Phenylephrine

Naphazoline
Xylometazoline

What are some effects of Phenylephrine?

contraindications and uses?

phenylephrine is an alpha-1 agonist.  It therefore increases BP and causes pupil dilation. it is also a decongestant

Contraindications

hypertension: will be exacerbated when the alpha-1 receptors cause constriction.
 cardiac diseases, cerebrovascular disease, hyperthyroidism

Uses

postural hypotension: alpha-1 constriction will help maintain BP

 nasal decongestion,

mydriasis- for opthalmology 

local vasoconstriction

Clonidine

Apraclonidine

Tizanidine

What are the actions of Clonidine?

what are its uses?

Clonidine is an alpha-2 agonist
It is used in the treatment of high blood pressure.  Its mechanism of action is through a decrease in central sympathetic tone by binding presynaptic Gi protein.   This results in decreased CO and decreased TPR.

Hypertensive crisis if withdrawn suddenly.  because continual stimulation will cause down-regulation of alpha-2 receptors, when clonidine is withdrawn suddenly, there will be too few alpha-2 receptors left to keep the central sympathetic tone in check.  This will result in an extreme influence by the sympathetics (increased HR, vasoconstriction) with the result of severe hypertension.

~100% oral bioavailability

Isoproterenol is a beta-1, 2, 3 agonist.  It will produce an increased HR (due to beta-1 and baroreceptor reflex tachycardia), vasodilation (beta-2). The systolic BP will remain unchanged because the decreased TPR from vasodilation will be balanced out by the increased cardiac output (heart rate). The diastolic BP drops because of the unopposed b2 vasodilation (there is no alpha-1 activation to cause vasoconstriction)

IV only

Uses: when low contractility and HR but high TPR, torsade de pointes, Beta-blocker overdose

Dobutamine is a beta-1 selective agonist.  It therefore increases HR and contractility by its stimulation of the cAMP pathway.

Dobutamine would be used in situations of cardiac failure or cardiogenic shock because it will help restore depressed Left Ventricle function.

Albuterol

Salmeterol

Terbutaline

Formoterol

Albuterol is a Beta-2 agonist.  It causes bronchodilation and enhances secretions and mucociliary clearance in the lungs.

It also suppresses the release of inflammatory compounds (mast cells have beta-2 receptors.  activation of these receptors inhibits degranulation and therefore inhibits histamine release)

Albuterol can also be used to prolong labor because b2 receptors in the endometrial smooth muscle cause relaxation of the uterus!

tolerance development (via down-regulation)

inhalation is main route of delivery

Like all beta receptors, beta-2 receptors activate Gs proteins, which stimulate adenylyl cyclase.  This increases cAMP levels, which activates PKA.  This stimulates Ca++ efflux and also increases the INACTIVATION of myosin light chain kinase, which no longer pplates myosin heads, which reduces contraction.

Beta-2 agonists (albuterol) can be given to relax the pregnant uterus and delay labor!

Epinephrine is an a1, a2, b1, b2, b3 agonist

Epinephrine is contraindicated in myocardial infarction because it increases cardiac workload and oxygen demand

BP up: increase in CO surpasses decrease in TPR
HR up: beta-1
systolic up: because of increased SV (contractility)

diastolic down: because of b2 mediated vasodilation in skeletal muscle

TPR down: because of beta 2 vasodilation

Norepinephrine is an a1, a2, b1 agonist

note that norepinephrine does NOT act at beta-2 receptors.  This will account for its different overall effects than epinephrine!

BP up:because of a1 vasoconstriction and b1 increased CO

HR down: despite b1 activation, the great increase in blood pressure stimulates the baroreceptor system.  This then produces a vagus-mediated depression of HR that overcomes the b1 influence.  (recall: beta in heart mainly effects contractility, parasympathetic mainly affects HR)

systolic up: because of increased SV from b1 and a1 constriction

diastolic up: because of unopposed a1 vasoconstriction

TPR up: because of unopposed a1 vasoconstriction

BP down: because of unopposed b2 mediated vasodilation

HR up: because of b1 and decreased baroreceptor firing

systolic up: because of b1-increased contractility

diastolic down: because of b2 mediated vasodilation

TPR down: because of unopposed b2 mediated vasodilation

cardiogenic shock is inadequate circulation of blood because the ventricular function is depressed.  Therefore, you would administer Dobutamine because its beta-1 agonist activity would increase the contractility and restore ventricular function.

Dobutamine is a selective b1 agonist

Norepinephrine

Phenylephrine

Dopamine (at HIGH doses)

Norepinephrine (drug of choice!) and Phenylephrine both agonize a1 receptors, but not b2.  They therefore constrict all vessels.

Dopamine is tricky in that at low doses it stimulates dopamine receptors in the kidney, leading to vasodilation and increased renal blood flow.  At moderate doses dopamine also stimulates beta-1 receptors, increasing contractility of the heart.  At high doses, dopamine also stimulates alpha receptors. At high doses, its actions therefore resemble norepinephrine, but with a selectively beneficial effect on kidney blood flow!

Epinephrine

Epinephrine inhibits inflammatory action by its beta-2 inhibition of mast cell degranulation. it also stimulates the heart to keep beating via b1 receptors, and opens airways via b2 mediated bronchodilation  These are all desired outcomes for someone suffering from anaphylaxis!

Clonidine

Methyldopa

Methyldopa is taken up and converted into a molecule that acts at a2 receptors and limits sympathetic tone, thereby decreasing BP.

Clonidine is an a2 agonist, which acts in the NTS and rostral ventrolateral medulla to decrease adrenergic tone as well

(recall a2 receptors work through Gi proteins)

Epinephrine

It causes local vasoconstriction through it's alpha-1 stimulation, minimizing systemic transportation of the anesthetic

Pretty much anything that activates beta2 receptors because this induces bronchodilation:

Albuterol (pure beta2 agonist)

Epinephrine (inludes beta2 activity)

Ephedrine (like epinephrine but less potent and longer lasting.  Can be taken orally, unlike epi)

HR up

SV up

CO up

all of these effects are mediated through stimulation of b1 (and b2) receptors

HR down (reflex bradycardia due to increased BP)

SV up
CO no change or down (decreased heart rate counteracts increased stroke volume)

HR up

SV up

CO up

all effects due to stimulation of b1 (and b2) receptors

HR down

SV no effect

CO down

Heart rate decreases due to reflex bradycardia.  Because phenylephrine is an a1 agonist only, it does not directly influence contractility, so there is little effect on stroke volume.  Because SV is the same and HR is decreased cardiac output also decreases (CO=SV x HR)

What effect does Phenylephrine have on BP, HR, Systolic, Diastolic, TPR?

BP up (or no change)

HR down

Systolic up

Diastolic up

TPR up

Timolol

Epinephrine
Apraclonidine

Latanaprost

Cholinomimetics

 Timolol is a b2 antagonist that decreases aqueous humor production.

Epinephrine (while it would increase production by b2, it's a2 stimulation decreases production and the a1 stimulation aids outflow.  These two effects overwhelm the b2 effect.

Apraclonidine decreases aqueous humor production

Latanaprost is a PGF2a drug that increases outflow through the uveoscleral route

Cholinomimetics these contract the ciliary muscle, fascilitating outflow through the trabecular meshwork and canal of Schlemm

Tyramine is an adrenergic agonist that increases the release of NE, EPi, Dopamine

It is a normal byproduct of tyrosine metabolism.

It is converted to octopamine, which displaces NE from the secretory vesicles and increasing its release.

Ephedrine is a sympathomimetic amine and
a1, a2, b1, b2 agonist (not b3)
It's actions are therefore similar to Epinephrine, though they are longer lasting and are not as potent.  Additionally, unlike epinephrine, ephedrine may be taken orally.

Ephedrine also increases Norepinephrine release.

 Used clinically as nasal decongestant and expectorant.

What is muscarine?

what are symptoms of muscarine poisoning and what is the antidote?

A muscarinic receptor AGONIST

Muscarine poisoning is characterized by increased salivation, sweating, and lacrimation

the antidote to muscarine would be an agent that antagonizes muscarinic receptors.  Therefore the antidote is ATROPINE

recall that pharmacological antagonists are far more effective than functional antagonists!

What is atropine

what are its uses and contraindications?

atropine is a muscarinic receptor antagonist.  It will therefore result in increased firing at the SA and AV node of the heart by reducing the parasympathetic (vagal) tone imparted my the M2 receptors.

Atropine is often used in the treatment of AV nodal block.  It is also used in cardiac failure if epinephrine does not adequately stimulate cardiac function.

In patients with BPH, dangerous because relaxation of the detrusor muscle further inhibits their difficulty in urinating

Reserpine blocks adrenergic storage in vesicles.  Therefore, more adrenergics are free in the axon terminal and are exposed to MAO enzymes. There is therefore increased MAO metabolism of catecholamines, which decreases their availability and release.

 Reserpine is an antihypertensive and antipsychotic drug

Metyrosine blocks the synthesis of catecholamines (up to 70%) by inhibiting Tyrosine Hydroxylase, the first step in catecholamine synthesis from tyrosine.

It is used as an antihypertensive drug and in the treatment of pheochromocytomas

yohimbine is an a2 antagonist

Yohimbine can be used to boost sexual performance and to increase blood pressure.  By inhibiting a2 receptors, their antagonism of central sympathetic tone is relieved and the sympathetic system now exherts a stronger influence (ejaculation, CO, and vasoconstriction)

Atenolol is a b1 antagonist

It is therefore in essence the opposite of dobutamine and is used to treat hypertension, and tachycardia.  It's selectivity for beta-1 receptors makes it better than a non-selective beta-blocker (propranalol) for asthmatic patients.  Recall the importance of beta 2 receptors in bronchodilation

Phenoxybenzamine is a non-selective alpha antagonist that irreversibly blocks alpha-1, and to a lesser extent alpha-2, receptors

It can be used in the treatment of pheochromocytomas

Propranolol

Timolol

Pindolol

Sotalol

Metaprolol

Atenolol

Esmolol

Esmolol is a quick acting drug with a half-life of 10 minutes, and is often used during surgery because of these properties.  Administration is by IV

Labetolol is an a1-antagonist, b1/b2 partial agonist.  This results in marked decrease in TPR due to the blocking of a1 vasoconstriction and the partial agonist action at b2... both of these actions result in vasodilation!

Labetolol also has a local anesthetic activity

Phenoxybenzamine is an irreversible non-selective alpha antagonist (majority of its effects are through alpha-1 receptors)

Phenoxybenzamine is used in the preopperative treatment of pheochromocytomas.

Its administration results in vasodilation and a reflex increase in heart rate due to depressed firing from the baroreceptor system

Prazosin is a reversible alpha-1 antagonist.  Because alpha-1 antagonist result in vasodilation, it is used in hypertensive emergencies (ex: clonidine withdrawal, pheo, tyramine syndrome)

It is also commonly used to treat Raynaud's Disease, which is characterized by excessive sympathetic vasoconstriction of peripheral vasculature (fingers and toes) through alpha-1 receptors.  This is especially pronounced in cold weather.

Tamsulosin is a reversible alpha-1 antagonist.  It is commonly used to improve urinary flow in a patients with benign prostatic hyperplasia (BPH) because it relaxes the sphincter of the bladder.

Propranolol is a non-selective beta antagonist.
It can therefore be used to decrease HR and contractility and decrease aqueous humor production. 

Another common use is the prophylactic treatment of migraines.

Propranolol also results in bronchoconstriction by inhibiting beta-2 receptors, so watch out for asthmatic patients.

Metoprolol,
Atenolol

Esmolol

These are all beta-1 antagonists

Beta 1 antagonist are used to treat hypertension, arrythmias, angina and Hypertrophic Cardiomyopathy.  In the treatment of pheochromocytomas,beta-1 antagonists are prescribed after the administration of an alpha-1 blocker.

Recall, esmolol is often the drug of choice to counter tachycardia during surgery.

LOG (protonated/unprotonated) = pKa-pH

For example, if the pKa of aspirin is 3.5 and the pH of the stomach is 1.5, what percent of the aspirin will be in the protonated form?

pKa-pH = 2, so protonated/unprotonated= 100, therefore approximately 99% of the aspirin will be in the protonated form.  When an acidic drug like aspirin is in its protonated form, it is uncharged and can diffuse across the gut walls.

through bulk-flow transfer, which depends on the local blood flow and the drug solubility.

can be hastened by warming or rubbing the injection site

What is the Volume of Distribution?

state the equation

the volume required to hold total amt of drug in body at the same concentration it is found in the plasma.

Vd= (D*F)/Co

D= dose/amt of drug

F= bioavailability
Co= plasma concentration

Oxidations, Reductions, Hydrolysis

Phase I reactions involve the unmasking or introduction of a polar group, thereby making the drug more water soluble

Conjugatoin reactions:

glucuronidation

acetylation

methylation

sulfation

the covalent attachment of small polar molecules

Barbiturates

Rifampicin

Phenytoin

Carbamazepine

Induction of the p450 system may severely limit the effectiveness of other drugs that are extensively metabolized through this system by hastening their inactivation

Cimetidine

SSRIs

Omeprazole

These may cause an otherwise normal dose of another drug to become toxic.

microsomal enzymes are found on the SER; they are the mixed function oxidases:

1) CYP450 enzymes

2) Monooxygenases

they act only on LIPID SOLUBLE COMPOUNDS

t1/2= 0.693/ke

t1/2= (0.693*Vd) / CL

(because ke= CL/Vd)

CL= (0.693*Vd) / t1/2

CL= DoseRate/Css

(Dose*F) / T = Css*CL (aka: Css=Dose rate/CL)

Css= (Dose*F) / (T*ke*Vd)

Css= (Dose*F*t1/2) / (T*0.693*Vd)

DR= (Dose*F) / T

where T is the dosing interval

four half lives

LD= (Css * Vd) / F

where Css is the desired plasma steady state concentration

Gq to PLC to increased IP3/DAG

You can always "quiz" yourself with norepinephrine:  quiz spelled QIS... a1=Gq, a2=Gi, B1=Gs

Carbachol is a quaternary choline ester.  It is therefore a muscarinic agonist that also stimulates nicotinic receptors.  Because it is a charged quaternary compound, it does not cross the blood brain barrier.

 Carbachol also has a low sensitivity to AchE and therefore benefits from a longer duration of action.

 action mainly on M1, M3 receptors

used to lower intraocular pressure after cataract extraction.  This occurs because M3 stimulation of the ciliary muscle opens up the trabecular meshwork and increases outflow through the canal of schlemm

A muscarinic agonist that does NOT stimulate nicotinic receptors

Like carbachol, bethanechol has a low sensitivity to AchE and therefore a long duration of action.

 action mainly on M1, M3 receptors

Like most agonists of the parasympathetic system, bethanechol is contraindicated in patients with asthma (bronchoconstriction) and peptic ulcers.

Carbachol

Bethanechol

Pilocarpine is a tertiary amine that activates muscarinic receptors M1, M2, M3

 It is used locally for open angle glaucoma and sometimes for xerostomia(dry mouth)

M3 receptors of ciliary muscle will increase lens curvature and make far-vision difficult, a common side effect. This also opens up the trabecular meshwork and allows for greater aqueous humor outflow. 

M3 receptor of the sphincter muscle of the eye will cause miosis and therefore make vision in low light more difficult.

a quaternary ammonium compound from mushrooms.

M1, M2, M3 agonist

Physostigmine (enters CNS)

Neostigmine (does not enter CNS)

carbamate AchE inhibitors have a longer half life because they undergo a 2-step degredation process

Edrophonium is a reversible AchE inhibitor with a short half life.  Because of its short half life, it is used in the diagnosis of myasthenia gravis.

 Edrophonium can also be used to differentiate between cholinergic crisis and myasthenic crisis as follows:

-In a cholinergic crisis, where there is an excess of Ach in the synapses, it will decrease muscle strength (via depolarization blockade) and cause fasciculations

-In a myasthenic crisis, in which there is a decrease of Ach stimulation of receptors,  it will increase muscle strength

Physostigmine is a tertiary amine AchE inhibitor.  Because it is a tertiary amine, it can cross into the CNS.  This drug also has a good bioavailability.

 because it enters CNS, moderate doses of physostigmine may increase alertness, high doses may cause confusion/ataxia/coma

Neostigmine is an AchE inhibitor.  it is a charged, quaternary compound and therefore does NOT enter the CNS (unlike physostigmine).  Also unlike physostigmine, neostigmine has poor oral bioavailability.

Neostigmine is the Drug of choice for the treatment of Myasthenia Gravis because it has no associated CNS effects.  Often, atropine is co-administered to block the muscarinic action of neostigmine and minimize GI effects.  Recall, myasthenia gravis affects only the nicotinic receptors, so there is no need to target the muscarinic receptors with neostigmine in this treatment.

Atropine, or other muscarinic antagonists.  These will pharmicologically counteract the excess acetylcholine created by cholinesterase inhibitors.

Additionally, if the choinesterase inhibitor was an organophosphate (parathion), cholinesterase reactivators such as Pralidoxime are efficient as long as the cholinesterase hasn't undergone aging

Pralidoxime

Obidoxime

These are AchE reactivators.  They are effective only for organophosphate poisoning and only if the cholinesterase enzyme has not undergone aging.  They are unable to reverse AchE blocked by carbamates(neostigmine, physostigmine)

Atropine is a non-selective muscarinic antagonist.  As a tertiary amine, atropine is capable of entering the CNS.

effects: Atropine results in tachycardia (decreased vagal tone on heart M2 receptors), decreased peristalsis, relaxation of detrusor muscle, mydriasis, cycloplegia(M3 receptors block relaxes peristalsis, detrusor muscle, and ciliary muscle), decreased sweating (M3) leads to increased body temperature = "atropine fever" and vasodilation of cutaneous vessels to release the built up heat = "atropine flush"

Uses: cardiovascular disorders, excessive salivation (M3 receptors in exocrine glands), visceral hypermotility and spasms, AchE inhibitor overdose, Ophthalmology

Nodal block in the heart

Scopolamine is a non-selective, muscarinic antagonist.  Similar to atropine, it is a tertiary amine, meaning it has effects on the CNS.

In total, its effects are the same as atropine, but it also depresses vestibular function and is therefore useful in treating motion sickness.  Like atropine, it can be used in opthalmology.

Again, like atropine, overdose may result in delerium, hyperthermia, and death.

Darifenacin is a selective M3 antagonist.  It would be used in URINARY/URGE INCONTINENCE because of its relaxing effect on the detrusor muscle.

Not surprisingly, this means it is contraindicated in patients with difficulty urinating (ex: BPH).

Glycopyrrolate

Ipratropium

What is an indication for ipratropium?

Glycopyrrolate and ipratropium are non-selective muscarinic antagonists.  They are both quaternary compounds, in this case meaning that they also exhibit antagonist activity at nicotinic receptors, including ganglionic (Nn).

 They both relax hyperactive smooth muscle of gut and are therefore used in treatment of irritable bowel syndrome

Ipratronium is special because it is chosen when a patient requires a muscarinic antagonist but has asthma.  Other antimuscarinic drugs decrease bronchial secretions and mucociliary clearance, whereas for unknown reasons, ipratropium does not affect these processes.

nicotine is a stimulating drug at nicotinic receptors (Nn and Nm), including autonomic ganglia (both sympathetic and parasympathetic)

when given at low doses it is activating.  Giving it at high doses, however, results in a depolarizatin blockade (prolonged depolarization inhibits the neurons from repolarizing, and therefore prevents further neurotransmitter release... this hinders neuronal transmission)

As far as toxicity is concerned, moderate doses yield effects similar to Epinephrine whereas toxic doses can lead to cardiovascular collapse

Nicotine stimulates the Nicotinic neuronal and muscular receptors.  Excessive stimulation of these receptors leads to salivation, nausea/vomiting, cold sweat, tachypnea, tachycardia, headache/dizziness, and muscle weakness (depolarization blockade)

(mixed sympathetic and parasympathetic effects)

 respiratory failure is one of the largest dangers, and may occur in minutes

B2 agonists (B2 receptors are found on mast cell surfaces! this one reason epinephrine is good in anaphylaxis)

Theophylline

Cromolyn Sodium

Glucocorticoids if IgE dependent (histamine has an IgE-dependent release mechanism. because glucocorticoids reduce IgE production, they reduce histamine release)

1st generation:

Diphenhydramine

Meclizine

Promethazine

2nd generation:

Loratadine

Fexofenadine

Cimetidine

Ranitidine

Famotidine

heart= increased HR and contractility

Vessels= increased dilation and permeability (H1, H2)

GI= increased HCl and Pepsin (H2)

Lung= contraction

Nerves= pain and itching

first generation antihistamines are also competetive antagonists of M, Alpha, 5HT receptors; therefore they can give similar symptoms to atropine poisoning by their inhibition of muscarinic receptors.

 first generation H1 antagonists can enter brain and induce sleepiness

many induce microsomal enzymes (ex: CYP450) thereby facilitating their own metabolism

Known on da streets as 'benadryl', Diphenhydramine is a first generation H1 antagonist.  As a first generation H1 antihistamine, it can cross the blood brain barrier, and therefore also exhibits sedative and antiemetic properties.

4-6hr duration

Promethazine is a first generation H1 antagonist

 with a STRONG sedative and antiemetic effect. Because it has such a strong sedetive effect, it is sometimes prescribed for insomnia

4-6hr duration

First generation H1 antagonist

antiemetic effect

12-24hr duration

Loratadine is a second generation H1 antagonist (Claritin)

It has no sedative effect! and is not an antiemetic

24hr duration

Fexofenadine is a second generation H1 antagonist

Like loratadine, it has no sedative effect! and is not an antiemetic

10-15hr duration

What conditions would you treat with Cimetidine?

Why should you be concerned about cimetidine administration in concert with other drugs.

Cimetidine is an H2 antagonist and therefore reduces gastric acid secretion.  Recall that histamine is a very stong stimulator of acid secretion in the stomach!

Cimetidine treatment is therefore indicated in ulcers, Zollinger-Ellison Syndrome, and GERD.

Systemic mastocytosis (a disease with tremendously increased numbers of mast cells and therefore excessive systemic histamine levels), is also treated with H2 antagonists along with H1-blockers

Cimetidine Inhibits CYP450 system and is one of the most powerful inhibitors.  Can increase the toxicity of other drugs metabolized by the CYP450 system (beta-blockers, phenytoin, carbamazepine, benzodiazepines, tricyclic antidepressants, lidocaine, quinidine, theophylline, warfarin)

Cimetidine can also can block androgen receptors at high doses

2hr half life

Ergotamine is a 5HT-1 serotonin agonist used in migraine therapy.  Specifically, it acts on the 5HT-1b and 5HT-1d receptors of the trigeminovascular system, causing vasoconstriction and relieving the painful headache.

ergotamine has a low oral bioavailability

Why would you prescribe Sumatriptan?

How does it work and when would it be contraindicated?

Sumatriptan is a member of the triptan drug family and is prescribed in migraine therapy.  It is a 5HT-1b and 1d agonist, which causes constriction of the trigeminovascular system. Recall that the dilation of the trigeminovascular system is implicated in the neurovascular hypothesis of migraines. 

 Similar to ergot alkaloids, triptans are contraindicated in patients with heart issues and pregnant women.

Why would ergonovine be administered in the birthing process?

What else is a use of ergonavine?

Ergonavine is a 5HT-1 and 5HT-2 agonist with good bioavailability (unlike ergotamine).  Additionally, ergonovine stimulates serotonin, dopamine, and alpha receptors!

Ergonovine may be used to stop postpartum bleeding because it causes very intense uterine contraction. 

Ergonovine and other ergot alkaloids are used in the treatment of migraines because of their stimulation of serotonin receptors.  They are contraindicated in pregnancy because the strong uterine contractions can cause abortion.  Propranolol is an acceptable drug to treat migraines with during times of pregnancy.

(induce vasoconstriction and such strong uterine contraction that they help prevent hemorrhage and decrease blood loss.  Because of increased uterine contraction, can also cause abortion)

Intestinal hypermotility!  Cyproheptadine is an H1 and 5HT-2A antagonist.  By inhibiting the 5HT2 receptors, it reduces mobilizing effect of serotonin in the GI

Cyproheptadine is also a useful addition to the treatment of serotonin syndrome. 

Ondansetron is a 5HT-3 antagonist.  Recall that 5HT-3 receptors are located in the area postrema, and their stimulation produces nausea and emetic effects.  Therefore, ondansetron is useful for the inhibition of chemotherapy-induced emesis.

Triptans are widely used drugs with a selective activation of 5HT-1b and 5HT-1d receptors. These receptors are found in the trigeminovascular system, the vasodilation of with is implicated in the neurovascular hypothesis of migraines.

Vasoconstriction of these vessels due to activation of the above receptors makes triptans the DRUGS OF CHOICE for migraines

Triptans are Contraindicated in cerebrovascular disease and patients at risk of coronary ischemia... triptans will constrict the already partially occluded vessels, causing increased likelihood of MI and stroke.  Additionally, they must not be administered to pregnant women for risk of abortion.

Bromocriptine is a dopamine (DA) receptor agonist.  Because dopamine inhibits the lactotrophs of the anterior pituitary, bromocriptine is a useful medication in the treatment of prolactinomas.

Serotonin syndrome is a potentially fatal state in which there are excessive levels of synaptic serotonin.  High serotonin levels will lead to hyperactive bowels, high blood pressure (vasoconstrictive), tachycardia, agitation and delerium, eventual coma, and muscle rigidity.  This condition may be caused by concomitant administration of a 5HT agonist (ex: ergotamine) while the patient is taking an MAO inhibitor or SSRI!

Additionally, increased tyrosine levels, found in wine and cheese, can lead to serotonin syndrome while the patient is on an MAO inhibitor.

What activates phospholipase A2?

what inhibits it?

Activates: Angiotensin II, bradykinin, epinephrine

Inhibits: Glucocorticoids

PGE1

IV administration

*maintain patency of ductus arteriosus

*impotence

PGE2

intravaginal administration

to induce labor, cervical ripening, abortion

PGI2

IV administration

for pulmonary hypertension

PGE1 analog

large oral bioavailability

intravaginal or pulmonary administration

To treat NSAID-induced ulcer

induce abortion

PGF2a analog

eye drop edministration

Glaucoma

(increases outflow through uvealscleral tract)

Selective COX-2 inhibitor ('celebrex')

anti-inflammatory drugs- rheumatoid arthritis, osteoarthritis

benefits: no effect on platelet aggregation, low incidence of gastric ulcers

Aspirin is an irreversible inactivator of cyclooxygenase enzymes

this is accomplished through acetylation of COX I & II

list the following NSAIDs in order of most to least potent:

Aspirin, Acetaminophen, ibuprofen, indomethacin

Indomethacin (0.1)

Ibuprofen (50)

Aspirin (164)

Acetaminophen (>1000)

values are concentrations (mcmol/L) needed for 50% enzyme inhibition

TNF and IL-1 stimulate fever by increasing synthesis of prostaglandins in the hypothalamus, which promote an increase in body temperature.

NSAIDs block this prostaglandin synthesis in the hypothalamus.  They thereby minimize the increase in body temperature, bringing the body back to (but not below) normal

Analgesic action is by blocking PGE2 synthesis.  PGE2 sensitizes nerve endings to the actions of bradykinin and other pain signals.

by irreversibly blocking cyclooxygenases, aspirin reduces platelet formation of TXA2 and endothelial formation of PGI2. 

Platelets cannot restore there supply of TXA2 (no transcription/translation machinery), whereas endothelial cells are capable of replenishing the lost PGI2.  Therefore PGI2 effects will dominate, favoring vasodilation and clot inhibition.

At high doses of aspirin, both TXA2 and PGI2 are inhibited equally and there is no effect from aspirin (no shift in the balance)

Beginning: as aspirin is absorbed it begins stimulating the respiratory center of the medulla, causing respiratory alkalosis with compensatory metabolic acidosis.

Late: continued aspirin absorption leads to depressed respiratory function and respiratory acidosis.  Increased aspirin(acidic) levels and its inhibition of TCA (organic acid buildup) also mean a furthering of the metabolic acidosis.

Make urine alkaline to help increase salicylic acid excretion

Also present: hyperthermia, abdominal cramps, nausea,

Mild= plasma salicylate 400-800

severe= plasmasalicylate > 800

1) salicylic acid

2) phenytoin

3) ethanol

Aspirin

NSAID

irreversible inactivator of COX-I, COX-II

moderate doses stimulate respiratory center in medulla and lead to decreased platelet aggregation, high doses depress respiratory center and also cause hypervolemia and a decreased GFR.

Also leads to erosive gastritis due to PGE inhibition.

(read: prolonged use of aspirin can lead to kidney problems and gastric ulcers)

Mesalamine

Sodium Salicylate

NSAIDS

 Salicylic Acid Derivatives

Mesalamine is the only NSAID indicated in the treament of Crohn's disease or ulcerative colitis.

also: ALL salicylates are contraindicated in G6P-DH deficiency because they may cause hemolytic anemia

"Advil"

NSAID

propionic acid derivative

Reversible inhibition of COX-I, COX-II

Similar effects to salicylates, but less pronounced gastrointestinal and CNS effects.

NSAID

propionic acid derivative (like ibuprofen)

NSAID

Acetic acid derivative

very potent (compared to aspirin, ibuprofen)

Inhibits cyclooxyganase pathway AND (to a lesser extent)lipoxygenase pathway.  greater anti-inflammatory efficacy than most NSAIDs

Used in acute musculoskeletal pain, inflammation of the eye, rheumatoid arthritis and ankyloasing spondylitis.

'feldene'

NSAID

of the oxicam family

one of the MOST POTENT inhibitors of the cyclooxyganase pathway.  Also inhibits PMN cell migration

meloxicam inhibits mainly COX-II

similar uses to diclofenac

most potent NSAID

highest efficacy

COX-I inhibited much more than COX-II

also inhibits phospholipase A2, thereby decreasing the synthesis of all eicosanoids and PMN migration.

uses: same as other NSAIDs,

also used to help close patent ductus arteriosus

*not indicated for general use as analgesic or antipyretic because of its toxicity.

analgesic-antipyretic drug but not anti-inflammatory ('Tylenol')

(no peripheral inhibition of prostaglandin synthesis)

use if NSAIDS are contraindicated (ex: hypersensitivity reaction), and if pain is not due to inflammation

Acetaminophen Poisoning: Hepatic toxicity due to intermediate (N-acetyl-p-benzoquinone)  Centrilobular necrosis.  Vomiting, abdominal pain, hepatic damage.

treatment: acetylcysteine administered w/in 16hrs protects from hepatotoxicity

1) decreased migration

2) decreased interleukin production (IL-2, TNF, IFN-g)

3) inhibition of histamine release

4) decreased fibroblast proliferation after IL-2 and growth factor inhibition

1) decreased phagocytizing ability

2) decreased interleukin production (IL-1, TNF)

3) decreased IL-1 leads to decreased TCell activation

1) Replacement therapy after surgical removal of adrenal ademona

2) Congenital adrenal hyperplasia

 3) All connective tissue disorders (arthritis, bursitis, rheumatics, lupus erythematosus, myasthenia)

 4) Cancers

5) Respiratory Distress Syndrome

6) myocarditis/pericarditis

7) cerebral edema

Epinephrine and IV glucocorticoids

Epinephrine blocks histamine release via beta-2 receptors, as well as dilating the bronchioles.  Glucocorticoids inhibit IgE synthesis and migration of inflammatory leukocytes.

A b1-blocker with rapid onset and short duration

used in surgery

Drug of choice if aortic dissection is suspected

half-life ~ 10min

a potent indole derived NSAID that is considered the drug of choice for acute attacks of gout

also drug of choice for closure of patent ductus arteriosus in newborns.  (common in premature infants)  This is achieve by the inhibition of vasodilatory prostaglandins: PGE1, 2, PGI2, which maintain the patency of the ductus.

Acetaminophen toxicity is due largely to its metabolic intermediates (N-acetyl-parabenzoquinone).  This is neutralized by the action of glutathione.  When acetaminophen is administered in toxic doses, the glutathione cannot keep up with toxic intermediate production and N-acetyl-parabenzoquinone accumulates.  It reacts with SH groups of hepatocyte proteins, causing damage to the cells and leading to centrolobular necrosis.  

Treatment involves administration of N-acetylcysteine, a compound with many SH groups that can help buffer the effects of N-acetyl-parabenzoquinone and give glutathione a fighting chance

because they block muscarinic, alpha-adrenergic, and serotonergic receptors they are contraindicated in:
 -Glaucoma -recall, we want M receptors stimulated to cause constriction of the ciliary muscle and promote outflow through Canal of Schlemm. 

-prostatic hypertrophy -inhibiting the M3 receptor of the detrusor muscle would only further decrease the ability of the patient to urinate 

-COPD -recall that antimuscarinics decrease bronchial secretions and mucociliary clearance (except ipratropium) 

the list goes on with GI obstructions, pregnacy..etc. --Second generation drugs like Loratadine have none of these contraindications.

A second generation h1-antagonist (loratadine or fexofenadine).  A 1st generation antihistamine would also antagonize the M3 receptors of the detrusor muscle, furthering the patients inability to urinate.

in the same line of reasoning, you wouldn't want to give him any antimuscarinics either

Administration of the ergot alkaloids like ergotamine or ergonovine result in strong uterine contraction, which could result in abortion.  These are therefore not given to pregnant women.

Alternatively, you could prescribe propranolol or other beta-blockers, which do not contract the uterus and are also listed as having negligible teratogenic effects.

ergot alkaloids (and triptans) are also contraindicated in patients with previous heart conditions because of their potent vasoconstrictive effects.