Autacoids😍

Autacoids

• Autacoids have autocrine effects (Local effects).

• They are classified based on chemical Structure:
• Peptide Autacoids:
• Angiotensin, Bradykinin.
• Amine Autacoids:
• Histamine, 5-HT.
• Lipid Autacoids:
• Prostaglandins, Leukotrienes, Thromboxane.

HISTAMINE

Receptors

H1 Blockers

5-HT (SEROTONIN)

Serotonin Receptors

• Mnemonic for blockers:
• Train (5HT3) AC (5HT2AC) block (Blockers) aaki

MIGRAINE

New Drugs for Migraine:

Lasmiditan (DITANS):

• Stimulates 5HT1F receptor and decreases CGRP release.
• Remember CGRP is very bad → Gripping ↑↑↑ Pain

• Prevents vasodilation and neuronal inflammation.

• Effective orally.

• Recently approved for acute attacks of migraine.

• Advantage over triptans:
• does not induce peripheral vasoconstriction.

CGRP Antagonist: (GEPANTS → Gene Peptide Antagonist):

• CGRP → Most Potent Vasodilator

• Used for acute attack.

• Effective orally.

• Drugs: Olcegepant, Rimegepant, Ubrogepant.

• Advantage over triptans:
• does not induce peripheral vasoconstriction.

Monoclonal Antibodies Against CGRP:

• Approved for prophylaxis of migraine

• Given by injectable route.

• Examples: Erenumab, Fremanezumab, Galcanezumab, Eptinezumab.

• Mnemonic:
• Laksmi (Lasmi) de pant (GEPANT) Maattiyapo (Mab) headache poi
• EFG mumab
• mab → maappu → Preman (Freman) kaalilveenu (Galcanezumab) Maappu (mab) Erennu (Erenumab)

Ergot Alkaloids:

• Ergotamine

NSAIDs:

• Paracetamol: mild - moderate attack

• Ketorolac: severe attack

Opioids:

• Intranasal butorphanol

• Oral codeine

In Pregnancy

• DOC: Paracetamol

• No response: Codeine/Caffeine/Metoclopramide

• No response: Triptans (Sumatriptan - Triptan of choice in pregnancy)
• Triptans: May block placental blood flow

Status migrainosus:

• Migraine lasting >72 hours;

• Prednisolone 60 mg/day

• may require IV fluids,

• Dihydroergotamine 1 mg IV
• Can cause Raynauds

PROSTAGLANDINS

• 1. General Effects:
• Fever
• Pain
• Inflammation

• 2. Platelets:
• TX A2: Aggregation.
• PG l2: Inhibition of aggregation.

• 3. Heart:
• DOC for medical closure of PDA in the preterm neonate:
• PG inhibitors → NSAIDs
• Ibuprofen (DOC d/t fewer side effects)
• Aspirin
• Indomethacin
• Mnemonic:
• Ind → End → Close the duct
• Prostaglandin E1 → P → keep oPen the duct
• Ductus Arteriosus is kept open by PGE1.
• Misoprostol
• Alprostadil

• 4. Uterus:
• PGs Contract upper segment of uterus.
• Used for abortion (Misoprostol is used).

• 5. Stomach:
• PGE2 protect the stomach from peptic ulcer disease.
• For NSAID Induced Peptic Ulcer Disease:
• Most specific drug is Misoprostol.
• DOC is proton pump inhibitors.

• 6. Eye:
• PGF2α → ↑ Uveo scleral outflow → Latanoprost → DOC for Primary Open Angle Glaucoma.

Phosphodiesterase (PDE) Inhibitors

PDE-4 inhibitor

• Drug:
• Roflumilast

• Use:
• COPD

• Roflumilast → for flu lasting 4 days (PDE 4)→ COPD

PDE-3 inhibitor

• Drug:
• Milrinone
• Use:
• CHF
• ↑ Inotropy
• I → no one (milriNone) → when i have CHF
• Theophylline and aminophylline
• aka Methylxanthines





• Given orally or by intravenous route
• Not available by inhalational route
• MOA of Bronchodilatation
1. Inhibit PDE 3 >> 4
• Thereby ↑ cAMP
• S/E due to PDE inhibition
• Nausea, Vomiting, Diarrhea
• Headache
• Arrhythmias
• Note: Sildenafil → PDE 5 ⛔
2. Adenosine A1 receptor antagonist
• S/E due to Adenosine A1 antagonism
• Arrhythmias
• Diuresis
• Epileptic seizures
• MOA of Anti inflammation
• PDE 4⛔
• ↑ IL 10
• Histone deacetylase stimulation → similar to steroid
• Theophylline is metabolized by microsomal enzymes
• Prone to drug interactions
• Enzyme inducers
• Like smoking
• Decrease the effect
• Therefore smokers require higher doses
• Enzyme inhibitors
• Like ciprofloxacin, clarithromycin and erythromycin
• Can result in toxicity
• Seizures, arrhythmias etc.

Platelet inhibitors

• Non selective PDE inhibitor

• Drugs:
• Cilostazol
• Dipyridamole

• Effects:
• Vasodilators

• Use:
• PAD

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

• COX 1:
• Constitutive Enzyme.
• Present normally at most places.

• COX-2:
• Inducible enzyme.
• Present normally in Kidney, Endothelium, CNS.

• NSAIDS act by inhibiting COX.

These may be:

Aspirin:

• Irreversible COX inhibitor

• Dose-Dependent Effects:
• 50-325 mg OD:
• Antiaggregant
• 325-650 mg SOS (max 4 doses/day):
• Analgesic, Antipyretic
• 3-4 g/day (divided doses):
• Anti-inflammatory
• In Kawasaki

• Some miscell uses
• Niacin induced flushing: DOC
• Kawasaki disease

• S/E:
• Bleeding (m/c)
• Reyes Syndrome
• Viral fever in children -> Aspirin -> Hepatic encephalopathy
• ↑ Uric acid → so not given in gout

• Salicylism (Toxicity):
• Dose > 10g
• Clinical features:
• Seizures
• Tinnitus
• Hyperglycemia
• Acidosis (Metabolic)
• Rx:
• Symptomatic management
• Alkalinisation of urine → ↓ reabsorption
• Dialysis (severe toxicity)

Paracetamol:

• Mechanism of Action:
• Downregulates PG synthesis:
• Analgesia
• Antipyrexia
• No anti-inflammatory action
• Stimulate TRPV1 receptors
• Stimulate Cannabinoid receptors
• COX - 3 inhibitor

• safe in CKD

• Do not produce peptic ulcer

• In toxicity
• NAPQI is toxic intermediate
• Casue liver damage
• Antidote NAC

Hepatotoxicity:

• Major mechanism:
• Paracetamol induced liver failure.
• ↑↑↑ NAPQI (Paracetamol metabolite) → ↓↓↓ Glutathione (free radical scavenger)
• Free radical damage to liver on hepatocytes
• Centrilobular necrosis + Periportal sparing

• Note:
• Major cause of drug poisoning → Paracetamol
• M/c drug to to cause Liver failure → Paracetamol
• Symptoms:
• Symptoms of renal tubular necrosis
• Hypoglycemic coma
• Hepatotoxicity

Dosage:

• Toxic Dose:
• 150-250 mg/kg
• > 10 g

• Fatal Dose:
• > 20 g

Prediction of hepatotoxicity:

• Rumack Matthew Nomogram:



• Plasma concentration vs. Time

Management:

• < 4 hr of consumption:
• Charcoal

• DOC:
• N-acetyl cysteine

• No response:
• Fulminant hepatic failure requiring Emergency liver transplant

Step ladder pain management

Suzetrigine

• Non opioid drug for moderate to severe pain

GOUT

• It is characterized by increase in serum uric acid

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Acute Gout

Chronic Gout 

a. Drugs decreasing production of uric acid

b. Drugs increasing excretion of uric acid (Uricosuric agents)

c. Drugs increasing metabolism of uric acid

Allopurinol

• DOC:
• Chronic gout
• Tumor Lysis Syndrome
• Lesch-Nyhan Syndrome
• Defective purine metabolism
• Organ transplant

• Side effects:
• Hypersensitivity (severe):
• Stevens-Johnson Syndrome (associated with HLA-B*5801)
• Orotate decarboxylase inhibition:
• Causes orotic aciduria
• DRESS syndrome
• Mnemonic: Allu (Allopurinol) arjun → Johnson (SJS) powder → Dress up () and Oridath irunn (Orotic aciduria) muthram ozhich

RHEUMATOID ARTHRITIS

• For B cell ⛔ → R/o hep B

• For TNF α ⛔ → R/o TB

• NSAIDs and Steroids
• ↓ Pain and Inflammation
• No effect on disease Progression
• Fast acting

• DMARDs or SAARDs
• Slow down the disease progression
• Slow acting
• Used now
1. Methotrexate (DOC)
2. Sulfasalazine
3. Leflunomide
4. Hydroxychloroquine
• Mnemonic - sulfikkar () met () and left () gave water with chlorine ()

• Biological agents
• TNF alpha inhibitors

1. DMARDs

Hydroxychloroquine

Leflunomide

• Fastest acting DMARD

• Mnemonic: Le F → Le fast

Methotrexate

• Drug of choice (DOC) for rheumatoid arthritis

• ⛔ DHFR → ↓ THF → ⛔ Purine synthesis → Lymphocyte toxicity

• ↑ Adenosine
• Anti inflammatory response
• Hepatic Fibrosis

• Side Effects
• ↓ Folic acid → BMS
• Hepatotoxicity + Liver Cirrhosis
• Needs Liver Function Test (LFT) Monitoring

Sulfasalazine

• DOC for ulcerative colitis

Other DMARDS

Penicillamine

• Used for Copper poisoning/Wilson’s disease

Chloroquine

• DMARD of choice in pregnancy

• Cause corneal opacity

Azathioprine

Gold salts

2. Biological DMARDs

i. Drugs Inhibiting TNF-α

• All are injectable

• Drugs:
• Adalimumab (A)
• Certolizumab (C)
• Etanercept (E)
• Infliximab (INhibitor)
• Golimumab (Goli)

• Mnemonic:
• (Ace Inhib Goli maro)
• Everything has “mab” except → Etanercept → Ethaan exception

• Risks:
• Increased risk of infections

• Contra-indications:
• Tuberculosis (TB)
• Hepatitis B

• Uses → "Alpha Inhibitors Prevent RA”
• Ankylosing spondylitis
• Inflammatory bowel disease
• Psoriatic arthritis, Plaque psoriasis
• Rheumatoid Arthritis (RA)

ii. IL-1 Receptor Antagonist

• Anakinra
• Mnemonic: AKINRA
• A - 1st letter
• KIN - Interleukin
• R - Receptor
• A - Antagonist

iii. IL-6 Receptor Antagonists

• Tocilizumab
• 1st IL-6 targeted monoclonal antibody
• Approved for cytokine release syndrome treatment
• If Cytokine get released → shoot him (Thokku → toclizumab)

• Sarilumab
• Used for rheumatoid arthritis
• Mnemonic:
• Difficult to wear Sari when u have RA
• S - Six (referring to IL-6)
• AR - Rheumatoid Arthritis (R.A.)
• MAB - Monoclonal antibody

• Mnemonic: 6 (IL6) thavana → Tokkuvach (Toclizumab) vedi vach → Saral (Sarilumab) madathe

iv. Co-stimulation Inhibitors

3. Inhibitors of JAK

• Jak (Jak inhib) With Bro (Abro) in Sofa (Tofa) in Bar (Bari)

• Tofacitinib

• Baricitinib

• Abrocitinib

Previous Years Questions (Q1 to Q15 of Chapter 3)

• Q1. Most specific antiemetic for Chemotherapy induced vomiting is: Granisetron.

• Q2. Buspirone is a drug used in chronic anxiety. It produce its action by acting on which of the following receptors?: 5HT1A.

• Q3. A boy is planning to travel by bus. Which of the following drug can be used to prevent motion sickness in this person?: Promethazine.

• Q4. Drug of choice for prophylaxis of migraine is: Propranolol.

• Q5. A young female presented with left sided severe throbbing headache associated with nausea, vomiting, photophobia and phonophobia. Which of the following drug can provide immediate relief to this patient?: Sumatriptan.

• Q6. Drug of choice in paracetamol overdose is: N-acetylcysteine.

• Q7. A 34 week pregnant female with polyhydramnios presents with labour pain. She was treated with indomethacin earlier. Which of the following can be likely outcome in the baby if delivery occurs at this time?: Premature closure of ductus arteriosus.

• Q8. A 60 year old female with renal disease was admitted for pyelolithotomy. Post operative analgesic of choice in this patient is?: Acetaminophen.

• Q9. Which of the following is the fastest urate lowering therapy in tumor lysis syndrome to prevent renal damage?: Rasburicase.

• Q10. A female patient presented with pain and redness in great toe. Serum uric acid level is 9.6 mg/dL. Apart from prescribing analgesics for relieving pain, the physician prescribed a drug which can decrease the formation of uric acid. Which of the following enzyme is likely to be inhibited by this drug?: Xanthine oxidase.

• Q11. Drug inhibiting granulocyte migration is: Colchicine.

• Q12. Pegloticase is used for treatment of: Chronic tophaceous gout.

• Q13. A patient diagnosed with Rheumatoid arthritis was on medications. After 2 years, he developed blurring of vision and was found to have corneal opacity. Which drug is most likely to cause this?: Chloroquine.

• Q14. Tocilizumab is an immunosuppressive drug used for Rheumatoid arthritis. It is a monoclonal antibody against: IL-6.

• Q15. A 40 year old male patient presents to hospital with pain in great toe. It was diagnosed to be a case of gout. Which of the following drug increases the excretion of uric acid in urine?: Probenecid.