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255 terms

Exam 4- Histamine and Histamine Blockers

STUDY
PLAY
histamine
Low molecular weight endogenous amine that is found in low concentrations in most tissue except for the brain:
mast cells
What cells are found in the skin, GOT and lungs and have high amounts of histamine?
basophiles
Besides mast cells, what other circulating cells have high amounts of histamine?
activated
In order for cells to release histamine, what state does the cell have to be in?
g-protein
Histamine acts through which transmembrane receptors?
2
How many mechanisms can break down histamine?
histamine N- methyltransferase
What metabolizes histamine first?
monoamine oxidase
What enxyme plays a role in histamine degradation that, if inhibited, will cause an increase in histamine response?
MAOIs
What drugs can inhibit monoamine oxidase resulting in increased histamine response?
diamine oxidase
What is the second way that histamine can be metabolized?
heparin
Histamine is stored in vesicles associated with what?
4
How any types of histamine receptors are there?
g protein receptors
When histamine binds to a receptor, what causes the physiologic and pathologic responses?
stimulates gastric acid secretion
Physiologic response to histamine receptor activation?
allergic reactions
Pathologic response to histamine receptor activation?
anaphylaxis
What is a pathological total body event?
H1
Which histamine receptor is found on all smooth muscle, endothelium, and CNS tissue?
all of it
Which smooth muscle are h1 receptors found on?
- vasodilation
- bronchoconstriction
- bronchial smooth muscle contraction
- separation of endothelial cells
- pain and itching due to insect stings
Five things that h1 activation causes:
because it causes bronchoconstriction
How can h1 receptor activation cause pulmonary HTN?
separation of endothelial cells
How does h1 cause hives?
- allergic rhinitis
- motion sickness
H1 receptors are primarily involved in what two things?
motion sickness
Which one of the 2 symptoms that h1 causes do we care about?
h1 antagonists
What types of drugs will reverse the effects of h1 activation?
parietal cells
Where are h2 receptors located?
stimulate gastric acid secretion
What is the primary action of h2 receptors?
alpha 2
H3 histamine receptor is like which adrenergic receptor?
CNS and peripheral nervous tissue
What 2 places are h3 receptors found?
histamine
acetylcholine
norepinehprine
serotonin
What 4 neurotransmitters are released by h3?
h4
Which receptor is found in basophils, bone marrow, intestines, thymus, and spleen?
chemotaxis
H4 plays a role in what?
h2
Which histamine receptor increases cAMP by stimulating adenylate cyclase?
h1
Which histamine receptor stimulates phophoinositide turnover and influx of calcium?
h3
Which histamine receptor has presynaptic regulation of neurotransmitter release (dopamine, GABA, glutamate, ACH, NE, and 5ht)?
h1
The effects of these receptors on smooth muscles is rapid and transient, they are sensitive to lower histamine concentrations, they cause constriction and increased GI motility:
h3
These receptors on neurons inhibits the release and synthesis of histamine:
h2
Response of these receptors on smooth muscle is slow and sustained and they cause dilation:
- hypotension from vasodilation
- reflex tachycardia
- increased capillary permeability
- decreased peripheral resistance
What are the 4 combined receptor responses of h1 and h2 on smooth muscle?
no
If a pt is on a beta blocker and they experience hypotension, will there be any reflex tachycardia?
- fluid
- increased capillary permeability causes total body edema and depleted intravascular volume
What is one of the major treatments of anaphylaxis and why?
contraction
What is h1's predominant action on the bronchi tissue?
relaxation
What is h2's action on the bronchi tissue?
opposite
The actions produced by h1 and h2 are the same or opposite?
- slows av conduction
- decreases HR
- coronary vasoconstriction
3 actions of h1 on the heart:
promotes ca influx
How does h2 act an a positive inotrope (increases myocardial activity)?
increases
What does the cardiac h2 response do to automaticity, chronotropy, and HR?
increases
What does h2 do to the frequency of arrhythmias?
dilates
What does h2 do to the coronary arteries?
parietal cells
Which cells do h2 receptors cause increased secretion of hydrogen ions?
allergic reaction
What is an immune mediated reaction due to prior sensitization?
no- they're one of several
Are histamines the only signals in allergic reactions?
variable
Are the signal responses by allergens the same or variable?
proteins
Anaphylaxis is an immune mediated response due to prior sensitization of what?
protamine
Which drug is protein from fish sperm and is the reversal agent for heparin?
if they've ever had a vascetomy becuase they will be sensitive to the protamine that is given
What do we have to ask male pts before having cabg and why?
medications
Which substance causes a predominant histamine response but is more responsive to histamine receptor antagonism?
bronchoconstrictors
Leukotrienes are predominant ____.
edema and pruritis
The variable effect of histamines in human is seen when they are blocked by a h antagonist with:
hypotension and bradycardia
The variable effect of histamines in human is seen when they are not completely blocked by a h antagonist with:
surface of the mast cell and inhibits histamine release
Where does cromolyn work and what does it do?
prophylactically
When does cromolyn have to be given to be effective?
anaphylaxis
You're in the OR, the pts PAP and PIP both increase rapidly and the PAOP falls, what is occuring?
fluid is leaving the vasculature and into the interstitium
Why does the PAOP fall in anaphylaxis?
- hypotension
- circulatory collapse
- bronchial artery vasoconstriction
- bronchospasm
- angioedema
- urticaria
6 clinical manifestations of anaphylaxis:
RV failure
What is a risk of acute bronchial artery vasoconstriction?
increased PIP
wheezing
altered ETCO2 curve
3 things that can mean bronchospasm:
B
Which ETCO2 waveform shows bronchospasm?
angioedema can still persist that you cannot see
Why should you let the cuff down a few minutes before pulling the ETT?
severe hypotension
When the IgE antigen stimulates histamine, tryptase, prostaglandins, leukotrienes, kinins, and nitric oxide, what occurs?
IgE
mast cells
basophils
Which antigen's mechanism is via cellular signaling via phospholipase C and what are the inflammatory cells?
IgG
neutrophils
thromboxane
Which antigen's mechanism is via complement activation and anaphylatoxin generation and what are the inflammatory cells?
anaphylactoid
Anaphylaxis or anaphylactiod:
No sensitization required and may occur at first drug exposure.
split dosing
What technique does Dr. Nolan suggest when trying to get around an anaphylactoid reaction?
NMBs
Which drug class has the highest incidence of anaphylactic reactions?
rocuronium, atracurium, succinylcholine
What are the alleged 3 most common NMBs associated with anaphylaxis?
latex
What is the agent that is the second highest in causing anaphylaxis?
antibiotics
What is the third highest in causing anaphylaxis?
PCN
cephalosporins
vanco
What 3 abx are the most associated with anaphylaxis?
PCN and cephalosporins
What two abx are cross reactive?
- bananas
- avocados
- kiwis
- mangos
- stone fruits
5 fruits that are associated with latex allergy:
multiple operations and other incidences of frequent contact with latex
What other situations place people at risk for developing latex allergy?
test dose
What can clinicians administer to see if a reaction is going to occur?
yes
Can nonreactive test doses be followed by analphylaxis?
speed of administration
What is important in drugs that are known histamine releasers, but not for anaphylaxis, since small doses may trigger reactions?
because they are histamine releasing events
Why doesn't pretreating work with dyes?
yes
Can pretreated patients for anaphylaxis with antihistamines or steroids still have anaphylaxis?
no
Are radiocontrast media reactions immunologically related?
hives
angioedema
hypotension
A true drug allergy or allergic reaction has what 3 signs?
5%
What percent chance can pts with penicillin allergies have a reaction with cephalosporins?
10 minutes
How many minutes before the initial loading dose of a drug should the test dose be administered?
1) Discontinuation of drug that caused it
2) 100% o2
3) IVF
4) IV epinephrine
5) diphenhydramine
6) rantidine or cimetidine
7) albuterol
8) cortocosteroids
What are the steps in managing anaphylaxis?
profound vasodilation causes hypovolemia
Why do we need to give volume with anaphylaxis?
norepi or vasopressin
If hypotension is refractory in anaphylaxis then what can we give?
refractory hypotension or vasodilitary shock
Why give vasopressin in anaphylaxis (2)?
5-10 mcg
Initial epinephrine bolus in anaphylaxis?
100-500 mcg
Epinephrine for vascular collapse:
after the epi
Give diphenhydramine when?
alpha 1 and beta 2 agonist
What kind of drug is epinephrine?
H1
Diphenhydramine blocks which receptor?
h2
Randitine or cimetidine blocks which receptor?
relax the bronchial smooth muscle
Why do we give albuterol and ipratropium in anaphylactic reaction?
- to prevent late or delayed symptoms
- early hours of the resuscitation period
Why do we give corticosteroids in anaphylaxis? When do we give them?
7.5
2 mg in 250 mL can run at what rate for 1 mcg/min?
Beta 2 agonists (terbutaline or albuterol)
What do we treat bronchospasm with?
make it longer
What do you need to do to the e time in bronchospasm?
milrinone, inhaled NO, inhaled prostacyclin
What are 4 pulmonary vasodilating drugs that can treat pulmonary HTN if blood pressure is stable?
no
Do histamine receptor antagonists inhibit histamine?
they prevent binding of the histamine to the receptor thus preventing the response
How do h blockers work?
2
How many generations of h blockers are there for the h1 receptor?
classical histamines
1st generation antihistamines are considered what?
nonsedating
Second generation antihistamines are what?
marked
moderate
3-6 hours
Diphenhydramine
- Sedative and anticholinergic effects:
- Antiemetic effects:
- DOA:
moderate
marked
4 to 24 hours
Promethazine
- Sedative effects:
- Anticholinergic and antiemetic effects:
DOA:
first generation H1 antagonists
Diphenhydramine and promethazine are what class?
fexofenadine
loratadine
cetirizine
Which second generation h1 antagonists have no sedative effects, anticholinergic activity, or antiemetic effects?
cimetidine
Which h2 blocker is the only one with mild sedative effects while the rest have none?
first generation h1 blockers
These h blockers are lipid soluble and can cross the BBB, they are well absorbed, and metabolized:
no
Are first generation h1 blockers able to be ionized?
sedation
headache
N&V
cough
constipation or diarrhea
dry mouth
blurred vision
urinary retention
Adverse reactions of 1st gen h1 blockers (8):
no
Are h1 blockers the best choice for inhibition of allergic rhinitis?
conjunctivitis
urticaria
H1 receptor blockers are useful in what symptoms?
PONV
motion sickness
Allergic reaction
sleep aid
H1 receptor blockers are prescribed for (4) in addition to conjunctivitis and urticaria:
H1 antihistamine overdose
Fever, excitement, pupil dilation, hallucinations, and convulsions are all signs of what?
intubate
activated charcoal
gastric lavage
IVF
Treatment for H1 antihistamine overdose (4):
hot as a stove
red as a beet
dry as a bone
mad as a hatter
Way to remember the S&Ss of H1 antihistamine overdose:
2nd gen h1 antihistamines
Lipid soluble with highly ionized functional group resulting in less CNS penetration, well absorbed, metabolized in the liver, and the half life is 5-6 hours:
peripheral receptors
The 2nd gen h1 antagonists are selective for which h1 receptors?
- sedative
- antipruritic
- antiemetic
- anticholinergic
Diphenhydramine actions (4) as a h1 antagonist (1st gen):
- allergenic and allergic reactions
- EPS
- sedation
- prevention of motion sickness
Indications of duphenhydramine (4):
10-50mg IV q4hours
400mg per day max
Adult dose of diphenhydramine:
primarily hepatic metabolism and renal excretion
Clearance of diphenhydramine and promethazine:
adverse effects of diphenhydramine
Hypotension, tachycardia, dizziness, urinary retention, seizures, sedation, delirium are all adverse effects of what drug?
hypotension
What adverse effect of diphenhydramine is the reason that we give epi first?
h1
d2
muscarinic
Promethazine antagonizes what 3 receptors?
antiemetic and sedation
What are the muscarinic receptors responsible for?
mild
The hypotensive and anticholinergic adverse effects of promethazine are mild or marked?
EPS
The action of the D2 receptor causes what adverse effects?
promethazine
What can occur with intraarterial or extravasated injections of promethazine?
yes
Can promethazine cross the placenta?
if the etiology is known
When should be the only time you use promethazine for vomiting?
A- 1st gen h1 antagonists
B- 2nd gen h1 antagonists
2nd gen h1 blockers
Astemizole
fexofenadine
cetirizine
loratidine
All of these are what?
they are considered non-drowsy
2nd gen h1 blockers have what main difference from 1st gen h1 blockers?
allergic rhinitis
2nd gen h1 blockers are recommended as the first line of treatment of what?
chronic urticaria
2nd gen h1 blockers are also used for what problem?
no
Are injected corticosteroids without major reactions?
fexofenadine
This 2nd gen h1 blocker shouldn't be given with fruit juice as it decreases the efficacy and is used to treat seasonal allergies like hay fever and chronic urticaria:
peripheral h1 receptors
Which receptor do histamine blockers work on to relieve chronic urticaria?
loratadine
Which 2nd gen h1 blocker has an active metabolite?
cetirizine
Which 2nd gen h1 blocker has adverse reactions of somnolence, fatigue, dry mouth, pharyngitis, and dizziness?
the risk vs the benefit
Some pts that take 2nd gen h1 blockers may benefit from higher than recommended doses but what needs to be considered?
h2
Which histamine receptors are responsible for the important stimulation of hcl acid release by the parietal cells?
- indirect parasymapthetic activation
- direct ACETYLCHOLINE parasympathetic activation on M3 receptor
2 ways in which activation of parietal cells occurs:
histamine
Indirect parasympathetic activation of the enterochromaffin cells causes what to be released?
gastrin
Indirect parasympathetic activation of the G cells causes the release of what?
vagus
Direct acetylcholine parasympathetic activation on the M3 receptor involves what nerve?
ECL
nerve
gastrin
What are the 3 stimuli that activate the proton pump to secrete hcl?
tidine
H2 receptor blockers all end in what suffix?
no
Does blocking the h2 receptors cease all production of stomach acid?
the ring
What part of the drugs chemical structure is the receptor binding site?
the branches off of the ring
What helps the molecule stay on the receptor longer?
histamine
proton
H2 blockers prevent ____ from stimulating the ____ pump thus inhibiting the release of hcl into the stomach.
gastrin and ach
Even though h2 blockers inhibit the release of hcl, what two substances are still actively at work?
competitive***********
H2 blockers exhibit what kind of inhibition at the parietal cell h2 receptor?
no, they are highly selective
Do h2 blockers affect h1 or h3 receptors?
basal
meal
H2 blockers suppress ____ and ____ stimulated acid secretion in a linear, dose dependent manner.
no
Do h2 blockers have sedation properties?
pepsin
H2 receptor blockers also reduce the volume of gastric secretion and the concentration of what?
50
The potencies of the 4 h2 blockers vary over a __ fold range.
60-70%
When given in usual prescription doses, h2 blockers inhibit acid what percentage of the total 24 hour acid secretion?
histamine
The efficacy of h2 blockers at inhibiting nocturnal acid secretion depends on what?
nocturnal
Are h2 blockers more effective on nocturnal acid secretion or meal stimulated acid secretion?
gastrin
ach
histamine
The acid secretion that occurs after a meal is stimulated by what 3 things?
smelling food and chewing gum
Despite being given h2 blockers to increase the acid ph in the stomach, what two things can cause the acid to go back down preoperatively?
4-5
What is the noctural and fasting intragastric ph is raised to what?
less
Is the impact of the h2 blockers on daytime and meal-stimulated acid production more or less than nocturnal and fasting intragastric ph?
1 to 3 minutes (oral is 1-3 hours)
Peak plasma concentration of IV h2 blockers:
slow
IVP speed:
yes
Can h2 blockers cross the placenta and BBB?
extensive
First pass hepatic metabolism of h2 blockers:
renal filtration
What is the preferred clearance of the IV route of h2 blockers?
liver
What is the preferred clearance of the oral route of h2 blockers?
- liver metabolism
- renal filtration
- renal tubular secretion
Clearance of h2 blockers is dependent on what 3 things?
renal
The dose of h2 blockers should be decreased in renal dysfunction, hepatic dysfunction, or both?
cimetidine
(rantidine is minimal)
Which h2 blocker interferes with metabolism of CYP-450 enzymes?
headache
somnolence
confusion
Antagonism of the cerebral h2 receptors causes what side effects of h2 blockers?
bradycardia
hypotension
heart block
3 CV side effects of h2 blockers:
acute pancreatitis
increased hepatic transaminases
2 GI side effects of h2 blockers:
thrombocytopenia
agranulocytosis
2 heme side effects of h2 blockers:
interstitial nephritis
1 renal side effect of h2 blockers:
warfarin and midazolam
Cimetidine and rantidine interfere with the cyp 450 system and can prolong what 2 drugs (Dr. Nolan mentioned)?
competitive
volume
hydrogen
H2 blockers produce ____ inhibition of histamine at h2 receptors of the gastric parietal cells resulting in reduced gastric acid secretion, gastric ____, and ____ ion concentration.
- pulmonary aspiration prophylaxis
- GERD
- gastric acid hypersecretion
- anaphylaxis prophylaxis (not a good idea per Dr. Nolan)
Indications for h2 blockers:
- bronchospasm
- inhibit coronary vasodilation
- inhibit increased cardiac contractility
H2 blockers may cause what 3 side effects?
h2
Which receptor mediates bronchodilation?
h1
Which receptor causes bronchoconstriction, decreased HR, and coronary vasoconstriction?
h2
Which receptor relaxes the bronchi, increases HR and contractility, and coronary vasodilation?
h1
So blocking the h2 receptors not only blocks their responses, but allows uninhibited responses of __ receptors.
cimetidine
What is the first h2 blocker?
renal elimination- adjust dose in renal failure
IV clearance is dependent on what?
inhibits it
(C=cimetidine and CYP)
What does cimetidine do to the CYP 450 system?
increases
decreases
Inhibiting the CYP 450 system causes an ____ in plasma drug levels and ____ their clearance.
diarrhea
rash
bone marrow suppression
central effects
elevated LFTs (d/c drug)
Both cimetidine and rantidine have what similar adverse effects?
- gynecomastia
- high skeletal muscle contraction (myalgia)
- SJS, epidermal necrolysis, erythema multiform
Side effects of cimetidine that are absent with rantidine:
rantidine
Cimetidine and rantidine both can have CNS effects but which one is rare?
low skeletal muscle contraction (no myalgia) and no gynecomastia
What two side effects does rantidine have that differs from cimetidine?
rantidine
Which of the two has a higher first pass effect for oral doses?
famotidine
Which of 3 h2 blockers (cimetidine, rantidine, or famotidine) has a higher renal elimination percentage of the IV dose?
decrease the clearance
What do cimetidine and rantidine do to the clearance of warfarin, phenytoin, and meperidine?
rantidine
These are all indications for what drug?
5 minutes
Rantidine should not be administered rapidly. It should be given over how long?
PVCs and or bracycardia
What can happen with rapid IVP of rantidine?
no
Do h2 blockers decrease the amount of acid or increase the ph of acid that is in the stomach before giving the drug?
famotidine
What h2 blocker does this describe?
the night before and the morning of
When used as a preop med, famotidine should be given when?
famotidine
What is the most common h2 blocker used for preop?
famotidine
Which of the h2 blockers should be decreased in pts with renal failure?
famotidine
These are all adverse effects of which h2 blocker?
famotidine
Which h2 blocker has the elast chance of bronchospasm and blood issues?
amotidine
Which h2 blocker can cause jaundice and hepatitis?
4-7%
What percentage of the US population experiences esophageal reflux?
PPIs
In comparison to h2 blockers, the agent of choice in moderate to severe GERD is what?
- GERD
- PUD
- Nonuclear dyspepsia
- prevention of stress ulcers
- gastrinoma or other hypersecretory conditions
- preop med
PPI clinical uses:
increase gastric pH and decrease gastric volume
The goal of preop therapy of PPIs is to achieve what 2 things?
prazole
PPIs end with what suffix?
H/K/ATPase
Which pumps do PPIs inhibit?
omeprazole
Which PPI is the most common to use?
mechanism of action
PPIs are substituted benzimidazoles that resemble h2 blockers in structure but have a completely different what?
liver
All PPIs are metabolized how?
high
How is protein binding in PPIs?
0.5 to 1.5 hours
Half lives of PPIs range:
true
True of False:
PPIs can block both fasting and meal stimulated acid secretion whereas h2 blockers only block fasting secretion.
the proton pump
PPIs can block 90-98% of all acid secretion because they block the final common pathway of acid secretion which is what?
H/K/ATPase pump (AKA proton pump)
No matter what source of gastric acid stimulation (histamine, gastrin, or ach), there is only one way it goes from the parietal cell to the gastric lumen- what is it?
inhibit the pump
In order to stop the secretion of all gastric acid, you have to inhibit the last step in the acid secretion process which is what?
no
When given in equivalent doses, do PPIs show a big difference in efficacy?
don't know why it would be in red
covalent
irreversible
TEST QUESTION:
Unlike h2 blockers that competitively and reversibly bind to the h2 receptor, PPIs form a ____ disulfide bond with the ATPase enzyme, leading to an ____ inhibition of the pump.
immediate
prolonged
The covalent disulfide bond that PPIs form with the ATPase pumps do not produce an ____ action, but the action is ____.
produce more
SO when the drug is stopped, what does the body have to do in regards to the ATPase pumps?
20mg night before AND
no < 3 hours before surgery
What is the ideal way to administer omeprazole as a preop dose?
extensive
Hepatic clearance of omeprazile:
80%
Percent of renal elimination:
headache
diarrhea
nausea
vomiting
4 adverse effects of omperazole:
inducer
Is omeprazole a CYP450 inhibitor or inducer?
decrease
PPIs may ____ absorption of itraconazole, ketoconazole, iron salts, and ampicillin.
pantoprazole
Fast and potent PPI:
UGI bleeds and h-pylori
Aside from the usual GERD, hypersecretory conditions, and preop treatments, pantoprazole is also used to treat what?
40mg IV and rantidine 50mg IV
What combination of drugs decreases gastric acid volume and increases gastric acid ph and should be given 1 hour prior to surgery?
tapered
Cromolyn can be like clonidine in respect to that it cannot be abruptly discontinued, it must be:
yes
Should pts take their preop dose of cromolyn?
mast
Cromolyn blocks degranulation of what cells?
no
Does cromolyn block IgE allergen binding or effect basophils?
MAST CELL
It prevents release of histamine, leukotrienes, prostaglandins, and platelet activating factors of what cells ONLY?
strictly prophylactic
Cromolyn cannot help in situations where reaction has already accured. It is: