Physostigmine

may be used to counteract the CNS effects

. Can we use

nesostigmine

?

The

lethal dose in adults is more than 0.5 gm of atropine and more than 0.2 -0.3 gm of scopolamine.

Slide36

NEUROMUSCULAR BLOCKING AGENTS

 

The prototype non-depolarizing agent is d-

tubocurarine

; the prototype-depolarizing drug is succinylcholine.

►Pharmacokinetics

Succinylcholine is composed of two acetylcholine molecules linked end to end.

Succinylcholine is metabolized by plasma cholinesterase (

butyrylcholinesterase

or

pseudocholinesterase

)

It has a duration of action of only a few minutes if given as a single dose. It is given by continuous infusion if prolonged paralysis is required.

 

►Toxicity

1-Respiratory paralysis:

succinyl

choline apnea.

Slide37

Is due to abnormal deficiency of pseudo-

cholinestrase

enzyme activity.

Treatment:

1-Artifecial respiration.

2-fesh plasma or blood

tranfusion

.

Dibucaine

number

: It is a test of the ability of

pseudocholinestrase

to metabolize succinylcholine.

Dibucaine

is an enzyme inhibitor, which inhibit 80% of normal enzyme and 25% of abnormal enzyme.

Slide38

Malignant Hyperthermia (Hereditary Condition)

Multiple Triggering Mechanisms

Anesthesia

Drugs (general anesthesia, succinylcholine)

Illness & Stress

Triggering Mechanism

Affects

reuptake of calcium by sarcoplasmic reticulum necessary for termination of muscle

contraction. It results in:

*Massive

Muscle Contraction

*Excessive

Lactate

Production (

acidosis, tachycardia,

hypercarbia

,

hypoxemia).

*Pronounced

Increase In

body Temperature due to

unccoupling

oxidative

phosphorylation

.

Teatment

:

1-I.V

dantrolene

.

Interferes

with excitation-contraction coupling

Reduces release of Ca

++

from the sarcoplasmic reticulum

Blocks contraction

2-cooling.

3-corecxt acidosis.

Slide39

ANALGESICS Opiate and Non-opiate analgesics.

Non-opiates (aspirin)

Opiates (morphine)

Low intensity pain (headache, toothache, muscle pain,..etc)

Any type of pain except itching

Type of pain relieved

Subcortex

(thalamus)

Cortex and

subcortex

Site of action

No euphoria, narcosis or modified emotional reaction

Euphoria, narcosis and abnormal emotional reaction for pain

Relief of pain is accompanied by:

Never occurs

Almost occur

Addiction

Slide40

MORPHINE



Pharmacokinetics

90% a given dose is excreted in the urine; the remaining 10% is excreted in the feces.



Pharmacologic effects



CNS effects

:

Dose-related analgesia.

patients taking morphine become euphoric (feel freedom for anxiety).

If morphine is given to a person who is pain-free, dysphoria, anxiety or mental clouding may be produced.

Morphine can treat all types of pain except itching.

 

Morphine stimulates the chemoreceptor trigger zone, producing nausea and vomiting.

Morphine produces

miosis

by stimulating the

Edinger-Westphal

nucleus and pinpoint pupils are indicative of toxic dosage prior to asphyxia.

Morphine is a powerful respiratory depressant, which acts by reducing the responsiveness of the respiratory centers in the brain stem to blood levels of carbon dioxide. Due to the depressed respiration and increased arterial carbon dioxide retention, cerebral vasodilatation can occur, causing an increase in intracranial pressure

Morphine is a potent cough suppressant.

Slide41

Autonomic effects

:

Cardiovascular effects:

Histamine release

:

Spasmogenic

effects

:

 

Uses: 3As

Slide42



Adverse effects



CNS

:

Dysphoria

, restlessness, hyperactivity and mental cloudiness can occur

Long-term chronic administration can result in physical dependence.

Increased intracranial tension.

Tolerance and dependence:

Physical dependence occurs within 24 hours if given /4 hours.

Slide43

Respiratory:

Depression is the most important effect and is dose dependent.

Bronchoconstrictive

action

 



Gastrointestinal:

Nausea and constipation.

Increased

biliary

tract pressure can occur

 



Genitourinary:

Urine retention.

Prolongation of labor.

 



Allergic reactions

:

can occur and skin rashes are a common manifestation (due to histamine release).



Eye:

Pinpoint pupils are a consistent finding in addiction.

CVS:

Postural hypotension

 

Slide44

 

A. Acute

opioid

(or morphine) toxicity:



Symptoms and signs

:

The patient is

comatosed

with depressed respiration, pin point pupils, hypotension

,

pulmonary

oedema

and shock may occur.

When death occurs

,

it is always due to respiratory failure.

 



Treatment

:

If large amounts are taken orally

,

gastric

lavage

is done with potassium

permnganate

solution.

Establish a patent airway and ventilate the patient by positive pressure ventilation if pulmonary

oedema

is present.

Opioid

antagonists as:



Naloxone

:

Naloxone

is a pure antagonist to opiates.

Can produce dramatic reversal of the respiratory depression.

It is given in a dose of 0.4 - 0.8 mg and repeated every 2 - 3 minutes for 2 - 3 doses.

Care should be taken as the antagonist may precipitate a severe withdrawal syndrome.



Nalorphine

:

Agonist-antagonist like

nalorphine

can be used only when the diagnosis of morphine poisoning is certain (its agonist effect aggravates respiratory depression).

 

Slide45

Chronic

opioid

(or morphine) toxicity (addiction)

It results from addiction. The patient is emaciated

,

constipated with frequent flushes and itching. The intellectual functions are also depressed.

Withdrawal:

It results in what is called the abstinence syndrome where the patient becomes irritable, nervous, having tremors, hypertension, sweating, vomiting and with abdominal cramps.

These manifestations usually start 6-10 hours from last dose and peak effect are seen at 36-48 hours, after which manifestations gradually subside over 5-10 days.

In severe cases cardiovascular collapse and death may occur.

Slide46

Treatment of morphine addiction:

Hospitalization.

Gradual withdrawal is essential otherwise acute abstinence syndrome may occur. This is with replacement by the synthetic morphine substitute methadone.

Once the patient is stabilized on methadone

,

its dose should be gradually decreased to an end.

Clonidine

Sedative can be used

Naltrexone

(pure antagonist).

Slide47



Classification of non opiate analgesics:

(Acetaminophen).

(

Glafenine

).

Nefopam

.

Dipyron

(

Novalgin

).

Non-steroidal anti-inflammatory drugs (NSAIDs).

Slide48

N.B

Prostaglandins are derived from

arachidonic

acid by the action of

cyclooxygenase

(COX) enzyme which has 3

isoforms

:

 

COX-1(physiological; constitutive):

Is normally present in the tissues

i.e. constitutive

and it is involved in synthesis of

protective

PGs (e.g. PGE

2

, PGI

2

) responsible for protection of stomach from

HCl

, regulation of RBF, regulation of platelet aggregation, etc.

 

COX-2 (pathological; inducible):

is involved in synthesis of

undesirable

PGs included in the inflammatory reactions,

bronchoconstriction

, etc., therefore COX-2 activity is markedly increased during these pathological conditions

i.e. inducible

 

COX-3 (central):

Found only in the

brain

and may be included in synthesis of PGs responsible for fever and pain sensation.

Acetaminophen

and

dipyrone

, analgesic/antipyretic actions are assumed to be due to selective inhibition of COX-3 enzyme..

Slide49

ACETAMINOPHEN (PARACETAMOL)

 



Pharmacokinetics

Acetaminophen is completely and rapidly absorbed from the gastrointestinal tract.

80%-90% is conjugated with

glucuronic

or sulfuric acid in the liver and then excreted in the urine.

At high doses, one of these metabolites undergoes spontaneous dehydration to form

N

-acetyl-

P

-

benzoquinone

, the metabolite thought to be responsible for

hepatotoxicity

.

Slide50



Pharmacologic effects:

Acetaminophen is an effective analgesic and antipyretic agent but it has no anti-inflammatory activity.

It appears to be an inhibitor of prostaglandin synthesis in the brain, and thus explaining its analgesic and antipyretic activity, but it is much less effective than aspirin as an inhibitor of the peripherally located prostaglandin biosynthetic enzyme system that plays such an important role in inflammation.

It exerts little or no pharmacologic effect on the cardiovascular, respiratory, or gastrointestinal systems, on acid-base regulation, or on platelet function as aspirin dose.

Slide51



Therapeutic uses

Acetaminophen provides an effective alternative as analgesic and antipyretic when aspirin is contraindicated (e.g. in-patients with peptic ulcer or hemophilia) and when the anti-inflammatory action of aspirin is not required.

 



Preparations and administration

Acetaminophen is available in tablet and liquid forms and is administered orally in dose of 500 mg

t.d.s

.

 



Adverse effects:

 

A. At therapeutic doses

, acetaminophen is well tolerated; however, untoward effects include:

*Skin rash and drug fever (an allergic reaction to the drug).

*Rare instances of blood

dyscrasias

(

haemolyticanaemia

in with G6PD deficiency, less than with

phenacetin

).

*Renal tubular necrosis and renal failure (more with

phenacetin

).

Slide52

B.An

overdose of acetaminophen

(about 15 gm in an adult; about 4 gm in a child)

can result in severe

hepatotoxicity

, resulting in

centrilobular

hepatic necrosis. Doses greater than 20 gm are potentially fatal.

The toxic metabolite of acetaminophen appears to be inactivated in the liver via glutathione.

It is thought that when glutathione stores are consumed, the N-acetyl-p-

benzoquinone

metabolite binds covalently to cellular constituents, producing

hepatocellular

damage.

Although clinical symptoms, such as nausea and vomiting, occur during the first 24 hours after toxic ingestion, signs of hepatic damage (e.g. enzyme abnormalities) may not occur for 2 - 6 days).

Slide53

Treatment consists of

:

Emptying the stomach & administering activated charcoal

Hemodialysis

, if begun within the first 12 hours after ingestion.

Administration of

sulfhydryl

compounds (e.g.

acetylcysteine

) which probably replenish hepatic stores of glutathione.

Slide54

NSAID:



Classification

 

A.Non

-selective COX inhibitors (inhibit COX-1 and COX-2):

 

Salicylic acid derivatives:

aspirin

,

aloxiprine

,

aminosalicylic

acid,

diflunisal

,

methyl

salicylate

, etc.

Acetic acid derivatives:

indomethacin

,

sulindac

,

diclofenac

Propionic

acid

derivatives:

iboprufen

,

ketoprofen

,

fenoprufen

, naproxen.

Fenamic

acid

derivatives:

mefenamic

acid,

fulfenamic

acid.

Pyrazolonederivatives:

phenylbutazone

,

azapropazone

Oxicams:

piroxicam

,

tinoxicam

.

 

B. Selective COX-2 inhibitors:

Celecoxib

,

valdecoxib

,

meloxicam

.

Slide55



Salicylate

toxicity

1.

Acute toxicity:

 

 

Cause:

ingestion of large doses of

salicylates

.

 

Manifestations:

Nausea, vomiting,

hematemesis

.

Acidosis and dehydration.

Pulmonary edema and cardiovascular collapse.

Hyperpyrexia, hyperventilation, irritability, convulsions, coma.

Treatment:

Repeated gastric

lavage

with activated charcoal.

Cold fomentations

for

hyperpyrexia.

Vit

K

10-30 mg

i.m

. to control

hemorrhage.

i.v

. fluids

to correct

dehydration.

i.v

. sodium bicarbonate

to correct

acidosis.

Alkalinization

of urine:

to enhance

salicylate

excretion.

Hemodialysis

in severe cases.

Slide56

2.

Chronic toxicity: (

Salicylism

):

 

Cause:

prolonged administration of

salicylates

.

Manifestations:

headache, tinnitus,

tachypnea

, respiratory alkalosis.

Treatment:

just stop

salicylates

. The condition is reversible.

Slide57

ADRENOCORTICAL STEROIDS

 The natural

adrenocortical

hormones are steroid molecules produced and released by the adrenal cortex. Secretion of

adrenocortical

steroids is controlled by the pituitary release of ACTH.

Slide58

Metabolic Effects:

 



On carbohydrate metabolism:

leading to increase in serum glucose levels



On fat metabolism

:

 

Catabolic and

Antianabolic

Effects:

Slide59

Anti-inflammatory and Immunosuppressive Effects:

Glucocorticoids

dramatically reduce the manifestations of inflammation.  

 

On the electrolytes and water balance:

On CVS:

 

Anti-shock effects:

Haematological

effects:

On CNS:

Slide60

On growth:

On bone:

Hormonal effects:

Glucocorticoids

given chronically suppress the pituitary release of ACTH, GH, TSH, and LH.

 

Development of the fetal lungs:

Enhance uric acid excretion

:

Slide61

Doses

Dosage requirements are variable and must be individualized.:

Short-term therapy:

The patient needs duration less than 2 weeks.

Alternate day therapy:

The recommended dose is multiplied by 2 given every other day (to give chance for the pituitary to release ACTH and prevent sudden withdrawal symptoms).

Long term therapy:

The patient needs duration more than 3 weeks.

Small and large dose therapy:

Slide62

Uses:

Replacement therapy:

 

A. Treatment of

adrenocortical

insufficiency:

In chronic

adrenocortical

insufficiency (Addison’s disease)

e.g. TB of suprarenal cortex.

B.

In acute

adrencortical

insufficiency (

Addisonian

crisis),

i.e. Prolonged corticosteroid therapy produce feed back inhibition of anterior pituitary which decrease ACTH secretion results in decrease corticosteroid release from adrenal cortex. When the exogenous

corticosreoid

therapy is stopped, its blood level markedly decrease leading to severe

hypoadrenal

function, severe hypotension and shock (adrenal crisis)



Treatment:

Therapy consists of correction of fluid and electrolyte abnormalities

Treatment of precipitating factors

Large amounts of

parenteral

hydrocortisone. Hydrocortisone sodium

succinate

or phosphate in doses of 100 mg intravenously is given every 8 hours until the patient is stable. The dose is then gradually reduced, achieving maintenance dosage within 5 days.

Slide63

Hypothalamo

-pituitary-adrenal axis suppression (

addissonian

crisis)

:

This can be avoided by:

*Gradual withdrawal of the corticosteroids to give chance for the pituitary to release ACTH and stimulate adrenal cortex to secrete endogenous corticosteroids.

*Alternate day therapy.

*Avoid prolonged use.

*Give long acting ACTH before

stoping

corticosteroids.

Side effects of

glucocorticoids

are related to large doses and/or prolonged administrations. When the

glucocorticoids

are used for short periods (less than 2 weeks), it is unusual to see serious adverse effects even with moderately large doses.

Slide64

Status

epileticus

:

Defined as recurrent or continuous seizure activity lasting longer than 30 minutes in which the patient

baseline consciousness is not regained between the seizures

.

OR occurrence of serial convulsions between which

there is no return of consciousness

Can lead to systemic hypoxia, acidosis, hyperpyrexia, cardiovascular

collapse and coma .

Death occurs in 5-10%.

Treatment

:

status

epilepticus is life-threatening and must be treated immediately with concomitant cardiovascular, respiratory and metabolic management.

1-diazepem 10 mg I.V.

repeat dose (5-10 mg) every 20-30 min.

2-clonazepam 1mg I.V.

repeat dose

(2-6

mg) every 20-30 min

3-phenytoin 10-20 mg I.V.

4-phenobarbitone 10-20 mg/kg slow I.V.

5-

general anesthesia with propofol or thipentone should be commenced immediately.

Slide65

Causes of Status Epilepticus

Prolonged febrile seizure (

commonest) cause.

Idiopathic status epilepticus

Non-compliance to anti-epileptics

Sudden withdrawal of anti-epileptics

infection

Symptomatic status epilepticus

Encephalitis, meningitis

Electrolyte disturbances, tumours

Slide66

Paralytic ileus:

Many causes but the postoperative (specially intraperitoneal) type is the commonest.

This type of ileus spontaneously resolves within 2-3 days after sigmoid motility returns to normal , however, the term postoperative adynamic ileus or paralytic ileus is defined as ileus of the gut persisting for more than 3 days following surgery.

There is no mechanical obstruction and there is accumulation of both gas and fluid within the bowel.

The longest duration of ileus is noted to occur after colonic surgery.

Slide67

Clinical picture:

Patient may have distended tender and tympanic abdomen, depending on degree of bowel distension.

Absent bowel sounds (unlike high pitched sounds of intestinal obstruction).

Treatment:

1-delay oral feeding until ileus resolves clinically

Most cases resolves with watchful waiting and supportive treatment.

2-discontinue medications which can cause ileus as morphine.

3-NSAID may improve the condition by improving local inflammation and by decreasing the amounts of narcotics analgesics used.

4-prokinetics as neostigmine

mosapride

.

5-check and treat electrolyte imbalance as

hypokalaemia

.

Slide68

Cardiac arrest:

Causes:

1-myocardial infarction.

2-anaphylactic shock.

3-…..

anaesthetic

agents….etc.

Clinical picture:

1-unconciousness.

2-pallor of the skin.

Absence of arterial pulse (radial and carotid). Try to listen to heart sounds.

4-lack of bleeding from a surgical wound.

5-pupill will be dilated (late).

Slide69

Treatment:

cardiopulmonary resuscitation should be performed immediately as brain death will occur if oxygen is cut off for 3 minutes:

Positioning of the patient to help venous return.

start external cardiac massage.

Artificial respiration…..

Adrenaline

intracardiac

(why?)

Slide70

Toxicity of Iron

 



Acute Iron Toxicity:

It is seen almost exclusively in young children who have accidentally ingested iron tablets.

Oral iron preparations should therefore always be stored in "childproof" containers and kept out of reach of children.

Large amounts of oral iron cause:

Necrotizing gastroenteritis, with vomiting, abdominal pain and bloody diarrhea followed by shock, lethargy, and dyspnea.

Subsequently, improvement is often noted, but this may be followed by severe metabolic acidosis, coma, and death.

 

Treatment

Gastric aspiration should be performed, followed by lavage within 1 hour with phosphate or carbonate solutions to form insoluble iron salts.

Desferoxamine

(

Desferal

), a potent iron chelating compound:

5 gm in 100 ml water should then be instilled into the stomach to bind any remaining free iron in the gut. It is not absorbed from GIT.

Deferoxamine

1-2 gm should also be given systemically by intermittent IMI or by continuous IV infusion of 15 mg/Kg/hour to bind iron that has already been absorbed and to promote its excretion in urine and feces.

Appropriate supportive or symptomatic therapy for gastrointestinal bleeding, metabolic acidosis, and shock must also be provided.

 



Chronic Iron Toxicity

:

Most commonly occurs in patients with

haemochromatosis

which is an inherited disorder characterized by:

excessive iron absorption

in patient who receive many red cell transfusions over a long period of time. It results in iron deposition in the heart, liver, pancreas and other organs.

Slide71

Keep calm and study hard