1.1 Autacoids: Histamin, Sertotonin, Prostaglandin

🔈 Histamine precursor is the amino acid

Histidine

Reversible, Competitive Antagonism or Inverse Agonism

. H1-RECEPTOR ANTAGONISTS

○ Strong HAM blockade, antiemetic + dystonias ○ Available in the Philippines parenterally.

PHENOTHIAZINE

Promethazine

You can use it for its antihistaminic properties but it is like using amitriptyline for urticaria. It is an overkill.

is the prototype of phenothiazine, which is where chlorpromazine originated from. They were trying to synthesize more potent antihistamines when they came across the mechanism of D2 antagonists.

Promethazine

The anticholinergic and antimuscarinic mechanism of what makes it useful for dystonias. Besides Diphenhydramine and Biperiden, we can use what for dystonias and pseudo-parkinsonism associated with antipsychotics.

Promethazine

may cause histamine to build up in the body when taken, triggering a flushing reaction.

Isoniazid

() is involved in wakefulness. It is more known to be related to itching and allergic reactions. has a role in balance (inner ear)
() are useful for managing allergic reactions while histamine itself mediates and causes allergy symptoms

Histamine
Antihistamine

an antihistamine drug, helps in relieving motion sickness

Meclizine

can be used to stimulate appetite for people with cancer. Histamine’s potency effects to appetite is greater if it both blocks H1 and 5-HT2C receptors.

Blocking H1 alone is not enough to induce appetite.

Olanzapine

● Triple response; red spot, edema, flare.

● Itch, Urticaria

● Motion Sickness, Wake Promotion

Vasodilation (NO; Flushing, Warmth)

H1

Triple response

; red spot, edema, flare.

H1

Gq

● Brain

● Smooth Muscle, Endothelium

Histamine Receptor for

● Gastric Acid Secretion

● Increased inotropy; increased pacemaker rate

H2

H2

Gs

● Gastric Mucosa

● Cardiac Muscle

● Mast Cells, Brain

Ethanolamines

Diphenhydramine
Dimenhydrinate

Doxylamine

○ Over-the-counter form is 25 milligram.

○ Students are not recommended to take this because it can affect cognitive function.

Diphenhydramine

Anticholinergics, sino inaalala natin?

Matatanda or people who will not be very fun when confused

Because its anticholinergic
Used for D2 blocker-induced acute dystonia

Can be used for EPS and Pseudoparkinsonism due to Acetylcholine and Dopamine being very linked in function. If you block the Acetylcholine receptor, you promote Dopamine release

Ethanolamine

Diphenhydramine

Dimenhydrinate

Doxylamine

8-Chlorotheophylline

Dimenhydrinate

Gargle for singaw.

○ Off-label. Diphenhydramine also blocks Na+ channels. It can mediate pain.mComplex instruction (swish and spit).

Ethanolamine

Diphenhydramine

Dimenhydrinate

Doxylamine

Scombroid Poisoning ○ Tuna has a tendency to have an abundance of histidine, when this fish is not stored properly, bacteria grow and convert histidine to histamine. Bacterial growth in sushi/tuna is not that visible or hard to tell.

■ Causes allergic reactions, so be careful in buying sushi.

Ethanolamine

Diphenhydramine

Dimenhydrinate

Doxylamine

Motion sickness prevention.

○ First-generation antihistamines are very anticholinergic. While it can be used in motion sickness, don’t use

diphenhydramine.

It was a marketing scheme since issue of sedation. This is true with first-generation antihistamines because they are lipophilic and can stay longer in the CNS. Staying in the CNS would block the wakefulness promotion since histamine can not bind to its receptor.

8-Chlorotheophylline (Dimenhydrinate)

diphenhydramine and theophylline (8-Chlorotheophylline)

DIMENHYDRINATE

Piperazine

Meclizine OTC
Hydroxyzine

Buclizine OTC

still has anticholinergic but less than diphenhydramine.

Piperazine

Diphenhydramine or Meclizine for Motion Sickness

Meclizine

HISTAMINE’S ROLE IN MOTION SICKNESS

Your brain has a system in tandem with the inner ear to integrate the inputs from your somatic sensation. Histamine will compare if there is a mismatch signal. If you block Histamine, less vomiting.

● Acetylcholine also plays a role in motion sickness. It processes all of the process.

● The acetylcholinergic neuron system is involved in the processes of habituation to motion sickness, including neural store mechanisms.

Between histamine and acetylcholine, which mechanism of actione has a greater effect on motion sickness

MOA of acetycholine

Scopolamine, Meclizine, Buclizine. Which for motion sickness?

Scopolamine, (not in PH)

Buclizine (not recommended)

Meclizine

Meclizine OTC Administration for motion sickness

Two hours before the event that can trigger motion sickness. Also, you can chew Meclizine.

○ Second-line for generalized anxiety disorder.

○ It is used, for example, if the patient has bipolar disorder and the patient can’t take SSRIs due to a possibility of manic switch and the patient has anxiety disorder, hydroxyzine is an option.

PIPERAZINE

○ Nakakataba does not mean pampataba.

Advertised in milk for weight gain but just because it has small weight gain as a side effect doesn’t mean that you can use it to gain weight. Sometimes side effects can be used as an indication, other times it is not worth it.

■ It is even unsure if Buclizine has weight gain.

Buclizine ^OTC

E. ALKYLAMINES

Brompheniramine OTC

Chlorpheniramine

These are antihistamine components of nasal decongestants.

Same with the other antihistamines from its generation, they are still anticholinergic and sedating. Anticholinergic because they are still antimuscarinic, sedating because they are still lipophilic and can penetrate the BBB.

Brompheniramine OTC

● Chlorpheniramine

T/F 1st Generation antihistamines (Brompheniramine and chlorpheniramine) are RECOMMENDED now if you have a runny nose and are sneezing.

F. not recommended

The second generation is more recommended (Retirizine, Loratadine)

By symptom approach

Patient has fever,

add paracetamol

By symptom approach

For recurring nasal decongestion

it should be intranasal corticosteroids but since it is a prescription drug, you can recommend saline nasal spray and 2nd generation antihistamines (Loratadine, Ceterizine) since they are OTC.

May recommend saline nasal spray

has been debunked as a nasal decongestant because it is not effective

Phenylephrine

Pero kawawa kita ng Neozep and big companies

For topical nasal decongestants (Oxymetazoline), do not use them for more than

3 days

rhinitis medicamentosa

Even among the second generation, it was found that these drugs are sedating

Cetirizine, Levocetirizine, Rupatadine, and Ebastine

Efficacy-wise, there is not much difference. Side effects-wise, there is a difference.

T/F use antihistamines as sleeping pills.

F. Do not use antihistamines as sleeping pills.

2nd GenerationLess anticholinergic; less sedating. This is because they have less affinity to the M1 receptor and they stay in the CNS less longer.

Cetirizine, Levocetirizine, Rupatadine

● Placebo, Ebastine‘

Weird, they advertise LEvocetirizine as 3rd generation

BUt 3rd gen should be less sedating but in actuality, medyo nakakaantok pa rin talaga siya.

2ND GENERATION ANTIHISTAMINES

● Terfenadine, Astemizole

● Cetirizine OTC*, Loratadine OTC

● Bilastine

● Ebastine

● Ketotifen*

● Azelastine* (Nasal)

● Olopatadine (Nasal, Eye Drops)

● Alcaftadine* (Eye Drops)

● Bepotastine* (Eye Drops)

○ QT-Prolonging; K + Blocker

Terfenadine, Astemizole

(Nasal) 2nd Gen

Azelastine

(Nasal, Eye Drops) 2nd gen

Olopatadine

* (Eye Drops)

Alcaftadine, Bepotastine

More lipophobic, penetrate CNS less

*Mast Cell Stabilizers ○ More lipophobic

Indicaions Allergic Rhinitis

F. 2ND GENERATION

Which is tried to phased out in allergy meds

1st generation

III. H2-RECEPTOR ANTAGONISTS A. DRUGS

● Cimetidine

● Ranitidine (75 mg OTC)

● Famotidine

● Nizatidine

receptors have a role in stomach acid secretion.

III. H2-RECEPTOR ANTAGONISTS

● Can be used for gastroesophageal reflux disease (GERD).

○ Peptic Ulcer Disease

○ Bleeding prevention in stress-induced gastritis.

○ HOWEVER, not as potent as proton pump inhibitors (PPI) in efficacy.

H2-RECEPTOR ANTAGONISTS

● Oldest H2

● So many problems

○ Anti-Male Sex Hormone

○ Inhibits binding of dihydrotestosterone to androgen receptors.

■ Antiandrogen effect

Inhibits metabolism of estradiol. ○ Increases serum prolactin.

For males, it causes rare gynecomastia and impotence.\

Causes galactorrhea in women.

CYP Inhibition (CYP1A2, 2C9, 2D6, 3A4)

Cimetidine

E. H2 DRUG INTERACTIONS

Reduced absorption of drugs that are better absorbed in acidic conditions due to reduced acid secretion (↑ pH).

Ketoconazole, Itraconazole, Fe

E. H2 DRUG INTERACTIONS

Increased Absorption → Toxicity

Raltegravir, Saquinavir

E. H2 DRUG INTERACTIONS

Compete for renal tubular secretion with creatinine, drugs

Procainamide

E. H2 DRUG INTERACTIONS

Inhibit gastric first pass metabolism of EtOH.

Except Famotidine

Lesser CYP interactions as compared to Cimetidine.

Ranitidine

Ranitidine Degrades easily to what?

a carcinogenic, regardless of brand with slight exposure to heat in a short period of time.

N-nitrosodimethylamine

The FDA issued a recall on Ranitidine regardless of brand.

Among the four drugs (Cimetidine, Nizaridine, Ranitidine, Famotidine),

Famotidine is most favored.

Famotidine OTC dose

10 mg

Famotidine Rx dose

20 mg, 40 mg

5-Hydroxytryptamine

● There are receptors that blocks the release of vasodilating peptides in the trigeminal nerve. This is important in headaches.

Serotonin

A. 5-HT RECEPTORS

Pain is like a band squeezing the head.

Tension

One side of the face.

Migraine

■ Concentrated on one eye.

■ Rarest and worst headache.

■ Has the least treatment options.

Cluster

C. 5-HT1B/1D AGONISTS i. DRUGS

● Sumatriptan ● Zolmitriptan ● Rizatriptan ● Naratriptan

Propranolol

Slower onset, longer duration

C. 5-HT1B/1D AGONISTS i. DRUGS

Naratriptan

Raises Rizatriptan levels.

Propranolol

C. 5-HT1B/1D AGONISTS MEMORY AID

-triptan

● Trip - 5-Hydroxytryptamine

● An - Agonist

● 5-Hydroxytryptamine Agonist

GOOD AT THE MOMENT

● Acute Migraine (Abortive)

● Cluster Headaches

● Not good as a prophylactic.

C. 5-HT1B/1D AGONISTS

i. DRUGS

● Sumatriptan

● Zolmitriptan

● Rizatriptan

● Naratriptan

Two Phases of Headache Management

Acute/Abortive

Prophylactic/Maintenance

When you want to immediately stop the headache

Acute/Abortive

● Prevention

● To stop recurring headaches.

Prophylactic/Maintenance

Migraine Prophylaxis

● First-Line

○ Valproate

○ Metoprolol

○ Propranolol

Migraine Prophylaxis

● Second-Line

Rimegepant

If a headache persists even if you undergo abortive treatment, maybe what you need is

prophylactic treatment

C. 5-HT1B/1D AGONISTS

i. DRUGS

● Sumatriptan

● Zolmitriptan

● Rizatriptan

● Naratriptan

CAUTIONS

● Limit use per month; only 10.

○ Side Effect: Medication Overuse Headache

● Can rarely cause coronary vasospasm (caution in CAD).

● Caution in ischemic stroke (see MOA).

○ Because a stroke means there is a problem with blood vessels in the brain. ○ These drugs affect the blood vessels in the brain. ○ Caution should be observed theoretically.

● Monitored Release

● If the first-line drugs do not work.

● Pag dumadami ang migraine, baka hindi na abortive ang need, baka preventive na.

Hindi siya first-line because of its expensive price (PHP 200).

D. RIMEGEPANT & ATOGEPANT

● Acute Migraine (Abortive)

● Chronic Migraine (Preventive)

● Pwede siya for both, although mahal.

D. RIMEGEPANT & ATOGEPANT

ii. MOA

● CGRP Receptor Antagonist

○ Calcitonin Gene-Related Protein (CGRP)

■ It is one of the vasodilating peptides. Instead of blocking its release, we block its receptor.

D. RIMEGEPANT & ATOGEPANT

Ge Protein Ant

All meds associated with Migraine treatment have medication overuse headache as their S/E; this drug does not have any documented occurrence so far.

PERO ITO WALA

NO Vasoconstriction

D. RIMEGEPANT & ATOGEPANT

● -MAB from “monoclonal antibodies.”

● They are made to target SPECIFIC proteins or antigens.

E. ERENUMAB

● Refractory Chronic Migraine (Preventive); Once Monthly (SC)

● It is applicable for prophylactic care; IF hindi lang gumagana yung ibang options.

○ Antibodies which are isolated to target just ONE thing is very hard to do, which requires complex biotechnology.

○ Expensive; nasa 5 to 6 digits.

E. ERENUMAB

● Anti-CGRP Receptor Monoclonal Antibody

○ The drug specifically targets the receptor itself

E. ERENUMAB

○ Injection Site Reactions

○ Hypersensitivity + Financial Toxicity

■ All MABs are expensive, automatic.

■ Since it is an antibody, there is a chance for the body to reject it; hypersensitivity.

E. ERENUMAB

G. 5-HT4 AGONIST ● Drug

G. 5-HT4 AGONIST

○ Prucalopride

○ Mosapride

Indication: ○ Constipation (Prucalopride; Adults) ■ Because promote GI motility.

○ Gastroparesis? ■ Delayed gastric emptying, which causes N/V, dyspepsia, fullness, etc. ■ MIGHT be usable to promote the gastric emptying process, but minimal evidence so far

G. 5-HT4 AGONIST

○ Prucalopride

○ Mosapride

■ Different moa; acetylcholinesterase (AChE) inhibition.

■ However, it may still be used for GI conditions.

Itopride

L. 5-HT3 ANTAGONIST

● Ondansetron

● Granisetron

● Palonosetron

● Ramosetron

● Tropisetron

○ Prophylaxis of Chemotherapy-Induced Nausea and Vomiting (CINV) and Postoperative N/V

○ The MOA is straightforward because in the brain, the Chemoreceptor Trigger Zone (CTZ) is connected to the vomit center. ○

One of the receptors involved is 5-HT3 , which is why drugs promoting serotonin will cause N/V.

5-HT3 Serotonin Receptor Antagonist

● Ondansetron

● Granisetron

● Palonosetron

● Ramosetron

● Tropisetron

Myth

Nausea and vomiting from chemotherapy are normal.

Fact

Nausea and vomiting from chemotherapy may be prevented with treatment.

One misconception of CINV is if magca-cancer chemotherapy ka ay masusuka ka automatically. The goal is NOT to wait and treat it but to PREVENT it from ever happening.

Myth

Nausea and vomiting from chemotherapy are normal.

FACT

● That is not the case, they DO NOT indicate whether or not the chemotherapy is working.

IBS-D

Ramosetron

Currently, Ondansetron is undergoing clinical trials for GI Indications too. If it causes constipation as S/E, can it be used for IBS with diarrhea?

Memory Aid: SETRON

5-HT3 Serotonin Receptor Antagonist

We have to counsel patients about what because of the presence of 5-HT3 receptors in the gut; hence, they would have to expect

Constipation

ADR of Setron

QT Prolongation, EXCEPT Palonosetron.