AUTACOIDS AND AUTACOIDS'

ANTAGONISTS

11/25/2021 1
 Histamine Antagonists:

Histamine release /the effects of histamine being released

in the body can be reduced by:
 Physiologic antagonists - Epinephrine
 Inhibition of histamine synthesis,
 Release inhibitors - Cromolyn and nedocromil

 Histamine receptor antagonists(H1 and H2)

Note: The inhibition of histamine synthesis has not been

employed clinically.
11/25/2021 2
 H1-antagonists:

 Divided into first-generation and second-generation agents

 The older first-generation –

Widely used (effective and inexpensive)

 However, most of these drugs penetrate the CNS and cause
sedation

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 Block autonomic receptors

(producing a variety of unwanted adverse effects)

 The second-generation agents are specific for H1

receptors

 Do not penetrate the blood-brain barrier

( Non sedating)

 Show less CNS toxicity than the first-generation drugs

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Fig. Effects of H1 antihistamines at histamine, adrenergic, cholinergic,
and serotonin-binding receptors.
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First generation - Hl‐Receptors Antagonists:

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Note:

 They are largely ineffective in asthma or systemic anaphylactic

shock because …

 Leukotrienes (C4, D4) and PAF are more important mediators

than histamine.

 Concentration of antihistamines attained at the site may not

be sufficient to block high concentration of histamine released
locally in the bronchi.

 Other local hormones are involved

(a physiological antagonist e.g. adrenaline, is used).

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Table- Clinical classification, doses and preparations of H1 antihistaminics

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Second generation H1‐Receptors Antagonists

E.g. Fexofenadine , Cetirizine, Loratidine, Terfinadine,

1. Cannot cross the blood brain barrier

2. No sedation

3. Less side effects

4. Longer duration of action

 BUT More expensive

11/25/2021 9
 Pharmacokinetics:

 H1-receptor blockers are well absorbed after oral

administration,
 Maximum serum levels occurring at 1 to 2 hours

 Plasma t1/2- Average - 4 to 6 hours

 High BA

 Distributed in all tissues, including the CNS.

 Most are metabolized by the hepatic cytochrome P450 system
 Also they induce hepatic cytochrome P450 enzymes (CYPs)
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 Loratadine and its active metabolite, desloratadine ,
undergoes extensive first-pass metabolism.
 Most excreted in the urine as metabolites

 Cetirizine and fexofenadine undergo little hepatic

metabolism and are eliminated mainly as unchanged.

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Therapeutic Uses:
1. Allergic and inflammatory conditions:
DOC-in controlling the symptoms of allergic rhinitis , urticaria, and
conjunctivitis , but
Ineffective in bronchial asthma, and anaphylaxis
2. Motion sickness and nausea:
Diphenhydramine , dimenhydrinate , cyclizine , meclizine

The most effective agents for prevention of the symptoms of motion

sickness

3. Somnifacients: Diphenhydramine and promethazine used in the

treatment of insomnia (as sleep aids for sleep induction)
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 Adverse effects:

1. Sedation:

Is the most frequently observed adverse reaction

Other central actions, dizziness, uncoordination, blurred vision,

2. Antimuscarnic effects-

Dry mouth and respiratory passages, urinary retention, and dysuria

Constipation and fatigue also have been reported.

3. Drug interactions:

Potentiation of the effects of all other CNS depressants, including

alcohol ,

MAOI , cholinesterase inhibitors ???

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B. Serotonin (5-Hydroxytryptamine)

 An indole ethylamine
 Formed in biologic systems from L-tryptophan

by hydroxylation of the indole ring & decarboxylation of

the amino acid.
 It is an important neurotransmitter,

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Clinical Uses of Agonists:

1. Sumatriptan (5‐HT1D) :
Treatment of acute attacks of
migraine by causing vasoconstriction of cerebral blood

vessels.
2. Buspirone (5‐HT1A) : Anxiety

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5‐HT2 receptors:
 It occurs in CNS and Periphery (B.V, platelets and autonomic
neurons).

Effects:

 Neural and smooth muscle effects are Excitatory

 2nd Messenger: Transduction by PLC/IP3/DAG

 Specific Agonists: Lysergic acid diethylamide (LSD) in the CNS

(partial agonist, it has hallucinogenic properties).

 Yet, it acts as an antagonist for 5HT2‐receptors in the periphery.

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 Specific Antagonists: Ketanserin, Cyproheptadine

Clinical Uses of Antagonists

 Ketanserin : It antagonizes platelet aggregation and VC

produced by 5HT2 receptor activation.

 It also blocks α‐ adrenergic receptors in B.V.

(Antihypertensive & tt of peripheral vascular diseases in some

countries).

 Cyproheptadine: Allergy, Carcinoid tumor and appetite

stimulant

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5‐HT 3 receptors:
 It occurs in CNS and Periphery

(nociceptive and enteric neurons)

Effects:
 Excitatory -Receptor‐Coupled Ion Channels (Na+ ‐ K+).
 Specific Agonists: 2‐Methyl‐5‐HT

 Specific Antagonists:

 Ondansetron, Tropisetron and Granisetron.

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Clinical Uses of Antagonists:
 5‐HT3‐antagonists block 5‐HT receptors in the CTZ and
used mainly as antiemetics during surgery and cancer
chemotherapy.

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5‐HT4 receptors:
 Occurs in CNS and Periphery (enteric neurons).

Effects:
 Excitatory, causing increased GI motility.

 2nd Messenger: Transduction by increase of cAMP.

 Specific Agonists: Metoclopramid and Cisapride

Clinical Uses of Agonists

1. Metoclopramid: Gastroprokinetic & antiemetic

2. Cisapride: Gastroprokinetic (withdrawn/limited: long QT)

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Note:

 5‐HT5‐7 receptors are located in the CNS and little is known

about their role in humans.

 5‐HT reuptake inhibitors E.g. Fluoxetine & paroxetine are

useful Antidepressants.

 5‐HT effects can be blocked also by blocking synthesis

[Parachlorophenylalanine (PCPA)] or blocking of storage

(Reserpine).

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The Triptans:
Examples- Sumatriptan , zolmitriptan , naratriptan , and
rizatriptan
 Are effective, acute antimigraine agents
 They can decrease the nausea and vomiting of migraine

 Interact potently with 5-HT1D and 5-HT1B receptors and

 Have a low or no affinity for other subtypes of 5-HT

receptors

 Inactive at α1 ;α 2 , β, dopaminergic, cholinergic, and

benzodiazepine receptors

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Table - Pharmacokinetics of triptans

Drug Routes Max. Dose Per Half-Life (h)

Day (mg)
Naratriptan Oral 5 5.5

Rizatriptan Oral 30 2

Oral, nasal,
Sumatriptan 200 2
SC
Oral, nasal
Zolmitriptan 10 2.8

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Adverse effects:
 Dizziness, muscle weakness, neck pain,
 Parenteral sumatriptan, injection site reactions

 Chest discomfort occurs in 1-5% of patients, and chest pain

has been reported
 Contraindicated in patients with coronary artery disease,
angina , and in patients who are taking monoamine oxidase
inhibitors…???
 Duration of effect is often shorter than the duration of the
headache
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Serotonin Antagonists

Cyproheptadine:

 Has potent H1-receptor-blocking as well as 5-HT2-blocking actions

 It prevents the smooth muscle effects of both amines but

 Has no effect on the gastric secretion stimulated by histamine

 It also has significant antimuscarinic effects and causes sedation

 Used in in the treatment of the smooth muscle manifestations of

carcinoid tumor and in cold-induced urticaria

 Usual dosage in adults is 12-16 mg/d in three or four divided doses

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Ketanserin:

 Is the prototypic 5-HT2A-receptor antagonist

 Potently blocks 5-HT2A receptors, less potently blocks 5-

HT2C receptors, and

 Has no significant effect on 5-HT3 or 5-HT4 receptors or any

members of the 5-HT1-receptor family

 Has high affinity for a adrenergic receptors and histamine

H1 receptors
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 Ketanserin lowers blood pressure in patients with
hypertension
 Inhibits 5-HT-induced platelet aggregation
 Severe side effects - have not been reported
 Its oral bioavailability is about 50%, and

 Plasma half-life is 12 to 25 hours

 The primary mechanism of inactivation is hepatic
metabolism

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II. Lipid-Derived Autacoids:

 The main phospholipids‐derived mediators include:

A. Eicosanoids:
 Prostaglandins

 Thromboxanes
 Leukotrienes

B. Platelet activating factor (PAF)

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EICOSANOIDS

 The eicosanoids are oxygenation products of

polyunsaturated long-chain fatty acids (20-carbon)
(Arachidonic acid or 5,8,11,14-eicosatetraenoic acid )
 Are among the most important mediators and modulators
of inflammatory reactions.
 The principal eicosanoids are the prostaglandins, the
thromboxanes, and the leukotrienes,

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A. Prostanoids
 The prostaglandins, thromboxane, and prostacyclin, collectivel

termed as prostanoids,

 Are generated from PGH2 through the action of isomerases and

synthases,

 PGE2, PGD2, PGF2α ,PGI2 and TXA2 are the principal bioactive end
products .
 In platelets- TXA2 predominates,

 In vascular endothelium PGI2 is the main product

 Macrophages, neutrophils and mast cells synthesise a mixture of

products.

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Degradation:

 Occurs rapidly in most tissues,

 Fastest in the lungs

 Most PGs, TXA2 and prostacyclin have plasma t½ of a few

seconds to a few minutes.

 First a specific carrier mediated uptake into cells occurs,

 The side chains are then oxidized and double bonds are reduced

in a stepwise manner to yield inactive metabolites.

 Metabolites are excreted in urine.

31
Clinical Uses of Prostanoids:

PGs and their analogues have restricted clinical application

because of:


Limited availability,


Short lasting action,


Cost and frequent side effects.

However, their use in glaucoma and in obstetrics is now

common place.

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 Gynaecological and obstetric:
 Termination of pregnancy: gemeprost (a prostaglandin

that ripens and softens the cervix), or misoprostol

(orally active synthetic analog of PGE 1)

 Effective during the second trimester

 Cervical priming (ripening)- Applied intravaginally or
in the cervical canal,
Low doses of PGE2 which do not affect uterine motility
make the cervix soft and compliant
 Induction of labour: Dinoprostone or misoprostol
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E.g. Prostin-E2 for induction/augmentation of labour,
midterm abortion.
 Vaginal gel (1 mg or 2 mg in 2.5 ml) 1 mg inserted into

posterior fornix, followed by 1–2 mg after 6 hour if required.

 Postpartum haemorrhage: Carboprost , especially in patients
unresponsive to ergometrine and oxytocin.
 0.25 mg in 1 ml amp; 0.25 mg IM every 30–120 min for

PPH, midterm abortion, missed abortion.

 Gastrointestinal

 To prevent ulcers associated with non-steroidal anti-

inflammatory drug use: misoprostol
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 Ophthalmic
 Open-angle glaucoma: latanoprost, travoprost, bimatoprost

Are FP receptor agonists are the first choice drugs in wide angle
glaucoma eye drops.
 Cardiovascular
 To maintain the patency of the ductus arteriosus : alprostadil
(PGE1) - 0.5 mg in 1 ml amp; dilute and infuse IV

 To inhibit platelet aggregation (e.g. during haemodialysis):

epoprostenol (PGI2), especially if heparin is contraindicated

Preparation: 0.5 mg vial for reconstitution

 Primary pulmonary hypertension: epoprostenol
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 Adverse effects of the prostaglandins

The ADRs of the prostaglandins are moderate

A slightly higher incidence of nausea, vomiting, and diarrhea

PGF2a has more gastrointestinal toxicity than PGE 2

No significant maternal cardiovascular toxicity in the recommended doses.

Uterine cramps, unduly forceful uterine contractions, vaginal bleeding, flushing, shivering,
fever, malaise, fall in BP, tachycardia, chest pain.

PGF2a is a bronchoconstrictor and should be used with caution in women with asthma.

Fetal toxicity is uncommon

Irreversible brown pigmentation of the iris and eyelashes,

Drying of the eyes, and conjunctivitis.

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 Preparations Available

Carboprost tromethamine

Parenteral: 250 mcg carboprost and 83 mcg tromethamine per mL ampule

Dinoprostone [prostaglandin E2]

Vaginal: 20 mg suppositories, 0.5 mg gel, 10 mg controlled-release system

Epoprostenol [prostacyclin]

  Intravenous: 0.5, 1.5 mg powder to reconstitute

Latanoprost-Topical: 0.005% ophthalmic solution

Misoprostol- Oral: 100 and 200 mcg tablets

        

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Routes and Dosage Ranges

 Carboprost tromethamine - IM 250 mcg q1.5–3.5h,

depending on uterine response, increased to 500 mcg per

dose if uterine contractility is inadequate after several

250-mcg doses.

 Dinoprostone (vaginal suppository)-Intravaginally 20 mg,

repeated q3–5h until abortion occurs

 Misoprostol- PO or intravaginally 200–400 mcg q12h for
second trimester termination.
 Termination usually complete within 48 h
38
 ANALGESIC-ANTI-INFLAMMATORY AND
RELATED DRUGS

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 INTRODUCTION
Pain, fever and inflammation
Pain: is the sensation of discomfort, hurt, or distress
 May occur with tissue injury and inflammation
 PGs sensitize pain receptors Increase the pain associated with
other chemical mediators such as

bradykinin and histamine…

Fever: is an elevation of body temperature above the normal range
 It may be produced by:
 Inflammation,
 Infectious processes,
 Brain injury, or diseases involving the hypothalamus
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Inflammation: is the normal body response to tissue damage
from any source .
 It is an attempt by the body to remove the damaging agent
and repair the damaged tissue
 May occur in any tissue or organ

 Local manifestations:- vasodilation, redness, swelling, heat,

pain, and loss of function.
 Systemic manifestations:- Fever, general filling of illness

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 The analgesic–antipyretic–anti-inflammatory drug group
includes chemically and pharmacologically diverse drugs
that
 Share the ability to relieve pain, fever, and/or
inflammation
 Some times called the Aspirin, NSAIDs, and
Acetaminophen
 Are among the most widely used of all drugs
 Now more than 50 different NSAIDs on the global market

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 NSAIDs Chemical Groups and Examples
1. Salicylates: Aspirin, Sodium salicylate , Magnesiumsalicylate,
Methylsalicylate
2. Propionic acid derivatives:Ibuprofen,Fenoprofen,
Flurbiprofen, Ketoprofen

3. Acetic acid derivatives:Indomethacin,Tolmetin, Sulindac,

Ketorolac

4. COX-2 inhibitors: Rofecoxib,Celecoxib,Valdecoxib,Etoricoxib,

Parecoxib.

5. Phenylbutazone: Antipyrine , Phenylbutazone, Dipyrone

6. Oxicams: Meloxicam , Piroxicam, Tenoxicam.

7.Paraminophenol (Acetaminophen [in USA]: Paracetamol

8. Phenylacetic acid derivative: Diclofenac

11/25/2021 43
 Beneficial actions due to PG synthesis inhibition:

 Analgesia: Prevention of pain nerve ending

sensitization

 Antipyresis

 Antiinflammatory

 Antithrombotic

 Closure of ductus arteriosus in newborn

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 Shared toxicities due to PG synthesis inhibition

 Gastric mucosal damage………?

 Bleeding: Inhibition of platelet function…..?

 Limitation of renal blood flow: Na+ and water Retention

 Delay/prolongation of labour……?

 Asthma and anaphylactoid reactions in susceptible

individuals ……?

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 At higher concentrations, NSAIDs –

 Known to reduce production of superoxide radicals,

 Induce apoptosis,

 Inhibit the expression of adhesion molecules,

 Decrease nitric oxide synthase,

 Decrease proinflammatory cytokines (e.g., TNF-α, interleukin-

1),

 Modify lymphocyte activity, and alter cellular membrane

functions

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 Indications For Use

 NSAIDs are widely used to prevent and treat:

 Mild to moderate pain and/or inflammation associated
with musculoskeletal disorders

(E.g. osteoarthritis, rheumatoid arthritis, gout),

 Headache, dysmenorrhea, minor trauma (E.g., athletic
injuries ),
 Minor surgery (E.g., dental extraction, episiotomy)
 Fever

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Other Clinical Uses:
 Systemic Mastocytosis-

(excessive mast cells in the bone marrow,

reticuloendothelial system, GI system, bones, and skin)

Large amounts of PGD2 release

Severe episodes of vasodilation and hypotension

 Aspirin or ketoprofen have provided relief

 Niacin Tolerability - To controll intense flushing mediated by
a release of PGD2 from the skin as aresult of niacin.
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 Adverse Effects

 Mechanism-based side effects :-

Gastric irritation, which may range from simple
discomfort to ulcer formation
 A tendency to prolong bleeding

 Lungs, hypersensitivity, allergic reactions

(Bronchospasm, urticaria, rhinitis)
Delayed parturition, dystocia (Uterine)
 Vascular Closure of ductus arteriosus

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 Renal:
 Salt and water retention

 Edema, worsening of renal function in renal/cardiac and

cirrhotic patients
 Decreased effectiveness of antihypertensive medications

 Decreased effectiveness of diuretic medications

 Decreased urate excretion (especially with aspirin)

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Adverse effects decreased with COX-2–selective drugs

 GI
 Abdominal pain,Nausea, Anorexia

 Gastric erosions/ulcers , Anemia

 GI hemorrhage, Perforation
 Platelets

 Inhibited platelet activation (Propensity for bruising)

 Increased risk of hemorrhage

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 Adverse effects that are not related NSAIDs MoA:

 Hepatic effects:

 Hepatitis, hepatic necrosis, cholestatic jaundice,

 Increased serum aminotransferases,

 Dermal effects:

 Photosensitivities, Stevens-Johnson syndrome, toxic epidermal

necrolysis,

 CNS effects:

 Headaches, dizziness, tinnitus, deafness, drowsiness, confusion,

nervousness, increased sweating, aseptic meningitis),

 Ocular effects - Toxic amblyopia, retinal disturbances 52

 Contraindications and Drug Interactions

 History of ulcer disease, advanced age, poor health status,

 Smoking, and heavy alcohol use
 Used with caution in patients with renal impairment, heart failure,
hypertension, and edema
 Concomitant treatment with corticosteroids (long term), other
NSAIDs

 The use late in pregnancy (may increase the risk of

postpartum hemorrhage)

 Hypersensitivity
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Table - Summery of NSAIDs Drug Interactions

11/25/2021 54
Ibuprofen
 A commonly used drug,
 Well absorbed with oral administration
 Its action starts in about 30 minutes,
 Peaks in 1 to 2 hours, and lasts 4 to 6
 Highly bound (about 99%) to plasma proteins

 A half-life of about 2 hours

 It is metabolized in the liver,and
 Excreted through the kidneys
Routes and Dosage Ranges

 OA, RA: PO 300–600 mg 3 or 4 times per day, maximum, 2400 mg/d

 Pain, dysmenorrhea: PO 400 mg q4–6h PRN,

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Maximum - 3200 mg/d
 The most frequently observed side effects are nausea,
heartburn, epigastric pain, rash, and dizziness
 Incidence of GI side effects is lower than with
indomethacin
 Ibuprofen inhibits COX-1 and COX-2 about equally
 It decreases platelet aggregation

 Should be used with caution in patients who have

coagulation deficits or are receiving anticoagulant therapy

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Fenoprofen

 Fenoprofen is chemically and pharmacologically similar to

ibuprofen and is used in the treatment of RA,OA, and mild
to moderate pain

 GI effects such as dyspepsia and pain are most common

Dosage:

 OA, RA: PO 300–600 mg three or four times per day

 Pain: PO 200 mg q4–6h PRN maximum, 3200 mg/d

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Naproxen

 Naproxen also has pharmacological properties and clinical

uses similar to those of ibuprofen

 Has stronger antiinflammatory activity and it is particularly

potent in inhibiting leucocyte migration.

 CNS complaints (headache, dizziness, drowsiness),

dermatological effects (pruritus, skin eruptions) are common

 More valuable in acute gout

 Recommended for rheumatoid arthritis and ankylosing

spondylitis.
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Ketoprofen

 Has additional action to stabilize lysosomes and inhibit

LOX

 Antiinflammatory efficacy is similar to ibuprofen, and

side effects are more.

Flurbiprofen

 More effective than ibuprofen, but gastric side effects are

also more.

 It is used as an ocular antiinflammatory as well.

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Indomethacin , sulindac , and tolmetin

 These drugs have strong anti-inflammatory effects and

 Also inhibits the motility of polymorphonuclear
leukocytes and depresses the biosynthesis of
mucopolysaccharides.
 Have more severe adverse effects than the propionic acid
derivatives
 Potentially serious adverse effects:
 GI ulceration, bone marrow depression,

 Hemolytic anemia,
 Mental confusion, depression, and psychosis
 GI symptoms are more frequent and severe 60
Indomethacin:
 Used in the treatment of acute gouty arhritis, RA,OA ,and
spondylitis
 IV indomethacin is approved for treatment of patent ductus
arteriosus
 It is not recommended for use as a simple analgesic or
antipyretic
 It produces more CNS side effects (vertigo, confusion, and
psychological disturbances)

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 Hematopoietic side effects:

E.g. Leucopenia, hemolytic anemia, aplastic anemia,

thrombocytopenia, and agranulocytosis
Dosage: PO, rectal suppository,

75 mg/d initially, increased by 25 mg/d

at weekly intervals to a maximum of
150–200 mg/d, if necessary

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Diclofenac:

 Is chemically different from but pharmacologically similar to

other NSAIDs

 Is approved for use in RA, OA, ankylosing spondylitis,

dysmenorrhea, and

 Topically for the treatment of ocular inflammation and

actinic keratosis

 Has a serum half life of about 2 hours and is excreted mainly

in the urine
11/25/2021 63
Dosage: OA: PO 100–150 mg/d in divided doses or 100 mg

once daily

 RA: PO 150–200 mg/day in two, three or four divided doses

 AS: PO 100–125 mg/d in four or five divided doses

 Pain, dysmenorrhea: (diclofenac potassium only)

PO 50 mg three times daily

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Pharmacokinetics:
 Most are distributed widely throughout the body. Celecoxib
is particularly lipophilic,
 Lumiracoxib is more acidic than the others,

(favor its accumulation at sites of inflammation)

 All are well absorbed from GIT

 Extensively protein-bound :

 Etoricoxib and rofecoxib approximately 90%,

 The others approximately 97% to 99%)

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Clinical Use:
 Aproved for relief from postextraction dental pain and

 To afford dose-dependent relief from inflammation in

osteoarthritis and rheumatoid arthritis.

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 Paracetamol (Acetaminophen [in USA])

 Paracetamol is one of the most commonly used non-narcotic

analgesic-antipyretic agents
 Inhibit CNS prostaglandin synthesis by inhibiting COX3

(disproportionately pronounced in the brain )

 It has only weak antiinflammatory activity

(poor ability to inhibit COX in the presence of high

concentrations of peroxides)
 It is not useful in the treatment of rheumatoid arthritis and
other inflammatory conditions.
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 Has two major advantages over aspirin:

 Does not cause gastric irritation or

 No risk of increase bleeding
 It is the drug of choice for:

 Children with febrile illness

 Elderly adults with impaired renal
function and
 Pregnant women

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 The major drawback to acetaminophen use is potentially fatal liver
damage with overdose
(Converted to highly reactive intermediate metabolite- N-
acetyl-p-benzoquinoneimine (NAPQI)
 Thus it is not the drug of choice for people with:
 Hepatitis or other liver disorders or
 Hypersensitivity
 Those who drink substantial amounts of alcoholic beverages

Routes and Dosage Ranges

 Adult :PO 325–650 mg q4–6h,or 1000 mg three or four times per day;
maximum 4 g/d
 Children: PO 10 mg/kg
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E.g. Piroxicam, Meloxicam

 Are as effective as indomethacin

 Long half-life (Qd dosing)

 Indicated for the treatment of OA and RA
 Adverse GI reactions have been the most frequently reported SEs
 Piroxicam can cause serious GI bleeding, ulceration, and perforation

Routes and Dosage Ranges:

 Meloxicam: OA- PO 7.5mg Qd; increased to 15 mg Qd if
necessary
 Piroxicam : OA, RA- PO 20 mg/d or 10 mg twice daily
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 II. Rheumatoid arthritis (RA) and anti rheumatoid
agents

 RA is a chronic, painful, inflammatory disorder

 It is one of the commonest chronic inflammatory

conditions
 Affects joints, tissues around joints, bone and articular
destruction
 Eventually other body organs (systemic effects)

 It is considered as an autoimmune disorder

 The immune system mounts an attack against synovial
tissue.
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 Five main drug classes that are currently used for RA
treatment:

1. Analgesics,

2. Nonsteroidal anti-inflammatory drugs (NSAIDS),

3. Glucocorticoids,
4. Disease-modifying antirheumatic drugs (DMARDS), or
slow acting antirheumatic drugs (SAARDs)
5. Anticytokine therapies.

 Differ with respect to time course of effects, toxicity, and

ability to slow RA progression. ???
11/25/2021 72
 The goals of drug therapy in RA are:

 Ameliorate pain, swelling and joint stiffness

 Prevent articular cartilage damage and bony erosions

 Prevent deformity and preserve joint function.

 Analgesics:
 Provide pain relief from mild to moderate arthritis.

E.g. - Acetaminophen, tramadol, and narcotics

 Do not exhibit any antiinflammatory properties,
 They are usually combined with NSAIDs,

glucocorticoids, DMARDS, and anticytokine therapies.

NSAIDs:
 Provide rapid relief of symptoms, but
 Do not prevent joint damage and do not slow disease
progression.
 Are safer than DMARDs and glucocorticoids
 Treatment requires less vigorous monitoring

E.g. Ibuprofen, aspirin, naproxen, and indomethacin

N.B: Both NSAIDs & glucocorticoids provide rapid relief of

symptoms.
11/25/2021 74
DMARDs or SAARDs:

 Can substantially reduce the inflammation of RA,

 Reduce or prevent joint damage,

 Preserve joint structure and function, and

 Enable a person to continue his or her daily activities

 Act more slowly than with the NSAIDs

 Are more toxic than NSAIDs,

 Close monitoring is required.

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 Subdivided into two basic groups— non biologic DMARDs and biologic
DMARDs (Anticytokines)
 Usually employed in combination with NSAIDs and sometimes

other DMARDs.

Non biological drugs:

1. Immunosuppressants: Methotrexate, Azathioprine, Cyclosporine

2. Sulfasalazine

3. Chloroquine or Hydroxychloroquine, 4. Leflunomide

Biological agents-

1. TNFα inhibitors:Etanercept, Infliximab, Adalimumab

2. IL-1 antagonist: Anakinra

 Are effective in slowing the joint deterioration that occurs early
Non biologic DMARDs:
Methotrexate:
Is the most widely prescribed agent

Acts faster than all other DMARDs

Now considered the DMARD of first choice to treat rheumatoid arthritis due to:


Its efficacy,

Relative safety, low cost, and extensive use in RA.

Also used for psoriasis, psoriatic arthritis, and systemic lupus erythematosus.

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Pharmacokinetics:
 Approximately 70% absorbed after PO administration
 Serum half-life is usually only 6-9 hours
 Metabolized to a less active hydroxylated metabolite,

 Excreted principally in the urine, but up to 30%

may be excreted in bile.

 Probenecid and aspirin increase Mtx levels and toxicity..???

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Routes and Dosage Ranges:
 Severe RA unresponsive to other therapy

PO 7.5 mg/wk as single dose, or

2.5 mg q12h for three doses once weekly

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Adverse Effects
 In the low-dose regimen used for RA, most side effects are
mild include:
 Nausea, stomatitis, GI discomfort, rash, diarrhea, and
headaches
 Mild to moderate immunosuppression

 With prolonged therapy, dose dependent progressive -

Liver damage leading to cirrhosis occurs in some patients.

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 Possible severe toxicities include:

 Hepatotoxicity progressing to cirrhosis,

 Pneumonitis progressing to pulmonary fibrosis,
and
 Bone marrow depression with anemia,
leukopenia, and thrombocytopenia

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Contraindications and Drug Interactions
 Contraindicated during pregnancy ( Teratogenic)
 Breast-feeding
 Kidney, liver, and lung disease;

 Moderate to high alcohol use;

 Immunodeficiency;
 Blood dyscrasias; and hypersensitivity

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 Elderly persons may be at increased risk for toxicity
 Clearance can be decreased by the co- administration of
NSAIDs;
 Can be displaced from PPB sites by phenylbutazone,
phenytoin, sulfonylureas, and sulfonamides

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Azathioprine:
 Purine synthase inhibitor acts after getting converted to
6-mercaptopurine
 It is a potent suppressant of cell-mediated immunity;
 It also suppresses inflammation
 Less commonly used
(Remission is induced in smaller percentage of RA patients)
 Given along with corticosteroids, it has a steroid sparing
effect, for which it is primarily used now, especially in cases
with systemic manifestations.
 It is not combined with Mtx….??

Dose: 50–150 mg/day;

84
Glucocorticoids:
 Have strong antiinflammatory effects
E.g. Prednisone and prednisolone
 May be taken by mouth, injected into a vein, or

injected directly into a joint

 Quickly improve symptoms of rheumatoid arthritis

( pain and stiffness and also decrease joint swelling and

tenderness).

 Used to treat RA that severely limits a person's ability to

function normally.
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Adverse Effects:

 Weight gain,

 Worsening diabetes,

 Thinning of bones (osteoporosis), and

 An increased risk of infection.

 When steroids are used, the goal is to use the lowest

possible dose for the shortest period of time.

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 DRUGS USED IN GOUT

Gout is a metabolic disease in which plasma urate concentration is raised

because of :

Overproduction or

Impaired excretion of uric acid

( normal plasma urate 2–6 mg/dl)

(

It is characterized by painful intermittent attacks of acute arthritis

produced by:

Deposition of crystals of sodium urate in the synovial tissue of joints &

cartilage
An inflammatory response by:

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 Activation of the kinin,
 Complement and plasmin systems,
 Generation of lipoxygenase products,
 Lysosomal enzymes, and interleukin-1

 Formation of uric acid calculi in the kidneys & interstitial

nephritis also occur

 Usually associated with high serum levels of uric acid

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 Drugs used to treat gout may act in the following ways:
By inhibiting uric acid synthesis: Allopurinol
By increasing uric acid excretion: Probenecid,
Sulfinpyrazone
By inhibiting leucocyte migration into the joint:
Colchicine
By a general anti-inflammatory and analgesic effect:
NSAIDs

11/25/2021 89
 Treatment Principles
I. Relieving the acute gouty attack

 Arthritis is treated 1st & hyperuricemia latter as sudden

reduction of serum uric acid often precipitates further episodes

of gouty arthritis.

1. NSAIDs
 Inhibit urate crystal phagocytosis & PG synthesis
 Indomethacine most commonly used
 All NSAIDs except aspirin, salicylates & tolmetin have also
been successfully used to treat acute gouty episodes
90
NSAIDs C/I to:
 Active peptic ulcer disease,

 Impaired renal function, &

 History of allergic reaction to NSAIDs

 For patients at risk for upper gastrointestinal bleeding

cox-2 inhibitors are 1st line drug of choice to treat acute
gout

 Long term use of cox-2 inhibitors is not recommended b/c

of ↑ed cardiovascular risk
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Colchicine:
 Colchicine is an alkaloid

 Can be used both to prevent and to relieve acute attacks

Mechanism of action
 Binding to tubulin (Depolymerization)

Disruptsion of cellular functions( the mobility of granulocytes)

Decreasing their migration into the affected area
 Also inhibits the synthesis and release of the leukotrienes

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 It prevents the release of the chemotactic factors and/or
inflammatory cytokines from the neutrophils, and

Decreases the attraction of more neutrophils into the

affected area

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Pharmacokinetic:
 Colchicine is given orally,

 Well absorbed, and reaches peak concentrations in about 1 Hr

 It is excreted partly in the GIT and partly in the urine

Routes and Dosage Ranges

 Acute attacks, PO 0.5 mg q1h until pain is relieved or toxicity

(nausea, vomiting,diarrhea) occurs;

IV 1–2 mg initially, then 0.5 mg q3–6h until response is obtained;

maximum total dose 4 mg

 Prophylaxis - PO 0.5–1 mg/d

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Adverse Effects:

 GI intolerance (diarrhea, nausea, vomiting, and abdominal

pain)

 Hair loss and bone marrow depression as well as

peripheral neuritis and myopathy (rare)

 Acute intoxication (overdoses):

 Burning throat pain, bloody diarrhea, shock,

hematuria, and oliguria

 Fatal ascending central nervous system

11/25/2021
depression has been reported 95
3.Corticosteroids
 Give dramatic symptomatic relief in acute episodes of
gout
 Most useful in patient with contraindication to NSAIDs

Eg. Prednsone, methyl prednisolone

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Allopurinol:
 Is a purine analog
 It reduces the production of uric acid by inhibiting xanthine oxidase

 Is the drug of choice in the long-term treatment of chronic gout, but

 Ineffective in the treatment of an acute attack

Pharmacokinetics:
 Completely absorbed after oral administration
 The primary metabolite is alloxanthine (oxypurinol)- active
metabolite
 The half-life of allopurinol is 2 hours
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 Uric acid
Fig.7 Inhibition of uric acid synthesis by allopurinol

11/25/2021 98
Routes and Dosage Ranges:
 Mild gout, PO 200–400 mg/d

 Severe gout, PO 400–600 mg/d

 Hyperuricemia in clients with renal insufficiency, PO 100–
200 mg/d
Adverse Effects
 Gastrointestinal intolerance (nausea, vomiting, and
diarrhea)
 Depression of bone marrow elements
 Peripheral neuritis and necrotizing vasculitis

 Aplastic anemia may also occur

 Hypersensitivity reactions, especially skin rashes, are the
most common
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 URICOSURIC AGENTS

 Are weak organic acids that promote renal clearance of uric acid

 They can compete with uric acid for transport sites

 At therapeutic doses, they block proximal tubular resorption of
uric acid
 Probenecid and sulfinpyrazone are the two most commonly used
uricosuric agents
 Useful as prophylaxis for patients with severe recurrent gout

Note: At low dosage, these agents block proximal tubular

secretion of uric acid

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Pharmacokinetics:

 Probenecid is completely reabsorbed by the renal tubules

 Metabolized slowly ( t1/2 5-8 hours)
 Sulfinpyrazone is rapidly excreted by the kidneys

Routes and Dosage Ranges

 Probenecid - PO 250 mg twice a day for 1 wk, then 500 mg
twice a day
 Sulfinpyrazone PO 100–200 mg twice a day, gradually
increased over 1 wk to a maximum of 400–800 mg/d

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Adverse Effects:

 Both cause GI irritation( more with sulfinpyrazone)

 Rash may appear after the use of either compounds

 Rarely cause aplastic anemia

 Probenecid can impair the renal active secretion of:

sulfonylurea's, indomethacin, penicillin, sulfonamides

 Thus their dosage should be modified appropriately

N.B. Treatment with uricosuric drugs is initiated with an

NSAID
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