Cholinergic Agents

Class Drug Mechanism Clinical Effects/Use Contra / Side Effects Notes

All over the map (if it could
even get to the receptors)
Workhorse of the ANS. The NT of all N= nicotinic
preganglionic neurons (N) as well as the NMJ (Adrenal
Bad as a drug: Notable toxins:
(N), adrenal medulla (N), sweat glands (M), and Medulla,
Polar bad absorption -Black Widow Venom =
postganglionic PNS neurons (M). NMJ)
lipase destroys cholinergic
ANS NT Acetylcholine Vasculature also has receptors (M) although these
Rapid degradation [AChE], ends. May be paralyzed.
M=
-Snake Venom
are NOT innervated, no endogenous ACh muscarinic
No specificity [nicotinic v. =Irreversibly block NMJ.
released (keep in mind with cholinergic drugs (CV and
muscarinic] Stop breathing.
though can act on these receptors causing Smooth
-Botulism Toxin = Prevents
vasodilation) Muscle/Gland)
release of Ach by blocking
influx of Ca2+
Muscarine: toxin that mimics Ach, binds Muscarine (Poison!) Eyes: Constrict (Miosis) Miotic,
muscarinic receptors (4.4 A). Profound activation of the Glands: Increase secretions. drooling,
PSNS Bronchi: Constrict w/ fluid runny nose,
Muscarine Activates postganglionic PNS response for heart, Bethanechol Use in Post Heart: Bradycardia crying, peeing,
smooth muscle, glands (rest & digest), sweat GI operation to recover GI (slowed) and sweating
Bethanechol glands peristalsis/motility GI: Increased Motility w/ bronchial
ACh (Sympathetic; yet has ACh end transmitter), and Methacholine Challenge Bladder: Incr. micturition constriction,
(Muscarinic) Methacholine causes vasodilation (no direct innervation; but test for asthma. Sweat: Increased fluid filled
Direct Agonist will NO release). Carbachol Glaucoma. Vasculature: dilate (low lungs, slow
Pilocarpine Canal of Schlemm BP) HR, Low BP,
Bethan = ACh + beta CH3 + terminal amino relaxation IOP Genitalia: Erection and erection
Carbachol added.
(see below) Methacholine = ACh + beta CH3 Beth Anne, call me if you
want to activate your bowels
and bladder
Nicotine is a toxin from cigarettes. Used in Smoking Cessation Highly addictive Nicotinic
Nicotine Nicotinic receptors = 5.9A Stimulates, arouses, Largest receptors
Ach (Nicotinic: memory, cognition, relaxes, morbidity/mortality toll of control
NN + NM) Direct Activates all preganglionic PSNS & SNS neurons anti-anxiety, pleases, any abused drug. Transmission
Agonist Carbachol (NN : non-specific, depends on which system increases BP, increases EPI between
(see below) predominates), NMJ (NM : contraction), and release, increases prolactin. ganglia!
adrenal medulla (NN : Epi / NE release)
ACh + terminal amino group added to it. Local application in eyes Glaucoma
Muscarinic /
Carbachol Acts at muscarinic receptors (CV, PSNS) at low used in treatment of
Nicotinic Direct doses, nicotinic receptors at high doses (ganglia, glaucoma (opens canal of
 Agonist adrenal medulla, NMJ) Schlemm = dec. IOP)
ATROPINE
Eyes dilate (mydriasis) w/
photophobia. Cycloplegia
(loss of accommodation).
Anti-PSNS = SNS actions Glandular secretions
(except at sweat glands) decline. Drymouth.
Bronchodilation.
Competitively blocks all muscarinic receptors Corrects bradycardia and Heart=Tachycardia!!
(blocks PSNS for: heart, smooth muscle/glands; atrioventricular block; (sympathetics take over)
Atropine and SNS for: sweat glands) relieve irritable bowel GI = stops (constipation).
symptoms; treat Body temp = Increases. (dry
Hot as a hare
Scopolamine Found in Jimson Weed. Nasty Drug anticholinesterase flushed skin). Urinary
Muscarinic Dry as a bone
poisoning (Used as antidote retention. Impotent.
Antagonist Red as a beet
Tolterodine Not given directly very often. to organophosphate Disorientation.
Antimuscarinics Blind as a bat
poisoning)
Anticholinergics Mad as a
Homatropine Tertiary amino, readily absorbed. Reversible ; antisecretory agent. Contraindicated: Additive
hatter
Competitive antagonist. anticholinergic effects w/
Tropicamide Scopolamine motion antihistamines and tricylic
Scopolamine oxygen bridge sickness antidepressants. Slows
absorption of other drugs by
Homatropine delaying gastric emptying.
Ophthalmological
evaluations May cause acute angle-
closure glaucoma in the
elderly, urinary retention in
men with BPH, and
hyperthermia in infants.
Nicotinic (NM) Induce flaccid muscle NM = NMJ
Antagonist NMJ Nicotinic (NM) receptor blocking agent = paralysis in surgery (10C)
D-Tubocurare
(10C) PARALYSIS at NMJ (decreases size of EPP =
(Curare) decreased probability of AP) (South American poison
Neuromuscular
Blockers darts)
Ganglionic blockade shuts
down the predominant NN = Ganglia/
Non-specific ganglionic receptor (NN) Blocker
autonomic system Adrenal Gland
(6C)
Nicotinic (NN) (sympathetics and parasympathetics)
Hex = No longer used. (SNS off = Arterioles/Veins
Antagonist (6C) Hexamethonium dilate, declined In general will
Used in experimental models to prevent vagal
Trimethaphan = Classically CO/venous return, see anti-
reflex responses to changes in blood pressure
Ganglionic Trimethaphan used for acute hypertensive hypotension, Sweat glands muscarinic
(shuts down predominant autonomic control).
Blocker crisis (see side effects) stop sweating) drug side
effects!!!!!
Side Effects: Severe orthostatic hypotension,
(PSNS off = heart rate Similar to
blurred vision, constipation, sexual dysfunction.
increases, iris dilates, GI atropine.
stops, Urinary retention, dry
 mouth, impotence).
AChE rapidly breaks down ACh (80 microsecond)
Physostigmine
at synapses (also present on RBCs). This is distinct
Glaucoma
from non-specific pseudocholinesterase. AChE has
was used to treat some
a negative binding site (for the charged amino
depressions, but is no longer
group) and a positive site with an imidazole (for
available.
the carboxyl group) and serine. The latter fifth
bond is unstable and causes choline to dissociate
Neostigmine
Physostigmine from the now acetylated AChE. Water then acts as Increased cholinergic
Used as anti-anesthesia
a nucleophile releasing acetic acid and activity particularly at
at the end of an operation, to
regenerating AChE. muscarinic receptors (such PHYS is for
Neostigmine reverse the effects of non-
as excess secretions, EYES
depolarizing muscle
Cholinergic enhancers work by blocking the Pupillary constriction, and
relaxants.
Acetyl- Pyridostigmine activity of AChE; they bind to the same pockets increased GI motility).
but prevent nucleophilic attack by water (the
cholinesterase It is used in the treatment
Rivastigmine release portion of the mechanism takes much NEO CNS =
(AChE) of myasthenia gravis, as
longer = 30 min vs. 80 micro seconds). Effects reduced by drugs NO CNS
Inhibitors well as to reverse the effects
with anticholinergic effects penetration.
Donepezil of NMJ paralysis (see also
Physostigmine is a tertiary carbanic acid (Atropine)
Pyridostigmine long
derivative results in a carbamylated (instead of
lasting)
acetylated) AChE, which allows ACh to work for
30 minutes (as opposed to 80s). Freely enters
Rivastigmine (given via
CNS. [no longer used medically]
patch)/Donepezil (both
cross BBB)
Neostigmine, a quaternary derivative does not
Alzheimers
enter CNS as well
Short-acting (10-15 min), weak inhibitor of AChE. Differentiate myasthenic Short action,
In myasthenic crisis, edrophonium will reduce the crisis from cholinergic makes it
Muscarinic effects
Edrophonium muscle weakness by effectively supplying more crisis. But especially used
(see above)
ideal post-
acetylcholine. In a cholinergic crisis, to release Neuromuscular operatively
edrophonium makes muscle weakness worse. blockade after surgery.
Echothiophate long-term
treatment of glaucoma.
Echothiophate Death, very quickly, and
Organophosphates, essentially irreversible AChE unpleasantly.
Acetyl- Nerve gas = death (analogs
inhibitors (no possible way water can act as a
cholinesterase Sarin nucleophile), toxin. = Ach overload
are used as pesticides) 1
CHOLINERGIC RAGE!
Soman, Tabun, drop on skin = death in < 3
Inhibitors Bronchoconstriction Toxic
Mustard Gas, VX minutes.
Organo- Aging is a process in which after one half-life, the along with secretions,
toxin is completely irreversible despite any respiratory paralysis,
phosphates Parathion Massive ANS storm
treatment attempts (removal of phosphate). seizures, and slowing of the
Malathion (whatever system
heart to a halt.
predominates,
DOMINATES)
Acetyl- Potent nucleophile (much stronger than water), Emergency reversal of Atropine (2
cholinesterase Pralidoxime displaces AChE inhibitors by cleaving them via nerve gases (must be mg) is given to
Regenerator nucleophilic attack. administered before aging reverse deadly
(Nucleophile!) occurs) bradycardia

Adrenergic Agents

Class Drug Mechanism Clinical Effects Contra / Side Effects Notes

All adrenergic Receptors: BP = CO x TPR Most of the
CO = SV x HR receptors are
2> 1> low doses SV = Blood Volume x CVP more sensitive
Systolic: Contractility &HR Difficult to control, very to Epinephrine
selective for 2 short duration of action.
Diastolic: TPR than they are to
Nor-
Will seem to act like NE at higher doses Pulse Pressure = Sys Dia Epinephrine at very high epinephrine.
MAP = 1/3 PP + Diastolic doses will act like NE
(raises MAP). This 1 receptors are
Gq activates PLC which converts PIP2 to activates the baroreceptor
1: Epi decreases TPR equally
(diastolic) (2), increases reflex which acts on the
IP3 and DAG (activates Ca2+ stores and PKC sensitive to
contractility (1, 1) and atria only; while the
respectively) Increased Ca2+ leads to vascular both.
HR (1/2) ( systolic), and ventricles remain under
smooth muscle constriction, dilates pupil, erects
Epinephrine influence (left
hair, contracts prostrate [ 1A], heart force of therefore increases PP (but
no effect on MAP, in a turbo-charged state). Note that
contraction
therefore no baroreceptor Thus the pace-making cAMP is
reflex) There is a slight purkinje fibers may degraded by
2: Gi inhibits Adenylate Cyclase which actually fire faster than the
canceling out of TPR phosphor-
decreases cAMP vascular smooth muscle SA node in the atria;
decrease due to alpha diesterase
Direct constriction, sympathetic outflow, insulin hijacking the pacemaking
Epinephrine receptor effect on (PDE) to AMP,
Sympathomimetic release, platelet aggregation, inhibits capability of the heart
contractility. terminating
adrenergic and cholinergic nerve terminals (PVCs = premature cAMP effects.
from releasing neurotransmitters (negative ventricular contractions
Epinephrine is a more Drugs that
feedback) [ 2B]. arise).
potent agonist than NE at inhibit
2 receptors. Its effects phosphor-
1: Gs activates Adenylate Cyclase which shunt blood from other Very limited access to the diesterase will
increases cAMP release of intracellular Ca2+ tissues such as skin, to CNS. keep cAMP
stores = contractility, HR, renin release, skeletal muscles. levels high,
lipolysis Ineffective orally prolonging beta
Epi is a potent (metabolized by COMT effects.
within gut and liver).
2: Gs activates Adenylate Cyclase which bronchodilator (asthma)
increases cAMP activates PKA [2], vasoconstrictor at high If the adrenal
lv (treat hypotension) [], Side effects are medulla is not
phosphorylates MLCK which allows MLCP to sympathetic overdose
dephosphorylate MLC = vasodilation of skeletal / and heart rate/contractility releasing
enhancer []. COPD. Hypertension, epinephrine, we
splanchnic vessels, bronchodilation, uterine tachycardia, ischemia,
relaxation (pregnant), HR, contractility, Anaphylactic Shock, will not see a
MI / heart block/arrest hyperglycemia. 2 response.
lipolysis, glucagon release (glycogenolysis).
[], local anesthesia
QiSS = Kiss (reduces systemic
 QiSS (kiss) and QiQ (kick) till your SiQ (sick) absorption via
of SQS (sex) vasoconstriction of area).
Glaucoma (open angle)
Hypotension treatment, but
Not very useful clinically
decreases renal perfusion.
1 (no 2 activity) (nonspecific w/ rapid
Okay, in Septic Shock and Atropine
reuptake; potent
other severe hypotensive would
Norepinephrine increases TPR [] ( diastolic), vasoconstriction)
states, because even though counteract the
NE increases contractility and HR [1] ( systolic) CO is not increased very baroreceptor
(initially), which increases Mean Arterial Decreases Renal
much, the increased cardiac reflex initiated
Pressure and triggers the baroreceptor reflex Perfusion [does not spare
force/BP increases by the increase
decreased HR overall the kidneys] Not good
perfusion pressure w/o in MAP.
for Cardiogenic shock.
increasing HR (HR
declines due to reflex).
Direct D1 > > This separation of effects
The Kidney-Friendly
Sympathomimetic by dose makes Dopamine
Epinephrine
-- Low Dose D1 effects (dilation of useful in some cases of
Causes: Nausea, vomiting
renal/mesenteric vasculature) Cardiogenic shock,
DA because it can increases HR
Increases CO output in Both used to
-- Dose effects in heart (stimulation) Shock w/o destroying the treat
(and BP) [ CO] [1] while
-- Dose 1 effects (vasoconstriction) kidney and w/o much Cardiogenic
sparing the kidney from
overrides renal/mesenteric vasodilation. increase in TPR! = GOOD Shock
renal failure [D1].
Inotropic effect > Increase CO w/o much
1 > 2 >>1 DO- not be
chronotropic effect (also increase in TPR.
shocked
Dobutamine slight decrease in TPR) In heart failure, after use
Selective increase in the force of cardiac Use to Treat: CO gets better so then
(B1 selective)
contraction (inotropic) more than rate of Cardiogenic Shock sympathetics (which were
contraction (chrontropic). CO > HR Acute HEART FAILURE overactive) settle down.
Tyrosine L-Dopa DA NE Epi Contraindicated:
(tyrosine hydroxylase, L-AAD, DBH, PNMT) Currently the most Use w/ MAOIs may
Catecholamine
L-Dopa important drug therapy for cause hypertensive crisis.
Synthesis Inducer Increases synthesis of all catecholamines in CNS, Parkinsons Disease. Dyskinesias, nausea,
as well as in the peripheral tissues (side-effects) vomiting, hallucinations
Contraindicated: Patients
on MAO-Inhibitors must
INdirect Increases NE release by entering the presynaptic be warned not to eat foods
Sympathomimetics cell via the NE reuptake pump and causes Pressor Agent rich in tyramine or get
(Ca2+-independent, dumping of NE in the synaptic cleft in the (vasoconstrictor) hypertensive crisis.
non-physiological periphery. 1) MAOIs will decrease
release) Tyramine Product of normal gut the metabolism of
physiological Normally rapidly metabolized by MAO in the gut bacteria and is Dietary Tyramine in the gut and
tolerance to all and liver so normally it doesnt reach the SNS. (aged cheese, beer, wine, liver.
these drugs! yogurt). 2) MAOIs will cause an
May reach nerve terminals if MAO was inhibited! extreme excess of
catecholamines within the
presynaptic terminal;
 introduction of tyramine
will cause an excessive
release of NE than normal
Complex effects on NE, DA, and 5-HT.
1) Competitively blocks reuptake pumps = NE and High abuse potential (due
Speed
DA have prolonged effects. to dopamine increase)
Used for its CNS actions: (Ritalin)
2) Enters axons and increases release of NE (and
Narcolepsy, obesity,
Amphetamine EPI) in periphery and NE, DA, 5-HT in the CNS Never should be used with
attention deficient Crank (meth)
(probably by inhibiting MAO and the reverse SSRIs or MAOIs.
(and related uptake pump).
disorder (ADD) one
drugs) acetylhydroxy
3) Inhibits VMAT & MAO. Reversing the Cardiovascular effects,
Enhances opioid group away
reuptake pump to move the excess cytoplasmic weight loss, CNS
analgesia. from
NE out (more powerful than Ritalin). stimulation, risk of
Ephedrine.
psychotic reaction.
Overall, less effect on 5-HT.
Increases NE release by entering the presynaptic Nasal decongestant () Tolerance.
cell via the NE reuptake pump and increases and bronchodilator (2), Tachycardia, increased Meth
release of NE in the periphery. Does not reach blood pressure, CNS (Sudafed)
Ephedrine brain (but modification to meth = it does). CNS appetite suppressant, stimulation
stimulant, treats urinary Herbal
Also, a weak agonist of adrenergic receptors incontinence, hypotension Easy to convert to supplements
(1(?), 1, 2) non-specific -agonist treatment methamphetamine
Blocks reuptake of NE, DA, and 5-HT thus Causes: Euphoria, anorexia,
Tolerance, Overdose? =CV
prolonging the neurotransmitter effect in the CNS w/ cardiac stimulation.
Cocaine (euphoria, anorexia) and periphery Causes vasoconstriction
high abuse potential effects, seizures,
Sensitization effects! respiratory
(vasoconstriction and cardiac stimulation). and is a local anesthetic
Does not produce euphoria
(a dopamine mechanism),
so less likely to be abused.

Prevents the actions of

drugs that must enter the
NE axon through the re-
Desipramine Blocks neuronal reuptake of NE > 5-HT;
uptake system (e.g.
(and several blocks muscarinic and -adrenergic receptors.
Guanethidine, Bretylium,
Antidepressant;
Tricylic Anti- TCAs see far Tyramine) CYP 2D6
Reuptake inhibition leads to accumulation of NE
Depressants below for more metabolism
and 5-HT in the cleft. However, it has no effect on Chronic Pain
in depth Avoid use w/ MAOIs
dopamine patients are thus less likely to abuse
and SSRIs
discussion) this drug (versus cocaine).
Lethargy, sedation,
blurred vision,
constipation, urinary
retention, increased
appetite and weight gain
Overdose can cause
 wide QRS complex
ventricular tachycardia

Phenelzine:
Orthostatic hypotension,
impotence, hepato-toxicity,
diarrhea, arrhythmias,
restlessness, blurred vision.

Both:
Phenelzine:
Do not mix with other
Hypertensive
drugs affecting biogenic
crisis with
amines = potentially fatal
amphetamines,
reactions: (SSRIs
methyldopa,
Tricyclic antidepressants)!
levodopa,
Inhibit metabolism of NE/EPI, 5-HT (MAO-A) Phenelzine: Sympathomime
Both Contraindicated:
[Phenelzine] and DA (MAO-B) [Phenelzine and Neurotic and atypical tic drugs (see
---Meperidine [Opioid]
Selegiline] thus leading to an increase of these depression. above),
may cause fatal rxn
Phenelzine neurotransmitters available in the cytoplasm, 3rd-line antidepressant (NE
(excitation, rigidity,
tyramine
eventually increasing their release from the nerve and 5-HT) containing
Monoamine (MAO A+B) terminal. (largely replaced)
hypertension, coma)!!!
foods.
Oxidase Inhibitors ---Hypertensive crisis in
(MAOIs) Also has downregulation of beta and alpha-2 Avoid
consumption of tyramine.
Selegiline receptors, as well as 5-HT1 and 5-HT2 receptors.
Inhibition of MAO allows
Fluoxetine for 5
(MAO B) Selegiline: weeks.
tyramine to escape
Irreversibly binds MAO. Adjuncts to Parkinsons Trazodone,
degradation in the gut and
Disease (DA); enhances carbamazepine,
liver and circulate in the
Effects last until new MAO is generated effect of levodopa cyclo-
blood, where it can enter
benzaprine,
peripheral NE axons.
Selegiline,
Tyramine is converted to
increases levels
octopamine by DBH in the
of MAO
sympathetic nerves. It
degraded
replaces NE in vesicles and
TRIPTANS
thus decreases the
concentration of NE
released by the nerve
terminal. However NE in
the cytoplasm is
dramatically higher than
normal due the inhibition
 of MAO. So excessive
amounts of NE can be
released with increased
consumption of foods
containing Tyramine.

Tyrosine Inhibits Tyrosine Hydroxylase (competitively) Adjunctive therapy for

(Tyr DOPA); decreasing NE and EPI synthesis pheochromocytomas and is used before surgery
Hydroxylase Metyrosine (adrenal tumors NE/EPI) to remove such tumors.
Inhibitor in the periphery and CNS.
Inhibits active transport of DA, NE, EPI, and 5- May be used in
May increase NE release
Catecholamine HT into vesicles by Vesicular Monoamine Classic antihypertensive, low doses, and
Transporter (VMAT). This disruption of storage largely replaced by other it is very cheap.
Vesicular Storage CNS side-effects. May
Reserpine NE in vesicles, leads to degradation of NE by more specific drugs now. Still used in
Inhibitor become severely
MAO in the presynaptic terminal in peripheral Also used as an developing
(VMAT Inhibitor) depressed; with an
tissues and the CNS. (thus less NE can be released antipsychotic nations.
increased risk of suicide.
into the synaptic cleft). SNS tone.
This toxin destroys SNAP-25 (a specialized Used cosmetically to
Although used to block
protein on the plasma membrane and cytosol paralyze small muscles of
Ach at the NMJ, it will in
Catecholamine involved in the formation of the exocytotic fusion the face (less wrinkles).
fact block release of NE
Botulinum Toxin complex in neurons). Thus vesicles containing Also for:
Vesicular Release (Botox) neurotransmitter can no longer dock and fuse to Cervical dystonia.
and other neurotransmitters
Inhibitor if it escapes into the
the plasma membrane to release their contents. Axillary hyperhydrosis.
circulation (similar to
Results in muscular paralysis when applied in Achalasia (LES
Tetanus toxin).
small amounts locally. constriction).
Selectively inhibits a cGMP specific Concurrent use w/
Phosphodiesterase (type 5). Nitric Oxide organic nitrates can cause CYP 3A4
stimulates guanylyl cyclase to make cGMP. reflex tachycardia, angina,
Treats Erectile
Sildenafil Increased cGMP w/ less degradation, activates a
Dysfunction
and death from myocardial VIAGRA
signal transduction pathway that relaxes the ischemia.
smooth muscles in the blood vessels and in the Headache, nasal cGMP
corpora cavernosa in the penis = ERECTION. congestion, back pain
Phosphodiesterase
Inhibits PDE. Aminophylline is the water Used to be used extensively Markedly increases
(PDE) Inhibitors soluble salt of theophylline. It increases cAMP to treat Asthma, cardiac stimulation
causing diverse effects similar to -Adrenergic Bronchospasm, and possible arrhythmias.
Agonists and other transmitters and hormones that COPD. [B-adrenergic Also produces CNS cAMP =
Theophylline increase cAMP. function]. Stimulates excitation possible NE release
Also potent agonists of Adenosine Receptors brains respiratory centers: convulsions.
(Adenosine is a local autonomic nervous system to treat neonatal Apnea Metabolism inhibited by
messenger). many drugs
 Potent cardiac stimulator. NOT good for Agonists =
Potent NONselective agonist
Asthma/Bronchospasm Cardiogenic shock. Drop down-
in DBP + CO + HR = regulation
(Similar action to medium dose EPI w/o the slight Isoproterenol increases HR less filling of the coronary tachyphylaxis
vasoconstriction of alpha-1. DBP and MAP will and contractility arteries. Infarction (over-
-agonist drop a bit lower than with EPI.)
Isoproterenol ( systolic) , and decreases possible. + Kills kidneys. stimulation
(nonselective) TPR ( diastolic) via effects SA/AV leads to
It is NOT a substrate for SNS reuptake or vasodilation, leading to a Beta agonists result in a decrease in
MAO degradation. (COMT degradation only) slight decrease in MAP (so down regulation of beta receptors!)
So its duration of action is longer than NE or no baroreceptor reflex) receptors (may result in drug
EPI, but still brief. MI / AV heart block -rare drug tolerance over time). tolerance
Less cardiac stimulation
Bronchodilator. Drug is inhaled to ensure action
Albuterol Asthma/bronchospasm than nonselective agents
at the bronchiole level (see asthma)
-agonist (e.g. Isoproterenol)
Ritodrine, Works effectively at relaxation of uterine Delays or prevents premat Pregnancy
Terbutaline smooth muscle in pregnant mothers. labor and contractions sensitivity
Nasal decongestant Rebound nasal
Activates 1 receptors, increasing IP3 and thus
(local use) congestion
Calcium levels, and causing contraction of
vascular smooth muscle.
Pupillary dilation w/o Hypertension (severe if
cycloplegia given w/ MAOIs or
-agonist Phenylephrine Systemically causes rise in TPR and BP via
(accommodation intact) Tricyclic Antidepressants)
vasoconstriction, with a reflex drop in HR (due to
baroreceptor reflex compensation stimulating
Treatment of Drug- Rebound hyperemia and
parasympathetic activation and sympathetic
Induced Hypotension, ischemia (if systemic
deactivation)
Spinal shock exposure)
Activates central 2 receptors; decreases Overall, decreases
sympathetic outflow from vasomotor center Dose dependent: typically Sympathetic tone.
(thus decreasing sympathetic tone to the heart); used as an
inhibits pain neurotransmission in spinal cord. antihypertensive Pressor at high doses
Especially
Clonidine Centrally acting, central adrenergic outflow by
(especially in Renal
useful as an
(used to lower Disease does not Abrupt withdrawal may
stimulating postsynaptic 2 receptors in the CNS anti-
decrease renal blood flow) cause severe rebound
BP) (brain stem cardiovascular centers) hypertensive in
due to its NE lowering hypertension
patients with
effects (it also goes to the
Decreases further NE release by binding to renal disease
-agonist Brimodnidine brainstem to act on the [Sedation, dry mouth]
(does not
(Sympathoplegic) (used to treat presynaptic 2 receptors (low doses) which vasomotor system to do
decrease renal
glaucoma) hyperpolarizes the NE axon terminal (autoreceptor this. Contraindicated:
blood flow).
mechanism). Additive sedation
At high doses (IV) it can (CNS depressants);
Methyldopa
Yet, it also stimulates postsynaptic 2 receptors be used as a additive hypotension w/
may be used for
-methyldopa on smooth muscle of vasculature leading to vasoconstrictor/pressor nitrates and
pregnancy.
vasoconstriction (high doses). because it stimulates 2 antihypertensives.
receptors in veins (this Antihypertensive effects
[note that methyldopa must be converted to its increases CVP and CO) decreased by tricylic
active form: methyl-norepinephrine to work] antidepressants and
 adrenergic receptor
antagonists.
Competitive inhibitor of 1 and 2 receptors: Management of Causes orthostatic Use of phen-
Phentolamine Causes Vasodilation pheochromocytoma hypotension. oxybenzamine
TPR, BP ( but w/ reflex tachycardia) (adrenal tumor excreting preferred
-blocker excess NE/Epi). Diagnosis, Reflex tachycardia due to
(pure) Noncompetitive (irreversible inhibition)
Phenoxy- control of symptoms pre- decreased baroreceptor
Alkylates -adrenergic receptors (1 > 2). Must
benzamine surgery (Block the Epi/NE stimulation.
wait for new receptors to be created; 3-4 days
vascular effects)
Useful as antihypertensive Orthostatic hypotension Urologic Agent
drug produces much on first dose = syncope (-
Highly selective blocker for 1
Prazosin (100x more than 2).
less reflex tachycardia than 2 receptors on veins -osin alpha1
non-selective agents. BPH eventually able to blocker
-blocker compensate to CVP)
1A selective. Causes relaxation of smooth muscle Treatment of urinary Usually produces less
in the prostate, the trigone muscle of the bladder retention in Benign orthostatic hypotension
Tamsulosin and urethra. Urologic Agent.Best of class for BPH Prostatic Hyperplasia
FLOMAX
(BPH). NOT hypertension!
Contraindicated:
1) Asthmatics (dont use)
constriction prevents
Non-selective beta blocker ( SV, HR, CO) bronchodilation = BAD
Preferred antihypertensive
2) Insulin-dependant May cause
treatment for essential
Inotropy: decrease cAMP, decrease Ca2+ current Diabetics depression
Propranolol hypertension (sustained
Partially blocks the
antihypertensive effect
HR: suppress abnormal pacemakers by slope breakdown of glycogen Blockers = up-
results from fall in TPR),
Timolol of phase 4, increase. AV refractory that occurs in response to regulation
EPI release during super-
Antiarrhythmic (Class II)
Nadolol Renin release (1 receptors of JG cells) hypoglycemia. (see sensitivity
V-tach, SVT, slowing
metoprolol for alternative) (blockade leads
ventricular rate during
Bronchodilation 3) Heart Block, slow HR to upregulation
atrial fibrillation and atrial
-blockers Labetalol* flutter.
4) Use caution in use with of receptors)
(non-selective) Propranolol T = 3.5-6 hrs Congestive Heart Failure withdrawal
Nadolol T = 14-24 hrs patients. reflex =
Post-MI,
5) NSAIDs overstimulate
Cardiomyopathy
HIGHLY lipophilic = CNS effects... Can also cause heart after you
Congestive Heart Failure,
bradycardia, AV block, stop taking the
portal hypertension,
Also increases Prostacylcin release (long-term and hypotension. Poor medication
exertional angina.
vasodilation and decrease in TPR) lipid profile. Impotence.

Sudden withdrawal =
super-sensitivity
Less likely to cause
Beta blocker with intrinsic Sympathomimetic
bradycardia in patients w/
Pindolol activity (ISA) = has partial agonist (low efficacy)
hypertension and low HR
activity at beta receptors (1 and 2).
(athletes). It does NOT
 slow HR as much as other
beta blockers, but still
blocks increase in HR and
CO produced by SNS.
Metroprolol Watch Atenolol dose in Atenolol
Metoprolol Antiarrhythmic Agent (Class II) Sinus tachychardia, renal insufficiency. mostly excreted
Atenolol supraventricular unchanged in
Selective for 1 blockers. Blocks sympathetic arrhythmias. the urine (=
stimulation of SA and AV Nodes; decreases HR, dose needs to
Metoprolol Slows AV conduction, Increases AV refractory Atenolol A BEAM of Beta-1 be reduced in
period. Angina, post-MI protect Blockers renal
-blockers Esmolol Greater exercise tolerance insufficiency).
These drugs may provide greater exercise Preferred for IDDM Little CNS
Acebutolol tolerance than nonselective agents (2 receptors in patients as non-selective access, fewer
skeletal muscle vasculature can still mediate beta blockade will dull CNS effects.
Betaxolol vasodilation in response to higher circulating EPI natural response to
levels). hypoglycemia (glycogen
release by epi)
Heart failure decreases Orthostatic hypotension,
Block 1, 2, 1 receptors (nonselective)
cardiac remodeling, disease dizziness, fatigue,
progression, and mortality bradycardia, worsening of
Blockade of beta receptors causes decrease in CO
while improving heart failure if dose is too
(eventually rises w/ drop in TPR) and blockade
symptoms. high.
of alpha receptors causes vasodilation (decreases
Non-Selective Carvedilol TPR) . Overall blocks baroreceptor reflex because
Useful for treatment of Begin w/ low doses in Labetalol
HR cannot increase reflexively with alpha and
Adrenergic beta blockage. Antioxidant and antiapoptotic
hypertension (no heart failure. safe for
Receptor Blocker baroreceptor reflex w/ pregnancy
Labetalol effects.
reduced TPR)
Carvedilol antioxidant and antiproliferative
Carvedilol shown to
properties
decrease mortality and days
in hospital visits in patients
Labetalol Hypertensive emergency treatment
w/ moderate heart failure.
NSAIDs and Steroids
Clinical Effects / Contra / Side
Class Drug Mechanism Notes
Use Effects
1) Decreases Inflammation Approved Therapeutic
Uses: Side effects at low and high doses
Process of inflammation: Injury leads to release of chemical mediators (His, LKs, are qualitatively the samebut a
PGs) and non-specific acids leads to capillary dilation, increased capillary Inflammation higher, more chronic dose has side
permeability, and irritation of nerves. Leading to erythema and heat w/ increased blood effects more frequently.
volume. Swelling/limited motion from exudates/cells and fluid; and PAIN.

Mediators recruit neutrophils acutely. If you decrease the mediators you can the Acute & Chronic
neutrophils/inflammatory reaction. Pain, Gastrointestinal:

Prostaglandins: Vasodilation, Fever, Pain 16,500 NSAID-GI associated

deaths/year.
Fever
10-20% heartburn, nausea,
Arachidonic Acid has 2 pathways: indigestion

1) Lipoxygenase pathway (predominant in the lungs makes leukotrienes: Primary 2-4% massive bleed and/or
vasoconstriction, bronchoconstriction, and vascular permeability). NSAIDs push AA Dysmenhorrea (not perforated ulcer (50-60% get
towards this pathway (careful in asthmatics) acetaminophen or asymptomatic/ spontaneously healing
NSAIDs aspirin) ulcers)
2) Cyclooxygenase pathway:
**Established Risk of gastric ulcers
Platelets (COX - 1) = Thromboxane A2 (Vasoconstriction, Platelet Aggregation) included advanced age, preexisting
Unstable ulcers, use of steroids/anticoagulants,
**NSAIDs Greater effect here (no nuclei/protein machinery = totally done for once Angina/Post MI high and chronic dosage, and the type
inhibited = TXA2 ) = inhibition of platelet aggregation and increased (Aspirin only), of NSAID used (Ibuprofen has less
vasodilation. risk).

Vascular Endothelial Cells (COX - 1 & 2) = Prostacylcin PGI2 (Vasodilation, *NSAID Mechanism of GI toxicity?
inhibits platelet aggregation, potentiates edema)] OPPOSITE EFFECT to that of Patent Ductus
Thromboxane A2 (platelets). Arterosus in Neonates Direct irritant, gastric epithelium
(Indomethacin only). concentrate NSAIDs (oxidative
**NSAIDs less effect in endothelium (COX reproduced) = good thing! phosphorylation and mucosal cell
proliferation), prostaglandin
AA is everywhere, path depends on the tissue. synthesis (PGs buffer luminal acid and
Future uses: stimulate duodenal HCO3- secretion). =
Alzheimers prevention, Less buffering of mucosa.
Colorectal cancer
COX-1 Constitutive (stomach, intestines, kidney, platelets, others). Housekeeping prevention (aspirin), **Misoprostol shown to be effective in
role, regulating normal renal and gastric function and vascular homeostasis. Inflammatory Breast counteracting: (restores GI
Cancers, Preeclampsia
COX-2 Inducible! (brain, kidney, prostate, uterus basally). Expression is management (aspirin), Prostaglandins).
ENHANCED by endotoxin (LPS) and cytokines. UP-regulated at inflammatory sites Prevention of colon
(macrophages, synoviocytes). polyps. **H2 blockers ineffective

**BOTH inhibited by NSAIDs** **Sucralfate ineffective

NSAIDs localize to inflammatory sites due to: a) acidic nature; b) high plasma **Combination of a **GI Sparing Therpaies have NO
protein binding nature [except acetaminophen]. NSAIDs dissociate from the plasma NSAID and a narcotic proven benefit(Pro-drugs, COX2-I)
proteins once they leak into inflamed/acidic tissue; they concentrate in synovial analgesic is additive and
membranes and inflammatory cells. raises the analgesic
ceiling. Better than
------------------------------------------------------------------------------------------ NSAID or narcotic at Renal
SAME dose ALONE.
2) Acute and Chronic Pain relief Less frequent than GI.
MUST use the
Most effective against pain which accompanies inflammation (Ex: stab wound Risk of acute reduction in renal
optimum dose of the
popping 2 Ibuprofen will probably not help with the painbut it will help when the blood flow and GFR; usually in
NSAID to see the
wound becomes infected and inflamed). patients with a disease accompanied by
additive effect
poor renal perfusion [normally PGs
Peripherally/locally acting analgesia. maintain a compensatory response to
maintain renal blood flow in the face
Prostaglandins and Bradykinin cause pain (together they create more pain than VS. NARCOTICS of increased NE and AG II
Bradykinin alone) NSAIDs shift the balance in these
1) Tolerance to patients towards renal
NSAIDs lower Prostaglandin levels to decrease PAIN. analgesic effects does vasoconstriction Renal Blood
NOT develop tolerance flow and GFR].
Analgesic Ceiling effects with increased dosage (not true of opioids). w/ chronic use.
Na retention/edema,
**How high the ceiling effect is depends upon the drug (but all eventually become 2) NSAIDS not Hyperkalemia, acute deterioration of
maxed out as dose increases). addictive renal function, Nephrotic
Syndrome/interstitial nephritis,
A COMBINATION of a narcotic analgesic and an NSAID is ADDITIVE and 3) NO dependence papillary necrosis.
raises the ceiling for analgesia = get a better analgesic effect (Ex: Tylenol III = concern
codeine + acetaminophen). **STOP the NSAID as treatment.
------------------------------------------------------------------------------------------ *Minimize effects? Use least potent
COX Inhibitor. Ask to weigh
3) Fever Relief themselves to look for fluid retention
Hypothalamus regulates a set-point for body temperature; which is thought to
be regulated by prostaglandins. When PGs increase in level, the body tries to conserve
heat (vasoconstriction, piloerection, epinephrine secretion, shivering) and body Hypersensitivity Rxns
temperature rises (fever) [not the same as in exercise].
10-20% Asthmatics (1-2% in general
NSAIDs decrease pyrogen-induced elevation of PGs in the hypothalamus (resets population). W/in mins/hrs. Not
the set point = promotes loss of body heat and decrease in core temperature). NO effect immunologic.
on normal body temp.
 Want effective, quick onset w/ relatively short T (because body has a self-limiting **ALL NSAIDS Cross-react
rise in body temperature [will decline in temp with time], NSAIDs only needed for 4-6
hours of treatment until no longer useful). Hypersensitivity to all other NSAIDs
(except acetaminophen must be
------------------------------------------------------------------------------------------ related to COX!!)

4) Primary Dysmenorrhea NSAIDs LKs = slow acting

substance of anaphylaxis.
50% menstruating women

Painful menstruation, headache, diarrhea, nausea.

Complications in Pregnancy
Involves Prostaglandins [pain and abnormally increased pressure and contraction
of the uterus] Most contraindicated (except
acetaminophen). In 3rd trimester,
Ibuprofen, Naproxen, Ketoprofen, Diflunisal, Rofecoxib relieves the pain from this NSAIDs: risk of maternal/fetal
condition. hemorrhage in delivery; uterine
contractions prolonging labor; may
Acetaminophen and Aspirin DO NOT cause premature closure of fetal
ductus arterioses. No evidence of
being Teratogenic.

Pharmacokinetic Interaction:

NSAIDs displace other drugs from

protein binding sites (relevance
depends on drug being displaced: Ex:
no relevance w/ penicillinbut
relevance with Phenytoin [anti-seizure
medicine]. Overall most drugs reach a
new steady state quickly. (Lithium,
oral hypoglycemics, Phenytoin,
Methotrexate [high doses],
anticoagulants, digoxin) all have
narrow therapeutic ranges

Pharmacodynamic Interactions:

NSAIDs decrease PG synthesis and

thus may blunt the effects of drugs that
depend on PG levels (Ex: beta
blockers, diuretics, anticoagulants).

------------------------------------------------
 -----

All NSAIDs are weak acids except

acetaminophen

**Anti-inflammatory efficacy is the

same for each NSAID at their optimum
doses = equivalent to Aspirin.

**Optimum doses for anti-

inflammatory efficacy can NOT be
determined by COX inhibition
potency of the drug.

**Analgesic effects vary in BOTH

potency and efficacy.

Metabolism for NSAIDs is 90%

hepatic (except for Aspirin,
Indomethacin, and Ketorolac)

Aspirin: Aspirin: Only approved Aspirin:

NSAID for Unstable
Anti-Inflammatory and Analgesic angina / Post Reyes Syndrome Life
Myocardial Infarction. threatening. Rare.
Aspirin Prophylactic treatment to
prevent MI. Vomiting, Lethargy, Liver enzyme
Aspirin is a UNIQUE NSAID in that it is an elevation, coma. Most frequent in
NSAIDs irreversible SUICIDE inhibitor of COX. (60-325 mg/day children recovering from a viral
Diflunisal recommended) only infection (flu or chicken pox)
Salicylates Its effect is NOT related to the T of the drug itself. low doses are
[Longer Half-Life and Permanent effect in platelets (never recover). protective
Transient effect in endothelium (must produce new
Analgesic Ceiling] COX enzyme). Basically the good effects recover more Aspirin:
[Aspirin does NOT
quickly and bad effects from platelets (aggregation and effectively relieve pain
vasoconstriction) are much less. from Primary First order kinetics at low doses.
Dysmenorrhea] Deacytlated very quickly T of 20
Overall effect = Inhibits platelet aggregation and min. (10% kidney elimination of
 causes vasodilation. salicylate, 80% liver).

Fever relief Zero order kinetics at high doses

[liver enzymes get saturated].

Salicylate levels increase
Diflunisal: (Very efficacious) [Dolobid] dramatically and the T increases
from 3-4 hrs to 12-24 hrs. Kidney
Anti-Inflammatory and Analgesic. Aspirin Poisoning: 20- excretion then predominates (up to
30 hrs 90%).
Higher analgesic ceiling, longer T than aspirin
(12-16 hrs vs. 3-4 hrs for aspirin). 1st CNS (tinnitus, **NOTE that a way to overcome
dizzy, nausea/vomiting, Aspirin overdose is to pump the
Has an equivalent analgesic ceiling to Codeine + respiratio n= CO2 stomach and alkalinize the urine to
Acetaminophen combo. respiratory alkalosis) keep Aspirin in the ion form and
prevent its reabsorption!
Diflunisal is an efficacious NSAID ALONE and is 2nd Uncoupled
an alternative to a narcotic combocool. Oxidative **When you are poisoned, the T of
Phosphorylation aspirin increases dramatically due to
(ATP, CO2, heat liver enzyme saturation.
[paradoxical fever!])

3rd
Fat/carbohydrate NOT APPLICABLE for other
metabolism ( ketone NSAIDs (they dont get saturated and
bodies in blood = do NOT show zero order kinetics in the
metabolic acidosis) liver). [Ketorolac and Indomethacin
show significant renal excretion
4th Electrolyte though]
Imbalance
(Convulsions, CV
collapse, Coma)

**Relatively poor anti- Acetaminophen, at toxic levels, is

Analgesic ONLY. inflammatory activity. converted to N-acetyl-para
benzoquinone imide (NAPQ1) which
reacts with sulfhydryl groups (GSH)
Analgesic ceiling is similar to Aspirin and produces liver necrosis.
**Does NOT effectively
Atypical (Dosage, T , Ceilings all the same).
relieve pain from IRREVERSIBLE LIVER EFFECTS.
Acetaminophen Primary Dysmenorrhea
NSAIDs
Same dose response curves. because it is NOT Major immediate complaint =
locally acting. nausea (few outward signs of liver
damage for 2-3 days). Serum
transaminases become elevated.
Acetaminophen + Narcotics have ADDITIVE effects!
Good! [Codeine + Acetaminophen equivalent to Analgesic
 Diflunisal for analgesic ceiling] Fever Relief Treatment of Toxicity?

Get plasma level of acetaminophen.

Unknown Mechanism (possibly COX-3 Inhibition) Acetaminophen is a Give n-acetylcysteine (NAC) as

SAFE antidote
ALTERNATIVE to
aspirin as an [replenishes the livers supply of
WEAK COX inhibitor analgesic/fever reliever glutathione]
in:
Weak Base (most NSAIDs are weak acids)
(1) Children
20% Plasma Protein Bound (others 98-99%) (2) Pregnant At therapeutic doses, the tiny amounts
women of NAPQ1 produced are detoxified by
NO ACCUMULATION at inflammatory sites hepatic glutathione S-transferase.
(3) Asthmatics w/
NSAID Can become saturated.
hypersensitivit
NOT locally acting as a result y,
(4) Renal
Susceptible Populations?
deficiency
(5) Bleeding P450 Inducer drug users (ex:
Should be used when patient cannot tolerate GI side disorders Phenobarbital) = level of NAPQ1
effects of other NSAIDs or patient needs to be treated (6) Gout metabolite; Fasting or protein deficient
for the analgesic effect (w/o the need for anti- diet; Pregnant; Alcoholic (low
inflammatory treatment/benefit). glutathione levels), children.

Probable Hepatotoxicity at 10g

[20 extra strength tablets in one dose]

38% of acute liver failure cases in the

US

Untreated mortality = 40-80%.

Ibuprofen Analgesic and Anti-Inflammatory Side Effects:

NSAIDs Analgesic Advil
See NSAIDS
Propionic ABOVE
Acids **All 3 have higher Analgesic Ceilings than Aspirin =
Ketoprofen Fever Relief Orudis
they are better analgesics than aspirin.
 [Ex: Ibuprofen at 400mg ALONE is equivalent to an Naproxen has a
Aspirin 650mg + Codeine 60mg combo] long half-life.
Ibuprofen: Aleve

Less Gastric Ulcer Risk

Naproxen Ibuprofen and Ketoprofen: T = 3-4 hrs (same as than other NSAIDs Ibuprofen and
aspirin) Ketoprofen have
[Long-Half Life] half-lives similar
to aspirin.

Naproxen: T = 12 hrs [LONGER Half-Life]

*All have higher analgesic ceilings when used in

combination with a narcotic.

Indomethacin Indomethacin and Sulindac: Renal Excretion?

Anti-Inflammatory:
[Patent Ductus Anti-Inflammatory ONLY Ketorolac
Indomethacin:
Arteriosus Closure] (40%)
Ketorolac: I
Patent Ductus
arteriosus closure in Indomethacin
SHORT-term analgesia ONLY (30%)
neonates.
Sulindac ------------------------------------------------------------ =MORE likely to
have renal side
[Renal/GI Sparing] Indomethacin: (Indocin) Ketorolac
Sulindac: effects
Potent COX inhibitor. Analgesic ceiling is equivalent to =
Renal or GI sparing
NSAIDs aspirin. ONLY Anti-inflammatory
indications
ONLY
Acetic Acids
IV
Sulindac: (Clinoril)
NSAID.
Renal/GI Sparing Prodrug, inactivated back to the
Ketorolac parent drug by P450 in the kidney; Anti-Inflammatory Ketorolac:
only; very little analgesic effect, comparable to Contraindicated in
[Short Term Pain aspirin in efficacy but with a much slower onset. patients with
Management] Short Term Analgesic: hypersensitivity to
Toradol and
Ketorolac: patients w/
Ketorolac: (Toradol)
complete or partial
Short-term syndrome of nasal
Oral, IV [less tissue irritability when injected], and IM
management of pain ~ polyps,
formulas. Greater water solubility and COX inhibition
 potency. ANALGESIA ONLY. 12 mg morphine angioedema, and
bronchospastic
Analgesic efficacy of IM Ketorolac is comparable Should only be used a reactivity to
to 12 mg morphine. It also DOES NOT depress maximum of 5 days Aspirin/NSAIDs
respiration (major advantage over an opioid like (side-effects otherwise). [cross-reactivity].
morphine).
Oral prep is
Analgesic efficacy of ORAL Ketorolac is NOT as
comparable to Ibuprofen. = BETTER w/ IV efficacious as
IV/IM [also
require lower dose
IV/IM]

Actually increases
the levels of
Selective COX-2 Inhibition. TXA2 (COX-1)
**COX-2 Inhibitors relative to PGI2
T = 12-17 hrs (comparable to Naproxen) are NOT better anti- (COX-2) levels.
inflammatory drugs
This may be the
Efficacy for anti- reason behind the
Selective Inhibition of COX-2 was originally thought to inflammation is
deleterious
be better than nonselective COX inhibition, since equivalent to aspirin.
Cardiovascular Vioxx
COX-2 is expressed at higher levels during
effects platelet
inflammation
aggregation
this turned out to NOT be the case. Celecoxib: increases and
vasoconstriction Celebrex
NSAIDs Rofecoxib Similar analgesic efficacy to existing NSAIDs Anti-Inflammatory increases.
indications

(Ibuprofen)
Hypersensitivity
COX-2 to people with
Inhibitors Do not surpass other NSAIDs in the treatment of
Celecoxib chronic inflammatory disorders. *NOT GI allergy to
Main advantage of sparing sulfonamides.
**Anti-Inflammation equivalent to Aspirin. COX-2 Inhibitors is that Celecoxib offers
they DO NOT increase NO proven safety
Not yet proven to be associated with fewer bleeding times. Since advantage over the
clinically relevant adverse effects compared to several Thromboxanes are NOT two older drugs in
other NSAIDs (Ex: GI = no advantage [likely that effected (COX-1 reducing ulcer
inducible COX2 plays a role in ulcer repair!). mechanism), platelet complications.
aggregation is not
Significant cardiovascular toxicities which require inhibited and
re-examination of a risk/benefit analysis when vasodilation does NOT
choosing a COX-2 inhibitor over another NSAID for Rofecoxib (taken
occur.
the patient. off the market by
Merck) no
longer available.
 Celecoxib
Black Box label

Steroids
Cortisol: Treatment of Prolonged use of
adrenal insufficiency. Glucocorticoids Cushings
Stress, IL-1, cytokines, drugs (opioids, cocaine), and
can cause HPA Disease
normal circadian regulation (greatest rise before
Anti-Inflammatory? axis depression loss of
awakening) act on/from the CNS on the hypothalamus.
Receptor mediated (Secondary circadian
The hypothalamus releases CRF (Corticotropin
effects on protein Addisons regulation of
releasing factor) CRF acts on the pituitary
synthesis resulting in Disease) may cortisol
pituitary releases ACTH ACTH acts on the adrenal
suppression of take 8-10 months release
cortex adrenal cortex releases aldosterone,
inflammatory cytokine before ACTH and (cortisol is
cortisol, androgens.
levels (varies from cell cortisol levels high ALL
to cell; only cells w/ reach normal the time in
Daily cortisol levels fluctuate between 2-20 ug/ 100ml.
glucocorticoid receptors range after Cushings)
are targeted time stopping therapy Primary
Cortisol is 10% free, 90% protein bound Cortisol
delayed action due to abruptly = excess
Binding Globulin (CBG) [high affinity, low capacity]
protein synthesis). cortisol from
and Albumin [low affinity, HIGH capacity]. Cortisol
Indirect Inhibition of Hypertension the adrenals
negatively feeds back on the hypothalamus and
PG synthesis (Induced w/ HPA axis
pituitary
Cortisol (hydrocortisone) synthesis of Lipocortins Mineralocorticoid depression
Gluco- = inhibit phospholipase s: sodium and
Uses of Glucocorticoids?
corticoids Cortisone In replacement therapy [Addisons Disease]
A2 = less Arachidonic water retention; Secondary
(short-acting) acid will be available to edema = Ectopic
should be administered in the early morning and late
make Prostaglandins). Corticotrop
afternoon (cortisol replacement)
T 8-12 hrs. COX-2 Inhibition Glucocorticoids: in secretion
Also they have negative feedback/suppress the HPA
Prednisone Lymphocyte increase or pituitary
axis.
trafficking effects ( catecholamine excess
Anti-Inflammatory/Immunosuppressive
blood neutrophils by synthesis in ACTH
------------------------------------------------------------
decreasing neutrophils adrenal medulla secretion
Cortisol:
adherence = cant get to
Anti-inflammatory [1] (glucocorticoid activity) = salt
sites of inflammation) Suppression of Primary
retention [1] (mineralocorticoid activity).
Lymphoctyes/monoctyes the immune Addisons
precipitously drop. response. Disease
Cortisone:
Adrenal
Less anti-inflammatory (0.8) /salt-retention (0.8)
*Allergic Disorders Impaired wound cortex does
activity than cortisol.
(contact dermatitis, drug healing. not produce
Weak version of cortisol.
rxns, urticaria), Asthma, enough
Arthritis, Many side effects cortisol.
Prednisone:
Inflammatory Bowel, related to effects Less
More anti-inflammatory (4) and less salt retention
Skin Disorders, Shock, on carbohydrate negative
(0.3) than cortisol.
Ulcerative colitis, metabolism: feedback on
relatively potent glucocorticoid.
Leukemia, Cortisol: HPA axis.
Neurological diseases, Anabolic effect to
 Autoimmune diseases. the liver to make
MORE
**Inject locally, use glucose!! all
lowest effective dose, other tissues
alternate day therapy, respond to this
periodically tape down signal (brain,
dosages, monitor for liver, heart, RBCs
infection, and spared and can
INCREASE dosage still utilize
during times of glucose).
STRESS!!! Decrease
protein synthesis
Increase
Proteolysis/AAs
Increase
lipolysis/FFAs
Increase
gluconeogenesis
Increase
Insulin
Increase fat
deposition
WBCs
Cell
profileration

Contraindicated:
Peptic ulcers
(cant heal)
Hypertension
(will )
Infections
(cant heal)
Diabetes
(hyperglycemia)
Glaucoma,
Psychosis,
osteoporosis
Gluco-
corticoids
Relatively POTENT glucocorticoid only.
(intermediate Good for someone
Triamcinolone More anti-inflammatory (5) activity than cortisol and Anti-Inflammatory
with Hypertension
) even prednisone. ZERO salt-retention (0).

T 12-36 hrs.
Gluco- Dexamethasone VERY POTENT glucocorticoid. Anti-Inflammatory and Good for someone
 corticoids High anti-inflammatory activity (30) immunosuppressant with hypertesnion
(long-acting) Devoid of mineralocorticoid activity
Zero salt-retention (0)
Good for someone with hypertension
T 36-72 hrs.
Treatment of
mineralocorticoid
Mineralocorticoids similar structure to aldosterone.
deficiency as seen in
They increase salt and water retention; thus
Mineralo- Adrenal Insufficiency Contraindicated
contraindicated in hypertensives.
and Chronic Salt in CHF, and
corticoid Fludrocortisone Wasting (21- Hypertensives. Florinef
POTENT mineralocorticoid (250) with relatively
Hydroxylase Salt/Water
T 8-12 hrs. LITTLE glucocorticoid activity (10). Thus it has very
Deficiency). retention
high salt-retention activity.
First line treatment of
orthostatic intolerance
Aminoglutethimide:
Inhibits the conversion of cholesterol to
pregnenolone (equivalent to an adrenalectomy).
Aminoglutethimide:
Treatment of Cushings
Aminoglute-thimide Metyrapone: Inhibits the enzyme 11--Hydroxylase.
Adrenocortic (w/ adrenal origin = 1)
Results in the buildup of 11-Deoxycorticosterone
al and 11-Deoxycortisol. Effectively blocking
Metyrapone Metyrapone: Used
Antagonists corticosterone/aldosterone and cortisol synthesis.
(Su 4885) diagnostically to test
This in turn stimulates ACTH secretion from the
competency of adrenal
pituitary (less negative feedback) [will clarify if
axis
excess ACTH is from the pituitary (rise in ACTH w/
Metyrapone) or ectopic (no rise in ACTH w/
Metyrapone)].
Class Drug Mechanism Clinical Effects Contra / Side Effects Notes
2/5 of patients diagnosed with cancer will Die. Horrible profile, make sure patient has cancer and that it is worth treating
Pancreatic Cancer 95% Die (e.g. aggressiveness of cancer, age of pt, prognosis, beware of
Ovarian Cancer 75% Die overtreatment)
Lung Cancer 71% Die
Leukemia 50% Die Side Effects of Cytotoxic Anticancer Drugs (Older Drugs):
Breast 30% Die Bone Marrow suppression
Prostate - 20% Die **Leukopenia, Lymphocytopenia, Immunosuppression, Thrombocytopenia,
2nd leading cause of death in children aged 1-14 Anemia
Cancer Tx
More people die from cancer than from heart disease (<85 yo) GI Tract
**Typically dont detect cancer until 1 cm in diameter (109 cells!) **Ulceration, Mucositis, diarrhea, vomiting
Hair Follicles
Optimal dose should be given for these drugs to attain benefit, and regimen **alopecia
can be changed mid-course to minimize side effects or attain greater benefit Gonads
short courses long-term benefit **PERMANENT premature menopause [66% <25 yo; 95% >25 yo]
**Amenorrhea
Goals of Therapy **Temporarily spermatogenesis
 relapse-free survival rate of patients (reclaims years lost to cancer, but Wound Healing is impaired
at a cost Fetal Teratogens
Secondary Cancers *when given to Children?*
Injection site tissue damage.

**Must be careful even HANDLING these drugs (many absorbed through

the skin)

Older: Cytotoxic Anticancer Drugs

Azathioprine Azathioprine - prodrug

Transplant
Prodrug that releases 6-Mercaptopurine
Childhood leukemia
6-Mercaptopurine Converts to 6-mercaptopurine which is
Purine Analogs Side Effects of Cytotoxic Anticancer Drugs
converted to thioguanine nucleotides that
Azathrioprine
interfere with DNA synthesis; thioguanine
Kidney Transplant
6-Thioguanine derivatives may inhibit purine synthesis.
Structural Analog of Folate

Inhibits Dihydrofolate-Reductase
Methotrexate
Thus blocks conversion of 7,8-Dihydrofolate
(DHF) to Tetrahydrofolate (THF)
(folate analog) **Prevents THF synthesis
-Inhibit Not enough THF to become methyl-THF =
Purine/Pyrimidine cannot donate methyl groups for the CMF Breast Cancer
synthesis Side Effects of Cytotoxic Anticancer Drugs
conversion of dUMP to dTMP via Thymidylate- Cyclophosphamide
Anti-Metabolites
Synthetase Methotrexate
Especially Bone Marrow Suppression
= inhibition of pyrimidine / purine / DNA Fluoro-Uracil
(Folic Acid
synthesis
Metabolism
Uracil mimic; w/ fluorine Also very effective
Inhibitors) Treat Methotrexate Toxicity with
Immunosuppressants
5-Fluoro- Leucovorin
Inhibits Thymidylate-Synthetase
Uracil
Converted to 5-fluorouridine [which
remains bound to the enzyme]
(Uracil analog)
Thus blocks conversion of dUMP to dTMP
-Inhibit
TS normally transfers a methyl group from
Purine/Pyrimidine
methyl-THF to dUMP
synthesis
= inhibition of pyrimidine / purine / DNA
synthesis
Form of folate that can function directly
Leucovorin without the need for reduction by
Methotrexate
Dihydrofolate-Reductase. Treats Methotrexate
Toxicity
**If you give too much MTX you might have so overdose
Treatment (Tx MTX toxicity) much bone marrow suppression that you kill
the patient.
 **Leucovorin is given to prevent this.
Analog of Cytidine
trans Cytarabine **Sugar hydroxyl group is trans instead of cis =
DNA Polymerase Side Effects of Cytotoxic Anticancer Drugs
cannot be inserted into DNA. Childhood leukemias
Inhibitor
(Ara-C) Inhibits DNA-Polymerase
Stops elongation of the DNA molecule
Contain two Chlorine alkyl residues
Cyclophosphamide
*Most commonly used anti-
Alkylates DNA
cancer Drug!
Crosslinks DNA [inter/intrastrand links]
*May be given orally
= inhibition of DNA replication / transcription Side Effects of Cytotoxic Anticancer Drugs
CMF Breast Cancer
/ repair
Cyclophosphamide Cyclophosphamide
Cyclophosphamide:
(Cystitis give MESNA) Methotrexate
(Leukopenia-give GCSF Cyclophosphamide: CYP450 metabolism Toxic Acrolein
Fluoro-Uracil
**Two inactive metabolites causes cystitis [give in combination with
**Two toxic metabolites: MESNA (Mercaptoethane-sulfonate] to
Mechlorethamine
(1) Alkylating Toxic Phosphoramide mustard reduce this effect]
Mechlorethamine
(2) Harmfully Toxic Acrolein causes cystitis Early in Tx also causes SEVERE
Sulfur mustard of MOPP therapy
Leukopenia [Give G-CSF to drive recovery
DNA Alkylating / Hodgkins Lymphoma
Mechlorethamine and eliminate this side-effect]
Crosslinking Mechlorethamine
Nitrogen mustard
Agents Oncovorine [Vincristine]
Procarbazine
Sulfur mustard
Prednisone
Chemical weapon
Chloroethyl- DNA crosslinking (see above) = nitrosyl + CNS penetration (brain
nitrourea chlorine tumors)
Side Effects of Cytotoxic Anticancer Drugs
Contains Platinum and two Chlorine residues.
Many Cancers
Protein cross-linking causes:
Cisplatin Crosslinks DNA [inter/intrastrand links] Solid tumors
Renal Insufficiency
(renal insufficiency) DNA Adducts
**Must be careful when using in combination
= Strand mutation, breakage *Injection ONLY*
with drugs that must be renally eliminated
= Inhibits DNA replication/transcription
[e.g. Aminoglycosides]
Bleomycin Intercalates with DNA, causes strand breakage Solid tumors Pulmonary toxicity
Side Effects of Cytotoxic Anticancer Drugs
DNA Anthracycline CAP Breast Cancer
Strand Breakers Doxorubicin Cyclophosphamide Cardiotoxicity
(Disrupters) (Adriamycin) Inhibits DNA Topoisomerase II Adriamycin Dose dependent, cumulative
(Cardiotoxic) irreparable strand breakage Paclitaxel Heart Failure, dilated cardiomyopathy
Much greater risk in women
 Epipodophyllotoxins
Etoposide Effective in a number of
Inhibits DNA Topoisomerase II
cancers Side Effects of Cytotoxic Anticancer Drugs
Cause failure of the DNA to re-ligate
Including Solid Tumors
Teniposide [strand is opened up, but cannot be put back
together]
Solid tumors
Vincristine Vincristine [vinca alkyloid] rosy periwinkle
(1/4 of MOPP regimen)
( microtubules) Inhibits microtubule formation in M phase
Mechlorethamine Side Effects of Cytotoxic Anticancer Drugs
Binds/sequesters tubulin
Oncovorine [Vincristine]
Procarbazine
Anti-Mitotics Paclitaxel Paclitaxel [taxane] pacific yew
Prednisone Peripheral Neuropathy
(Microtubules) ( microtubules) Enhances microtubule formation in G2
Hodgkins Lymphoma **Dose Dependant
Prevents microtuble depolymerization
**Disrupts neuronal survival
**Freezes the polymerized form
CAP Breast Cancer Tingling, numbness, gait disturbances.
*Peripheral Cyclophosphamide
Neuropathy Pac = pack the tubules together
Adriamycin
Paclitaxel
GMCSF / GCSF Reduces hematologic side effects of cytotoxic anti-cancer drugs
Growth Factors (esp. attenuation of leukopenia) and allow chemo drug dosage increase
(Bone Marrow EPO
Restoration) EPO used to induce growth of erythrocytes in patients with significant
IL-2 / IL-6 anemia illegal substance in sports.
Newer: Biological response modifier Anticancer Drugs
G3139 Bcl-2 antisense oligonucleotide
*Bcl-2 normally inhibits apoptosis
Bcl-2 *Bax causes Apoptosis Investigational
Antisense
Oblimersen Kills cells with
Drugs Targets bcl-2-mRNA expression upregulated BAX?
Bcl2 (BAX:bcl-2 ratio increases, cell death surpasses
BAX ratio proliferation)
Apoptosis
 Trastuzumab:
**Humanized IgG antibody
HER2 receptor Inhibitor
**Overexpressed in 25-30% of Breast Cancers
**HER2 (+) = Survival, Aggressiveness Trastuzumab:
Trastuzumab:
cardiotoxic heart failure (HER2 in
Restores disease to
Trastuzumab Cetuximab: heart)
HER2(-) Prognosis
**Chimeric **Interrupts biochemical stimulation of heart
(HER2) Very effective in HER2+
EGF-Receptor Inhibitor cells = heart cells DIE
(Cardiotoxic) breast CAs
**Never combine with Adriamycin
Survival
Rituximab: Arthralgias, headache
Cetuximab **Chimeric
Cetuximab:
(EGF) CD20 Receptor Inhibitor Cetuximab: Rash
survival by 2 months of
Monoclonal (Rash) Colorectal Cancer
Bevacizumab: Rituximab:
Blocking Abs **Not dramatic**
Neutralizing Antibody for VEGF COST $$$
Rituximab **Humanized
Rituximab:
(CD20) Binds directly to growth factor: VEGF Bevacizumab:
B-cell lymphomas
Inhibits blood vessel growth into tumors Hypertension
**over-express CD20
*Any drug that inhibits VEGF will do this
Bevacizumab Sorafenib or Sunitinib
(VEGF) Bevacizumab:
Antibodies (chimera or humanized): *VERY Expensive.
Colorectal cancer
(HTN) Physically block activity of molecules
Survival (4 months)
Can aid in recognition by immune system Binds externally
*Slight improvement
(cell-dependent cytotoxicity)

Bind to growth factor receptors, used in

conjunction with standard chemotherapy

Gefitinib Inhibit Tyrosine Kinase Receptors from Gefitinib: **NOT as selective as monoclonal
(EGF) INSIDE the cell. Non-small cell carcinoma antibodies**
(Rash) of the Lung
Gefitinib: Erlotinib: Gefitinib/Erlotinib:
Inhibits EGF-Receptor kinase (1st mutant) Non-small cell carcinoma Papulopustular Skin RASH
Erlotinib T790M mutants have resistance of the Lung T790M **Face/Upper Trunk (45-100%)
(EGF-mutant) Erlotinib: EGFR mutant **Worse the rash better the survival!
Kinase Inhibitors (Rash) Inhibits EGF-Receptor kinase * Responsiveness to Abnormal Hair Growth (21%)
Treats the T790M mutant! treatment, but shifts Dry, itchy skin (12-16%)
*NOT antibodies* Imatinib survival curve only Periungual inflammation/tenderness
(Gleevec) Imatinib: slightly (12-16%)
(Bcr-Abl Inhibits Bcr-Abl fusion Kinase ***These side effects are because EGF is like
(PDGF) **Stops progression of the disease. Imatinib: TLC for the skin w/o it you see arrest and
(Pancytopenia) Inhibits PDGF-Receptor, CD117 (C-Kit) CML premature differentiation along with
**Inhibits blood vessel supply of tumors. (targeted **Bcr-Abl migration of inflammatory cells to skin.
vs. non-specific cytotoxic) Gastrointestinal
Ti = TYrosine Kinase stromal tumors (GIST) Imatinib:
 Imatinib Resistance: **PDGF-R Hematological milder than cytotoxic
Important Issue of Concern **Pancytopenia, reversible
(1) Insensitive Bcr-Abl allele mutation Edema
(2) Activation of Secondary Kinase (pathway) Skin Rashes
(3) Efflux pump activity
(4) Extracellular sequestration
(5) Bcr-Abl Overexpression
Reversible Proteasome inhibitor
Prevents protein processing/degradation
Bortezomib
(GI) Prevents degradation of pro-apoptotic
GI toxicity
(Peripheral proteins?
Proteosome Peripheral Neuropathy (30%)
Neuropathy) Multiple Myeloma
Inhibitor Neutropenia
**Tumors make a lot of trash proteins if you
(relatively mild)
Bort Abort the block this you can kill the cells?
Proteasome
Causes cancer cell Apoptosis by activating
p53 tumor suppressor gene?
Administered at maximal
tolerated dose due to side
effects Indiscriminate apoptosis and terminal
differentiation = skin dryness, GI, hepatic
Retinoids
All-Trans Nuclear hormone receptors, arrest cells in G1 and
acute promyelocytic toxicity, teratogenic, 15% RA syndrome
Retinoic Acid stop cell proliferation
leukemia (10% fatal, fever, resp. distress, weight gain,
edema, hypotension, renal failure)
Generally better tolerated
than cytotoxic drugs
SERM T 7 Days - parent compound 2nd Line adjuvant therapy
for Estrogen Receptor (+)
Resistance after 5 years of continuous use
Displaces Estrogen Receptors helix 12 - blocks Resected Breast Cancer
coactivator binding = competitive antagonist of and metastatic Breast
P450 metabolism
estrogen Cancer
(1) 4-hydroxytamoxifen (major active
*1st line = aromatase
metabolite, potent antagonist at Estrogen
Inhibits Osteoporosis inhibitors
Receptor) T = 14 days
(2) N-desmethyltamoxifen (partial agonist)
In the Breast: Also approved as a
Anti-Hormone (3) Metabolite E (low affinity)
Breast Cancer Tamoxifen (1) Blocks estrogen dependent proliferation chemopreventive agent for
(4-6) three others
(2) Blocks Progesterone receptor synthesis BRCA carriers and Li-
(3) Blocks DNA polymerase activity (mid G1) Fraumeni sufferers.
Partial agonist side effects:
also stimulates production of TGF- (growth
incidence of endometrial carcinoma
inhibitory factor) /
and hepatocellular carcinoma
No effect on ER ()
Retinal opacity at high doses
In the Endometrium: tumors.
Menopausal symptoms (hot flashes)
(1) Acts as a full agonist = Cancer Risk
Thrombocytopenia, DVT, CVA, PE
Also inhibits osteoporosis
Tamoxifen is actually proliferative in some Bone Mass Density
 tissues
serum cholesterol and
LDL
Faslodex SERD (downregulator) GI upset
Post-Menopausal women
Headache
(Fulvestrant) Full estrogen antagonist
who have Estrogen
Back pain
Receptor (+) Resected
Proteolysis of Estrogen Receptors Menopausal Symptoms (hot flashes)
Breast Cancer that is
*Full estrogen Tamoxifen Resistant
Antagonist **IV once a month** **Difficult to Tolerate**
Aromatase:
Converts Androstranedione to Estrone
Amino- Converts Testosterone to Estradiol Anastrazole/Letrazole:
**Never use in Premenopausal Women**
**Blocking this enzyme prevents estrogen
glutethimide st Blocking estrogen production will
synthesis. These drugs reduce serum estrogen to 1 line treatment in ER(+)
breast CA in post- FSH/LH levels dramatically
nearly undetectable levels.
Undesirable effects on the ovaries!
menopausal women
Anastrazole Aminoglutethimide:
Side Effects:
Prototypic Aromatase Inhibitor disease free survival
Menopausal symptoms (hot flashes)
Letrazole Not used because of significant side effects overall survival
Osteoporosis
[anti-glucocorticoid synthesis effects] incidence of Resistance does appear to be developing
contralateral tumors
Overall WELL Tolerated!
compared to Tamoxifen
*Blocks Estrogen Anastrazole/Letrazole:
*Much more expensive than Tamoxifen*
Production Selective aromatase inhibitor
Do not significantly change the levels of
cortisol or aldosterone.
**Requires intact pituitary function**
Pulsatile: stimulates more
Side Effects:
natural levels of FSH / LH
Goserelin Hypogonadism
than direct menotropin
**Hot Flashes, Vaginal Dryness/Atrophy,
injection
bone density, Libido
Continuous administration of a GnRH agonist
GnRH Leuprolide leads to GnRH receptors on the pituitary = Continuous: negative
**Therapy is usually limited to 6 months
unless add-back therapy with estrogens or
Agonists LH/FSH release = prevents luteinization feedback used to treat
progestins is incorporated.
(prevents transformation of mature follicle into Polycystic Ovary Disease
*Must give with Corpus Luteum). and Cancer
Altered lipid metabolism.
SERM initially to
prevent tumor flares Initial administration may cause Tumor
*reversible Chemical
Flares (dangerous spina compression?)
Castration*
**Given initially with an estrogen receptor
antagonist
Non-steroidal anti-androgen Advanced Metastatic
Flutamide Competitive inhibitor of testosterone / DHT Prostate CA
libido
Hormone Gynecomastia
Regression of target tissue (prostate)
(Prostate) LH = *Give with GI disturbances
*Given with GnRH
Liver failure
GnRH agonists to Limited by LH = testosterone (due to agonist to compensate for
 prevent blockade of negative feedback by androgens) LH*

*Metabolized to hydroxyflutamide *Oral*

(higher affinity)

Alternative to surgery in
treatment of BPH,
Steroidal anti-androgen
Finasteride Selective competitive inhibitor of 5- -
decreases incidence of
libido, impotence
(Propecia) prostate CA (but CAs that
reductase
do develop are more
malignant)
MOPP / CHOP Resistance (defective glucocorticoid receptor
function)
Leukemia, lymphoma
Glucocorticoid (active metab. prednisolone),
(ALL, CLL, MM, Severe glucocorticoid effects if given for
lymphocytolytic at high doses, directly
Steroid Prednisone Hodgkins, non- prolonged duration at high doses
stimulates apoptosis in T cells in receptor
Hodgkins), Truncal Obesity
mediated fashion
cancer pain Psychosis
Aseptic Necrosis
ALL - 81% remission MANY others

Resistance to Anti-Cancer treatments:

1) p53 mutation decreased apoptosis

2) bcl-2, BAX (increased ratio) bypasses p53 regulation
3) efflux pump expression
4) alteration of drug target
5) rapid metabolism of drug (metabolic changes)
6) change in cell membrane permeability

Combination therapy:

1) CMF (Cyclophosphamide, Methotrexate, 5-FU) - relapse free and overall survival; 7.5 years of life gained after mastectomy
a. Breast Cancer Tx. Only the highest dose therapy was effective.
b. Adriamycin [doxorubicin] often added to regimen (CAMF)
c. Newer agents added if CMF doesnt work
2) CAP (Cyclophosphamide, Adriamycin, Paclitaxel)
a. Breast Cancer Tx
b. **May add Trastuzumab for HER2(+) Breast Cancer
3) MOPP (Mechlorethamine, Oncovorine [Vincristine], Procarbazine, Prednisone)
a. Hodgkins Lymphoma Tx
4) ABV (Adriamycin, Bleomycin, Vinblastine)
 a. MOPP resistant lymphoma
5) CHOP (Cyclophosphamide, Adriamycin [hydroxydoxorubicin], Oncovorine [Vincristine], Prednisone)
a. Lymphoma
b. **May add Rituximab for CD20(+) B-Cell lymphomas
Immunosuppressant Drugs
Class Drug Mechanism Clinical Effects Contra / Side Effects Notes
Nephrotoxicity

11-amino-acid cyclic peptide Hemolytic Uremic Syndrome,

Hypertension, Neurotoxicity, Gum
Cyclosporine Binds to Cyclophilin Hyperplasia, Skin Changes, Hirsuitism,
Complex inhibits Calcineurin Phosphatase and Diabetes Mellitus, Hyperlipidemia
T-Cell Activation
**Trough monitoring or checking levels 2 hrs
after administration required.
Macrolide Antibiotic

Tacrolimus Binds to FKBP12 Used to coat STENTS Similar side effects to Cyclosporine.
Complex inhibits Calcineurin Phosphatase and
T-Cell Activation.
Triene Macrolide Antibiotic
Hyperlipidemia, Thrombocytopenia, Delayed
wound healing, delayed graft function, mouth
Immuno- Sirolimus Binds to FKBP12 Used to coat STENTS
ulcers, Pneumonitis, interstitial lung disease,
Suppressants Complex inhibits target of Rapamycin and IL-
lipid monitoring required
for 2-driven T-Cell Proliferation.
Organ Transplants Prodrug that releases 6-Mercaptopurine

Converts 6-mercaptopurine to tissue inhibitor of Leukopenia, bone marrow suppression,

Azathioprine metalloproteinase which is converted to macrocytosis, liver toxicity; blood count
thioguanine nucleotides that interfere with monitoring required.
DNA synthesis; thioguanine derivaties may
inhibit purine synthesis.
Chimeric monoclonal Antibody
Against CD25 [IL-2 receptor -chain]
*Binds to and blocks the IL-2 receptor -chain Hypersensitivity Reactions (uncommon)
Basiliximab (CD25 antigen) on activated T-Cells
*Two Doses required*
*Depletes T-Cells and inhibits IL-2 induced T-
Cell activation.
Humanized monoclonal Antibody Hypersensitivity Reactions (uncommon)
Daclizumab Against CD25 [IL-2 receptor -chain]
*Similar to Basiliximab *5 Doses recommended, two may suffice*