Histamine, serotonin and eicosanoids Flashcards
(84 cards)
1
Q
Types of histamine receptors
A
- H1: Gq
- H2: Gs
- H3: Gi pre synaptic
- H4: Gi on leukocytes
2
Q
Effects of H1 receptor
A
Gq ➡️ increases Ca 1. Bronchoconstriction 2. Vasodilation: NO (produced by Ca dependent endothelial NOS) 3. GIT: contraction 4. Hypothalamus: Anorexia Wakefulness
3
Q
Effects of H2 receptor
A
Gs ➡️ increases cAMP
- Myocardial contraction
- Increased acid secretion in stomach
4
Q
Effects of H3 receptors
A
Gi ➡️ stimulates H3 receptors ➡️
Decreases histamine release ➡️
decreases effect of H1 and H2
H3 blockers/ inverse agonists are used
5
Q
Effects of H4 receptor and the drugs affecting this receptor
A
Gi - chemotaxis
Present in leukocytes
Drugs: H4 blocker
Used in atopic dermatitis
6
Q
H3 blockers/ inverse agonists
A
Examples:
Tiprolisant
Pitolisant
They increase histamine ➡️ H1 stimulation ➡️ increased wakefulness ➡️ treatment of narcolepsy
7
Q
First generation H1 blockers
A
Anti-muscarinic effects Reduced potency Lipid soluble ➡️ crosses BBB ➡️ side effects: sedation CI: 1. Drivers 2. Pilots 3. Children 4. Elderly people
8
Q
Second generation H1 blockers
A
Increased potency
Lipid insoluble: do not cross BBB
Less sedating
Preferred in drivers and pilots
9
Q
Examples of first generation H1 blockers
A
- Promethazine: anti-emetic
- Diphenhydramine: local anaesthetic
- Dimenhydrinate: insomnia
- Doxylamine: morning sickness
- Chlorpheniramine
- Hydroxyzine: anti-pruritic, anxiolytic
- Doxepin: TCA
- Cyprohepadine
- Meclizine/cyclizine: motion sickness
10
Q
Promethazine, diphenhydramine and dimenhydrinate
A
First generation H1 blocker
Maximum antimuscarinic effect
Uses: treatment of
1. EPS (Extra pyramidal side effects) like acute dystonia and Parkinsonism
2. Motion sickness: 1hr before travel (oral)
3. Ménière’s disease
11
Q
Promethazine specific properties and uses
A
First generation H1 blocker (,anti muscarinic) and α1 blocker ➡️ causes hypotension
Uses:
1. In chemotherapy induced nausea and vomiting
2. As local anaesthetic
12
Q
Specific uses of diphenhydramine and dimenhydrinate
A
Both are first generation H1 blocker Diphenhydramine: As local anaesthetic Dimenhydrinate: For treatment of insomnia
13
Q
Doxylamine
A
First generation H1 blocker
DoC for morning sickness (used with vitamin B6)
14
Q
Chlorpheniramine
A
Least sedating 1st generation H1 blocker ➡️
Day time use
15
Q
Hydroxyzine, cetirizine and levocetirizine
A
Hydroxyzine: 1. First generation H1 blocker 2. Anti pruritic effect ➡️ used in skin allergy 3. Anti emetic 4. Anxiolytic Cetirizine: 1. 2nd generation H1 blocker 2. Metabolite of hydroxyzine 3. Most sedating 2nd generation drug Levocetirizine: 1. more potent derivative of cetirizine 2. 3rd generation H1 blocker
16
Q
Doxepin
A
First generation H1 blocker
Used as TCA (Tricyclic antidepressant)
17
Q
Cyprohepadine
A
First generation H1 blocker
Used as 5HT2 blocker, muscarinic blocker
18
Q
Meclizine/cyclizine
A
First generation H1 blocker
Treatment of motion sickness, though less effective
19
Q
2nd generation H1 blockers example
A
- Cetirizine
- Astemizole: not used
- Terfenadine: not used
- Loratidine: bronchodilator
- Rupatadine: anti-inflammatory
- Acrivastine: nasal decongestant
20
Q
Astemizole, terfenadine and fexofenadine
A
First 2 are 2nd generation H1 blockers
Astemizole and Terfenadine:
QT prolongation
Not used now
Fexofenadine:
Derivative of terfenadine (used)
Least sedating H1 blocker
Substrate for P glycoprotein in brain ➡️ efflux
21
Q
Loratidine
Acrivastine
A
Both are 2nd generation H1 blocker
Loratidine:
For prophylaxis of exercise induced bronchoconstriction
Acrivastine:
Used along with pseudoephedrine as a nasal decongestant
22
Q
Rupatadine
A
2nd generation H1 blocker
Inhibits PAP (platelet activating factor) ➡️
anti inflammatory effect
23
Q
Topical H1 blockers
A
- Alcaftadine
- Azelastine: AR
- Epinastine
- Olopatidine: AR
- Ketotifen
- Levocarbastine
All are used for: allergic conjunctivitis and ocular pruritis
Azelastine and Olopatadine: used for allergic rhinitis
24
Q
3rd generation antihistaminics
A
Derivatives of 2nd generation antihistaminics
- Levocetirizine
- Fexofenadine
- Desloratidine (most potent H1 blocker)- derivative of loratidine
25
Uses of H1 blocker
```
1. Allergic rhinitis (hay fever):
DoC: steroid
Antihistaminic of choice: 2nd generation H1 blocker
2. Non allergic rhinitis:
1st generation H1 blocker
(anti muscarinic effect ➡️ decreased secretion)
3. Urticaria:
DoC: 2nd generation antihistaminics
```
26
Bradykinin synthesis
Kininogens ➡️ kallikrein (intermediate) ➡️ kallidin and bradykinin,
both stimulate bradykinin receptors B1R and B2R, leading to:
1. Increased synthesis of PG ➡️ pain and inflammation
2. Increased synthesis of NO ➡️ vasodilation
27
Bradykinin related drugs
```
Against hereditary angioedema
Blocker of B2R:
Icatibant: treatment
Kallikrein antagonists:
1. Aprotinin
2. Lanadelumab: prophylaxis
3. Ecallantide: treatment
Aprotinin (inhibits plasmin) to reduce risk of bleeding on CABG patients
```
28
Hereditary angioedema
```
1. Treatment:
DoC: C1 esterase inhibitor
Alternatives: icatibant, ecallantide
2. Prophylaxis:
DoC: Danazol
Alternatives: Lanadelumab
3. Prophylaxis prior to surgery
EACA (E Amino Caproic Acid)
```
29
Serotonin receptors
5HT1-5HT7
| All are GPCR except 5HT3 (which is a ion channel)
30
5HT1 receptors
```
5HT1:
Gi coupled
Presynaptic on location
Two types:
1. 5HT1A:
Location serotonergic neurons
2. 5HT1B/1D:
Location 5th cranial nerve
```
31
5HT1 agonists
1. Buspirone
2. Ipsapirone
3. Gepirone
Anxiolytics as they reduce serotonin release
32
Pathology of migraine
The CGRP neurotransmitter released by trigeminal nerve causes vasodilation of meningeal blood vessel via CHRPR.
Excess activation of the nerve ➡️ increased vasodilation ➡️ migraine
33
Treatment of migraine
1. 5HT1B/1D agonist like triptans
2. Ergot alkaloids like dihydroergotamine
3. NSAIDs in mild attack
4. Opioids like pethidine
5. D2 blockers in acute type like chlorpromazine
34
5HT1B/1D agonist uses
Of Frovatriptan and Navatriptan:
1. More preferred for a prolonged attack of migraine
2. Treatment of migraine precipitated by menstruation
Of Rizatriptan and Eletriptan:
Best for acute attack of migraine
35
5HT1B/1D agonists
| Examples
1. Sumatriptan:
Least oral bioavailability, PPB, BBB penetration, efficacy, but safest in pregnancy
2. Frovatriptan-longest acting
3. Navatriptan
Last 2 have slow absorption and onset ➡️ long acting
4. Rizatriptan-faster and maximum efficacy
5. Eletriptan
Last 2 have fast absorption and onset
36
New drugs for prophylaxis of migraine
```
CGRP blockers:
1. Fremanexumab
2. Glacanezumab
CGRPR blocker: Erenumab
Calcitonin gene related peptide
```
37
5HT1B/1D agonists CI and side effects
```
1. Causes vasoconstriction so CI in:
• Ischaemic heart disease
• Stroke/ TIA
• Peripheral vascular disease
2. Arrhythmia
3. Pain in jaw, sweating
```
38
Ergotamine
```
Stimulates:
1. 5HT1B/1D - CGRP
2. 5HT2 - VC
3. α1 - VC
Can cause gangrene of organs with end arteries. Eg., fingers
Then DoC is:
1. Nitroprusside
2. Nitroglycerin
```
39
Dihydroergotamine
```
Stimulates:
1. 5HT1B/1D - CGRP
2. 5HT2 - VC
3. α1 - VC
Less potent vasoconstrictor compared as ergotamine
Well tolerated
```
40
Opioids against migraines
Butorphanol (Intranasal)
Pethidine (intramuscular)
Used only in case of drug resistant attacks
41
D2 blockers against migraines
Chlorpromazine
Metoclopramide
Decreases dopamine effect
42
Drugs used in migraine prophylaxis
```
Flunarazine.
Can. Cyprohepadine, Candesartan, clonidine
P. Propranolol (DoC), pizotifen, phenelzine
R. } increases GABA like
E. } Gabapentin
V. Valproate
E.
N. Nortriptyline
T. Topiramate
Migraine. Methysergide
```
43
5HT2 antagonists examples
1. Cyprohepadine: migraine prophylaxis
2. Methysergide: migraine prophylaxis
3. Ketanserin: HTN
4. Flibanserin: HSDD
44
Cyprohepadine
```
5HT2 antagonists
Uses:
1. Prophylaxis of migraine
2. Cold urticaria
3. Serotonin syndrome
4. Carcinoid syndrome
5. Weight gain in cancer patients
```
45
Methysergide
```
5HT2 antagonist
Uses:
1. Prophylaxis of migraine
But it can cause fibrosis:
1. Pulmonary
2. Cardiac
3. Retro peritoneal
```
46
Ketanserin
5HT2 and α1 blocker
Uses:
1. Treatment of HTN
2. Treatment of erectile dysfunction
47
Flibanserin
5HT2 blocker and 5HT1 agonist
Uses:
1. Treatment of HSDD
48
5HT2 receptor agonist
Locaserin
Anorexic agent
Treatment of obesity
49
Treatment of obesity
1. Anorexic agents
2. Lipase inhibitor
3. Lipolysis stimulator
4. Unknown mechanisms
50
Anorexic drugs used for treatment of obesity
1. Locaserin
2. Liraglutide
3. Phentermine
51
Lipase inhibitors and lipolysis stimulants that are used for treatment of obesity
Lipase inhibitors: Orlistat
| Lipolysis stimulants: Mirabegron (β3 agonist)
52
Drugs with unknown mechanisms that are used for treatment of obesity
1. Topiramate
2. Naltrexone
3. Bupropion
53
Banned drugs for obesity
1. Rimonabant: suicidal tendency
2. Sibutramine: MI
3. Phenylpropanolamine: stroke
54
General uses of 5HT3 inhibitors and 5HT4 stimulants
5HT3 inhibitors: anti emetic
5HT4 stimulants: prokinetic
Involved in GIT
55
Synthesis of eicosanoids
```
Arachidonic acid is acted on by COX-1 and 2 and 5-LOX
1. COX-1 and 2:
PG: pain, inflammation and pyrexia
TX-A2: aggregant, vasoconstriction
2. 5-LOX:
Leukotrienes-C4,D4: bronchoconstriction
```
56
Drugs which inhibits the leukotrienes
```
Drugs inhibiting 5-LOX:
Zileutron
Drugs inhibiting leukotriene-C4D4:
Montelukast, Zafirlukast
Used in bronchial asthma as they cause bronchodilation
```
57
PG E analogies
```
PG E1 analogues (patency of ductus arteriosus):
1. Misoprostol
2. Alprostadil
PG E2 analogue:
Dinoprostone: cervical ripening
```
58
Misoprostol
```
PG-E1 analogue
Uses:
1. Maintain patency of ductus arteriosus (like alprostadil)
2. Abortion
3. Post Partum Haemorrhage
4. Gastric ulcer
```
59
Alprostadil
PG-E1 analogue
Uses:
1. Maintain patency of ductus arteriosus (like misoprostol)
2. Erectile dysfunction (vasodilation)
60
Dinoprostone
```
PG E2 analogue
Uses:
1. DoC for cervical ripening
2. Post partum haemorrhage
3. Abortion
```
61
PG I2 (thrombocyclin) increasing drugs
```
All are used in pulmonary hypertension
1. Analogue: Epoprosterenol
2. Synthetic PG I2:
• Iloprost
• Beraprost
• Treprostinil
3. PG I2 receptor agonist: Selexipag
```
62
PG F2α analogues
1. Carboprost:
Used in PPH and abortion
2. Latanaprost and Bimatoprost
DoC for open angle glaucoma and normal tension glaucoma
63
Non selective NSAIDs
1. Acetaminophen: osteoarthritis
2. Aspirin: R arthritis and niacin induced flushing
3. Indomethacin: Gout and Bartter syndrome
4. Ibuprofen and its 3 derivatives
5. Piroxicam: chronic pain
6. Ketorolac: potent analgesic
7. Meloxicam, Etodolac and Diclofenac
64
Acetaminophen or paracetamol
Non selective NSAID
Good analgesic and anti pyretic- in osteoarthritis
Poor anti inflammatory drug
Most common cause of drug poisoning, features:
1. Hypoglycaemic coma
2. Renal tubular necrosis
3. Hepatotoxicity
65
Acetaminophen poisoning
| Mechanism and microscopy
NAPQI-Metabolite of acetaminophen ➡️ depletes glutathione ➡️ increased free radicals ➡️ liver damage
Microscopy:
Centrilobular necrosis with periportal sparring
66
Acetaminophen toxicity
| Dosage and prediction
```
Dosage for toxicity:
>10 gm
>150-250 mg/kg
If more than 20 gm, then fatal
Prediction is using Rumack Mathew nomogram
```
67
Treatment of acetaminophen toxicity
1. Charcoal:
If less than 4 hours of consumption
(Gastric lavage is not done)
2. N-Acetyl cysteine: DoC
Block NAPQI and it replenishes glutathione
If no response ➡️ Fulminant liver failure (most common cause)
Treatment: emergency liver transplantation
68
Aspirin
| Effects
```
Irreversible inhibitor of COX (non selective NSAID)
At low doses:
50-325 mg/day
Anti aggregant
At high doses:
3-4 gm/day
Anti inflammatory
```
69
Uses of aspirin
```
1. Analgesic of choice in:
• Rheumatoid arthritis
• Rheumatic arthritis
2. DoC: niacin induced flushing (which occurs due to increase in PGs)
3. Anti aggregant
```
70
Aspirin toxicity
```
Dose: >10 gm
1. Respiratory alkalosis followed by compensatory metabolic acidosis
2. Hyperthermia
3. Hypoglycaemia
4. Seizures
5. Pulmonary oedema in elderly
Treatment: urine alkalinisation
In case of pulmonary oedema, dialysis is done
```
71
Indomethacin
```
1. DoC for:
• acute gout
• Bartter syndrome
2. Analgesic of choice for:
• psoriatic arthritis
• reactive arthritis
3. Closure of PDA (DoC: ibuprofen)
```
72
Side effects of indomethacin
Non selective NSAID
1. Nephrotoxicity
2. Pancreatitis
73
Ibuprofen
Non selective NSAID
Used as analgesic and anti inflammatory drug
DoC: closure of PDA
Side effects:
1. MCC of drug induced aseptic meningitis
2. Ocular: blurring of vision and toxic amblyopia
74
Derivatives of ibuprofen
1. Ketoprofen
2. Flurbiprofen: miotic agent
3. Nimesulide
75
Ketoprofen
Derivative of ibuprofen (non selective NSAID)
Extra effects:
1. Stabilises lysosomes
2. Inhibits bradykinin
76
Flurbiprofen
Derivative of ibuprofen (non selective NSAID)
| Used in intraoperative miosis in ocular surgery
77
Nimesulide
```
Derivative of ibuprofen (non selective NSAID)
Use:
1. Analgesic
2. Anti inflammatory
Side effect: Hepatotoxic
CI:
1. Children <12 years
2. Adults for more than 15 days
```
78
Piroxicam
```
Non selective NSAID
Longest acting (enterohepatic circulation) with slow onset of action
Use: chronic pain
```
79
Ketorolac
Non selective NSAID
Very potent analgesic (as opioids)
Post operative analgesic
Also used as eye drops (topical) as analgesic
80
Side effects of non selective NSAIDs
1. GIT ulcer:
DoC- PPI
Most specific drug: Misoprostol
2. Nephrotoxic: renal papillary necrosis
3. All are cardiotoxic except low dose aspirin
4. Hypersensitivity like urticaria, rashes,...
5. Decrease diuretic and anti hypertensive effect
Not effective in neuropathic pain
81
Selective COX-II inhibitors
1. Celecoxib: least selective
2. Lumiracoxib > Etoricoxib:
Most selective
Longest acting
3. Valdecoxib: shortest acting
4. Parecoxib:
water soluble
Used in post operative pain
82
Side effects of selective COX-II inhibitors
1. Refecoxib and Valdecoxib increases risk of MI
2. Lumiracoxib (from diclofenac) is hepatotoxic
These drugs are banned
83
Dual 5-LOX and COX inhibitors
1. Licofelone
2. Tepoxalin
Future anti inflammatory drugs
Lesser GIT side effects
84
NSAIDS more selective for COX-II among the non selective drugs
1. Etodolac (most selective)
2. Meloxicam
3. Diclofenac
Use: analgesic
Diclofenac:
• hepatotoxic
• Formulated with Misoprestol to protect GIT
