25

Dana EL-khader

Moutasem

Ayoub

SCIENTIFIC TEAM 1 –الفريق العلمي

م بسم الله الرحمن الرحي

Non-narcotics analgesics

Effects of PGs Inhibition:

( اذا يعمل على زيادة pathological( ك )PGs*ذكرنا سابقا دور )

(pain,fever,inflammation( ودوره )physiological beneficial اذا يعمل على )

(VD & prevent platelets aggregation )عندما نقوم بعمل تثبيط انتاج وانه

(PGs( فان ذلك يحدث من خلال طريقتين اما عن طريق )NSAIDs او عن طريق )

(Corticosteroids )

1. NSAIDs: they inhibit COX enzymes→↓ PG synthesis →

Analgesic (reduce pain), Anti-inflammatory (reduce inflammatory) and

Antipyretic effect(reduce fever)

Subject: Non-narcotics analgesics

Lecture 25

Date : 29/12/2020

الأسود: كلام الدكتور ✓

السلايد الأزرق: ✓

الأخضر: شرح أو توضيح خارجي ✓

SCIENTIFIC TEAM 2 –الفريق العلمي

2. Corticosteroids: induce inhibitory protein (Lipocortin) →

inhibit phospholipase-A2 → ↓ PGs, LTs & PAF

synthesis → - Anti-inflammatory effects (so, it considers strong anti-

inflammatory drug) ( تفاصيلها بهذا الكورس ما بتهمنا )

*Analgesics are drugs that relieve pain due to multiple causes. (chemical or physical)

(non-narcotic analgesics كلاهما مبدأ عمله قائم على ) ( تثبيطCOX enzyme )

( وبالتالي PGs synthesizeمما يؤدي الى )

1. Decrease number of PGs which causing fever (antipyretic

2. Decrease number of PGs which causing inflammation (anti-

inflammatory) except paracetamol.

Classification of

Analgesics

-Non-narcotic Analgesics

Nonsteroidal anti-

inflammatory drugs

(NSAIDs) Analgesic

, antipyretic ,anti-

inflammatory )

• Paracetamol.(Analgesic

, antipyretic, NO anti-

inflammatory)

Used in mild to

moderate pain

(headache toothache,

dysmenorrhea)

Doesn’t cause addiction

Narcotic Analgesics/

used upon CNS

• Morphine.

• Synthetic opioids.

( مشتقات المورفينمن )

Used in moderate to

severe/ Used in cases of

cancer& trauma & bone

fractions (severe cases)

These drugs can cause

addiction and can’t be

prescribed without DR

permission

SCIENTIFIC TEAM 3 –الفريق العلمي

3. Decrease number of PGs which causing sensation to pain

(Analgesic)

Cyclooxygenase Enzymes

• COX-1: constitutive (present normally in tissues regulating its

physiologic functions), forming protective PGs involved in the essential

physiological functions such as platelet aggregation, cytoprotecting in the

stomach and maintenance of normal kidney function.

• COX-2: inducible (only expressed by inflammatory mediators such as

endotoxin and cytokines, forming PGs which exacerbate pain and

inflammation)- [constitutive in endothelium & kidney].

-anti)( فان ذلك سيفيد الجسم من خلال COX1& COX2*اذا استخدمنا دواء عمل تثبيط )

inflammatory due to inhibition of COX2( ولكن سيضره ايضا حيث ان )COX1 سيتم )

inhibition of the protective PGs role in essentialتثبيطه وسوف يؤدي الى )

physiological function )

( ولكن تم اكتشاف ادوية قادرة على COX1& COX2*قديما كانت معظم الادوية تعمل على تثبيط )

( ولكن هذه الادوية COX1( وبالتالي استطيع المحافظة على الاستخدام الايجابي ) COX2تثبيط )

ذكرها لاحقا. ايضا لها مضاعفات جانبية سيتم

• COX-3 (COX-Ib): present in the CNS??

فكرة ( وبالتالي يتلائم مع CNS( اذا انه يتواجد ب)paracetamol*هذا الانزيم مختص ب)

( CNSوبالتالي هذا الانزيم متواجد ) تهابات ل ( ليس له نشاط ضد الاparacetamolان ال)

المعلومات اصلا، و ( لكان له نشاط مضاد للالتهاباتperipheryفقط حيث لو تواجد ب)

المتعلقة بهذا الانزيم هي قيد الابحاث.

1. Non-selective COX inhibition

1. Salicylic acid derivatives: Aspirin Irreversible inhibition

of COX enzymes

Other NSAIDs cause reversible inhibition of COX enzymes.

2- Pyrazolone derivatives: Phenylbutazone.

3- Acetic acid derivatives: Indomethacin & sulindac- Diclofenac

4- Fenamic acid derivatives: Mefenamic acid, flufenamic acid.

5-Propionic acid derivatives: Ibuprofen, ketoprofen, naproxene.

6- Oxicams: Piroxicarn, Meloxicam

*غير مطالبين

باسماء مجموعات

عدا الادوية

مجموعة الاسبرين.

الاسبرين هو

المسكن الوحيد

الذي يرتبط ب

(cox enzymes

irreversibly )

SCIENTIFIC TEAM 4 –الفريق العلمي

2. Selective COX-2 inhibitors: Celecoxib, Rofecoxib

I. ACETYLSALICYLIC ACID (ASPIRIN)

Mechanism: Aspirin Irreversible inhibition of COX-1 & COX-2 enzymes

Pharmacological actions:

1- Analgesic action(inhibition of PGs synthesize, then inhibition of nerve

ending sensation which will finally inhibit felling pain)

2- Antipyretic action (PGs usually increase the thermo set point of the

thalamus, so inhibiting PGs will reset this setpoint)

3- Anti-inflammatory action (PGs usually increase the signs of acute

inflammations so, Aspirin will lead to decrease the signs of acute

inflammation (pain, VD, vascular permeability)

*(1+2+3) caused by inhibition of COX2.

4- GIT:

1. Gastric irritation, nausea and vomiting.

2. Hyperacidity, ulceration induced (PGs were decresing HCL secretions

unlike is Aspirin):

- locally (Ion Trapping)

- systemically by ↓ PGs→↓ mucus secretion (No protection).

5- Blood:

1. Small dose (75-150mg/d) → Inhibit TXA2→ ↓ platelet aggregation

(it does affect compounds responsible for synthesizing of TXa2)

2. Large dose (5 g/d) → Hypoprothrombinemia: ↓synthesis of vit. K

dependent factors (10,9,7,2) (doesn’t depend upon inhibiting PGs but instead it

does reduce Coagulation by decrease the synthesize of vit. K coagulation factors)

• Inhibition of COX-1 is responsible for the adverse

effects of NSAIDs.

• Inhibition of COX-2 is responsible for their therapeutic

effects.

SCIENTIFIC TEAM 5 –الفريق العلمي

6- Kidney:

1. Large dose (>5 g/day) → ↓ uric acid reabsorption by PCT→

treats gout

( تقوم باعادة transport proteins( هناك )PCT/proximal convoluted tubule*في )

( فانه ينافس salicylic acidامتصاص الاحماض مرة اخرى وارسالها الى الدم، وفي حالة)

(gout( وبالتالي يقلل كميته بالدم وبذلك يستخدم كعلاج ل)uric acidال)

2. Nephropathy (large dose for prolonged time of combined NSAIDs)

( combination of NSAIDs( لا يسببه، بل يحدث نتيجة الاستخدام المتواصل لل)aspirinال)*

Therapeutic uses:

1. Small (infantile)-Dose (75-150mg/d) (infantile indicates small tablets)

Prophylaxis for:

Transient ischemic attacks (the blood vessels for brain not enough), unstable

angina, acute myocardial infarction.

لزيادة سيولة الدم وبالتالي تقليل من احتمالية حدوث *الاشخاص المعرضين للذبحة الصدرية بخذوه

.الجلطة

2. Intermediate dose (325 mg tab) 1-2 tab/4-6 hrs

• Antipyretic in fever.

• Analgesic:

o Mild to moderate pain e.g. arthritis, dental pain.

o Headache

o dysmenorrhea.

3. High-Dose (4-8 g/d) (combined with high adv. Effects)

Anti-inflammatory

1. Rheumatic fever.

2. Rheumatoid arthritis

3. Other inflammatory joint diseases.

Adverse Effects:

A. Effects Common to all NSAIDs (related to PGs inhibition)

1. GIT (most common; direct mucosal irritation &↓protective PGs)

• Epigastric pain, Nausea, vomiting, gastritis ( لذلك تعطى هذه الادوية بعد الاكل)

Aspirin is characterized

from other NSIDs by:

1.it irreversibly binds to

COX enzymes

2.the therapeutic action

depends upon dose.

SCIENTIFIC TEAM 6 –الفريق العلمي

• Acute & chronic peptic ulcers with ↑ risk of bleeding. (shedding of mucosa

will increase the amount of HCL reaching the submucosa which will affect

blood vessels)

2. Nephrotoxicity (less frequent with aspirin)

* Analgesic nephropathy: irreversible chronic nephritis due to

prolonged use of high doses of combinations of NSAIDs.

3. Hypersensitivity reactions (more common in NSAIDs)

- Skin rash, rhinitis

- Asthma in susceptible patients

4. Bleeding tendency

- Displacement of warfarin from plasma proteins potentiating

its effect.

B. Effects Specific to Aspirin

1. Bleeding tendency

1. Antiplatelet effect by small dose

2. Hypoprothrombinemia by large dose

طرق 3*نلاحظ انه الاسبربن ممكن يسبب نزيف ب

2. Reye’s syndrome: encephalopathy and liver damage in children with

fever due to viral infection.

( كخافض للحرارة فان ذلك aspirin( عند اعطاهم ) viral infection*بعض الاطفال المصابين ب)

( كخافض paracetamol( لذلك يتم اعطاء)Reye’s syndromeسيؤدي الى اصابة الطفل ب)

( للاطفال Aspirinللحرارة ويمنع استخدام )

Contraindications:

1. GIT disorders: peptic ulcers, gastritis

2. Bleeding disorders: hemophilia, thrombocytopenia

( بيكونوا بيعانوا hemophilia*ممنوع اعطيه للمرض الي بيعانوا من سيولة عالية في الدم، فمثلا )

( سببها thrombocytopenia( وهو مرض وراثي، بينما)coagulation factor 8من نقص قي )

( لذلك تكون هناك صعوبة في حدوث تجلط. thrombocytesنقصان في عدد)بكون

3. Chronic renal impairment

*لانه الاسبرين ييم اخراجه عن طريق الكليتين، ففي حالات الفشل الكلوي انا ما بعطيه عاساس ما

يسببه ( الذي قد Nephrotoxicityبالاضافة لل)( accumulation of drugيصير عندي )

(Aspirin&NSAIDs)

SCIENTIFIC TEAM 7 –الفريق العلمي

4. Chronic liver diseases (bleeding tendency)

coagulation)( للاسبرين، بالاضافة لنقصان كفاءة الكبد في تصنيع metabolismيؤثر على ) *

factors ( وبالتالي قد تزيد احتماليةbleeding لذلك يمنع اعطاءه الاسبرين لكي لا تزيد من النزيف )

5. Hypersensitivity to aspirin

6. Children < 12 y (to avoid Reye’s syndrome)

II.OTHER NON-SELECTIVE NSAIDs

• Mechanism: Reversible inhibition of COX enzymes

• Action: All have analgesic, antipyretic & anti-inflammatory effects.(not

dependent upon dose)

• Members: Ibuprofen - Piroxicam – Diclofenac

• Uses:

1. Inflammatory joint diseases (osteoarthritis, rheumatoid arthritis,

gout)

2. Dysmenorrhea 3. Renal colic 4. postoperative pain

Adverse effects: see before (common adverse effects of NSAIDs)

III. SELECTIVE COX-2 INHIBITORS

Celecoxib

• Selective COX-2 inhibitors were developed to avoid the adverse effects

resulting from inhibition of constitutive COX-1 in GIT and kidney.

( الذي يتواجد بصورة COX1تطوير مثل هذا الادوية لتجنب الاعراض الجانبية الناتجة عن تثبيط ال)تم *

(constitutiveفي اغلب الانسجة ). (بالاضافة الى كون COX2 is inducible اي تعمل في حالات )

( لذلك أخذ هذه الادوية قد kidney& EC( في )constitutive( ك )COX2،ولكن تم اكتشاف وجود)الالتهابات

يؤدي الى احداث اعراض جانبية

Uses:

1. Anti-inflammatory: chronic inflammatory musculoskeletal disorders

(with less risk of gastric ulceration).

2. Progression of Alzheimer disease (anti-inflammatory effect) (as they

found that COX2 has role in progression of Alzheimer)

3. Risk of colorectal cancer (COX-2 is responsible for tumor growth). (used

as prophylaxis in family cancers cases as PGs has role in tumor growth)

Found in markets as

(Voltaren, Cataflam)

SCIENTIFIC TEAM 8 –الفريق العلمي

Adverse Effects of COX-2 Inhibitors

1. Nephrotoxicity (COX-2 is constitutive in kidney).

2. Stroke & infarction (COX-2 is responsible for endothelial PGI2 synthesis).

*PGI2 or Prostacyclin cause VD and decrease platelets aggregation so, when I

inhibit the synthesize of PGI2 this will lead to VC and increased platelets

aggregation which indicate increase possibility of having stroke in brain or

infraction in heart

3. Skin rash with celecoxib (structurally related to sulfonamides).

*As it has similar structure of sulfonamide which is common in causing

allergy reaction this will cause skin rash.

IV. PARACETAMOL (Acetaminophen) (حفظ الاسمين هام)

• It is an analgesic antipyretic with NO anti-inflammatory action.

As paracetamol work on COX3(COXB1) that is founded only in CNS.

• It is preferred to aspirin in:

1. Patients Allergic to aspirin.

2. Bleeding disorders (does not affect platelet function).(as paracetamol

doesn’t cause bleeding)

3. Peptic ulcer (no GIT disturbances).( )

4. Children with viral infections (to avoid Reye’s syndrome with

aspirin).

5. Gout (aspirin may cause hyperuricemia).

( uric acid( قد يزيد من ) Aspirin in low dosesمعلومة غير مطالبين فيها، ولكن باختصار فأن ال) *

Dose: - Oral: 500 mg /4hrs or 6hrs/day

- Can be given IV or rectal

Kinetics

*well absorbed orally and can cross through BBB towards CNS& it is

metabolized in liver • Paracetamol is metabolized in liver by two pathways:

1. Major pathway: 95 % undergoes sulphation and glucuronic acid

conjugation → inactive metabolites

SCIENTIFIC TEAM 9 –الفريق العلمي

2. Minor pathway: Only 5% is converted by CYP450 to a hepatotoxic

metabolite N-acetyl-p-benzoquinone imine (NAPQI) deactivated

by conjugation with glutathione (GSH).

• In toxic doses saturation of sulphation and conjugating enzymes

↑ conversion of the drug to the toxic metabolite (NAPQI) >> the capacity

of liver to conjugate it with glutathione hepatotoxicity (centrilobular

necrosis).

Adverse Effects and Toxicity

• Minimal adverse effects (such as vomiting and Nausea) - well tolerated( safe

drug compared with other drugs)

• Nephrotoxicity: with high doses for long periods.

كل المسكنات الها اضرار على مستوى الكلية لذلك لازم نوخذها بوصفة طبية وعند الحاجة فقط.

• Paracetamol hepatotoxicity in toxic doses [10 gm or 150 mg/kg]:

nausea and vomiting, followed in 24-48 h by liver damage

Treatment: - Precursors for glutathione synthesis to prevent liver damage

- should be given early within 7-14 hrs

( ولكن بعد dialysisبحاول اقلل من امتصاص الدواء او كميته بالجسم عن طريق )ساعات 7*قبل

14( عشان اتخلص من المواد السامة ولكن بعد GTH precursorsعطي ) اساعات لازن ابلش 7ال

(irreversibleوالضرر الي بنتج بكون ) (hepatic necrosisساعة رح يصير عندي )

* N-Acetylcysteine (orally or IV) or methionine (orally).

*I give these drugs to join NAPQI and deactivate them& they belong to

essential Amino acids.

The treatment of paracetamol toxic dose

indicates lowering the absorbance of the

drug or dialysis (before 7 hours)

The antidot for toxicity cases indicated SH

donors or GTH precursors to join with

NAPQI and deactivate them.

( على هاي الرسمة بس kinetics*الدكتور شرح )

نفس الكلام الي فوق.