2005 wk 8 lec

Histamine chemical structure

Synthesised via histidine

• Histidine (amino acid) contains carboxylate group

• Decarboxylation occurs (via HDC)

• Formation of Histamine

Can come from diet and foods as well eg. wine

Where is histamine found?

• Mast cells

• Basophils (in blood)

The lungs, GIT, and skin have the highest no. of mast cells

Hence the reason for most allergic reactions occurring at these sites ?

How does Histamine act?

Acts as an agonist to different Histamine receptors

eg. H1, H2, H3, H4 receptors (all of which are G-protein coupled receptors)

These H receptors have constitutive activity

• Meaning they can be activated and inactivated regardless of Histamine binding (eg. can initiate contraction of lungs without histamine)

Why are antihistamines called antihistamines instead of antagonists?

They are classified as inverse agonists

• Inhibit histamine from activating the receptor

• Even though they block the H1 receptors, they cannot be classified as antagonists as they are acting on the constitutive activity

• They stabilise and preserve the inactive form, so even though histamine can still bind → it cannot trigger an action

Stimulation of H1 receptors

• Directly (eg. on bronchial smooth muscle)

  • Contraction of smooth muscle

  • eg. bronchoconstriction

• Indirectly (eg. vascular smooth muscle / blood vessel)

  • Relaxation (vasodilation)

  • Release of Nitric Oxide which induces relaxation of VSM

• Itchiness

  • As sensory neurons become increasingly sensitive

• CNS arousal and awakening (feeling awake

  • Which is why 1st gen antihistamines cause drowsiness and feeling sleepy

Histamine Triple Response

An experiment to observe whether scratching the skin would stimulate the same response as injecting histamine locally

Both of which caused:

• Redness of skin

• Surrounding flare of skin (beyond the scratch site redness - spreading a little further out)

• Weal (the slight bump)

Conclusion: Scratching replicates the stimulation of H1 receptors

Type 1 Hypersensitivity

IgE Allergic reaction

• Occurs when a harmless substance is mistaken by the immune system as a threat

  • Lack of tolerance leads to sensitivity

• Prior exposure to the allergen causes the immune system to produce IgE antibodies against it

  • IgE antibodies bind to mast cells and basophils, ready to initiate an immune response for future exposure

• Majority of people do not react or produce sensitivity to these allergens, but some may develop it

Examples of Allergens =

- Peanuts

- Pollen

- Seafood

- Penicillin

Important to note: there are many additional mediators to allergic reactions eg. which is why antihistamines are not first line treatment for asthma due to other contributing factors (eg. Mast cells, basophils, histamines + more)

Sensitisation TH2 driven process *****

TH2 = Type 2 Helper T cells ?

• Antigen presentation to Antigen Presenting Cell (APC)

• Consumed by APC

• APC binds to TH2 cell

• IgE production

• Mast cell degranulate and release cytokines (this does not occur immediately; but rather following the initial exposure to the allergen, it is prepared for the next exposure)

Cytokines = trigger for TH2, Histamines is the trigger for Type 1

→ Clinical effects:

- Asthma

- Eczema

- Anaphylaxis

- Allergic Rhinitis (Hay fever)

IgE receptor activation

• Antigen binds to IgE antibodies

• Once antigen binds, the antibodies must cross-link

• Degranulation is triggered and initiates release of cytokines

Non-IgE receptor mast cell activation

Pseudoallergic reaction

• Can occur on first exposure (as opposed to IgE mediated = first exposure triggers hypersensitivity for the next exposure)

Mas-related G protein-coupled receptors:

• Morphine

• Vitamin K1

• Substance P

Allergic Rhinitis

Histamine release from mast cells stimulate H1 receptors to produce:

• Vasodilation

• Itchy, swollen red eyes

• Itchiness
  Runny nose

• Sneezing

Skin rash and Hives

Histamine release from mast cells stimulate H1 receptors to produce:

• Vasodilation

• Skin rashes

• Weals

• Itchiness
  Redness

First-line for Allergic Reactions

F.A.S.T

Face

• Rash

• Swelling of lips

• Eyes

Airway

• Breathing difficulties

• Swallowing

• Speaking

Stomach

• Abdo pain

• Vomiting

• Diarrhoea

Total Body

• Rash

• Swelling

• Weakness

Role of Epinephrine in Anaphylaxis

MOA:

• Alpha Agonist → Vasoconstriction, reverse hypotension and reduce oedema

• B1 Agonist → Increase Cardiac output

• B2 Agonist → Bronchodilation

Use of Epipen:

• Use ASAP to reduce mortality risk

• Injected into mid-thigh - slow release

Antihistamines

• Inverse agonists

• Act on H1 receptors and induce inactive state of constitutive activity

H2 receptor Antagonists

eg. Famotidine

Sedating Antihistamines

• Promethazine (allergies)

• Doxylamine (Sleep Aid)

Sedation is caused when these drugs cross BBB acting on the CNS H1 receptors → causing sedation

Therapeutic Uses:

• Allergies

• Insomnia

• Motion Sickness

→ be ware they may induce antimuscarinic effects due to non-selectivity and action in the CNS

Effects can last from 8 - 30hrs

SEs of Sedating Antihistamines

• CNS depression

  • Should not be combined with benzo’s, opioids, alcohol etc. due to antimuscarinic effects)

• High drug interactions risk

Treatment of Motion Sickness

• Dimenhydrinate

• Diphenhydramine

  • H1 antihistamine and anticholinergic effect

Hay fever treatment ****

Non-sedating Antihistamines

• Loratadine (Claratyne)

• Cetirizine (Zyrtec) → Slightly more sedating than Loratadine

• Longer half lives

• More selective for H1 receptors

• Used for allergic rhinitis etc.

Can be used with CNS depressants as opposed to sedating Antihistamines

Antihistamine transport from CNS

Antihistamines have high affinity for P-glycoprotein transporter

• Easily transported from CNS to systemic blood circulation

• Loratadine > Cetirizine for affinity

  • Green = P-glycoprotein transporter

• If antihistamine remained in CNS, histamine would continue to be antagonised → Inducing drowsiness and sleepiness as blocking histamine blocks the promoting of wakefulness

Sedating vs Non-sedating antihistamines

Why do we use NSAIDs / Paracetamol?

• Pain

• Inflammation

Mediators that induce pain:

• Prostaglandins

• Leukotrienes

• Substance P

• Bradykinin

NSAID examples

Traditional:

• Aspirin (> 300mg)

• Ibuprofen

• Naproxen

• Diclofenac

COX-2 inhibitors:

• Celecoxib

• Meloxicam

Use of NSAIDs

• Back aches, headaches

• Muscle aches and pain

• Gout

• OA / RA

etc.

How do NSAIDs do?

• Analgesic (decrease pain)

• Anti-inflammatory (deactivates cells)

• Antipyretic (decrease heat)

• Antiplatelet

By blocking the production of prostaglandins through the inhibition of COX enzymes

Production of Prostaglandins and Leukotrienes

• Phospholipase A2 activated

• Generates Arachidonic Acid

• Arachidonic acid becomes metabolised through many pathways; the main two being

  • COX → Prostaglandins

  • 5-Lipoxygenase → Leukotrienes

Eg. of production of Prostaglandins through COX

1) Arachidonic Acid

2) COX metabolism

3) PGG2 & PGH2

4) Production of Prostaglandin types through Isomerase / Synthase

• Depends on the cells type and what type of the enzymes are available

5) Formation of different types of prostaglandins (and their respective subtypes)

How do NSAIDs work?

• Blocking COX enzyme responsible for metabolism of Arachidonic Acid; reducing production of prostaglandins

COX-1 Enzymes

• Found in most cells

• Constitutive (always making) enzyme that synthesises production of prostaglandins involved in homeostasis 

  • AKA the “good” prostaglandins

COX 2 Enzymes

• Induced by inflammatory response

• Synthesises prostaglandins in response to pain and inflammation

  • Considered the “bad” prostaglandins

SOME COX 2 enzymes are constitutive (initially thought to always be induced by pain / inflammation)

eg. in the kidneys, vascular tissue

• Therefore important to be wary of inhibiting to an extent through NSAIDs

What do prostaglandins do?

Act on G-protein coupled receptors

Eg.

• PGE2

• PGI2

Involved in pain and inflammation

• Induce vasodilation

• Increase permeability of blood vessels

• Increase sensitivity of nerves to pain stimuli (They do not directly produce the pain; but rather increase the sensitivity and detection to minor stimuli inclusive)

Traditional NSAIDs MOA

Block the production of ALL prostaglandins

• Inhibition of both COX 1 + COX 2

Why is this important?

• It can provide beneficial therapeutic effects by blocking COX-2 induced pain and inflammation

  • Analgesic & anti-inflammatory effect

• Inhibition of COX 1 can induce potential ADEs and disruption to homeostasis

Example of “housekeeping” / “good” prostaglandins

• Those that help maintain mucosal layer in stomach

• Those that reduce gastric acid secretion

Stomach and NSAIDs

• Highly acidic pH

• Pepsin (digestive enzyme)

NSAIDs may reduce the protective gastric mucosal barrier which in turn exposes the stomach lining to highly acidic and dangerous fluids and enzymes that can cause PUD 

What does COX 1 do for the stomach?

• Increase bicarbonate secretion

• Increase mucosal blood flow

• Increase mucous secretions

• Reduce gastric acid secretion

Another example of “Housekeeping” Prostaglandinds

• COX 1 that regulates platelet function

  • Eg. TXA2, PGI2

TXA2 & PGI2*****

Thromboxane is formed in platelets by COX 1

• Induces platelet aggregation

• Produces vasoconstriction

• Contributing to clotting factors

Prostacyclin is formed in the endothelial cells by COX 1 and COX 2

• Inhibit platelet aggregation

• Vasodilation

COX 1 / COX 2 in platelet aggregation

Thromboxane = COX 1 produced

• Promotes platelet aggregation

• Vasoconstriction

Prostacyclin = COX 2 and COX 1 produced

• Inhibits platelet aggregation

• Vasodilation

These 2 balance each other out by inducing opposite effects in order to control platelet aggregation

Low dose Aspirin

Inhibits COX 1 in platelets → inhibiting TXA2 production

• Which in turn reduces platelet aggregation

• Reduces the effects of vasoconstriction

• Aspirin binds irreversibly to COX 1 - meaning COX 1 in platelets cannot regenerate in comparison to COX 1 & 2 in vascular tissue (which can regenerate)

How does lose Aspirin work?

Background info:

• COX 1 converts Arachidonic Acid in platelets into Prostaglandin Thromboxane A2 (TXA2)

• TXA2 induces platelet aggregation and vasoconstriction

Now what does Aspirin do?

• Irreversibly binds to COX 1

• COX 1 in platelets cannot regenerate - therefore binding to COX 1 in platelets allows for the reduction in platelet aggregation and vasoconstriction

Vascular Tissue can regenerate COX 1 & COX 2 - therefore inhibiting it would not induce as much of a therapeutic effect

More “Housekeeping” Prostaglandins

• Those that help maintain renal function

  • eg. PGI2, PGE2 (COX 2)

• Those that help airway function in patients with asthma

  • Eg. PGE2

+ Assist implantation of fertilised ovum

ADEs of NSAIDs

• GIT bleeding and PUD

• Reduced renal function

• Na + water retention

• Miscarriage

• Asthma AE

  • Bronchoconstriction

NSAIDs in asthma / lung function

When using NSAIDs, Arachidonic acid cannot be metabolised via COX as the pathway is blocked

• Decrease of prostaglandins

• However, the AA has to metabolise in some form, therefore Leukotrienes conc increases

• Leukotrienes promotes narrowing of the airways (bronchoconstriction)

NSAIDs for elderly patients

• More susceptible to ADEs of NSAIDs due to reduced renal clearance

Use of NSAIDs with caution; why?

• Potential PUD

• Cardiac failure

• Renal failure

• HTN

• Asthma

• Pregnancy

Antipyretic effect of NSAIDs

• Inhibition of prostaglandins in the hypothalamus

• Only reduces elevated temperatures - NOT regular body temp.

Drug interactions of NSAIDs

• ACE i

• ARBs

• Diuretics

• Warfarin

• Methotrexate

COX 2 inhibitors (selective ?)

• Celecoxib

• Meloxicam

Produce the same analgesic and anti-inflammatory effect as traditional NSAIDs

Benefits of COX 2 i

• Produce less GI bleeding and ulcers ADEs

• Do not inhibit platelet aggregation and vasoconstriction

  • As TXA2 is responsible for this; via COX 1

ADEs of COX 2 selective NSAIDs

• Renal effects

  • Use with caution in renal impairment

  • Use with caution in cardiac failure

• HTN exacerbation

• Stroke

This is because inhibiting COX 2 reduces prostacyclin conc, which leaves elevated levels of TXA2. When TXA2 levels are elevated and there is an imbalance, platelet aggregation and vasoconstriction is increased

Drug interactions of COX 2 inhibitor NSAIDs

• ACE i

• ARBs

• Diuretics

Precautions to consider when using NSAIDs

• High doses and term of use

• CVD risk

• Stroke risk

• Renal function

Aim to use for shorter durations and lower doses where possible; this includes ALL NSAIDs

Paracetamol

Max dose: 4g / 24hrs → Typically well tolerated

• Analgesic effect

• Antipyretic effect

• NO anti-inflammatory effects

MOA = not fully understood

When to use Paracetamol

When NSAIDs are contraindicated

• CVD

• Renal impairment

• Severe asthma

• HTN

• Previous ACS

• Elderly (eg. OA where NSAIDs are necessary)

Benefits of of using Paracetamol in comparison to NSAIDs

• Fewer drug interactions

• Does not induce PUD or GI bleeding

• No exacerbation of renal function

• No effects of platelet aggregation

ADEs of Paracetamol

Liver toxicity and metabolic ADEs

• Over production of NABQI via CYP450 enzymes

• NABQI is toxic; though typically conjugated with glutothione in an inactivated form

What happens when Paracetamol overdose occurs?

• As glutathione is typically conjugated with NABQI, Glutathione stores become depleted

• When there is no more Glutathione, NABQI becomes activated

• NABQI on its own can bind and with other cell components - causing liver toxicity and death

Symptoms of Paracetamol OD

• N / V (initial symptoms)

Serious liver damage symptoms:

• Jaundice

• Metabolic disturbances

Although, typically undetectable until lab tests eg. LFT

Treatment of Paracetamol OD

Restore Glutathione levels

• Provide IV Acetylcysteine

Goal is to deactivate NABQI → Aim to treat within 12hrs post-OD