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The descending control system, showing postulated sites
of action of opioids on pain transmission. Opioids excite
neurons in the periaqueductal grey matter (PAGPAG)) and in
the nucleus reticularis paragigantocellularis (NRPG
NRPG),),
which in turn project to the rostroventral medulla, which
includes the nucleus raphe magnus (NRMNRM).). From the
NRM, 5-HT-
HT-and enkephalin-
enkephalin-containing neurons run to
the substantia gelatinosa of the dorsal horn, and exert
an inhibitory influence on transmission. Opioids also act
directly on the dorsal horn. The locus ceruleus (LCLC))
sends noradrenergic neurons to the dorsal horn, which
also inhibit transmission. The pathways shown in this
diagram represent a considerable over-
over-simplification, but
depict the general organisation of the supraspinal control
mechanisms. Light pink boxes represent areas rich in
(DLF = dorsolateral funiculus)
opioid peptides. (DLF funiculus) (For
more detailed information, see Fields & Basbaum 1989)
1989)
Non--Steroidal Anti-
Non Anti-Inflammatory Drugs (NSAIDs)
Three major effects of NSAIDs:
Š Anti
Anti--inflammatory effect (edema=congestion, ü of blood
flow in the blood vessels, vasodilation, leakage of the
fluid from the vessels & migration of the immune
component)
Š Analgesic effect
Š Antipyretic effect (only can be seen during the increased
body temperature)

The effect is due to the inhibition of arachidonate


cycloxygenase (COX) which inhibit PG and thromboxane
production (mediators of pain and inflammation)
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A main types
1. COX 1
- constitutive enzyme
- regulate tissue homeostasis

A. COX A (related to inflammation and it is time


dependent)
- inducible enzyme
- produced in inflammatory cells (when cell are
activated)
- produced PG (mediators of inflammation)

- COX 3 (less important, the pharmacological action is not


clear)
Š NSAIDsinhibit both enzymes . The anti-
anti-
inflammatory & analgesic effects are due
to COX A inhibition.

Š Sideeffects is due to COX 1


inhibition..GIT. (now, there are drugs that
are selective to inhibit COX A)
O    
-   
Body temp. is regulated by Ơthermostatơ center in
hypothalamus that make sure the balance between heat
gain and heat loss. NSAIDs can reset this center by
vasodilatation and sweating´
sweating´ heat loss

!    


- inhibition of PG in hypothalamus
- during inflammation, IL-
IL-1 (pyrogen) stimulates PGE
production by induction of COX A and this elevate body
temp.

/during inflammation, bacterial endotoxins cause the


/during
release IL-
IL-1 (pyrogen), which stimulate the generation
of PG E in the hypothalamus, & this in turn will cause the
elevation of the set point for temperature
- Analgesic action
ƥ Mainly effective in inflammatory pain &
tissue damage.
ƥ Useful in arthritis, bursitis, muscle pain,
vasceral pain, toothache, dysmenorrhea,
postpartum pain & metastasis bone
cancer.
ƥ Central effect in the spinal cord

Note: PG effects BDK & 5-HT


Anti-inflammatory action
Anti-
- Inhibit the inflammation caused by the
interaction between Ag and Ab (e.g.
rheumatoid arthritis) by reducing the
inflammatory component involving COX-
COX-A
action

- vasodilatation´
vasodilatation´ facilitate the production
of histamin´
histamin´ ü the permeability of
postcapillary venule ´ edema
- edema
- pain
!     
Š The main action is to inhibit COX-
COX-A (metabolite of
arachidonic acid)
Š inhibition COX-
COX-1 instantaneously but reversibly
Š The inhibition of COX-
COX-A is time dependent ((ü
ü by time)
- the main action of COX-
COX- gives PGGA
PGGA
- perioxidase action-
action-converts PGGA
PGGA to PGH
PGHAA

 NSAIDs only inhibit the main action (not the


perioxidase action)

  
   
- oxygen radical (produced by neutrophil and
macrophages) scavenging´
scavenging´ tissue dammage
- Inhibit the expression of transcription factor NF-
NF- B-
aspirin (transcription of gene inflammatory mediator) ´
no inflammatory intermediate
|    
 !
- Most common
- Caused by COX- COX-1 inhibition (affect the mucosal lining of
the GIT)
(PGE provide a cytoprotective effect against gastric ulcer by inhibition of
gastric acid secretion)
- Common effects:
dyspepsia,
diarrhea & constipation (depends on the agent),
nausea & vomiting,
gastric bleeding,
ulceration

Treatment of GI disturbance is by giving misoprostol (PG


analog)
COX--A selective agent produces less gastric damage
COX
Skin reaction (mefenamic acid & sulindac)
Š And most common
Š Mild rashes, urticaria & photosensitive reaction
(very rare)

Adverse renal effects


Acute renal insufficiency (with chronic consumption & high dose)
- occur through PGEA
PGEA, PGIA
PGIA & prostacyclin
(maintain renal blood flow) inhibition.
Analgesic nephropathy (with chronic consumption & high dose) ƛ
chronic nephritis & renal papillary necrosis
Other unwanted effects (< common)
Bone marrow disturbance
Liver disorder (likely occur if there is renal
impairment)
Precipitate asthma-
asthma-(especially with aspirin)
Table of classificationƦwanted
Some important NSAIDs
Salicylates (irritating)
Š Most common is aspirin
Š Pharmacological property
1. analgesia
- relief low intensity pain (superficial rather
than visceral pain e.g. headache myalgia)
- via peripheral action
A. antipyresis
- lower elevated body temp. (rapid &
effective)
- toxic dose-
dose- sweating & increase dehydration
o  
- CNS toxicity-
toxicity-stimulation followed by depression (action of
Ach & nicotine)
- confusion, dizziness, tinnitus, high-
high-tone deafness,
delirium, psychosis, stupor (nearly unconscious) & coma.
- nausea, vomiting-
vomiting- through the stimulation of medullary
CTZ

" #
- increase OA consumption & COA production
- stimulate medulla respiratory center ´ hyperventilation
- toxic effect-
effect- respiratory depression & circulatory collapse
- respiratory acidosis (ü
(ü COA production)
5. Acid-
Acid-base balance & electrolyte
- disturb acid-
acid-base balance & electrolyte pattern
6. Cardiovascular effect
- Depress circulation-
circulation-directly or by central
vasomotor paralysis
- high dose cause non-
non-cardiogenic pulmonary
edema.

7. GIT effects
- epigastric pain, nausea & vomiting
- high dose-
dose- gastric ulceration, execerbation of
peptic ulcer, GI haemorrhage, & erosive gastritis
8. Hepatic & renal effect
- high dose cause hepatic injury (>160
(>160 gm/ml)
- salt & water retention
- reduced renal function (in patient with CHF or
hypovolemia)]
9. Uricosuric effect
- in low dose (1
(1-A gm/day)
gm/day)-- urate excretion (ü

plasma urate conc.), block probancid & other
uricosuric agents
- intermediate dose (A(A-4 gm/ml
- high dose (>5
(>5 gm/ day)-
day)-uricosuria ( plasma
urate conc.)
10. Effect on blood (used as antiplatelet
10.
agent)
- prolong bleeding time (irriversible
acetylation of platelet cycloxygenase ´
TXA
- should be avoided in sever hepatic
damage, hypothrombinaemea, Vit. K
deficiency or hemophilia (´ severe bleeding)
-
11. Metabolic effect
11.
- oxidative phosphorylation (inhibit ATP
reaction)
- carbohydrate metabolism (in high dose
´ hyperglycemia, glucosuria, deplet liver
& muscle glycogen, glucose metabolism
blood glucose conc.)
- Nitrogen metabolism (-
(-ve a.a in urine)
- fat metabolism-
metabolism- lipogenesis by the
incorporation of acetate into FA´
FA´ FFA in
plasma, accumulation of fats in the
muscles
1A. Endocrine effect
1A.
- high dose ƛ stimulate steroid secretion
- long term use-
use- thyroid uotake &
clearance of iodine

13. Local irritant effect


13.
- by destroying endothelial cells
Pharmacokinetics:
Š rapidly absorbed in the stomach & upper
small intestine after oral intake
Š rapidly absorbed from the skin
Š Metabolites
Metabolites-- SA, Phenolic glucoronide &
acyl glucoronide
Š Excreted in urine
Š Aspirin t ½ 15 min.s
 
Š   
- sodium salicylate, aspirin, salsalate (hydrolyzed to SA),
choline salicylate, Mg. salicylate
- diflunisal-
diflunisal- potent anti-
anti-infl. agent than aspirin. Used in
osteoarithritis, musculoskeletal strains. Not to be
converted to SA, cause less S/E, less antiplatelate, no
anti--pyretic effect (poorly absorbed by the CNS)
anti

Š O 
- mesalamine-
mesalamine- used locally in inflamatorry bowel
syndrome, ulcerative colitis (not effective orally, poorly
absorbed from the stomach & small intestine
- sulfasalazine-
sulfasalazine- contains mesalazine (IBS, ulcerative
colitis)
Š Toxicity
Salicylism (mild salicylate poisoning/intoxication)
poisoning/intoxication)
- headache, dizziness, blurred vision, mental confusion,
lassitude, drawsiness, sweating, thirsty, hyperventilation,
nausea, vomiting, & diarrhea.
- sever intoxication-
intoxication-CNS disturbance (coma) , skin
eruption, alteration in the acid-
acid- base balance &
dehydration. in children-
children- hyperpyrexia
- Haemorrhage ƛ occational (in adult at therapeutic dose)
- toxicity in adults-
adults- non-
non-allergic pulmonary odema,
neurological abnormalities, acid-
acid-bace abnormality,
prolonged prothrombin time
- treatment ƛ cardiovascular/ respiratory support & cprrect
acid--base balance
acid
Š Para-aminophenol derivative
Para-
Paracetamol (PCT) (acetaminophen)
Pharmacological property
- analgesic and antipyretic similar to aspirin (in
the brain no peroxide conc. ´ effective)
- weak anti-
anti-inflammatory, week inhibitor of COX
due to the peroxides produced during
inflammation
- no effect on CV, Respiratory system, acid-
acid-base
balance & GIT
- no effect o blood
- quite safe-
safe- no effect on the platelet
Pharmacokinatics
Š Rapid & complete absorption from the GIT
(unlike aspirin)
Š Hepatic conjugation with glucoronic acid
(60%)
60%) , sulfuric acid (30
(30%)
%) and cystein
5%.
Š Excreted in urine t ½ A hr.s
Š CYP 450
450--mediated N-
N-hydroxylation to
form N-
N-acetyl-
acetyl-benzoquinoneimine (NAB)
Therapeutic use
Analgesic /antipyretic substitute for aspirin
Toxicity
- Well tolerated
- Occasional skin rash & allergy in certain
individuals.
- Overdose - hepatotoxicity (fetal hepatic
necrosis), also renal tubular necrosis,
hypoglycemia & coma

Note / the dose should >4


>4gm/day (8(8 tab/day) ´
glucoronic acid will be saturated´
saturated´ liver damage
and death within A-4 days
Mechanism of hepatotoxicity
- Involve the production of metabolic intermediate
(NAB) N-
N-acetyl-
acetyl-benzoquinoneimine (reactive
electrophilic electrophilic )

- In normal condition-
condition- NAB is conjugated with
GSH (glutation) & metabolized to mercapturic
acid & excreted.

- In overdose-
overdose- GSH depleted & hepatocytes
become susceptible to oxidant injury & reactive
intermediate can bind covalently to
macromolecules & cause dysfunction of
enzyme´ hepatotoxicity
- Early symptoms-
symptoms- nausea, vomiting,
anorexia, diaphoresis (sweating)
abdominal painƦ..persist for week or
more.
- Hepatic damage ƛ within A-4 days
- Increased aminotransferase & bilirubin,
prolong prothrombin time
- Antidote-- administration of sulfydryl
Antidote
compounds (acetylcystein, methionine)
replenish GSH (inactivate intermediate by
conjugation)
 $   
 
Analgesic, anti-
anti-inflammatory and antipyretic
- Potent inhibitor of COX
- It also inhibitmotility of polymorphnuclear
leukocytes
- Uncouples oxidative phosphorylation & depress
mucopolysaccharide biosynthesis
- Rapid & complete absorption
- Metabolized by O- O-demethylation (50
(50%),
%),
glucoronic acid conjugation (10(10%)
%) & N-
N-
deacylation (small portion)
- Plasma t ½ A.5 hr.s
- Propancid can increase indomethacine plasma
conc.(block tubular excretion)
- Used as antipyretic in certain conditions..long
term fever (eg. Fever in Hodgkin's disease)
- Adverse effects-
effects-
1. GI disturbance (gastric ulcer, pancreatitisƦ
give proton pump inhibitor e.g omprazole)
A. CNS effects (long term usage lead to sever
frontal headache , vertigo, dizziness,
lightheadedness, depression, psychosis,
hallucination, mental confusion and suicidal
attempt.
3. Haemopoietic reactions (leucopenia,
thrombocytopenia, aplastic anemia, impaired
platelet function,
Sulindac
- Less potent than indomethacine
- Prodrug
Prodrug-- converted to sulfide metabolite (500
(500 times
>potent vs. sulindac)
- Oxidized to sulfone & then reduced to sulfide
- t ½ 7 hr.s
- Sulfide metabolite t ½ 18 hr.s
- Therapeutic uses-
uses- rheumatoid arthritis, osteoarthritis,
ankylosing spondylitis (chronic inflammation of the spine
and the sacroiliac joints) , acute gout
- S/E: less vs. indomethacine, mild GIT (nausea ,
abdominal pain) & CNS effects (drowsiness, dizziness,
headache, nervousness, skin rash, pruritis)
Etodolac
- Selective COX-
COX-A
- Rapidly & completely absorbed orally
- t ½ 7 hr.s
- Uses
Uses-- postoperative analgesia (6
(6-8 hr.s of
analgesia), osteo and rheumatoid arthritis
- Less GI toxicity
- S/E: skin rash & CNS effects
Heteroaryl acetic acid
Š Tolmetin & ketorolac (heteroacyl acetic
derivatives)
Š Diclofenac (phenylacetic acid derivatives)

Tolmetin
- Effective anti-
anti-inflammatory
- t ½ 5 hr.s
- Metabolized to carboxylic acid
- Uses
Uses-- osteo & rheumatoid, juvenile arthritis
- Better tolerated
- S/E: GI effects (most common), CNS effect less
vs. ASA (tinnitus, vertigo, deafness)
Ketorolac
Potent analgesic, moderate anti-
anti-
inflammatory
Used parenterally by IV, damaged by gasric
acidity
Inhibit PG biosynthesis & platelet
aggregation, promotes gastric ulceration
Uses-- postoperative pain, short term pain
Uses
(not more than 5 days pain)
Topical ƛallergic conjuctivitis & ocular
inflammation
Diclofenac
- non
non--selective COX inhibitor
- Inhibit COX, reduce arachidonate in
leukocytes
- t ½ 1-A hr.s
- Metabolized by CYP450
CYP450 ACAC into 4-
hydroxydiclofenac
- Uses
Uses-- rheumatoid & osteoarthritis,
ankylosing spondylitis
- S/E: GI disturbance (common), CNS
effects, skin, rashes, allergy, fluid
retention, edema
Arylpropionic acid
effective COX inhibitor, better tolerated in terms of adverse effects vs.
ASA & indomethacine

Š Ibuprofen, naproxen (A0


(A0xx > ASA), flurbiprofen, fenoprofen (
equipotent with ASA), ketoprofen & oxaprozin
Š Under investigation: carprofen, piprofen, indobufen & tiaprofenic
acid

!
- The 1Ast
1Ast member
- Rapidly absorbed after oral
- t ½ A hr.s
- Rapid & complete excretion
- Metabolites
Metabolites-- hydroxylated & carboxylated compounds
- Uses
Uses-- in GI intolerance for other analgesics
- S/E: less epigastric pain, nausea, heartburn, Ơfullnessơ vs. ASA &
indomethacine
%
- Fully absorbed from the GIT
- Metabolism-
Metabolism- 6-demethylation, excretion as glucoronide
- S/E: equal to indomethcine but better tolerated (nausea,
vomiting, dizziness, CNS effect)

&
- Equally potent as ASA
- Metabolic transfprmation
- Into 4-hydroxy analog
- t ½ 3 hr.s
- GI effects-
effects- abnormal discomfort & dyspepsia, less
intense
- Also CNS effects
&!
- Used as antiplatelet in Europe
- t ½ 6 hr.s
- Metabolized by hydroxylation & conjugation
- Potential for soft tissue treatment
- Adminstration by transcutaneous patch

'
- Stabelize lysosomal membranes & antagonize BDK action
- t ½ A hr.s
- Conjugate with glucoronic acid
- S/E: common GI effects but mild & less frequent
- Also cause fluid retention & increase plasma creatinine
- Excreted in urine

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