Pharmacology I and II Flashcards
What are autacoids?
They are released in the body for short term and they act through paracrine signaling
Definition: endogenous molecules secreted more than one type of cell and act on different types of cell
They act like local hormones, have short duration
-proinflammatory - so you want to inhibit the synthesis of autacoids for pharmacological action
Eicosanoids
They are related to each other because they come from arachidonic acids
They are potential disease mediators
Resulting products are dependent on tissue and enzymes present
Thromboxanes
Responsible for clotting (platelet aggregation and vasoconstriction)
released exclusively like platelets
synthesized by COX pathway
very harmful for cardiovascular disease
Leukotrienes
Allergic response
synthesized from AA from the Lipooxygenase pathway
involved in asthmatic reactions
sustain inflammatory response
Lipoxins and isoprostanes
are not involved in disease process
What are the eicosanoids?
prostaglandins (PE), prostacyclin, thromboxanes (TAX), leukotrienes (LTs), isoprostanes, liproxins
Cytokines
Interleukins and TNF
Protacyclins
exclusively released by endothelial cells of the vasculature
Phospholipase A2
Activated by inflammation
(TNF and gamma-IF)
cause the release of arachadonic acid from the cell membrane
AA gives rise to different eicosanoids
through different enzymes
housekeeping enzymes - Lipooxygenase, COX, cytp450 epoxygenases
COX pathway gives rise to which molecules
thromboxane, prostacylins, and prostaglandins
Interferon
Prevents the synthesis of prostacyclin and may produce ischemia (mediate vasoconstriction)
Arthritis (rheumatoid, osteoparthritis)
COX2 is induced
pathological signal
PGE2 - important in central rheumatoid arthritis
Prostaglandins
various effects
synthesized from AA in the COX pathway
PGE2
Vasodilator
Contraindication : lowers the threshold of pain - feel more pain
used as a vaginal supposition to dilate the cervix
Dysmenorrhea
mediated by PGE2
Erectile dysfunction
managed by PGE1 (ALPROSTADIL)
causes vasodilation
Inject 10 minutes before desired erection (can cause penile pain)
ALPROSTADIL
PGE1
TREAT ERECTILE DYSFUNCTION
causes vasodilation via intracavernosal injection
Second line drug for this
Glaucoma
PGE1 or 2
Effective in treating NARROW ANGLE GLAUCOMA
Causes increased opening of CANAL OF SCHELM
PGE1 or 2 treat narrow angle glucose
open canal of schelmm
Labor and abortion
Induction of labor by giving PGE2 and PGF2a
cause pain
DINOPROSTONE
PGE2
induce labor and abortion
cause cervical relaxation and uterine contraction
PGE2 can be used as a progesterone to induce labor
DINOPROST
PGF2a
also induces labor and abortion
cause uterine contraction
LTB4 (leukotriene)
mediate asthma, glumerelonephritis, and ulcerative colitis (leukocyte infiltration)
Cancer
Inhibitors of autacoids e.g. NSAIDs aspirin is associated with reducing the rates of colon cancer
but no direct association that autacoids induce cancer
Pulmonary hypertension
PGI2 is a vasodilator
inhibit platelet activation
Prostacyclin
These are administered by subcutaneous infusion
Glaucoma
condition that increases intraocular pressure
blocks the canal of schlemn
cannot drain aqueous humor that is constantly generated
Ductus arteriosus
open channel congenitally in the heart
in stances when opening is needed to be maintained, use prostaglandins to keep it open (use vasodilator) and closed (use vasoconstrictor)
PGI2 and prostacyclins
treat pulmonary hypertension
PGI2 via specific target effect - dilate vessels in lungs
TREPROSTINIL - administered by subcutaneous infusion
EPOPROSTENOL -> give hypotension, rash,Gi problems, and muscle pain
-synthetic PGI2
PGE1
glaucoma
erectile dysfunction
maintenance of patent ductus arteriosus -ALPROSTADIL - can cause apnea, bradycardia, hypotension
Angiotensins
target is angiotension II
use ACE inhibitors
treat hypertension
Neuropeptides
released with NE and adrenergic
Prostaglandins
Constrict/dilate blood vessels
Trigger inflammatory response
depends on location (what tissues) and
availability of certain enzymes
What are the housekeeping enzymes?
COX1
Asthma
PGD2 (patient feel more pain)
LTB4, C4, D4
Crohn’s disease
erosions of GI portions
Glumerulonephritis
Abnormal elevation of LTB4 complement proteins !!! complement deposition
Cysteinyl leukotrienes CysLT
decrease glomerular filtration
Anti-eicosanoids
selective targeting is important
bonding
Corticosteriods drugs
use classification by plasma half lives
PREDNISONE - short acting
DEXAMETHASONE and BETAMETHASONE- long acting
TRIAMCINOLONE-intermediate acting
classification may be via half life, mode of administration, ability to cross over barriers
GLUCOCORTICOID agents
high anti-inflammatory potency- have a longer duration of action
inhalend
Treat arthritis
Glucocorticoids
Can’t use glucocorticoid for which disease?
Osteoarthritis
because prolonged use will cause osteoporosis
Inhibitors of leukotrienes
Zafirlukast, motelukast,
Zileuton
Treat ASTHMA to inhibit the high inflammatory leukotrienes present
Inhibitors of thromboxanes
Dazoxiben
Pirmagrel
Ridogrel
anti-clot formation like aspirin
Problem using this is the inability to clot but useful for ischemic disease prone patients
Contraindication: patients with hemophilia
ADVERSE EFFECT: BLEEDING
Corticosteriod
large class of drugs
anti-inflammatory , anti-eicosanoid drugs
IMPORTANT IN TARGETING ARTHRITIS, ASTHMA, SYSTEMIC LUPUS ERYTHEMATOSUS
can be used in autoimmune diseases as a replacement therapy e.g. primary and secondary adrenal insufficiency (addision’s disease)
MOA of corticosteriods
indirect inhibition of phospholipase A so no AA released for synthesis of thromboxanes and prostaglandins
Overall effect is to decrease immune and inflammatory response
Increase IL-10 expression (anti-inflammatory)
Increase expression of Beta 2 receptor in bronchioles (bronchodilation)
Increases expression of IL-1 receptor antagonist (inhibitoy) to control IL2-6
Decrease expression of IL2-4
IL-4 is important in mediating asthma through IgE effect from mast cells
Triamcinolone
corticosteriod
can be aerosolized - mostly localizing in the respiratory (asthma)
swallowing -> 60% of the dose
Corticosteriod will increase the expression of what protein that indirectly acts on PLPA
Lipocortin (annexin)
which inhibit PLPA
NSAIDs drugs
ASPIRIN INDOMETHACIN -can close patent ductus arteriosus IBUPROFEN NEPROXEN SULINDAC COLECOXIB
DAZOXIBEN/PIRAGREL/RIDOGREL
investigatory drugs of thromboxane inhibitors
DAZOXIBEN/PIRAGREL - inhibits TXA synthesis in platelets
RIDOGREL - inhibit TXA-a2
NSAIDs action
used to treat all sorts of pain, inflammation, fever, arthritis
Aspirin is the only one out of the NSAIDs that is used for cardiovascular diseases, the other ones will most likely be for inflammation
COX selectivity is important
Adverse effects of NSAIDs
gastric irritation
nephrotoxicity
hepatotoxicity (DICLOFENAC, SULINDAC)
Non-selective COX inhibitors
ASPIRIN
COX1 > COX2
INDOMETHACIN
SULINDAC
COX1=COX2
MECLOFENAMATE
IBUPROFEN
COX1<COX2
COLECOXIB (celebrex) ROFECOXIB (vioxx) KETONES (NABUMETONE) - treat arthritis Less GI bleeding than most NSAIDs Tx: arthritis- both forms, Useful in treating familial Adenomatous polyposis - which is a colon cancer with many polyps Adverse effects: INCREASES STROKE VIOXX causing MI
ASPIRIN
COX1 and COX 2 inhibitors
COX2 inhibition leads to increased synthesis of aspirin-triggered lipoxins but negative inhibition feedback keeps this normal
Tx: mild-moderate pain, headache, myalgia, arthalgia (PAIN IN JOINTS), prophylaxis for stroke and MI (CARDIOVASCULAR)
(variety of conditions)
Adverse: GI ulcers, BLEEDING, asthma excervation, bronchospasm, angioedema
Proprionic acid
IBUPROFEN
NAPROFEN
-PROFEN
COX1=COX2 INHIBITION
Tx: pain, fever, OSTEOARTHRITIS, RHEUMATOID, DYSMENORRHEA, GOUT
Adverse effect seen in STEVENS-JOHNSONS SYNDROME (cause skin to become itchy)- give acetaminophen
STEVENS JOHNSON SYNDROME
skin itchy - adverse effect of ibuprofen
give acetaminophen
ACETIC ACID
INDOMETACIN SULIDAC COX1>COX2 inhibitor Tx: long term tx of RHEUMATOID ARTHRITIS, INDOMETHACIN close patent ductus arteriosus Adverse effect: GI disturbances, TINNITUS
Oxicam
PIROXICAM
non-selective COX inhibitor
Tx: RHEUMATOID ARTHRITIS, OSTEOARTHRITIS, PRIMARY DYSMENORRHEA
Adverse: GI bleeding (more than aspirin) !!!!!!!!
Acetaminophen
COX3 inhibitor not true NSAIDs No effect on inflammation Tx. fever, pain NO INFLAMMATION Adverse: hepatotoxicity, nephrotoxicity, hypothermia
Acetaminophen and hepatotoxicity
•Enzyme polymorphism will affect how fast it will acetylate the byproduct of acetaminophen → needs to be glutathionated to be removed safely
◦ fast metabolizers or OD will become toxic
Lipoxygenase inhibitors
Inhibition of lipotoxin, leukotrienes
ZILEUTON
Prevent neutrophil chemotaxis (infiltration of leukocytes) …The neutrophils which synthesize the enzymes in the pathway and produce release LT
Tx. ASTHMA via upstReam- not as effective drug as beta 2 AGONIST or receptor blockers
Adverse: HIVES - urticaria, insomnia, dizziness
NOT AS EFFECTIVE as MONTELUKAST, ZEFIRLUKAST due to specificity (AFFINITY?)
-> these are also leukotriene inhibitors but they are receptor blockers of LT
LT RECEPTOR antagonist
MONTELUKAST
ZAFIRLUKAST
Treat ASTHMA downstream
Block CysLT1 receptors (reducing the constriction of airways, build-up of mucus, inflammation, or effect on glumerulus)
Tx: chronic asthma, seasonal allergic rhinitis
Adverse: GI distress, VASCULITIS (allergic granulomatous angitis), hallucination
GOOD EFFICACY
Female Reproductive System Eicosanoids I
DINOPROSTONE
DINOPROSTONE - PGE2
Used for “ripening” the cervix and induce labor
CAN BE USED FOR 2ND TRIMESTER abortion
HYDATIDIFORM MOLE, and missed abortion
Advise: BLEEDING of the vagina, severe menstraul cramps
Female Reproductive System Eicosanoids II MISOPROSTOL
Tx. NSAID induced peptic ulcer
****very effective abortificient agent when combined w/ mifepristone
Morning after pill (MIFEPRISTONE)
MIFEPRISTONE - a progesterone receptor antagonist
Female Reproductive System Eicosanoids II
CARBOPROST
PGF2a - potent vasocontrictor
2nd trimester abortion
Resist postpartum hemorrhage (vasoconstriction of the vessels)
Adverse: GI effects, Pulmonary edema
Tx Dysmenorrhea
Using early NSAID
IBUPROFEN
Proponoic acid
PDA
when treated with PGE1 ALPROSTADIL
-contradict with sickle cell anemia if tx patent ductus arteriosus
PGI2
can cause paradoxical pulmonary hypertension while treating pulm hypertension
PGF2 TREATING NARROW ANGLE GLAUCOMA
LATANOPROST, (new drugs: TRAVOPROST, UNPROSTONE)
LONG ACTING
used as DROPS
Can cause IRREVIERSIBLE PIGMENTATION OF THE EYES, conjunctivitis, drying eyes
Accelerates the exertion of aqueous humor
Tx Crohn’s disease or ulcerative colitis
Autoimmune erosion of the GI tract
Corticosteriod can block production of leukotriene responsible for the leukocyte infiltration in the mucosa
- stops the damaging inflammatory response
Histamine - autacoids
Made significantly in mast cells and basophils, and enterochromaffin-like cells of gastric muscosa
in response to allergens - Act on smooth muscles
High amounts in the lungs
Preformed IgE/Fc-mediated release due to allergic response will cause type I response
CNS effect of Histamine
Effects circadian rhythm
Increase wakefulness
Decrease appetite, thirst, ADH release, body temperature, pain perception
BP control , anxiety, aggression, locomotion
Which drugs will increase the release of histamine?
Tubercurine
Morphine
Vancomycin - CAUSE REDMAN SYNDROME
venom
What mechanical stimulus will increase release of histamine?
Na+ causes release of histamine from granules
-when cells are damaged
Histamine functions
Allergy and inflammation -Anaphylaxis
Gastric acid secretion
Histamin-induced contractions in pregnancy
Pathophysiology of Histamine
Nervous (H1, H2): pain and itching (hives, bites, stings)
H2 agonists decrease release of Ach, amines, and peptide transmitter
Cardiovascular (H2): decrease bp, increase HR and contractility
Bronchiolar (H1): constriction - asthma
GI Tract (H2): gastric acid secretion
1st generation Anti-Histamines are inverse agonists
Tx. rhitnitis, condunctivitis, uritcaria (hives)
parkinsonism, motion sickness, INSOMNIA (cross BBB)
Adverse: sedation, dizziness, dry eyes, dry mouth, urinary retention,
Contraindications: narrow angle glaucoma, peptic ulcer
1st generation Anti-histamins
ETHANOLAMINES (-AMINE) PHENOTHIAZINE HYDROXYZINE, CYCLIZINE, MECLIZINE CYPROHETADINE, PHENINDAMINE ALKYLAMINES (CHLORO AND BROM-AMINE) ETHELENEDIAMINE (PYRILAMINE, TRIPELEAMINE)
2nd generation Anti-histamines
**just memorize these
Piperazine or CERTIRIZINE
Tx : allergic rhyinitis, allergic urticaria
Adverse: somnolence, dry bout, headache, fatigue
Alylamines - ACRIVASTINE
Tx: allergic rhynitis
Piperidine - LORATADINE, FEXOFENADINE
Tx: allergic rhyinitis, allergic urticaria
H2 Blockers
CIMETIDINE - work on enterochromaffin-like cells in GI (not that effective)
RANINTIDEIN
FAMOTIDINE
NISATIDINE
Tx: stomach acid
Adverse: diarrhea, headache, fatigue, constipation
REDMAN SYNDROME
vancomycin causes this due to release of high histamine
1st generation of Anti- Histamine drugs cross what?
BBB due to non-ionization at blood pH
cause drowsiness
can cause anti-emetic due to affect on neurons
Tx Allergy and insomnia with what generation of anti-histamine?
1st generation
Cardiovascular effects of histamine
can be both contractor and dilator depending on which tissue bed it acts on
Increase HR, BP - H2
Vasodilation - H1 coupled to NO in the endothelium
Edema (hives)
Serotonin 5HT receptor agonist
Less PSYCHOMOTOR effects than antihistamine drugs and benzodiapezines
5HT receptor agonists I
BUSPIRONE 5HT1A
BUSPIRONE
PARTIAL AGONIST
NON BENZODIAPEPINE SELECTIVE
Relieves anxiety without euphoria, sedation
Does not affect driving skills
Adverse: tachycardia, palpitation, nervousness, paresthesia
5HT receptor agonist II **TRIPTANS
SUMATRIPTAN 5HT1D/1B
Tx: acute migraine and cluster headache attacks
Contraindication: coronary artery vasospasm
hepatic and renal insufficiency (NARATRIPTAN, ELETRIPTAN)
5HT receptor agonist III
CISAPRIDE AND TEGASEROD 5HT4
Tx. irritable bowel syndrome w/ constipation
Don’t use CISAPRIDE DISAPRIDE
ONDANSTERONE
is a 5HT RECEPTOR ANTAGONIST
e.g. prevent nausea and vomitting W/ CHEMO
Adverse effects of antihistamine (1st and 2nd generation comparison)
1st generation: sedation, dizziness,
2nd generation: headache, fatigue
both: dry eyes and mouth
