URTICARIA

Background:
Information from: Habif's Clinical Dermatology - 7th Edition - Elsevier

SLIDE 3:
Hives often appears as a raised, itchy rash. There can be many causes, including
exposure to an allergen, a physical trigger, such as pressure from tight clothing, or
an underlying health condition. Urticaria, ultimately, is caused by mast cell activation
in the superficial dermis.
Mast cells, when they degranulate, release histamine, which is why it's very pruritic,
and they release a variety of vasodilators. And that's what causes the localized
swelling and these classic raised flat lesions.

SLIDE 4:
There's 2 main ways in which mast cell activation occurs.
There's the IgE-mediated type and then the non-IgE mediated type.
Let's talk about IgE first. So, the IgE-mediated type is essentially a type 1 immediate
allergic reaction in which the patient has previously been exposed to some trigger,
has developed antibodies, and those antibodies are now binding to mast cells in the
skin. When that patient is then re-exposed to that allergen, the IgE immediately
recognizes it, triggers the mast cell, and massive degranulation occurs very readily.
The most common allergens or drugs, like beta-lactams, food allergies can do this,
insect bites like from Hymenoptera, mosquitoes, etc., infections like viruses,
mycoplasma, and parasites. What you'll typically see on physical exam is a very
asymmetric distribution of lesions, and they are abrupt in onset, intensely pruritic --
again, due to all that histamine -- with very well demarcated, erythematous papules
with central pallor.

SLIDE 5:
Next up, we're going to talk about the non-immune mediated causes of urticaria.
Essentially, mast cells are still involved, but IgE is not part of the equation.
So specific medications can do this. NSAIDs, particularly, COX inhibitors, can block
prostaglandin synthesis, which allows mast cells to degranulate.
Opioids and vancomycin actually directly stimulate mast cell activation in some
circumstances. And then ACE inhibitors are acting via inhibition of kinin metabolism.
In addition, there are some physical conditions that can lead to urticaria to form in
susceptible hosts. Certain physical stimuli, like cold, vibration, or pressure, can lead
to urticaria's emergence.

SLIDE 6
So, urticaria is our classic type 1 hypersensitivity reaction. We also call it "hives".
These lesions will be anywhere from 1 mm to 10 cm large. They can be huge or
small. These lesions are profoundly itchy, and they're stimulated by skin contact,
which means the more you scratch them, the more they itch.
What you'll notice about them is that they sort of "come and go" even before your
eyes.
You may walk in, see a patient with hives, and before you're done with your
conversation, the one you were looking at on the leg is gone, and there's a new one
on the arm.
They may be associated with angioedema, which is another type of type 1
hypersensitivity reaction.

SLIDE 7
What's key is that these are acute and generally short-lived.
Patients usually only have this reaction for maybe days to maybe a week out, from
when they first encountered that antigen, and had a response to it, which would be
the second time they encountered the antigen.
Alternatively, occasionally they can become chronic.
These are when hives last longer than 6 weeks.
This can really be problematic when it happens.

IF TATANUNGIN NI DOC YUNG IBANG TYPES OF HYPERSENSITIVITY

REACTION:

TYPE 2
Similar to type 1, type 2 hypersensitivity reactions also involve antibodies. In fact, type 2 and type 3
hypersensitivity both result from the same class of antibody, called IgG. The difference between them
lies in the form of antigens that generate a response. Additionally, type 2 can also involve IgM
antibodies. Type 2 hypersensitivity causes cytotoxic reactions, meaning that healthy cells die as they
respond to the antigens. This can cause long-term damage to cells and tissues, resulting in conditions
such as:

TYPE 3
In type 3 hypersensitivity, antigens and antibodies form complexes in the skin, blood vessels, joints,
and kidney tissues. These complexes cause a series of reactions that lead to tissue damage. Causes
of a type 3 hypersensitivity reaction can include:

● drugs that contain proteins from different organisms, such as antivenins

● the drug infliximab, which people use to manage autoimmune conditions
● animal sources, such as insect stings or tick bites

Type 3 hypersensitivity reactions can lead to:

● serum sickness
● lupus
● rheumatoid arthritis
● small-vessel vasculitis

TYPE 4
Unlike the other types, type 4 hypersensitivity reactions are cell-mediated. Instead of antibodies, white
blood cells called T cells control type 4 hypersensitivity reactions. Experts can further subdivide these
reactions into type 4a, type 4b, type 4c, and type 4d based on the type of T cell involved and the
reaction it produces. This type also differs from the other three in that it causes a delayed reaction.

Risk Factors:
Information from: Harrison's Principles of Internal Medicine, Twentieth Edition

SLIDE 8:
According to Harrison’s:
Acute or chronic urticaria can occur at any point in the life span with the third to fifth
decades the most common for chronic disease. Women are affected more often than
men with a slight predominance for those with a history of atopy. Acute urticaria is
most often the result of exposure to a food, environmental, or drug allergen or viral
infection, while chronic urticaria is often idiopathic. More than two-thirds of new-onset
urticaria cases are ultimately diagnosed as acute.

SLIDE 9
There are many things that can trigger urticaria such as foods, medicine and
environmental factors

SLIDE 10
Foods, especially food additives, include legumes, tree nuts, seafood, eggs, dairy,
shellfish, berries. These are all very common.
In fact, among children who have type 1 hypersensitivity reactions to food about 85%
of them are to food when we know what the allergen is.
Still, remember, at least a third of the time we have no idea what triggers the allergy.

SLIDE 11
Also, patients can be allergic to medications.
Probably penicillins and sulfas are the most common, but they could also be allergic
to salicylates to certain vaccines or to anaesthetics.

SLIDE 12
Also patients can have environmental allergies.
Bee stings and wasp stings are particularly problematic.
Patients may be allergic to temperature changes to exercise, to latex.

Clinical Manifestation:
Slide 13
History of exposure to triggering agents for acute and chronic:
Many substances can trigger hives, such as:
1. Some food (especially peanuts, shellfish, fish, eggs, milk, chocolates)
2. Medications, such as antibiotics (especially penicillin and sulfa), aspirin and
ibuprofen
3. Insect stings or bites
4. Physical stimuli, such as pressure, cold, heat, exercise or sun exposure

SLIDE 14

● In some cases, urticaria

can occur concomitantly with angioedema that typically
involves deep dermis and subcutaneous fat, such as in the
periorbital tissues, lips, tongue, and hands. Angioedema can
persist for up to 72 hours and accompanied by burning
sensation and/or mild pain. Itching is not common in
Angioedema.

ADDITIONAL:
SYMPTOMS
1. Itchiness.: When the patient has an allergic reaction to a substance, the body releases
histamine and other chemicals into the blood.
This causes itching, swelling, and other symptoms.
2. Swellings on the skin (wheals) are a frequent reaction. Persons with other allergies, such
as hay fever, frequently get hives. When swelling or welts occur around the face, especially
the lips and eyes, it is called angioedema.
Swelling can also happen around the hands, feet, and throat.
a. Raised itchy bumps, either red or skin-colored
b. Swelling of the surface of the skin into red- or skin-colored welts (called wheals) with
clearly defined edges.
c. Wheals may get bigger, spread, and join together to form larger areas of flat, raised skin.
d. Wheals can also change shape, disappear, and reappear within minutes or hours.
e. The patient knows the patient have hives when the patient press the center of a wheal, it
turns white. This is called blanching.
f. The rash is typically itchy and appears rapidly as localized red swelling on the skin
measuring a few mm to more than 10 cm in size in different shapes.
g. The swelling can also occur on eyelids, lips, palms and soles.

Pathophysiology:
YT LINK: Urticaria (Hives) and Angioedema – Pediatrics | Lecturio - YouTube

Slide 16.

The main pathophysiology of Urticaria is that it involves dilation of vascular

structures in the superficial dermis.
- There are two types of mast cells activation as explained earlier, the immunologic
infection urticaria or the IgE dependent and the non-immunologic urticaria or IgE
independent.
-This is the brief presentation of IgE dependent, first is the initial exposure to the
triggers such as the allergen. This causes the production of an antigen-specific IgE
and the IgE binds to the mast cell. ( Mast cells serve as a first line of defence
against antigens entering the body due to their location in the skin and mucosa. They
synthesize and secrete histamine, proteases, prostaglandin D2, leukotrienes,
heparin, and a variety of cytokines.)

- Subsequent exposure will result to mast cell degranulation.

- Mast cell degranulation releases inflammatory mediators including

histamine , cytokines and so on: of which, the most important is
HISTAMINE.

*** SUPPLEMENTAL:

Histamine - causes vasodilation -> increase in capillary permeability ->

erythematous edematous plugs (urticaria)

The mechanism of a type 1 hypersensitivity reaction process starts when allergen

such as pollen is inhaled in the respiratory system and is processed by an antigen
presenting cell (APC), the APC presents a portion of of the pollen to a naive T helper
cell and the APC also releases cytokine IL-4 onto the helper T cell which causes the
naive helper T cell to differentiate into a T helper 2 cell (th2). B cell also presents a
portion of the pollen or allergen to th2 which activates a classic switch of B cell
causing it to become a plasma cell that produces IgE antibodies.

IgE binds to FC receptors located on mast cells & basophils on subsequent

exposure to allergen. The allergen binds to 2 separate IgE antibodies on mast cells
or basophils, so this is known as cross linking and causes degranulation. Then, this
causes releases of inflammatory mediators such as Histamine and Cytokines.

Slide 17.
In this diagram we will focus on non-immunologic urticaria or the non-IgE dependent
mast cell activation.

- The activation of membrane receptors involved in innate immunity, examples are

the complement, cytokines and chemokines. The direct toxin stimulation such as
opiates, non-steroidal antiinflammatory drugs (NSAIDs) and aspirin, the emotional
stress, and the physical stimuli including water, solar. Heat sweating and cold are
examples that can directly displace histamine from granule stores or mast cells.
- So now, what does histamine do following its release?
- Histamine exerts its effect by binding to various histamine receptors found on many
different cells in the body.
- There are 4 types of histamine receptors (WE CAN REFER TO SLIDE 38 FOR
THE TABLE OF DIFFERENT HISTAMINE RECEPTORS AND THEIR LOCATION)
but we will focus on the first 2 types as they are the main targets of clinically
useful drugs.

- H1 receptors are expressed primarily on smooth muscle cells, endothelial cells,

CNS neurons. These receptors mediate mainly inflammatory and allergic reactions.
So when histamine binds to vascular endothelial receptors it causes blood vessels to
dilate thus making them more permeable ultimately to redness (local erythema) and
edema (wheal). Now, when histamine binds to peripheral nerve endings it leads to
pain and itching sensation (Pruritis).

TRIPLE RESPONSE OF LEWIS: 1. red line/flush 2. Wheal (edema) and 3. Flare

(diffuse reddening)
The red reaction appears at site of stimulus within 10 second due to capillary
dilation, this is followed by local swelling (edema) around injury within few minutes
due to increase permeability of the capillaries and post capillary venules with
extravasation of fluid. The redness spreading out from the injury (flare) is due to
arteriolar dilation.

- Next is the H2 or the type 2 receptors. So this type 2 receptor is expressed

mainly on gastric parietal cells when histamine binds to receptors it causes
gastric secretions.

(Sa pharmaco management na ‘to) Now let’s discuss the drugs that block the action
of HISTAMINE.

- H1 receptor blocker or H1 antihistamines can be divided into older or 1st

generation and newer or 2nd generation agents. These agents act as inverse
agonists meaning they bind to H1 receptors on a target tissue and stabilize its
inactive conformation. This leads to inhibition of histamine’s actions and
gradual relief of allergy related symptoms such as inflammation, itchy runny
nose and sneezing
- The 1st generation antihistamines can cross the blood-brain barrier and
thus cause sedation and potentially impair cognitive function. Also, they have
poor H1 receptor selectivity and as a result they are capable of occupying
other receptors such as cholinergic receptors which can lead to a number of
side effects, examples are blurred vision, dry mouth and urinary retention.
- Examples of drugs included in 1st generation antihistamine will be discussed
later on pharmaco management.
-Second generation agents are bulkier and less lipophilic structure, therefore they do
not cross blood-brain barrier as readily, additionally they are more selective to H1
receptors therefore they provide the same allergy symptom relief but with less side
effects.

-Lastly, the H2 receptor blockers or antagonists block the histamine receptors in

parietal cells to decrease the amount of acid produced.

Diagnosis:
SLIDE 18

ACUTE:
● Careful history to identify potential triggers — ask for atopic disease, known
allergies, drug intake, signs of infection
● Physical examination (BP, PULSE, Lung auscultation)
● If no causes identified from history, no further investigation needed due to self
limiting nature with this type of urticaria

CHRONIC:
● Infection- culture, and sensitivity, serology
● Autoreactivity- serum skin test, cellular activation test (ex: Serum induced
histamine release, thyroid auto abs, antinuclear antibodies
● Non allergic Hypersensitivity– consider triggering by aspirin/Nsaids, in rare
cases—do allergen low diet test

Slide 19:
CBC with differential: A measure of the number of red blood cells, white blood
cells, and platelets in the blood, including the different types of white blood cells
(neutrophils, lymphocytes, monocytes, basophils, and eosinophils)
*erythrocyte sedimentation rate (ESR), is a blood test that can reveal inflammatory
activity in your body
*C-reactive Protein (CRP) test measures the amount of CRP in the blood to detect
inflammation due to acute conditions or to monitor the severity of disease in chronic
conditions
Thyroid function test: looks at levels of thyroid-stimulating hormone (TSH)
and thyroxine (T4) in the blood.
*antinuclear antibody(ANAs) test checks to see if you have an autoimmune
disorder, a condition where the immune system attacks healthy cells
*Autologous serum skin test (ASST) is a rapid, in-vivo clinical test to detect
functional autoantibodies in patients with chronic spontaneous urticaria

Slide 36-39
● In urticaria, in which histamine is the primary mediator, the H1 antagonists are
the drugs of choice and are often quite effective if given before exposure
(katzung 14th pg 283)
 ● H1-receptor antagonist antihistamines- these are the drugs of choice for
urticaria, or the first line treatment.
There are two kinds of h2 receptor antagonists. 1st generation and second
generation. The older members of the first-generation agents, typified by
diphenhydramine, are highly sedating agents with significant autonomic
receptor-blocking effects. The second-generation H1 blockers, typified by cetirizine,
fexofenadine, and loratadine, are far less lipid soluble than the first-generation
agents and have greatly reduced sedating and autonomic effects. All H1 blockers
are active by the oral route. Several are promoted for topical use in the eye or nose.
Most are metabolized extensively in the liver. Half-lives of the older H1 blockers vary
from 4 to 12 h. Second generation agents have half-lives of 12–24 h. (katzung 14th
ed. Page 147)
*In simpler terms diba ang nag cause ng hives is naactivate ang histamine 1
receptors ng histamines, the result of histamines is pruritus, and allergic like
reactions, so para matigil ang pag release ng histamine, kailangan natin ng h1
receptor antagonist!
1st gen
1. Hydroxyzine - Hydroxyzine is a sedating peripheral H1 receptor antagonist. It
is very effective in urticaria. Hydroxyzine also may suppress histamine activity
in the subcortical region of the CNS.(medscape)
2. Diphenhydramine is a sedating peripheral H1 receptor antagonist. It is used
for symptomatic relief of allergic symptoms caused by histamine released in
response to allergens.
Dun sa warnings kung tatanungin bakit sya dapat in caution with narrow angle
glaucoma is because pag may glaucoma ka consistent sign of glaucoma is
mydriasis, kaya may blurring of vision diba, antihistamines is like
anticholinergics that can also cause mydriasis so ma aggravate nya pa lalo
ang glaucoma.

Katzung pg 296
Pabasa nalang din po itong pic, sa moa naman nya ung drug is nagkipag compete
sya kay histamine na magbind sa h1 receptor ha,( iba ung h2 kasi pag h2 gastric
acid secretion na un) para hindi matuloy ung masamang balak ni histamine forda
person
Effects : blocks muscarinic( parasympathetic effects like watery eyes, red skin)
*Inverse agonist A drug that binds to the non-active state of receptor molecules and
decreases constitutive activity
*Constitutive activity Activity of a receptor-effector system in the absence of an
agonist ligand
Boxed warning: can cause QT prolongation due to the inhibition of repolarization
potassium channels, which leads to prolongation of the action potential and QT
interval, and the development of early after-depolarization, which triggers
TdP(Torsades de pointes). Patients at risk of developing TdP, such as those with
congenital long QT syndrome, cardiac disease, liver disease, electrolyte disturbance,
or those taking drugs that can prolong QT interval, should avoid nonsedating
antihistamines that are also capable of prolonging the QT interval.
Contraindications:
Hypersensitivity - Immediate-type hypersensitivity reactions to both
first-generation and second-generation AHs often involve acute cutaneous
manifestations, such as urticaria and angioedema, but systemic reactions
(anaphylaxis) have also been described.
Prolonged QT interval- They may occasionally cause an increase in the
pulse rate because they have an atropine-like effect. In some individuals,
the heart rate may become rapid.

Side effects:
Drowsiness,Headache,Hallucination- First-generation H1 antihistamines cross
the blood-brain barrier, and in usual doses, they potentially cause sedation
and impair cognitive function and psychomotor performance.
Dry mouth- Antihistamines used to treat allergies and asthma can also cause
dry mouth. This is because they have a similar anticholinergic effect on
your body.
WARNINGS AND MONITORING:AHs that cross the blood-brain barrier and bind to
H1 receptors in the brain suppress central nervous system (CNS) arousal and disrupt
circadian sleep-wake rhythmicity , thus impairing both cognitive function and
psychomotor performance, including attention, memory, sensorimotor coordination,&
information processing.

2nd gen: from medscape

*SAME LANG EXPLANATION SA MGA SIDE EFFECTS, ETC
1. Cetirizine - Cetirizine selectively inhibits peripheral(outside CNS KAYA IT DOES
NOT CROSS BBB) histamine H1-receptors and is minimally sedating.
2. Fexofenadine - Fexofenadine selectively inhibits peripheral histamine
H1-receptors and is minimally sedating.
3. Levocetirizine - Levocetirizine is a histamine1-receptor antagonist. It is an active
enantiomer of cetirizine. (kakambal ni cetirizine, ung configuration is in
LEVOROTATORY FORM kaya LEVOcetirizine)Peak plasma levels are reached
within 1 hour and the half-life is about 8 hours. Levocetirizine is available as a 5-mg
breakable (scored) tablet. It is indicated for seasonal and perennial allergic rhinitis.
4. Loratadine- Loratadine selectively inhibits peripheral histamine H1-receptors and
is minimally sedating.
5. Desloratadine- Desloratadine is a long-acting tricyclic histamine antagonist
selective for H1-receptors. It is a major metabolite of loratadine, which, after
ingestion, is extensively metabolized to the active metabolite
3-hydroxydesloratadine.
● Dun sa notes part ng 2nd gen antihistamines eto po explanation ko:
-Do not take more than recommended because it can cause oversedation,
there is still sedation dito kahit na sinabing nonsedative sya but mnimal lang
ang sedation nito, kung bga tolerble compared to 1st gen.
- dont take together aluminum-magnesium hydroxide oral bec. It will increase
the level or effect of cetirizine(antihist.) oral by affecting how the drug is
eliminated from the body through the kidneys if the urine is not acidic. So may
tendency of overdose ulit dto
- do not take with fruit juices esp grapefruit juice because it is an enzyme
(cyp450) inhibitors, this cyp 450 is an enzyme for metabolism, so ang
ginagawa ng grapefruit juice iniinhibit nya ang further metabolism( metabolism
is a preparation for a drug to be excreted) so matatagalan ngaun ang
excretion ng drug sa katawan, na memetabolize sya lalo, mag accumulate
ang dose then can lead to overdosage na naman.
- stop if allergic to the drug bec it can lead to anaphylaxis and we all know that
anaphylaxis is fatal if severe.

Pharm mngt in general

1. Epinephrine is specifically intended for anaphylactic shock, if
grabe na ung urticaria nya.
Antihistamines have no role in the acute treatment of anaphylaxis
because intramuscular adrenaline (epinephrine) must be given.
Parenteral antihistamines(eg.diphenhydramine) can potentiate
hypotension and worsen anaphylaxis.
- Timely transport to the ED(emergency dept) for any patient with
signs or symptoms of a life-threatening allergic reaction,
including urticaria (hives), angioedema, or anaphylactic shock is
essential. Acute urticaria may progress to life-threatening
angioedema and/or anaphylactic shock in a very short period,
although anaphylaxis usually presents as rapid-onset shock with
no urticaria or angioedema. (epinephrine ang ginagamit dito)
- If associated angioedema is present, especially if laryngeal
angioedema (eg, hoarseness, stridor) is suspected, prehospital
administration of 0.3-0.5 mg of intramuscular epinephrine may
be warranted.
Contraindications:
 Narrow angle glaucoma- These agents stimulate both alpha-1
and alpha-2 adrenergic receptors, administration can induce
transient mydriasis. In patients with narrow angles, any degree
of pupillary dilation can provoke an acute attack of angle-closure
glaucoma.
Coadministration during general anesthesia with halogenated
hydrocarbons or halothane - Cutaneous infiltration of dilute
solutions of epinephrine for hemostasis during halothane
anesthesia can result in ventricular dysrhythmias.
Side effects: EPINEPHRINE is a direct acting sympathomimetic, it
activates both alpha and beta adrenoceptors, and all the side effects indicated
all fall under sympathomimetic response

2. Prednisone drug class is Glucocorticoids - stabilize mast cell

membranes and inhibit further histamine release. They also reduce the
inflammatory effect of histamine and other mediators. Oral
glucocorticoids are effective in acute urticaria but are not suitable for
long-term use.
Contraindications:
Untreated serious infections-This medicine may cause you to
get more infections than usual.
Administration of live or attenuated live vaccine, and
Varicella- Prednisone may lower your body's resistance and the
vaccine may not work as well or you might get the infection the
vaccine is meant to prevent. In addition, you should not be
around other persons living in your household who receive live
virus vaccines because there is a chance they could pass the
virus on to you.
Side effects:
weight gain, sleep- The longer you’re on prednisone, the more likely
you are to gain weight.prednisone increases appetite the drug also causes fluid
retention, which leads to swelling, often of the hands, legs, and feet, along with the
face(moon facies). Prednisone may also interrupt a normal sleep-wake cycle,
leading to inadequate sleep and a disruption of the hormones that help regulate
appetite.
Osteoporosis- Steroids have major effects on how the body uses calcium
and vitamin D to build bones. Steroids can lead to bone loss, osteoporosis,
and broken bones. When steroid medications are used in high doses, bone
loss can happen rapidly.

Monitoring:
Why hindi pwede for long term use?
 - Steroid tablets taken for longer than 3 weeks can potentially
cause: increased appetite – which can potentially lead to weight
gain if you find it difficult to control what you eat.
- Long-term use of glucocorticoids can cause a loss of muscle
tissue. It can also result in Cushing's syndrome(a disorder that
occurs when your body makes too much of the hormone cortisol
over a long period of time), which can lead to: a fatty hump
between your shoulders. round face.
- Sa monitoring kailangan tignan kung may behavioral changes
na ung patient kasi its a sign na overdose na sya ng
glucocort.(prednisone) rapid mood swings and mood changes –
such as becoming aggressive, irritable and short-tempered with
people.
- Monitor for kaposi sarcoma bec. Steroids(prednisone is a
steroid) are a risk factor for Kaposi's sarcoma-immune
reconstitution inflammatory syndrome and mortality in HIV
infection
- a patient w/ kaposi sarcoma is already immunocompromised,
prednisone is an immunosuppresant drug, so therfore it can lead
to drop in immune system.
*Kaposi sarcoma is a disease in which cancer cells are found
in the skin or mucous membranes that line the
gastrointestinal (GI) tract, from mouth to anus, including
the stomach and intestines. These tumors appear as purple
patches or nodules on the skin and/or mucous membranes and
can spread to lymph nodes and lungs.

3. Omalizumab
Moa: Omalizumab binds free IgE in the serum, forming trimers and
hexamers. The drug binds to IgE at the same site that the high-affinity
IgE receptor (Fc-epsilon-RI) binds, so IgE bound to drug cannot bind its
receptor on mast cells and basophils.
- Monoclonal antibodies(drug class of omalizumab) directed to IgE
binding may reduce release of mediators that provoke an allergic
response. These agents may be considered when H1-anagonists are
ineffective.
- Omalizumab is a recombinant humanized monoclonal antibody
administered by subcutaneous injection every 4 weeks. It selectively
binds to IgE and inhibits binding to IgE receptors on the surface of
mast cells and basophils. It is indicated for chronic idiopathic urticaria
in adults and children aged 12 years or older who remain symptomatic
despite H1 antihistamine treatment.
 Topical products are not safe for children , strictly for adult dose only.
Safety and efficacy is not yet established in children
Boxed warning: There is also the possibility that polysorbate, one of
the formulation's excipients, is responsible for anaphylactic reactions
*polysorbate- It is utilized as a surfactant in soaps and cosmetics and
also as a lubricant in eye drops. In food or pharmaceutical products, it
can act as an emulsifier(added to drugs to prevent particular parts from
separating.). Polysorbate 80 is an excipient that is used to stabilize
aqueous formulations of medications for parenteral administration or
vaccinations.
CONTRAINDICATIONS: same as above mentioned
SIDE EFFECTS:
Hair loss- may interfere with mast cell release, and mast cells
have an influence on the hair growth cycle. They also state that
because hair loss is transient with omalizumab, treatment
should continue in patients with a positive effect.

4. Doxepin - Doxepin is a TCA(tricyclic antidepressant) that has potent

H1-blocking activity, making it quite useful for urticaria. However, it has
very potent sedative and anticholinergic effects. It can be quite effective
if used at bedtime because the sedative effects can help a patient with
pruritus sleep. Widespread use produces sedation, as does use in
areas of high percutaneous absorption (eg, genitals). Many individuals
develop an allergy to topical doxepin.

Contraindications/ cautions
Sa contraindication part, Why contraindicated to maois?
MAOIS(Monoamine Oxidase Inhibitors) - it increases levels of doxepin
by pharmacologic synergism . maois and doxepin same silang
antidepressant drugs, pag sumobra ka naman ng antiddepressants
drugs edi sobrang saya mo na nyan? Sana all char… pag nasobrahan
sa antidepressants it can make you high, like the effects of
adrenoceptor agonist- mydriasis, tachycardia, nervousness, tremors,
insomnia, dry mouth, constipation etc. we learned all about it in the
lecture before diba?
Sa urinary retention din contraindicated bec un nga adrenergic agonist
tong drug na to so, mapapalala ang retention leading to no urine
output, and delikado ang walang urine output diba,
Sa glaucoma na part same with antihistamine explanation kanina.
Why sa MI, contraindicated- bec it can aggravate the irregular rhythm
of the heart
In hepatic failure naman, nag fail na ung liver mo, and liver is the main
organ for metabolism, so mahina na din ang metabolism mo,
 mahihirapan kang ieliminate ang drug can lead to overdose, kaya pag
may hepatic failure adjusted lagi ang dose ng mga gamot nila depende
sa creatinine clearance ng patient.
Thyroid dysfunction- reduce T4 hormone levels by 11.2%(accdg to
medical news.com) , papano kung hypothyroidism ang patient edi
kawawa naman sya. For hyperthyroidic patients naman, they are
known to be grabe mag tremors, and palpitate so if you give this
antidepressant/antihistamine doxepin, it can aggravate that.
and seizure- tricyclic antidepressants (TCAs), like doxepin, should be
used with extreme caution in patients with a preexisting seizure
disorder because tricyclic antidepressants (TCAs) can lower the
seizure threshold. If seizures occur during TCA therapy, the TCA
should be discontinued (pdr.net)
A high seizure threshold means that a seizure is less likely to occur,
while a low seizure threshold means that a seizure is more likely to
occur.(epilepsyontario.org)

Side effects:
dizziness, drowsiness - Compared with other antidepressants,
doxepin has extremely high selectivity for the postsynaptic
histamine H1 receptor. Since histamine is a potent stimulating
neurotransmitter, antagonist activity predictably will produce
sedation.
Emotional changes- People taking doxepin can experience
worsening depression and suicidal thoughts or behavior. The
risk of suicidal thoughts or behavior is higher in people aged 24
years and younger with depression or other mental health
conditions.

Management:
Please indicate source of info (eg. book title, weblink)

Prevention:
Please indicate source of info (eg. book title, weblink)
CORONARY ARTERY DISEASE

Background:
We all know that cardiovascular disease is a global and local burden of a disease
and in the Philippines, cardiovascular diseases ranked among the top 10 leading
causes of morbidity and was the leading cause of mortality.

CAD is commonly due to obstruction of the coronary arteries, usually the epicardial
arteries, by atheromatous plaque.

There is no uniform syndrome of signs and symptoms is initially seen in px with

CAD, but CHEST DISCOMFORT or ANGINA PECTORIS is usually the predominant
symptom

Px usually uses adjectives like constricting, suffocating, crushing, heavy, and

squeezing as to describe the pain or distress they experience.

Obstructive CAD also has many non-atherosclerotic causes, including congenital

abnormalities of the coronary arteries; myocardial bridging; coronary arteritis in
association with the systemic vasculitides;
and radiation-induced coronary disease. May also occur with people with Myocardial
ischemia.

Risk Factors:

Non-modifiable risk factors such as AGE, FAMILY HISTORY - that we need to

watch out for, GENDER, and ETHNICITY.
Age: CVD is most common in people over 50 and your risk of developing it
increases as you get older.
Gender: men is more risky
What gender is most affected by coronary artery disease?
Men generally develop CVD at a younger age and have a higher propensity of
developing coronary heart disease (CHD) than women. Women, in contrast,
are at a higher risk of stroke, which often occurs at older age.
Why do females have less coronary heart disease than males?
Before menopause, a woman's own estrogen helps protect her from heart
disease by increasing HDL (good) cholesterol and decreasing LDL (bad)
cholesterol. After menopause, women have higher concentrations of total
cholesterol than men do
Ethnicity : Black adults are more likely than white adults to die from a heart
attack. Asian adults are less likely than other groups to have coronary artery
 disease. But there are some differences by ethnicity. Asian Indian men,
Filipino men and Filipino women have a higher risk compared with white
people. (cleveland.org)

For modifiable risk factor

- SMOKING
- DIABETES MELLITUS
- HYPERTENSION
- HYPERLIPIDEMIA
- SEDENTARY LIFESTYLE
- OBESITY OR PHYSICAL INACTIVITY
these risk factors accelerate or modify a complex and chronic inflammatory process
that ultimately predisposes the patient into developing a FIBROUS
ATHEROSCLEROTIC PLAQUE leading to a much higher risk in developing CAD.

reference:

Clinical Manifestation:
Please indicate source of info (eg. book title, weblink)

Slide 9.

Referring to the case, the patient manifested a recent-onset of chest discomfort

when running that was relieved with rest. Pain is dull and poorly localised.

In general, clinical symptoms of CHD include:

● Chest pain or discomfort (angina)
● Weakness, lightheadedness, nausea or a cold sweat
● Pain or discomfort in the arms or shoulder
● Dyspnea
● Syncope

Various clinical manifestations of coronary heart disease occur in its spectrum of

clinical presentations.

Slide 10.

Coronary Heart Disease can present as:

● Angina pectoris, either stable or unstable

● Myocardial infarction

Angina Pectoris
Angina can range from mild discomfort to severe pain. It may feel like heaviness,
tightness, pressure, aching, burning, numbness, fullness, squeezing or a dull ache.
The discomfort may spread to your shoulder, arm, neck, back or jaw.

The typical quality of pain is that it is retrosternal in location and it may be dull or
squeezing.

The two kinds of angina, stable and unstable, differ mainly in their onset: stable
angina usually occurs in the presence of triggers such as physical and emotional
stressors, and increased oxygen demand. (I.e. if the patient is exercising, or pagod,
or nagulat). This has predictable triggers and timing. In unstable angina, on the
other hand, chest pain occurs even when the patient is at rest, even in the absence
of triggers previously mentioned. So, timing is usually unpredictable.

Stable angina is usually relieved by rest and administration of nitrates, while unstable
angina is not.

Slide 11.
In the case of MI, there is evidence of myocardial injury or necrosis.
Chest pain is more severe and prolonged than angina and does not resolve with rest
or nitrates. Diaphoresis (excessive sweating) also occurs.

Pathophysiology:
SLIDE 12
As discussed earlier, coronary heart disease is caused by the hardening and
narrowing of the arteries caused by a buildup of plaque or what we call as
atherosclerosis. This is our main culprit in the pathogenesis of CAD. This plaque
build-up is the end product of chronic inflammatory process. Here, we should take
note that this process will not begin without endothelial injury.

SLIDE 13
Low-density lipoproteins (LDLs) then cross the damaged endothelium into the wall of
the artery. Overtime, cholesterol becomes part of the plaque where they start to
compromise circulation which ends up with a higher risk for myocardial infarction.

SLIDE 14
To make things easier, let’s take it step by step.
As said earlier, arterial injury is the first requirement for the process of plaque
build-up to begin. These may be brought about by hypertension, hyperlipidemia, or
even diabetes mellitus.

SLIDE 15
Because of this injury, fatty materials such LDLs, cholesterol, triglycerides plus the
inflammatory mediators, macrophages and WBCs infiltrate the lining of the damaged
artery.

SLIDE 16
They then recruit platelets which release growth factor at the site. These growth
factors stimulate smooth muscle to proliferate.

SLIDE 17
The lipids and other substances are trapped in the wall of the artery, which is
thickening, and blood flow becomes increasingly reduced as the opening becomes
smaller.

SLIDE 18
Over time, the fatty deposits harden and become a tough and fibrous plaque. They
can be seen on just one side or all the way around the lumen of the artery. As blood
flow decreases, the arteries will not be able to supply enough oxygen-rich blood to
meet the demands of the heart muscle which produces the different manifestations
such as angina pectoris. As the process continue, the patient usually start to
experience ischemia and has an increased risk of MI.

SLIDE 19
Here is an expanded presentation of the pathophysiology as discussed earlier.
(Pakibasa na lang yung laman ng mga boxes since same lang naman sa explanation
earlier)

SLIDE 20
HELLO MGA PHARMA! PAKI-EXPLAIN NA LANG PO :(((

Diagnosis:
Source: 2014 PHA Clinical Practice Guidelines for the Diagnosis and Management
of Patients with Coronary Artery Disease

Slide 21.
A resting 12-lead electrocardiogram (ECG) IS RECOMMENDED during initial
evaluation, and during or immediately after an episode of chest pain suspected to
indicate clinical instability.

ECG or EKG Measures the electrical activity, rate, and regularity of your
(electrocardiogra heartbeat.
m)
 Echocardiogram Uses ultrasound (special sound wave) to create a picture of
the heart.

Exercise stress Measures your heart rate while you walk on a treadmill. This
test helps to determine how well your heart is working when it has
to pump more blood.

Chest X-ray Uses x-rays to create a picture of the heart, lungs, and other
organs in the chest.

Slide 22..
It IS RECOMMENDED that the following initial laboratory tests be performed to
establish CV risk factors, identify possible causes of ischemia and determine
prognosis:

1. Fasting lipid profile (total cholesterol, high density lipoprotein [HDL] cholesterol,
low density lipoprotein [LDL] cholesterol and triglyceride levels)

2. Fasting glucose and/or glycated hemoglobin (HbA1c) level if available; additional

oral glucose tolerance test (OGTT) if both are inconclusive;

- Knowledge of lipid and glucose levels is important because of the

well-recognized association between elevated levels and adverse CV
outcomes
- The lipid profile and glycemic status should be re-assessed periodically to
detect development of dyslipidemia and diabetes, respectively, and to
determine efficacy of treatment if initiated

3. Complete blood count (CBC);

- The CBC provides information related to possible cause of ischemia (e.g.,
anemia) as well as prognostic information (e.g., total white cell count)

4. Biochemical markers of myocardial injury (Troponin T or I)

- If there is a clinical suspicion of AcuteCoronarySyndrome, biochemical
markers of myocardial injury, such as Troponin T or Troponin I, should be
determined because troponins have a central role in identifying ACS
Management:
Source: European Cardiology Review. Current Treatment of Familial
Hypercholesterolaemia
Slide 23:
*Referring to the case of the patient having FH. Early detection and treatment of
FH is recommended to reduce risk of cardiovascular events. The goal of treatment is
to reduce the LDL-C by 50 % from baseline levels.
*Lifestyle modification is the first step in the treatment of FH patients, and one of the
suggested changes is adopting a heart-healthy, plant-rich eating plan. The table here
is the recommended dietary intake for the treatment of FH from the National Lipid
Association and International FH Foundation (read table).
*However, lifestyle changes alone will be insufficient as the sole treatment to achieve
LDL-C goal. Lifestyle modification will at most reduce LDL-C concentration by 10–15
% and most patients will require further pharmacological therapy or the medications
for high cholesterol and high blood pressure.
* Also, for patients with type 2 diabetes they are at high risk of cardiovascular
disease thus, they are advised to keep it in control, or papasok din dito yung lifestyle
changes.. so healthy lifestyle and regular exercise is recommended din.

*In a more severe cases, procedures or surgeries like Percutaneous coronary

intervention (PCI), also known as coronary angioplasty may be recommended if
the patient has a severely narrowed coronary artery to reduce the risk of a heart
attack.(Percutaneous coronary intervention (PCI), also known as coronary
angioplasty, is a procedure that's used to open blocked or narrowed coronary
(heart) arteries. PCI can improve blood flow to the heart and relieve chest pain.)
*So, There are two main ways to improve blood flow to the heart: First is angioplasty
(unblocking of blood vessel, especially the coronary artery) and coronary bypass
surgery (redirects blood around a section of a blocked or partially blocked artery in
your heart)

Prevention:
Source: Source: European Cardiology Review. Current Treatment of Familial
Hypercholesterolaemia
Slide 38:
*For the prevention of CHD, ABCDEs of primary prevention derived from American
Heart Association (AHA) provided a definition of ideal cardiovascular health using 7
metrics collectively called "Life's Simple 7".
* First is assess risk, aspirin: to assess the risk of having CHD, pooled cohort
equations should be used by the clinician to estimate 10-year CHD risk. Aspirin or
the antiplatelet therapy should be used infrequently for primary CHD prevention and
should be reserved for high risk individuals after other risk factors have been
addressed.
*2nd is blood pressure: lifestyle modification are recommended for all those with
elevated blood pressure and hypertension
*3rd is cholesterol: statins are recommended for adults 40-75 yrs old with 10 year
CHD risk of >7.5%. Diabetics, and those with >190mg/dL
*4th is cigarettes: for those who use tobacco, a combination of behavioral
intervention and pharmacotherapy should be recommended to assist quitting.
*5th is diabetes: metformin is the main first line therapy for patients with type 2
diabetes.
*6th is diet and weight: a diet rich in legumes , vegetables, nuts, wholegrains and
fish is recommended.Intake of trans and unsaturated fat should be avoided.
*7th is exercise: clinicians should encourage adults to engage in atleast 150
minutes of moderate-intensity exercise or 75 minutes of vigorous-intensity exercise
weekly.

DRUGS FOR C.A.D

*Ratio for doses for drugs with extended release(ER), sustained release, or
controlled release drugs: Time-release drugs use a special technology to release
small amounts of the medication into a person's system over a long period of time.
This is also referred to as sustained release, extended release, or controlled release.
These tend to come in pill form and are simply made to be more potent but dissolve
slowly.
Coat release: Enteric coating is a useful strategy for the oral delivery of drugs which
rapidly degrade in the stomach, as it prevents the drug being released in the acidic
conditions of the stomach before reaching the intestine.

Beta blockers—
MOA: decrease sympathetic stimulation particularly in the heart..
Decrease din ang HR and contractility which in turn decrease myocardial oxygen
demand

—Adults bisoprolol

The dosage should be individually adjusted. It is recommended to start with 5 mg per

day. The usual dose is 10 mg once daily with a maximum recommended dose of 20
mg per day.

Metoprolol is used alone or in combination with other medications to treat high blood
pressure. It also is used to prevent angina (chest pain) and to improve survival after
a heart attack. Metoprolol is in a class of medications called beta blockers. It works
by relaxing blood vessels and slowing heart rate to improve blood flow and decrease
blood pressure.

Bisoprolol is used alone or together with other medicines to treat high blood pressure
(hypertension). High blood pressure adds to the workload of the heart and arteries. If
it continues for a long time, the heart and arteries may not function properly. This can
damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke,
heart failure, or kidney failure. High blood pressure may also increase the risk of
heart attacks. These problems may be less likely to occur if blood pressure is
controlled .This medicine is a beta-blocker. It works by affecting the response to
nerve impulses in certain parts of the body, like the heart. As a result, the heart beats
slower and decreases the blood pressure. When the blood pressure is lowered, the
amount of blood and oxygen is increased to the heart .

—----

SIDE NOTES:
WHY DO WE NOT STOP TAKING BETA BLOCKERS SUDDENLY? Do not stop
taking a beta blocker suddenly without consulting your doctor. This is important
because when you take a beta blocker regularly, your body becomes used to it.
Stopping it suddenly could cause problems such as palpitations, a recurrence
of angina pain or a rise in blood pressure.
****Some of the more common medicines that can interact with beta-blockers
include:NSAIDS(aspirin)– it will cause hypotensive

Boxed warning: beta blocker withdrawal or abrupt discontinuation can lead to a

rebound hypertension characterized by tachycardia and hypertension.

ContrIndications: beta blockers are the most common culprits in causing

bradycardia, they target the Beta 1 receptor of sympathetic nervous system( that
causes tachycardias ) and have negative chronotropic and inotropic effects because
they block the positive inotropic and chronotopic effect of Beta 1. Beta blockers are
also contraindicated in cardiogenic shock bec. It can aggravate the symptoms of
cardiogenic shock. ( read the meaning of cardiogenic shock)
*Positive chronotrpic- increase HR
*POSITIVE inotropic- makes heart muscle contractions stronger. Raising CO to a
normal level and increasing amt of blood your heart can pump.
*Cardiogenic shock - your heart cannot pump enough blood and oxygen to the brain
and other organs.
CONTRAINDICATIONS SA PPT:
Sinus bradycardia is a cardiac rhythm with appropriate cardiac muscular
depolarization initiating from the sinus node and a rate of fewer than 60 beats
per minute (bpm).
CARDIOGENIC SHOCK- happens when your heart cannot pump enough blood
and oxygen to the brain and other vital organs
COMPLETE HEART BLOCK - occurs when the electrical signal can't pass
normally from the atria, the heart's upper chambers, to the ventricles, or lower
chambers. If the atrioventricular (AV) node is damaged during surgery,
complete heart block may result.

Side effects: because they drop the HR, if you drop HR, the amount of blood that
the heart is pumping forward may also drop creating symptoms of fatigue,
impotence, drowsiness. Also it can cause DOB bec they block the sympathetic
effects of Beta 2 receptors that causes bronchodilation, in contrast they can cause
bronchoconstriction.

SIDE EFFECTS: SA PPT

Also it can cause DOB bec they block the sympathetic effects of Beta 2 receptors
that causes bronchodilation, in contrast they can cause bronchoconstriction.

Monitoring: always monitor the BP and HR to avoid severe drop in BP and HR

Which is another case to treat.
CCB(CALCIUM CHANNEL BLOCKERS)- dilation–to increase BF(BLOOD FLOW)
kasi diba pag nagbuild up ang plaque decrease ang BF ang magiging resulta.
● Calcium channel blockers. One of these drugs may be recommended
if you can't take beta blockers or beta blockers don't work. Calcium
channel blockers can help improve symptoms of chest pain.
● Calcium channel antagonists block the inward movement of calcium by
binding to the L-type “long-acting” voltage-gated calcium channels in the
heart, vascular smooth muscle, and pancreas. CCBs have inhibitory effects
on the sinoatrial (SA), and atrioventricular (AV) nodes resulting in a slowing of
cardiac conduction and contractility. This allows for the treatment of
hypertension and reduces oxygen demand. The dihydropyridines, in
therapeutic dosing, have a little direct effect on the myocardium, and instead,
are more often peripheral vasodilators, which is why they are useful for
hypertension, post-intracranial hemorrhage associated vasospasm, and
migraines.

Boxed warning: amLodipine is classified as category c where in this category,

drugs should be used ONLY if the potential benefit justifies the potential risk to the
fetus. Some studies say, Accdg to NCBI, CCB used in third trimester was associated
with increased risk of neonatal seizures, jaundice and hematologic disorders

Contraindications: some people are allergic to amlodipine and its constituents like
microcrystalline cellulose, dibasic calcium PO4 anhydrous, sodium starch glycolate,
and magnesium stearate that causes allergy to some people. In severe hypotension
it is contraindicated bec. It can aggregate the drop in blood pressure, if your Bp gets
too low it can cause dizziness, fainting or death. Do not use nicardipine in patients
with advanced aortic stenosis because of the afterload reduction effect of
nicardipine. Reduction of diastolic pressure in these patients may worsen rather than
improve myocardial oxygen balance.
Calcium channel blockers do not reduce the risk of initial or recurrent infarction
or death when given routinely to patients with acute myocardial infarction or
unstable angina.

Special precautions: for hypertensive crisis, immediate treatment is needed, like

intravenous administration of nicardipine, amlodipine and other oral drugs are not
effective in treating hypertensive crisis bec. The effect will be slow as they undergo
first pass metabolism,it is also contraindicated in pregnancy like it is indicated before.
Side effects: somnolence, dizziness, fatigue and nausea are the effects of your
blood pressure already getting low, headache and flushing is due to the vasodilator
effect of calcium channel blockers, swelling and edema of ankles happens bec ccbs
dilate blood vessels which can improve blood flow. But this can put pressure on
smaller blood vessels (capillaries) causing fluid to leak into surrounding tissues
causing edema
Monitoring : bp and HR should be monitored to avoid severe hypotension and
severe symptoms of heart failure.
*Heart failure occurs when the heart muscle doesn't pump blood as well as it should.
Blood often backs up and causes fluid to build up in the lungs (congest) and in
the legs. The fluid buildup can cause shortness of breath and swelling of the legs
and feet. Poor blood flow may cause the skin to appear blue (cyanotic).

ACE inhibitors
MOA: The ACE inhibitors lower blood pressure by reducing peripheral vascular
resistance without reflexively increasing cardiac output, heart rate, or contractility.
These drugs block the enzyme ACE which cleaves angiotensin I to form the potent
vasoconstrictor angiotensin II ACE is also responsible for the breakdown of
bradykinin, a peptide that increases the production of nitric oxide and prostacyclin
by the blood vessels. Both nitric oxide and prostacyclin are potent vasodilators.
Vasodilation of both arterioles and veins occurs as a result of decreased
vasoconstriction (from diminished levels of angiotensin II) and enhanced vasodilation
(from increased bradykinin). By reducing circulating angiotensin II levels, ACE
inhibitors also decrease the secretion of aldosterone, resulting in decreased sodium
and water retention. ACE inhibitors reduce both cardiac preload and afterload,
thereby decreasing workload on the heart.

Uses: ACE inhibitors are medications used to treat and manage hypertension, which is
a significant risk factor for coronary disease, heart failure, stroke, and a host of other
cardiovascular conditions
—-moa: Angiotensin II causes direct vasoconstriction of precapillary arterioles and
postcapillary venules, inhibits the reuptake of norepinephrine, stimulates the release of
catecholamines from the adrenal medulla, reduces urinary excretion of sodium and water,
stimulates synthesis and release of aldosterone, and stimulates hypertrophy of both vascular
smooth muscle cells and cardiac myocytes.
Boxed warning: during gestation, taking captopril may cause fetal death,
intrauterine growth retardation, hypotension, acute renal failure, and ductus
arteriosus patency in newborn
*patent ductus arteriosus- after birth , the ductus arteriosus normally closes within
two or three days. In premature infants, the opening often takes longer to close. If
the connection remains open, it’s referred to as patent ductus arteriosus, the
abnormal opening causes too much blood to flow to the baby’s lungs and heart.
Contraindications: hypersensitivity like the case of CCBs
Side effects :
cough- The same activity that allows ACE inhibitors to lower blood pressure
can cause other substances, like bradykinin, to build up in the airways and
make a person cough a lot.
 Flushing- Captopril blocks the conversion of angiotensin I to angiotensin II
and prevents the degradation of vasodilatory prostaglandins, thereby
inhibiting vasoconstriction and promoting systemic vasodilation, thus your skin
complexion will turn out reddish.
Headache- Vasodilatation explains headache induced by most cardiovascular
drugs such as calcium-channel blockers and ACE inhibitors. In these cases,
headache is a side effect
Monitoring : When you start on an ACE inhibitor, you will need blood tests to
monitor your kidney function and potassium levels. Be aware: If you take an
ACE inhibitor, keep a written log of your heart rate (pulse) and blood pressure. Track
your heart rate by taking your pulse daily.Acute renal failure has been reported
during captopril therapy of hypertension due to renal artery stenosis with a single
kidney or bilateral renal artery stenosis.(ncbi.nlm.nih.gov)

SIDE NOTES: (MONITORING) — Renal function and electrolytes need to be checked

regularly due to the effects of the drug on the renin-angiotensin-aldosterone system. For
patients with increasing potassium, drop-in GFR, or increasing creatinine, the drug needs to
be adjusted accordingly or discontinued

STATINS (ATORVASTIN, SIMVASTATIN, FLUVASTATIN)

MOA- Inhibit nya si HMG-COA reductase which plays a role sa conversion ni
HMG-CoA to mevalonate.. Ang step kasi na ito rate limiting sya sa cholesterol
synthesis so kapag na inhibit –iactivate nya is LDL receptors(upregulation) para
magpasok ng LDL dun sa cell kasi nga decrease cholesterol–so decrease naman
ang LDL sa blood eh diba nga LDL (bad cholesterol) play an important role sa
formation ng fatty streaks that cause plaque build up..
INDICATIONS: Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, also known
as "statins," are used adjunctively to diet and exercise to treat hypercholesterolemia by
lowering total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides
concentrations while increasing high-density lipoprotein cholesterol (HDL-C) concentrations
Boxed warning: Statins could also be causing cognitive impairment by interfering
with mitochondrial function in the brain. Malfunctioning mitochondria have been
linked to diabetes, heart disease, Alzheimer's disease, Parkinson's disease and even
normal aging.
How does mitochondrial dysfunction affect the brain?
Mitochondrial dysfunction impairs hippocampal development and leads to loss
of NSCs(neural stem cells) and adult neurogenesis. Genetic diseases that result
in mitochondrial abnormalities often show progressive clinical signs of impaired
cognitive function.
*Neural stem cells (NSCs) are the stem cells of the nervous system. During
development they give rise to the entire nervous system.
CONTRAINDICATIONS: Pregnancy and lactation.
Pregnancy : A study that reviewed data from thousands of women,
approximately half of whom took statins during their first trimester of
pregnancy, showed that babies were not at increased risk of birth defects due
to statin use. However, patients who did take statins in the first trimester
had a higher rate of miscarriages(https://utswmed.org/)
Lactation: Patients should not breastfeed when taking a statin because the
medicine may pass into breast milk and pose a risk to the baby. Many can
stop statins temporarily until breastfeeding ends. However, patients requiring
ongoing statin treatment should not breastfeed and instead use infant formula
or other alternatives.
Side effects: Most common is muscle pain- can cause potassium to build up in
the body (another type of electrolyte imbalance), which can lead to leg cramps and
achy joints, bones and muscles.

Monitoring: Low HDL-C and elevated triglycerides (TG) are both independent risk
factors for cardiovascular disease. This lipid profile helps predict your risk for
heart disease and stroke.

Drugs and food that interact with statins

Grapefruit juice—Grapefruit juice contains a chemical that can interfere with the
enzymes that break down (metabolize) the statins in your digestive system.
Some drugs that may interact with statins and increase your risk of side effects
include: (INCASE TANUNGIN PO NI DOC)
● Amiodarone (Cordarone, Pacerone), a medication for irregular heart
rhythms
● Gemfibrozil (Lopid), another variety of cholesterol drug
● HIV treatments called protease inhibitors such as saquinavir (Invirase) and
ritonavir (Norvir)
● Some antibiotic and antifungal medications, such as clarithromycin and
itraconazole (Onmel, Sporanox)
● Some immunosuppressant medications, such as cyclosporine (Gengraf,
Neoral, Sandimmune

FIBRATES FENOFIBRATES, GEMFIBROZIL

MOA– nag aact sya sa tissue–pacheck nlng dun sa pathophysio
Eto naman i activate peroxisome proliferation activated receptor (PPAR-alpha
found in active tissues such as: LIVER AND ADIPOSE TISSUES) THE BINDING OF
FIBRATES TO PPAR-alpha induces activation and inhibition of certain genes that
code for proteins involved in lipid metabolism one of the main effects induced by
fibrates is increased expression of lipoproteins lipase which in turn increases
the removal of TG from ciculation and their breakdown to FA——fibrates
decrease expression of protein called Apo-CIII which inhibits lipoprotein lipase
activity and lastly fibrates also increase expression of proteins Apo-A1 and Apo-AII
which are major components of HDL thus leading to increase conc of drugs that
belong to this class include fenofibrate and gemfibrozil
—side effects GI disturbances
Boxed warning: Fibrate treatment causes adverse changes in biliary lipid
composition and decreases bile acid excretion, leading to an increased
incidence of cholesterol gallstones. These drugs increase biliary cholesterol
excretion, there is a predisposition to form gallstones.

Contraindications:
Hypersensitivity - some people are allergic to its contents, so as
much as possible avoid taking these drugs to avoid anaphylaxis
Severe renal impairment, ESRD, px receiving dialysis- Fenofibrate
has been observed to increase serum creatinine concentrations in
patients with CKD, patients with these disease have already increased
creatinine levels, thus statins can aggravate it. High levels of creatinine
in the blood or urine can be a sign that the kidneys are not filtering the
blood effectively
active liver disease- Liver toxicity usually is signaled by an
asymptomatic increase in transaminase levels, but rare episodes of
severe hepatotoxicity and liver damage have been reported. For this
reason, statins have been contraindicated in patients with active liver
disease and persistent elevated transaminase levels.
Gallbladder disease - FIbrates can increase the concentration of
cholesterol in the gallbladder. This may lead to gallstones. Thus it can
also aggravate the disease.
Prenancy and lactation - considered under pregnancy category c
(where benefits outweigh the risk) risk of major congenital disabilities,
adverse maternal or fetal outcomes, or miscarriage-related risk
associated with this drug. Patients should not breastfeed when taking a
statin because the medicine may pass into breast milk and pose a risk
to the baby.
Warning: The simultaneous usage of HMG CoA reductase inhibitors (statins)
with gemfibrozil enhances the probability of developing rhabdomyolysis or
myopathy. Therefore, simvastatin is contraindicated, and rosuvastatin use
should be avoided while administering gemfibrozil.

* Rhabdomyolysis (rhabdo) is the breakdown of damaged skeletal muscle.

Muscle breakdown causes the release of myoglobin into the bloodstream.
Myoglobin is the protein that stores oxygen in your muscles. If you have too
much myoglobin in your blood, it can cause kidney damage. It also releases
huge amounts of potassium into the bloodstream, which can disrupt the
electrical rhythm of the heart.

Side effects: The myopathies are neuromuscular disorders in which the

primary symptom is muscle weakness due to dysfunction of muscle
fiber. Other symptoms of myopathy can include include muscle cramps,
stiffness, and spasm.
Fibrates may have a direct toxic action on muscle cells in patients with an
 unrecognized predisposition to myopathy. One of the mechanisms by which
they cause muscle damage is they cause breakdown of skeletal muscle
tissue. This will lead to rhabdomyolysis (pls read the meaning stated above)

Monitoring: Monitor serum transaminases since fibrates can sometimes elevate

these levels.
Monitor PT/INR levels at least thrice a week when co-administering with coumarin
anti-coagulants to prevent bleeding complications as fibrates are known to potentiate
the effects

Bile acid sequestrants COLESTIPOL

MOA: -bile acids are produced in the liver and stored in the gallbladder excreted to
the gut where they facilitate digestion and absorption of lipids
-now bile acids sequestrants basically serve as an ion exchange resins that bind
negatively charge bile acids and salts in the SI(Small intestine) the formation of this
insoluble complex prevents the reabsorption of bile acid and thus leads to their
excretion this increase in bile acid excretion in turn creates increased demand for
their production since bile acids are made from cholesterol liver cells increase their
number of LDL receptors to bring in more LDL cholesterol in order to meet this new
demand so the end result is decreased levels of circulating LDL

Why is the dose adjusted with 1-2 month intervals? Colestipol is given 1- 2 months
only because it can cause vitamin K deficiency and can increase tendency to bleed if
injured.
Boxed warning: You should never take the granule formulation in the dry form,
because there is a choking risk. Imagine yourself swallowing 2g granules of
drug, wouldn't be that uncomfortable?

Special precautions: These drugs have the potential to cause fetal toxicity.

Side effects: bile acids in the intestine help control how much water is in your stool.
By binding to extra bile acid in the intestines, this medication may remove some
water in your stool, causing constipation. Due to constipation, feces may become
impacted, due to the difficulty of defecation leading to abdominal discomfort. In worst
cases cause blood in stool because pinipilit mong matae despite constipation.

Monitoring: Serum cholesterol and triglyceride levels should be determined

periodically based on NCEP(National Cholesterol Education Program) guidelines to
confirm a favorable initial and adequate long-term response. Colestipol hydrochloride
tablets may produce or severely worsen pre-existing constipation,if taken too long.
So better na check mo na ang serum cholesterol and TGs mo para maitigil na ang
pagtake ng colestipol at para d kana mag ka constipation.
DOSING
- Colestipol is available as powder packet ( 5 gm ), granules packet ( 5 gm ), and oral
tablets ( 1 gm ) of colestipol hydrochloride.
- It is administered as 2 g tablets once, or twice daily, and the dose can be increased by
one tablet once or twice daily at 1 to 2-month intervals. The maximum dose is 20 gm
daily.
- The recommended daily adult dose for colestipol is one to six packets or scoopfuls
administered preferably in divided doses. Starting dose is one packet once or twice
daily and should be increased by one dose per day every one to two months.
Colestipol powders are mixed with water or juice to avoid esophageal distress and
accidental inhalation.
- Safety and effectiveness in the pediatric population have not been established.

CHOLESTEROL ABSORPTION INHIBITOR

-mechanism of cholesterol absorption in the small intestines
-So yung free cholesterol that comes form either bile or dietary sources first binds to
protein NPC1L1 is located in the plasma membrane of cell known as enterocytes
that line the intestinal walls this binding then triggers endocytosis which utilizes
protein complex calles clathrin AP2 that works in the cell membrane to internalize the
cholesterol upon endocytosis the cholesterol is released and NPC1L1 return back to
the plasma membrane..
-Now, the cholesterol absorption inhibitor binds to NPC1L1 and inhibits the ability to
interact with clathrin AP2 complex that is necessary for endocytosis.. This leades to
DECREASED delivery of intestinal cholesterol to the liver which in turn caused
DECREASED hepatic cholesterol levels—-kaya mag INCREASE yung clearance of
LDL from the circulation..
-Currently the only drug that belongs to this class is EZETIMIBE
*NPC1L1 = Niemann-Pick C1-Like 1 is a protein found on the gastrointestinal tract
epithelial cells as well as in hepatocytes. Specifically, it appears to bind to a critical
mediator of cholesterol absorption

Why it is used?
Cholesterol absorption inhibitors are used to treat high cholesterol in people who
cannot take a statin. This medicine lowers total cholesterol and LDL (bad)
cholesterol.
This medicine is used along with lifestyle changes including diet and exercise to
lower cholesterol.

CONTRAINDICATIONS: Hypersensitivity(alam nyo na dahilan paulit ulit na kanina

nabangit)
Side effects: why may abdominal pain at diarrhea? Dko mahanap
Monitoring: Monitor PT/INR levels at least thrice a week when co-administering with
coumarin anti-coagulants to prevent bleeding complications as ezetimibe are known to
potentiate the effects.Ezetimibe was associated with decreased platelet aggregation leading to
bleeding.

NIACIN
Dosage explanation: high doses of 500 mg/day or more can cause diarrhea, easy
bruising, and can increase bleeding from wounds. Even higher doses of 3,000
mg/day or more can cause nausea, vomiting, and liver damage
Contraindications:
Hypersensitivity- alams na yan
If you have liver disease, peptic ulcer disease or severe low blood pressure
(hypotension), don't take large amounts of niacin. The supplement has been
linked with liver damage, can cause hypotension and might activate a peptic
ulcer.
Hepatic disease - Niacin can cause mild-to-moderate serum aminotransferase
elevations and high doses and certain formulations of niacin have been linked
to clinically apparent, acute liver injury which can be severe as well as fatal
Hypotension- niacin lowers bp so they can aggravate the symptoms of
hypotension
Arterial bleeding- niacin increases prothrombin time.When the PT is high, it
takes longer for the blood to clot , therefore more prone to bleeding.
Side effects:
Flushing and pruritus- The flush happens when niacin causes the small
capillaries in your skin to dilate, which increases the flow of blood to the
surface of the skin. Niacin flush is a very common side effect, with almost
everyone who takes large doses of niacin experiencing the reddening. Niacin
flush is a common side effect of taking high doses of niacin supplements. It's
uncomfortable, but it's harmless. It appears as a flush of red on the skin,
which may be accompanied by an itching or burning sensation

MOA: —works in adipose tissue where it inhibits an enzyme called

hormone-sensitive lipase which is responsible for the breakdown of TG to free fatty
acids
— now normally liver uses these FFA to make its own TG which then become
important component of VLDL so by reducing levels of FFA available for transport to
the liver
—niacin effectively decreases hepatic VLDL synthesis which in turn lead to
decreased levels of LDL
—— furthermore, Niacin increases HDL levels by few different mechanisms that are
still being investigated now when it comes to side effects one of the most common
one is flushing caused by Niacin induced prostaglandin release which results in
cutaneous vasodilation
—Next, niacin can compete with uric acid for excretion by the kidney which can
increase risk of hyperuricemia and gout
—lastly at large enough doses Niacin may also cause liver toxicity

PCSK9-
MOA—is an enzyme circulating in the blood that binds to LDL receptors on the
surface of liver cells and promotes their degradation in other words the activity of
PCSK9 reduces the removal of LDL from the circulation
—now the PCKS9 inhibitors are monoclonal antibodies that bind to and inactivate
PCSK9 in the absence of PCSK9 there’s more LDL receptors available to bind and
clear LDL from the circulation leading to decreased levels of LDL cholesterol
‘’Pag walang inhibitor ng PCSK9, DADAMI ANG LDL SA KATAWAN’’
(Proprotein convertase subtilisin/kexin type 9 is an enzyme encoded by the PCSK9
gene in humans on chromosome 1. It is the 9th member of the proprotein convertase
family of proteins that activate other proteins. )

Dosage : Long-lasting drugs, which your doctor may call long-acting injectables,
improve symptoms the same way as daily pills. They stay longer in your body so
they are given every 2-4 weeks( monthly).
CONTRAINDICATIONS: Hypersensitivity
SIDE EFFECTS: inj site reactions, The most common kinds of reactions reported in
Repatha's studies were discoloration, pain, and bruising at the injection site.
Monitoring: PCSK-9 inhibitors also cause hepatocyte damage, presenting as
elevation in serum transaminases. PCSK-9 can enhance the liver injury in patients
with risk factor of liver injury like hepatic steatosis.

Nitroglycerin
MOA: Organic nitrate which causes systemic venodilation, decreasing preload
Cellular mechanism: enters vascular smooth muscle and is converted to nitric oxide
(NO) which induces synthesis of cGMP and vasodilation
Relaxes smooth muscle via dose-dependent dilation of arterial and venous beds to
reduce both preload and afterload, and myocardial O2 demand
Also improves coronary collateral circulation. Lower BP, increased HR, occasional
paradoxical bradycardia

ROA: ROUTE OF ADMIN

Angina: Sublingual form for acute episodes
- oral and transdermal forms for prophylaxis
- IV form for acute coronary syndrome
SIDE EFFECTS: headache, dizziness, hypotension, flushing
Due to the vasodilator property of nitroglycerin, you experience flushing, headache
dizziness and hypotensive is due to the blood pressure lowering effect of this drug.

MONITORING: Continuous monitoring of BP, HR, RR to prevent severe hypotension.

NOTES: Patient should not chew or swallowing nitroglycerin tablets. Nitroglycerin
sublingual tablets should not be chewed, crushed, or swallowed. They work much
faster when absorbed through the lining of the mouth. Place the tablet under the
tongue or between the cheek and gum, and let it dissolve.

Questions
10 mcq on CAD

1. What drugs are recommended if you cant take beta blockers or beta blockers
don’t work?

A. ARBS
B. CCB
C. ACE INHIBITORS

- Answer: b. calcium channel blockers

- Calcium channel blockers relax blood vessels and lower your blood
pressure. These medications can reduce your heart's workload, help
coronary arteries open, and relieve and control angina.
- They work by preventing calcium from entering the cells of the heart
and arteries.
- Calcium causes the heart and arteries to squeeze (contract) more
strongly. By blocking calcium, calcium channel blockers allow blood
vessels to relax and open.

2. Why should you always monitor the blood pressure of a patient taking drugs
for hyperlipidemia?

a. To be able to know if the drug is given at the dose

b. To know if the drug is effective
c. To be able to prevent further hypotension
d. All of the above

Answer : D
 -One of the most important things you can do to manage high blood pressure is to
track it every day to measure the success off your treatment and to spot trends
that may indicate complications(ex: to reduce cardiac events) .

- Lowering high blood pressure decreases death from stroke, coronary

events and heart failure, slows progression of renal failure, prevents
progression to severe complications of hypertension, and reduces
all-cause mortality.

3. Why are some antihypertensive drugs(captopril, CCB) is

contraindicated to pregnant women? What are you going give if the
patient is pregnant ?

a. Hydralazine b. MgSO4 c. methyldopa d. All of the

above- correct answer

4. How do extended and immediate release tablets work?

a. By delaying their release at desired time to deliver a therapeutic dose

needed.
b. To mask the drug against the acidic property of the stomach, to avoid
degradation of the drug.
c. both

Answer C *Ratio for doses for drugs with extended release(ER),

sustained release, or controlled release drugs: Time-release drugs use a
special technology to release small amounts of the medication into a person's
system over a long period of time. This is also referred to as sustained
release, extended release, or controlled release. These tend to come in pill
form and are simply made to be more potent but dissolve slowly.

Coat release: Enteric coating is a useful strategy for the oral delivery of drugs which
rapidly degrade in the stomach, as it prevents the drug being released in the acidic
conditions of the stomach before reaching the intestine.

5. Which among the following drug has a boxed warning due to cognitive
impairment including memory loss:

A. Cholestyramine

B. Ezetemibe

C.Fenofibrate
D.Atorvastatin

Answer: D–

Ratio: Atorvastatin competitively inhibits 3-hydroxy-3-methylglutaryl-coenzyme A

(HMG-CoA) reductase. By preventing the conversion of HMG-CoA to mevalonate,
statin medications decrease cholesterol production in the liver. Atorvastatin also
increases the number of LDL receptors on the surface of hepatic cells.

Drugs (statins) that lower blood levels of cholesterol may impair memory and other
mental processes by depleting brain levels of cholesterol as well. In the brain, these
lipids (cholesterol, glycosphingolipids (GSLs and phosholipids) are vital to the
formation of connections between nerve cells — the links underlying memory and
learning.

6. Why does captopril causes dry cough as its side effect?

a. Due to bradykinin build up in the airways

b. Due to increase in substance P
c. Due to allergic reaction to the drug
d. Both a and b

Answer : D

- The means by which ACE inhibitors affect the respiratory

system is thought to be through an increase of substance
P, which is released from the vagal and glossopharyngeal
sensory nerves in the pharynx and upper airways, and is
naturally degraded by ACE
- Bradykinin induces sensitization of airway sensory nerves via
rapidly adapting stretch receptors and C-fiber receptors that
releases neurokinin A and substance P. This causes airway
smooth muscle to constrict leading to bronchoconstriction and
cough.
- The same activity that allows ACE inhibitors to lower blood
pressure can cause other substances, like bradykinin, to build
up in the airways and make a person cough a lot.

7. Why do most statins are usually given at night?

A. Because of shorter half lives

B. Bec there is a greater reduction of LDL cholesterol at night
C. Both
 Answer: both

- Some statins have half-lives of less than six hours. These

statins are best taken at night.
- Simvastatin is an example of a statin that works better if taken in
the evening. Studies show that when simvastatin is taken at
night, there’s a greater reduction in LDL cholesterol than when
it’s taken in the morning.
- But there is a medication that is taken better in the morning,
HMG-CoA reductase inhibitors such as atorvastatin and
rosuvastatin are more potent than older statins. They have
half-lives of at least 14 hours. Extended-release fluvastatin, can
be taken at any time of day.

8. What happens when you swallow a drug which is intended to be sublingual?

a. Will lead to Reduced efficacy of the drug

b. There will be No effect of drug
c. The person will be poisoned

Answer: A

- Sublingual drugs: They work much faster when absorbed

through the lining of the mouth. Place the tablet under the
tongue or between the cheek and gum, and let it dissolve. If you
have swallowed the drug, the efficacy will be reduced.

9. Why are some drugs given once a month only?

A. Because these drugs are expensive
B. Dosing is based on patient’s preference only
C. Because they are long acting drugs
D. Because they are short acting
Answer : C
-Long-lasting drugs, which your doctor may call long-acting injectables,
improve symptoms the same way as daily pills. They stay longer in
your body so they are given every 2-4 weeks( monthly).

10. What drug is used to prevent hyperlipedemia?

a. Paracetamol
b. Ibuprofen
c. Carvedilol
d. Aspirin
Answer: D
Ratio:
10 mcq on urticaria

1. What is the drug of choice for urticaria?

a. Diphenhydramine
b. Loratadine
c. Cetirizine
d. All of the above

- Answer: D, all can be possible bec they are all H1 antihistamines,

and h1 antihistamine is the first line

-Diphenhydramine (1st generation)- is a sedating peripheral H1 receptor

antagonist. It is used for symptomatic relief of allergic symptoms
caused by histamine released in response to allergens

-Loratidine and cetirizine (2nd generation) - selectively inhibits peripheral

(outside CNS KAYA IT DOES NOT CROSS BBB) histamine H1-receptors
and is minimally sedating.

2. How does h1 antihistamines help in the treatment of urticaria?

A. primary mechanism of antihistamine action in the treatment of allergic

diseases is believed to be competitive antagonism of histamine binding to
cellular receptors (specifically, the H1-receptors)
B. H1-antihistamines are the cornerstone of symptomatic treatment in acute and
chronic urticaria, in which they not only relieve itching, but also reduce the
number, size, and duration of urticarial lesions.
C. BOTH
D. NONE OF THE ABOVE

3. What is the difference of 1st generation and 2nd generation antithistamines?

a. 1st generation are older generations and are sedating.

b. First-generation antihistamines block both histaminic and muscarinic
receptors as well as passing the blood-brain barrier. Second-generation
antihistamines mainly block histaminic receptors and do not pass the
blood-brain barrier.
c. 2nd generation AH causes sedation also but lesser compared to 1st gen.
d. All of the above

Ans: D

4. Why are h1 antihistamines contraindicated with glaucoma?

 a. they have atropine like properties
b. They also cause mydriasis
c. They stimulate the adrenergic alpha 1 receptors
d. All of the above

Answer: D Sympathomimetics (applies to chlorpheniramine/pseudoephedrine)

glaucoma. Sympathomimetic agents can induce transient mydriasis via
stimulation of alpha-1 adrenergic receptors. In patients with anatomically
narrow angles or narrow-angle glaucoma, pupillary dilation can provoke an
acute attack. Chlorpheniramine is an antihistamine (h1 antagonist, 1st gen)

5. why are these anti-allergy drugs still contraindicated to patients with

hypersensitivity when their main action is to block hypersensitivity to an allergen?

a. Because of their additive ingredients

b. Because they fail to deliver their therapeutic dose
c. Because the drug is cheap and a generic one only
d. All of the above

- answer A: Because of the additive ingredients( ingredients other

than the active ingredient/ generic name of drug) which can sometimes
cause allergic reaction to some patients. For example captopril, In
addition, each tablet contains the following inactive ingredients:
microcrystalline cellulose, corn starch, anhydrous lactose, colloidal
silicon dioxide, talc and palmitic acid. The talc content causes allergic
reaction to some patients.

6. Why should you not take the drug with fruit juices?

a. Becuase they can irritate the stomach and cause hyperacidity leading to
decreased absorption of the drug
b. Fruit juices like grapefruit juice is an enzyme inhibitor
c. Bec the taste is not pleasant
d. Taking drugs with fruit juices can make you vomit

- answer b: do not take with fruit juices esp grapefruit juice because it
is an enzyme (cyp450) inhibitors, this cyp 450 is an enzyme for
metabolism, so ang ginagawa ng grapefruit juice iniinhibit nya ang
further metabolism( metabolism is a preparation for a drug to be
excreted) so matatagalan ngaun ang excretion ng drug sa katawan, na
memetabolize sya lalo, mag accumulate ang dose then can lead to
overdosage na naman.

7. How can glucocorticoids help in the treatment of urticaria?

 a. stabilize mast cell membranes and inhibit further histamine release.
b. They reduce the inflammatory effect of histamine and other mediators
c. Both a and b
d. None of the above
Ans: c

8. Why is prednisone not recommended for long term use?

a. Bec. it Can make you fat

b. Can suppress your immune system
c. It can lead to cushings syndrome
d. All of the above

Answer: D, nandto sa report guide ung ratio nasa part ng prednisone

9. why is doxepin contraindicated with MAOIs?

a. It can aggravate the side effects of maois

b. It is a competitive inhibitor of maois
c. Both
d. None of the above

Answer: A

- Nasa report guide din

10. What drug is used in cases of anaphylaxis?-

Answer: Epinephrine (DOC of anaphylactic shock)

a. Dopamine
b. Dobutamine
c. Norepinephrine
d. Epinephrine