James Pharmacology Study Notes

4/21/2011 8:38:00 AM

Module 1 General Principles of Pharmacology

Pharmacology a branch of medicine dealing with interaction of drugs within
living animals, mechanisms of drug action as well as therapeutic and other
uses of the drug
Brand names, generic names and chemical names
Drug-Receptor Interaction
K1 = D + R -> DR
K2 = DR -> D + R
Ka = affinity constant
Kd = dissociation constant
Kd = K2/K1
The lower the Kd, the more affinity the drug has for the receptor
Dose response curve measurement of drug-receptor interaction
EC50 - Concentration of drug that causes 50% of maximal response/efficacy
Log dose-response curve is easier to analyze mathematically and
compresses the scale
EC50 = dose/concentration of a drug that produces 50% of maximal
response
Emax = max effect produced by a drug; a measure of efficacy of a drug
Efficacy/Intrinsic activity = ability of a bound drug to change the receptor in
a way that produces an effect; some drugs have affinity but not efficacy
(just occupy the receptor)
Kd = concentration of a drug that occupies 50% of the total number of
receptors at equilibrium
Potency of the drug
Potency is determined by the affinity plus intrinsic activity of the
drug
A more potent drug is not clinically superior

o Low potency is a disadvantage only if the dose is so large that

it is awkward to administer
If the dose-response curve is shifted left and steep, its considered
more potent

Spare receptors
If EC50 = Kd there are no spare receptors
If EC50 < Kd then it suggests the existence of spare receptors
Spare receptors allow maximal response without total receptor
occupancy increased sensitivity of the system

Spare receptors can bind and internalize extra ligand preventing an

exaggerated response if too much ligand is present

Agonist has affinity and efficacy

Partial agonist has affinity but less efficacy (compared to a full agonist);
would therefore have a lower Emax
Antagonist has affinity but NO efficacy
Can be competitive (reversible) or non-competitive (irreversible)
A partial agonist acts as an antagonist in the presence of a full agonist
Good because they have some efficacy and at the same time block
the endogenous full agonists ex: Pindolol for high BP and abN heart
rhythms
Competitive Antagonism
Require a higher dose of agonist in the presence of competitive
antagonist to produce the same effect
Can still get to Emax but require a higher concentration
Non-competitive Antagonism
In the presence of non-competitive antagonist even a higher dose
of agonist cannot produce the original Emax
Emax is depressed in the presence of a non-competitive antagonist
Quantal dose-response curve indicates sensitivity of a given population to
the doses of a drug for a given effect

Frequency distribution or cumulative frequency

Therapeutic Index
ED50 = effective dose in 50% of ppl
TD50 = toxic dose in 50% of ppl
LD50 = lethal dose in 50% of ppl
Therapeutic Index/TI = TD50 or LD50/ED50
Higher the ratio, safer the drug
Therapeutic window reflects [plasma] range that provides efficacy w/o
unacceptable toxicity
TW is the difference between the minimum effective concentrations
(ED) for desired response and an adverse response (LD)
Signal Transduction Pathways
Ion channel receptors/Ionotropic
G-protein coupled receptors (half of all known drugs work through
this mechanism)
o Subsequently cAMP, IP3, DAG

Enzyme receptors (tyrosine kinase, etc)

Nuclear receptors

Up/Down-Regulation of Receptors
Agonists tend to desensitive receptors
o Homologous decrease receptor #
o Heterologous decreased signal transduction
o Ex: Overuse of B2 agonists in asthma
Antagonists tend to upregulate receptors
Pharmacokinetics

Drug absorption
o Passage of drug from site of admin into general circulation
(except for drugs applied directly to target tissue)
A drug given IV is immediately and completely 100%
absorbed

o Generally:
Better absorbed
Non-charged, small, lipid soluable drugs
Poorly absorbed
Charged, large molecules
o Ionization: Effect of pH on absorption
pKa of a drug is defined as the pH at which the
drug is half ionized
most drugs are either weak acids/bases
acidic drug in a basic medium gets ionized and is

Ion

less well absorbed

basic drug in acidic medium gets ionized and is
less well absorbed
trapping
At steady state, an acidic drug will accumulate on
the more basic side of the membrane and a basic
drug on the more acidic side (trapped in the
compartment)
Signifcant for fetus and in poisoning

Acidification or alkylation of urine can

accelerate excretion of basic or acidic drugs
that have reached toxic concentrations in
blood (respectively)

First Pass Metabolism

phenomenon where a drug is prevented from reaching the systemic
circulation due to metabolizing enzymes (especially in the GI
epithelium and liver)

Ex: Wine and cheese reaction high in tyramine normally

tyramine is metabolized by MAO, but if pt takes a MAO inhibitor,
tyramine will get absorbed and stimulate adrenergic receptors
causing tachycardia and high BP

Bioavailability
The fraction of orally given drug that reaches the circulation
= (AUC orac/AUC IV) x 100

some drugs bind to plasma proteins, displacement of a drug from

plasma protein binding generally causes no change in overall effect
except for drugs with very SMALL volume of distribution (like
warfarin, low Vd)

Distribution
The REVERSIBLE movement of a drug b/w body
compartments
Fxs affecting drug distribution
o Ionization
o Capillary permeability (in liver and spleen, they are very
leaky)
Drugs leave capillaries regardless if they are poorly lipid
soluable, large or polar
Only lipiphilic drugs diffuse across the blood brain
barrier (tight junctions) unless they are transported
across by active transport
o Blood flow
More blood flow more drug (brain, liver, kidneys >
muscle > fat)
o Plasma protein binding

Volume of Distribution (Vd) = dose administered / [plasma]

High Vd indicates that most of the drug is in the extravascular
compartment, low Vd means most is in vessels, like warfarin (99%
bound to plasma proteins
Redistribution of Drugs
Organs that are highly profused (brain and kidney) get a lot of
drug, but over time drug is redistributed to storage areas with less
perfusion (fat and muscle) removing the drug from the brain and
kidney; drug wears off
Ex: anesthetics like thiopental used to induce anesthesia, where
induction and recovery of anesthesia are rapid and lower
concentrations are given to take advantage of redistribution

Biotransformation (Drug Metabolism)

Chemical modification of drugs
Drugs metabolizing enzymes found in LIVER, GI wall, lungs,
kidneys, etc
Prodrugs are inactive, after metabolism are converted to an active form
Ex: Olsalazine for Tx of IBD, and PPI for ulcers
2 Phase Biotransformation
Phase 1/Functionalization rxns
o Oxid/reduction and hydrolytic rxns tend to make drug more
polar, but not necessarily deactivate
o Microsomal cytochrome P450 monooxygenase family of
enzymes
Oxidize drugs
Metabolize widest range of drugs, in most cases
inactivates them
o CYP Polymorphism genetic variations in population
Mutations in drug metabolizing enzymes in some pts

Most common one is CYP2D6 in Caucasians; lack this

enzyme:
Slowly metabolize b-antagonists, neuroleptics,
anti-depressents and codeine
Prone to get bradycardia during BB Tx
Codeine not good for analgesia in these pts, as it
needs to be metabolized to morphine to work
Also CYP2C9
Warfarin (also CYP1A) and phenytoin are

substrates for this enzyme

Drugs with narrow therapeutic windows must be
given with caution in these pts

o Factors Affecting Drug Biotransformation

Induction/inhibition of cytochrome P450 enzymes
Inducers expression of more CYP enzymes and
faster elimination

Lower drug levels than usual result in treatment

failure
Ex: Rifampin (Abx), St. Johns Wort
Inhibitors inhibit CYP enzymes and decrease
elimination of drugs
Higher drug levels than usual can cause toxicity
Ex: Grapefruit juice, cimetidine,
erythromycin

Phase 2/Conjugation rxns

o Conjugation to polar groups (glucuronate, sulfate, acetylate)
most result in inactivation of drug
o Conjugated drugs are rapidly excreted, and required enzymes
are usually located in cytosol
o Autosomal variations: 50% of Americans have reduced
expression of acetylating enzyme (slow acetylators)
Slowly metabolize isoniazid (TB drug), and caffeine

Significance of Drug metabolism

If a pt is taking 2 or more drugs, possibility of interactions should

be considered
When a pt is taking a single Rx metabolized by cytochrome P450
enzymes, interactions due to food or herbs should be considered
In cases of drug toxicity or treatment failure, genetic variation in
metabolizing enzymes should be considered

P-Glycoprotein
An ATP efflux pump that pumps compounds from inside to
outside
o Plays a role in drug resistance to cancer chemotherapeutic
agents
Over expressed in tumors and pumps out anti-cancer
drugs
o CCBs inhibit P-glycoprotein and may be useful to reverse
resistance

o St. Johns Wort and Rifampin induce more expression of Pglycoprotein

Also found on CNS BBB to protect it from unwanted compounds
Digoxin is transported by P-glycoprotein so inhibition of it can
elevate plasma digoxin levels to toxic range (verapamil, quinidine,
erythromycin can cause dig toxicity)

Enterhepatic Recirculation
Compound conjugated in liver, excreted in bile, deconjugated in
intestine by bacteria and reabsorbed into circulation

This phenomenon prolongs the half-life of a drug

Significance: 95% of bile acids are reabsorbed and are used in
cholesterol synthesis; bile acid binding resins like cholestyramine,
interrupts bile acid recycling and reduces cholesterol synthesis and
its level in plasma
Also, OCPs and antibiotics, abx removes intestinal bacteria,
preventing deconjugation and interrupts recycling of estrogen

Clearance

The volume of blood from which a drug is irreversibly

removed per unit of time (ml/min/kg)
o Cl = rate of constant elimination (k) x Vd
Used to calculate maintenance dose of a drug
o Maintenance dose/rate of admin = rate of elim
Systemic clearance of a drug is the sum of the clearance by all
organs (kidney, liver, lungs, etc)

Renal Clearance

Only FREE drug is filtered, not protein bound drug

Net removal = filtered + secreted reabsorbed
Creatinine Clearance
o Kidney function is usually assessed by GFR
Creatinine clearance used to estimate GFR
Creatinine plasma concentrations are stable and is
produced endogenously so doesnt have to be
administered

Freely filitered by the kidneys, not reabsorbed and

minimally secreted, therefore good to measure GFR
Urine and serum creatinine levels measured along with
urine volume in 24 to calc clearance
Clearance (ml/min) = ([Urine] (mg/ml) x Urine
flow rate (ml/min) / [plasma creatinine] mg/ml)

Drug Elimination Kinetics

First-Order
o Constant fraction of drug is eliminated per unit time

Rate of elim is proportional to plasma concentration

o Blood concentration declines in a linear fashion
o Most drugs eliminated this way
Zero-Order
o A constant AMOUNT of drug is eliminated per unit time
o Because it is the maximum rate of elimination when the
pathway for elimination is saturated

Half-Life

The time required for the plasma concentration of a drug to be

reduced by 50%
It takes about 5 half-lives for more than 90% of a drug to be
effectively eliminated from the body
If a fixed dose of drug is given repeatedly at fixed intervals, it takes
about 5 half-lives for that drug to achieve steady state plasma
concentration
o Ex: if half-life is 20 hours for a drug, it will reach steady state
in 100 hours

Time to reach steady state depends only on the half-life

t1/2 = 0.693 x Vd/Cl

Loading Dose
Dose of a drug sufficient to produce a plasma concentration of drug
that will fall w/in therapeutic window after only one or very few
doses over a very short interval. It is larger than the dose rate

needed to maintain the concentration w/in the window and would

produce toxic concentrates if given repeatedly
IV Loading Dose = (target [plasma]) x (volume distribution)
Oral loading dose = (target [plasma]) x (volume distribution) / F
o F = fraction bioavailable (0-1)

Maintenance Dose
Dose needed to maintain the given concentration w/in the
therapeutic window when given repeatedly at a constant interval
Maintenance dose = steady-state plasma concentration x

clearance of the drug

o For oral dosing, divide by fraction bioavailable
If clearance does not change, doubling the dose will double the
blood concentration of the drug
Steady State Concentration = rate of admin/clearance

Drug Development and Therapeutics

Drugs in Children

Hepatic enzymes not fully developed in infants, esp premature ones

Gray Baby syndrome side effect of IV admin of abx
chloramphenicol
o Blue discolouration of skin and lips and CV collapse
o UDP-glucuronyl transferase enzyme system of infants is
immature and incapable of metabolizing the excessive drug
load
Changes in clearance
o Clearance increases from birth till age 1, then plateaus
till puberty, decreases a bit then plateaus again in
adulthood

Drugs in The Elderly

Physiologic changes
o Reduced GI motility reduced drug absorption
o Increased body fat increased Vd

o Reduced GFR decreased clearance of water soluable

drugs
o Reduced hepatic blood flow decreased clearance of
some drugs
Drug Development
Patent life = 20 yrs
Preclinical ->Clinical ->Marketing ->Generic
QALY Quality Adjusted Life Year involves both quantity and
quality of life generated by healthcare interventions
Interchangeability
The area under the curve for the plasma concentration and
the maximum plasma concentration need to be within 80 to
125% of the original drug. Time to reach Cmax would also
be taken to account.
o Tmax and Cmax should be within 80-125% of the
original innovator drug.

Autonomics

4/21/2011 8:38:00 AM

ANS innervates smooth muscle, glands, and organs that arent

under conscious control (functions like breathing and HR, etc)
ANS divided into sympathetic and parasympathetic
o Function in parallel to maintain homeostasis
Enteric NS (ENS) considered third division of ANS and consists of
nerves innervating the GI tract, pancreas and gall bladder
o Innervated by both parasympathetic and sympathetic
o But local control seems to predominate its function
Sympathetic Preganglionic NT = Acetylcholine
Sympathetic postganglionic NT = NE
Parasympathetic Preganglionic and post ganglionic NT =
Acetylcholine
Sympathetic postganglionic fibers are longer and non-myelinated
therefore have a more diffuse effect that parasympathetic because
their postganglionic fibers are shorter and closer to effectors.
Exceptions: Adrenal medulla is innervated directly by sympathetic
preganglionic fibers, causing the release of Epi; also postsynaptic
fibers of sympathetic acting on sweat glands uses acetylcholine

Catecholamines

Biosynthesis
o From tyrosine -> DOPA -> Dopamine -> NE -> Epi
Metabolism
o Very brief activity b/c metabolized rapidly
o Circulating catecholamines metabolized by catecholamine-Omethyltransferase (COMT) to metanephrine on
postsynaptic membrane
o NE metabolized to normetanephrine
o Monoamine oxidase (MAO) converts them to VMA and
MAO is in neuronal mitrochondria
o Liver and GI conjugate them with sulfate or glucuronide and
excrete them in urine by kidney

o Levels of VMA and metanephrine provide a measure of

catecholamine production in medullary or sympathetic
system
o Uptake 1 Neuron takes up NE; Uptake 2
tissue/effector takes up NE
Physiological Actions of Catecholamines on receptors:
o A1 (IP3 pathway)
Vasc. Smooth muscle (vasocontriction); increase
TPR and BP
Nose (decongestion)
Eye (mydriasis/pupil dilation)
o A2 (decrease cAMP)
Presynaptic receptor on sympathetic nerve (decrease
NE release)
o B1 (increase cAMP)
Heart (increase HR, contractility, automaticity)
Kidney (increase renin)
o B2 (increase cAMP)
VSM (vasodilation)
BSM (bronchodilation)
Liver (glycogenolysis)
Uterus (relaxation)
Mast cells (decrease histamine release)
o B3 (increase cAMP)
Brown adipose tissue (increase lipolysis)

Catecholamines:
Agonists

Epinephrine
o A and B receptors
B1, A1, B2
o Good for emergency bronchospasm treatment (acute
asthma or anaphylactic shock) and open-angle glaucoma
o Also gives longer duration of anesthetic action via
vasocontriction and reducing systemic absorption
o Increases sBP lowers dBP

Norepinephrine
o A and B in therapeutic doses, most A receptor influence
o Good to increase peripheral resistance (A1)
o Good for shock treatment (increase TPR and BP); increases
sBP and dBP
Isoproterenol
o Synthetic: B1 and B2, little A stimulation
o Strong cardiac stimulation (b1), dilation of skeletal vessels
(b2), and bronchodilation (b2)
o Increases sBP lowers dBP
Dopamine
o Precursor to NE; A and B activity and dopamine receptors
in renal and mesenteric vasculature causing
vasodilation
o B1 stimulation of the heart
o Therapeutic: choice drug for shock as it increases BP via
cardiac stimulation and also increases kidney blood
flow (increased GFR and Na diuresis)
Dobutamine
o Synthetic B1 agonist
o To increase CO in CHF
o Watch out in Afib as it may increase AV conduction
Phenylephrine
o Synthetic A1 agonist for nasal decongestion
Methoxamine
o Synthetic A1 agonist for hTN in surgery
Clonidine
o A2 agonist
o Used to lower pressure in essential HTN (via CNS effect,
diminishing sympathetic outflow)

In-direct Agonists
Amphetamine
o A on vasculature and B on heart stimulation
o Acts via release of stored catecholamines therefore
indirect

Tyramine
o Not a useful clinical drug, but found in fermented foods (ripe
cheese and wine)
o It enters nerve terminal and displaces stored NE and may
cause vasopressor episodes

Antagonists
Prazosin, terazosin, Tamulosin
o A1 blockers
o Good for HTN, and benign prostatic hypertrophy

Propanolol
o Nonspecific BB (B1 and B2)
o Bronchoconstriction, depresses heart, decreases sBP and dBP,
decreased glycogenolysis and glucagon secretion
o Not for asthmatics/COPD or DM
o Good for lowering BP in HTN by decreasing CO
Timolol, Nadolol
o Nonspecific B1 and B2 blocker
o More potent than propanolol and longer duration of
action
o Timolol used topically in treating chronic open angle
glaucoma
Atenolol, acebutolol
o Preferentially block B1 at low concentrations w/o
blocking B2 (cardioselective)
o Good in diabetic HTN
Carvediol, Labetalol
o A and B antagonist
o Decreases lipid oxidation and vasc wall thickening
o Has some anti-arrhythmic properties

Drugs affecting NT Release

Reserpine
o Blocks Mg2+ ATP-dependent transport of biogenic amines
(like NE, dopamine) from cytoplasm to storage vesicles
in sympathetic nerves

o Therefore depletes NE stores as MAO metabolizes

cytoplasmic NE
o Slow onset and long duration of action
Guanethidine
o Blocks release of stored NE

Uptake Inhibitors
Cocaine
o Blocks Na/K ATPase which is necessary for uptake of NE
o NE accumulates in cleft and potentiates actions of NE or
epi

Increases duration of action of NE

Causes exaggerated catecholamine response
Amytriptyline
o Tricyclic antidepressant
o Prevents uptake of NE and serotonin

MAO inhibitor
Phenelzine
o Irreversibly inactivates MAO
Cholinergics:
Synthesis
Acetate + Acetyl-CoA + Choline acetyltransferase = Acetylcholine
Ach transported into synaptic vesicles by Ach-H exchanger
Uptake of choline into nerve fiber is rate-limiting step
Termination

Acetylcholinesterase cleaves Ach into choline and acetate in the

synaptic cleft
Choline taken up by a Na-coupled high affinity uptake system that
transport it into the neuron, where it is acetylated and then stored
until released by subsequent action potential

Receptors
M1 Neural (CNS, parietal cells)

M2 Cardiac (SA/AV nodes), presynaptic ganglia

M3 Glandular/Smooth muscle (secretion and contraction of
visceral smooth muscle)
M4, M5 CNS
Nicotinic Ganglionic and NMJ

Muscarinic Agonists
Acetylcholine
o M (M2, M3) and N activity
o No therapeutic importance due to multiplicity of action and

rapid inactivation
Carbachol
o Carbamic acid ester of Ach
o M and N activity
o Poor substrate of AChEsterase
o Rarely used therapeutically, except in glaucoma for pupil
constriction
Pilocarpine
o Alkaloid containing tertiary amine resistant to AChEsterase
o
o
o
o

Less potent than Ach

Muscarinic activity
Causes miosis
Drug of choice for both closed and open-angle
glaucoma (cause opening of canal of schlemm thus dropping
intraocular pressure by increased drainage of acqueous
humor); timolol (B1 blocker used in chronic treatment)

Muscarinic Antagonists

Atropine blocks all muscarinic receptors

Scopolamine
o For motion sickness
Cholinesterases:
Acetylcholinesterase specific for ACh
Butyrylcholinesterase non-specific, in plasma and other tissues
Anticholinesterases:

Effects are due to enhancement of cholinergic transmission at

autonomic synapses and at NMJ
Short acting Edrophonium used in Dx of myasthenia gravis
Reversible:
o Physostigmine
Duration 2-4 hours
Can cross blood brain barrier and stimulate
cholinergic sites of CNS (increase intestinal and
bladder motility; good for atony of either organ)
o Neostigmine
Synthetic, more polar so doesnt get to CNS like
physostigmine
Shorter duration (30 min)
For Sx Tx in myasthenia gravis
Pyridostigmine for chronic Tx of myasthenia
gravis (longer activity, 3-6 hours)
Irreversible:
o Organophosphate compounds, bind covalently with AChE;
long lasting increase in Ach

o Many are highly toxic and are used as nerve agents

o Ex: Isoflurophate aka DFP (diisopropylflurophosphate)
Pralidoxine can reactivate AChE but it cant get into
CNS; but has to be given before the aging of
DFP; once DFP ages, its hard to break the bond.
Neuromuscular blocking drugs
Block choline uptake:
o Hemicholinium, trieythlcholine (neither used clinically)

Block ACh release:

o Aminoglycoside antibiotics, botulinum toxin
Nondepolarizing and depolarizing drugs
o Non-depolarizing block is reversible by
anticholinesterases; depolarizing is not
Tubocurarine (Non-depolarizing)
o Reversible by high conc ACh or antiAChEs like neostigmine

o Small rapidly contracting muscles (like face and eye) are

most susceptible to blockade
Succinylcholine (depolarizing)
o 2 phases of activity
1 succinylcholine binds, resulting in initial
depolarization causing transient fasiculations then
flaccid paralysis
2 membrane repolarizes but receptor is now
desensitized to effects of ACh
o no ganglionic block unless at high doses
o used when rapid tracheal intubation required to induce
anesthesia (avoid aspiration of gastric contents)
These are drugs used to cause paralysis during anesthesia
(Succinylcholine and tubocurarine)

Ganglionic Stimulators:
Nicotine
o Stimulatory at low conc., blockade at high concentrations
o No therapeutic uses
DMPP
Ganglionic Blockers:
Block nicotinic receptors on sympathetic and
parasympathetic autonomic ganglia
Nicotine
Hexamethonium
Trimethaphan, Tubocurarine
o The above block ALL autonomic and enteric ganglia
hTN and loss of CV reflexes, inhibit secretions, GI

Drug Review:
Catecholamines:

paralysis, impaired micturition

Clinically obsolete

Agonists
Epinephrine a1, b1, b2 good for anaphylactic shock; increase sBP,
decrease dBP
Norepinephrine a and b, mostly a1 at therapeutic doses increase TPR,
sBP and dBP increase
Dopamine a and b, also d1 d2 (dopamine receptors) for shock b/c also
vasodilates renal vasculature
Phenylephrine a1 for nasal decongestion
Methoxamine a1 prevent hTN in surgery
Dobutamine b1 for HF
Clonidine a2 for essential HTN, decreases sympathetic outflow
Salbutamol/salmeterol b2 bronchodilators
Indirect agonists
Amphetamine release of stored catecholamines (a and b)
Tyramine displaces stored NE (wine and cheese)
Antagonists
Phentolamine a1 and a2 competitive antagonist postural hTN
Phenoxybenzamine nonselective a noncompetitive antagonist
pheochromocytoma (catecholamine secreting tumor in adrenals); given prior
to surgical removal
Prazosin, terazosin, tamsulosin a1 blocker for benign prostatic
hypertrophy, hTN
Propanolol nonspecific b blocker for HTN by decreasing CO, glaucoma,
migraines, hyperthyroidism, angina, MI prophylaxis; not for
asthamtics/COPD or pts with DM; withdrawal syndrome
Timolol/Nadolol nonspecific b blocker more potent than propanolol; for
open-angle glaucoma
Atenolol/Acebutolol b1 blocker cardioselective, lower BP in HTN; good for
diabetic HTN
Carvediol/Labetalol a/b blocker decrease BP and lipid oxidation and vasc
wall thickening
Butoxamine b2 blocker
Drugs affecting NT release/uptake:

Reserpine blocks transfer of catecholamines into storage vesicles, gets

broken down by MAO.
Guanethidine blocks stored NE release
Cocaine blocks NE uptake 1; increases NE duration of action
Amitriptyline inhibits NE and serotonin uptake antidepressant
Phenelzine MAO inhibitor
Mixed-Agonist:
Ephedrine causes release of NE and also stimulates sympathetic receptors
on post-synaptic

Cholinergics:

Cardiovascular Drugs

4/21/2011 8:38:00 AM

Regional Ischemia
Double Product
o Exercise tolerance test, pt runs on treadmill until they get
angina
o Double product is a clinical index of myocardial O2
demand/consumption
o Double Product = HR x sBP

Angina
o Exertional/Stable CP on exertion or excitement,
depression of ST segment
Stable Angina occurs at the SAME double product
o Variant CP resting assoc with ST elevation
Due to spasm of coronary artery
Angina occurs at variable double products
o Unstable change in character, freq, and precipitating
factors in patients with stable angina, and when there
is pain at rest
Signals impending MI

Determinants of O2 supply/demand
o O2 Supply
Diastolic perf pressure
Coronary vasc resistance
O2 carrying capacity
o O2 Demand
Wall tension
HR
Contractility

Aims of Therapy
o Decrease O2 demand (same double product)
Most drugs we have decrease O2 demand
o Increase O2 supply (higher double product)

Anti-Anginal Drugs
Nitrates
o Liberation of NO

o Cause venodilation, decrease VR and ventricular filling

pressure and wall tension; therefore decrease O2
consumption
o Problem with Tolerance fix with intermittent
administration (patch 12hrs on 12hrs off)
o Often offered sublingually or transdermally
Beta-Blockers
o Reduce myocardial O2 demand by decreasing HR and
contractility; blocking B1
o Contraindicated in variant angina, good for chronic
prophylaxis of stable angina
Calcium Channel Blockers
o All existing CCBs block L-Type channels
o 1st Generation; 3 Classes:
Phenylalkalamines (ex: Verapamil)
Benzothiazepinones (ex: Diltiazem)
Dihydropyridines (ex: nifedipime)
Less depressant activity on heart than the
other 2

Assoc with reflex-tachycardia from

baroreceptors
Problem in pts with angina

Intermittent Claudication
Vasodilators and BBs contraindicated
Pentoxiphulline reduces blood viscosity and thus
resistance and improves blood flow to ischemic area
Antihypertensives

Essential/Primary HTN due to unknown factors

Secondary HTN due to known cause
BP = CO x TPR
Labile HTN BP elevated b/c of increased CO
Established HTN BP elevated b/c of increased TPR

o Eventually in labile HTN, increased CO causes over perfusion

of tissues causing autoregulation and subsequent increase in
TPR (evolution to established to HTN)
o Possible causes for increases in CO in labile HTNs
Increased contractility
Increased venous return (decreased venous
capacitance, increased plasma volume)
Increased HR
Control of BP
o Short term sympathetic NS, RAAS, ADH system,
endothelin, etc
o Long-term kidney fluid and electrolyte balancing

Anti-HTN Rx

Diuretics: Thiazide and Thiazide-like Diuretics

o Decrease BP by decreasing blood volume and venous
return; this causes underperfusion of tissues (decrease CO)
and causes autoregulatory vasodilation and decrease in
TPR
o 50% of patients do not respond to these diuretics, they
tend to have exaggerated activity of RAAS system
o Adverse effects
K+ depletion
Lipid hostile
Impaired glucose tolerance
o Often used in combo with other anti-HTN to prevent the
increase in plasma volume as a result of the other drugs

o Used for HTN

Beta-Blockers (Propanolol, acebutolol, atenolol)
o Initially reduce CO but long term reduce TPR
Block renin release
Decreases SNS activity
Peripheral pre-synaptic inhibition of NE release
from sympathetic nerve terminals

o BP lowering effect more pronounced in pts with normal

or high renin activity; but in those with low renin, a BB
+ a diuretic is good
o Adverse effects
Lipid hostile (increase plasma TAGs, and reduce
HDL-cholesterol)
Withdrawal syndrome (tachycardia, increased BP,
severe angina, and sometimes MI)
b/c upregulation of B-receptors
Alpha1-Blockers (Prazosin, Tamulosin)
o Dilates resistance vessels and capacitance vessels
b/c they dilate capacitance vessels they reduce BP more
in standing position than in supine
adverse effects
Postural/orthostatic hypotension
(venodilator)
Commonly on first dose
Vasodilators
o Hydralazine, Minoxidil
Weak anti-HTN b/c of reflex increase in CO (b/c
reflex venoconstriction, sympathetic increase in renin.
Adding a diuretic and a BB will block the changes
above
o CCBs (Nifedipine, verapamil, dilitiazem)
Less of a problem with RAAS compensation than with
BBs
Good in elderly and preferred over BB and ACE-Is
o ACE-Inhibitors

Block formation of ANG II, and secondarily b/c it

potentiates bradykinin
Severe hTN can occur in hypovolemic patients and
cause renal failure in patients with renal artery
stenosis
Adverse Effects:
Cough, could be b/c of higher bradykinin
o ANG II Antagonists

Share common effects and adverse effects of ACEIs

Not assoc with cough

Heart Failure
Most common causes are HTN, CAD and Diabetes

Drugs to Decrease Preload

o Diuretics, venodilators
Help reduce congestion in HF

Drugs to Increase Contractility

o Digitalis glycosides
Inhibition of Na/K ATPase
Favors increased movement of extracellular
Ca2+ into the cell
Direct increase in automaticity, decrease in conduction
velocity and shorter refractory
Indirect vagal effect reducing conduction
through AV node
Protects ventricles from A-fib (a therapeutic
use for dig)
Narrow therapeutic window
Problem with toxicity, esp in pts in renal
failure
Hyperkalemia exacerbates dig toxicity
Drug is cleared primarily by the kidneys, half-life
~40hrs
Drugs to Decrease Afterload

o Prazosin A1 blocker
o Hydralazine dilates resistance vessels not capacitance
vessels; decreases TPR but causes reflex increase in CO
These 2 drugs increase CO by decreasing afterload
o ACE-Is
Decrease afterload and preload, but increase in
CO due to reduction in TPR
o BBs

Prevent cardiac remodeling from sympathetic

stimulation
o Aldosterone Receptor Blockers aka Spironolactone
K+ sparing
SEs - gynecomastia

Antiarrhythmics

Phase 0 in myocytes due to Na influx, in nodal cells due to

slow Ca2+ influx

The number of Na channels open and therefore the slope of 0

is decreased and the recovery time is increased as the cell
becomes more depolarized
o Antiarrhythmics often exaggerate these

Antiarrhythmics drugs
o Class I Na+ Channel Blockers (ex: Quinidine)
Have a greater effect when cells are depolarizing
rapidly b/c these cells spend greater time in

activated and inactivated states than in resting

state
Also true in ischemic tissues
Reduce slope of phase 0
b/c they depress conduction in areas with already
depressed conduction (ischemic areas) they make
a bidirectional block -> abort reentry b/c it needs
unidirectional block
In Afib, quinidine has atropine like effects (M

blocker) and increase conduction through AV

node and worsen ventricular rate
Therefore before giving quinidine, give
digitalis, its indirect effect on AV node will
protect the ventricles from high atrial rate
o Class II BBs
More effective in conditions with high sympathetic
activity

o Class III K+ Blockers (ex: Amiodarone, sotalol BB with

class III activity)
Prolong QT interval
Can lead to TdP
o Class IV CCBs
Drug of choice for SVTs
Recall verapamil (phenylalkalmine) and diltiazem
(benzothiazepine) are more affect on cardiac
tissue than vascular tissue
Nifedipine (dihyrdopyridine) more effect on
vascular; also reflex baro-receptor tachycardia

Drugs Affecting the Lung or the Kidney

4/21/2011 8:38:00 AM

KIDNEYS!
Classes of Diuretics & Site of Action

Carbonic Anhydrase inhibitors (Acetazolamide) PCT

o Prevent HCO3- formation, increased bicarb excretion ->
meta. Acidosis (low pH with low plasma HCO3-)
o Less bicarb formed means less H+, preventing Na+
reabsorption in PCT
Distal channels get more Na and pump out more K+
o Therefore Weak natriuresis, hypokalemia + meta.
Acidosis
o Used in glaucoma
Loop Diuretics (furosemide) ThickAHL
o Reduced Na/K/2Cl reabsorption
Distal channels get more Na and pump out more K+
Na+, K+, Cl-, H+ loss
Bicarb retention
Decreased Ca2+ reabsorption
o High ceiling natriuretic, hypokalemia, hypochloremia,
meta. Alkalosis (high pH with high plasma HCO3-)
o For CHF and hypercalcemia
Thiazide Diuretics (Hydrochlorothiazide/HCTZ) early DCT
o Reduce NaCl reabsorption
Distal channels get more Na and pump out more K+
Na+, K+, Cl-, H+ loss; bicarb retention
o Similar to loop diuretics, a bit less natriuresis, also uric
acid retention; b/c they use the same transporter
o For HTN
Potassium sparing diuretics (spironolactone) late DCT
o Aldosterone antagonist
o Reduce Na-K, H+ exchange
Na+ loss, K+ and H+ retention
o Weak natriuresis, hyperkalemia and acidosis
o Also reduces androgen activity (blocks androgen
receptors and inhibits 5alpha-reductase)

Side effect = gynecomastia

o Usually used w/ other diuretics, and with digoxin to
prevent hypokalemia
Osmostic diuretics (mannitol) in DLoH
o Osmotic diuretic
o Prevent water reabsorption in PCT and DLoH
o For cerebral edema/to decrease intracranial pressure
ADH antagonists (lithium, demeclocycline) Collecting Duct
o Used is chronic SIADH (Syndrome of Inappropriate
ADH secretion)

Uses of Diuretics:
Thiazides and loop diuretics to decrease volume, preload
thereby decreasing CO (for CHF and HTN)
Spironolactone prevent or treat low K+
CA inhibitors not used as diuretics but in glaucoma (reduce
intraocular pressure)
Uses lowest dose!... Why?
o b/c of starlings law of heart (increasing preload too much
eventually overwhelms the heart, decreasing CO)
o and b/c low K+ can cause death!
Tolerance to Diuretics
Reasons:
o Reduced GFR (b/c volume depletion)
o Increased Na reabsorption in unaffected sites of tubule
o Increased RAAS
Overcoming tolerance:
o Increase dose
o Reduce Na/H2O intake
o Add another diuretic
Respiratory!
Functions of Resp System
Maintains PO2 and H+ (via PCO2)

o H+ = 25 x PCO2/HCO3Protection from irritants

Hypoxic vasoconstriction to prevent V/Q mismatch
(redirecting blood from poorly ventilated parts of lung)

Cough Suppressants
Opiates (Codeine, morphine) suppress cough
o Use lower doses than ones for analgesia
Dextromethorphan not an opiate, for OTC use
Recall, ACE-I side-effect is cough
Asthma
Recurrent SOB, cough, wheezing (exhalation)
o Due to small airway narrowing b/c of bronchospasm,
edema and mucus (obstruction)
o Airway inflammation (inflammatory cells and mediators)
People with methylcholine sensitivity tend to get asthma
Measurements in Resp Medicine:

Peak Expiratory Flow Rate (PEFR)

o <200L/min is bad
FEV1/FVC
o <70% = obstructive

Drugs Used in Asthma

Beta2 Agonists
o Bronchial smooth muscle relaxation (via increased cAMP
and reduced [Ca2+]intra)

o Most common for asthma

o Inhaled or systemic
o B2 and some B1; also stimulate receptors in other sites (side
effects: tachycardia, etc)
o Salbutamol (short), Salmeterol (long-acting); albuterol
Methylxanthines (Theophylline)
o Bronchodilator

Lots of actions (adenosine antag, phosphodiesterase

inhibit., NE release, stim CNS resp center to increase
RR)
o Low Therapeutic Index
o Less effective in asthma than B-agonists, additive effect
o Good for COPD with Bronchospasm
Muscarinic Antagonists (ipratropium)
o Block M3 on bronchial smooth muscle
o Inhaled
o Additive effect with B-agonists; as good as beta2

agonists in COPD w/ bronchospasm

Leukotriene Receptor Blockers (montelukast)
o Blocks LTD4 receptors
o Steroid sparing
o Oral only
o Good for aspirin induced asthma
Not as good as B2s, or steroids for asthma
Release Inhibitors (cromolyn, nedocromil)
o NOT BRONCHODILATORS
Hyperpolarize cells (vagus nerves and mast cells)
preventing release of mediators
Inhaled only, can cause bronchospasm
For allergic rhinitis, conjunctivitis
Corticosteroids
o Reduce # of inflamm cells and inhibit release of
cytokines
o Not bronchodilators
o Take longer to act

o Systemic initially, topical later

o Lowest dose possible
Oral candidiasis (Thrush)
o Inhibits growth in kids

Pharmacology of Anesthesia

4/21/2011 8:38:00 AM

Local Anesthetics
Types:

Esters
o Cocaine, benzocaine, etc
o Hydrolyzed by esterases (broken down quick in the blood
and tissues)
o Allergic reactions
Safe to give amides if allergic to esters
Amides
o Lidocaine, Bupivicaine, etc
o Metabolized by microsomal enzymes (liver)
Slower therefore systemic toxicity more likely
than esters
Way to distinguish the 2:
o Amides have an I in prefix, prior to the caine

Mechanism of Action:
Prevent conduction of AP
o Block Na channels from intracellular side (when drug is
in protonated form)
o The non-protonated form allows it to enter axon
Factors affecting Local Anesthetic Action
pH
o Acidosis
Acidic environment protonates drug and reduces
ability to enter nerves

Ex: Infection
o Alkalosis
Adding HCO30, favors non-protonated form
increasing drug uptake into nerves
Lipid Solubility
o Lipid soluable/high protein binding longer acting
o Less lipid soluable/less protein binding shorter acting
Blood flow

o To and from site

o Vasoconstrictors prevent systemic absorption +
vasodilation; makes drug stay around longer; so you
can get away with lower doses of anesthetic
Ex: Epinephrine
Misc.
o Bulk flow
o Diffusion
o Non-specific binding

Nerve Fibers & Local Anesthetics

Small axons > large w/ regards to sensitivity
o Pain > temp > touch/pressure > motor (size of axons)
o Allows for concept of differential blockade
Ex: epidural local anesthetic giving in dilute
concentration that only affects the small pain fibers;
leaving motor intact (epidural during labor)
o Rapidly firing axons more sensitive than slow ones
o Myelinated more sensitive than non-myelinated
o Large nerve trunks
When given, anesthesia works proximally first
and spreads distally
Adverse Effects
Amides > esters b/c of difference in metabolism
CNS
o Dizziness, seizures, coma
CV

o Heart depressed, vasodilation, arrhythmias

Toxic range is different for diff anesthetics
See H&N Sxs first because they get a lot of blood
Tx:
o ABCs
o Raise seizure threshold (benzodiazepines, hypervent)
o Supportive
O2, secure airway

Support circ. If CV effects

Lipid emulsion/albumin to bind excess

Clinical Applications of Local Anesthetics

Less disturbance with co-existing diseases than with general
anesthetic
Less systemic effects (resp, CV)
Good for post-op analgesia
Cheap
Good outcomes
Techniques
Topical (skin: EMLA, wounds: TAC)
Infiltration (injection)
Peripheral nerve blocks (specific nerve blocks or plexus)
o Surgeons often do these
Intravenous Regional Anesthesia
o Ex: Tourniquet on arm to stop blood flow and give high
volume local anesthetic for hand surgery

Neuaxial anesthesia
o Epidural, spinal
Intravenous
o Continuous throughout surgery
Results showed decreased narcotic use postsurgery
o Danger of systemic toxicity

General Anesthesia
Consists

of:
Inhaled agents (sevoforane, nitrous oxide, halothane)
Induction/IV agents (Pentohal, Propofol)
Benzodiazepines (Lorazepam, diazepam)
Opiods (Demorol, morphine)

Muscle Relaxants (depolarizing/non-depolarizing) recall,

neuromuscular blockers from Autonomics: tubocarine,
succinylcholine
o Depolarizing succinylcholine (irreversible)
o Non-depolarizing pancuronium (reversible)
Reversal drugs
o NM reversal (neostigmine) Anti-Ch-E
o Benzodiazepine antag (anexate)
o Opiod antag (Naloxone)

GOALS of General Anesthesia

Amnesia/Hypnosis
o Impaired perceptive awareness/dont remember
anything
Inhalants and benzos
Analgesia
o Lack of pain
Narcotics, opiods
Akinesia

o Loss of movement
Muscle relaxants
Control physiological parameters
Goal is to control the first 3 factors and blunt sympathetic
responses to adverse stimuli during procedures
o If patient is not deep enough, will see sympathetic
responses (increase HR, rise/drop in BP, etc)

Balanced Technique

One agent can achieve all goals, so use a combo of inhaled

and IV agents

Mechanism of Action of Inhalational Agents? -> We dont really know!

Minimum Alveolar Concentration (MAC)
Miminum alveolar concentration at 1 atm that causes
immobility in 50% of patients exposed to a noxious stimulus

o Considered a measure of potency

o 1.3 MAC = 95% of pts are immobile
o MAC values for gases are ADDITIVE
Add MACs together for multiple drugs, gives you
an idea of the depth of anesthesia
Ex: nitrous oxide (1 MAC = 104%); Desflurane (1 MAC = 6.0%)
o so you need A LOT of nitrous to get to 1 MAC, so its not good
for general anesthesia
Factors affecting MAC:
o
o
o
o

Age (younger people tend to need more)

Temperature (colder need less)
Pregnancy
Extreme physiological states (hTN, acidosis, etc)

Pharmacokinetics
Concentration Gradient
o Delivered > inspired > alveolar > arterial > brain
Factors:
o Inspired concentration of drug (how much you gave)
o Alveolar ventilation (pts breathing or if you ventilate them
with positive pressure)
o Solubility (decreased solubility means faster onset of
anesthesia)
o CO (low CO makes it easier to saturate blood with drug,
better transit time)
o Pa-Pv gradient
Systemic Effects of Inhaled Anesthetics
Resp
o Rapid shallow breathing (decrease TV, increase RR)
o Decrease drive to breathe (blunted bodys response to
higher PCO2)
o Bronchodilation! (sometimes given to asthmatics who
arent responding to other Rx)
CV

o
o
CNS
o
o

Vasodilation (hTN)
Decrease CO (decreased contractility and BP)

Decreased cerebral metabolic rate and O2 demand

Increased cerebral blood flow
Cerebral vasodilation
Also Renal, hepatic, uterus etc
Malignant Hyperthermia
o Autosomal dominant hypermetabolic disorder
When exposed to certain gases, every cell in body
goes hyperactive; bad prognosis

4/21/2011 8:38:00 AM
Anticoagulants
Maintenance of blood fluidity
Balance b/w
o Procoags:
Thrombin (factor II)
Tissue factor (extrinsic pathway)
Thromboxane (from arachidonic acid,
vasoconstrictor, from plts)
ADP (from act. Plts, plt aggregation)
o Anticoags:
Heparan sulfate (on endothelium, potentiates
antithrombin III)
Prostacyclin (from arachidonic acid)
Nitric Oxide
Drugs:

Antiplatelet
o Aspirin/ASA

Works on Cyclo-oxygenase (AA -> thromboxane)

Low dose (80-160 mg/day) irreversibly inhibits plt
COX, and they cant make new COX b/c they have
no nucleus
Some inhibition of endothelial COX but not much,
therefore prostacyclin (anti-coag) synthesis isnt
affected much
Benefit is greater after thrombolysis
SE is bleeding

Prophylaxis for MI or TIA (80mg/day), higher

doses for post-MI/TIA (160-325mg/day)
Contraindications (bleeding risk):
Vit. K def., Hemophilia,
Hypoprothombinemia, pregnancy & childbirth
o Clopidogrel/Plavix
ADP antagonist

Competes with ADP for P2Y receptor

(prevents lowering of cAMP)
Less incidence of neutropenia/thrombocytopenia
Used in combo with ASA
o Ticlopidine
ADP antagonist, prodrug
Often used in combo with ASA (synergistic)
May cause severe neutropenia (1%)
o Dipyridamole
phosphodiesterase inhibitor (prevents cAMP

breakdown)
o GpIIb-IIIa inhibitors
Eptifibatide, Abciximab, Tirofiban
Block the receptor for fibrinogen blocking plt
aggregation

Heparin (& derivatives)

o Stimulates natural anticoags (antithrombin)
o Heparin

Monitor using aPTT (add negative charges)

Negatively charged, therefore cannot cross
membranes (given IM, IV, parentally)
Good for pregnancy
Eliminated by RES & macrophages
Potentiates AT III (in the plasma) inhibits IIa,
Xa, IXa and VIIa
Toxicity hemorrhage
Antidote protamine sulfate (1mg for every
100 units of heparin)
Heparin-Induced Thrombocytopenia (HIT)
occurs 5-10 days after, stop heparin immediately;
use alternatives lepirudin/danaparoid
Good for PE and DVT and during pregnancy

o LMWH better bioavailability, can be given subcut.

w/o lab monitoring as outpatient, less risk of bleeding

More expensive, not good in renal failure, not for

pregnancy
DOES NOT inhibit IIa (but inhibit Xa)
Good for DVT, PE and UA
o Danaparoid promotes inhibition of Xa by AT (for HIT)
o Lepirudin direct thrombin inhibitor (for HIT)

Coumarin (Oral) anticoags

o Warfarin
Monitored using PT (add tissue factor)

Inhibit Vit. K Epoxide reductase in liver

Prevents carboxylation of Vit.K dependent factors
Takes 4-5 days to get effective (carboxylated fxs
in plasma need to be cleared before inactive ones
take over)
Small volume of distribution, steep dose-response
curve (small therapeutic window)
Teratogenic
For DVT and PE, prosthetic heart valves or Afib, MI
Metabolized by CYP1A and CYP2C9
Efficacy measured by INR, pts PT time divided by
PT time in pooled plasma
INR = (PTpt/PTref)^ISI (target is 2.0 3.0)
Warfarin overdose
Give Excess Vit.K, goes through a diff
enzyme that isnt inhibited by warfarin
(Diaphorase)

Fibrinolytics (lyse formed thrombi)

o Streptokinase turns plasminogen -> plasmin
Plasmin breaks down fibrin (lysis of formed clot)
Dissolves clots post-MI/DVT/PE
SE bleeding (systemic plasminogen activation),
allergy, hTN, fever
Streptokinase has an additive effect with ASA

o Tissue plasminogen activator (tPA) acts on fibrin and

circulating plasminogen -> plasmin
Less systemic plasmin
Same indications as streptokinase
More expensive
Hyperlipidemia & Obesity
Lipid Cycling:
Dietary fat + cholesterol in GI -> chylomicrons cleaved by

LPL in plasma into FFAs (used by muscle or stored in

adipose) and remnants broken down by liver.
Liver -> VLDL -> IDL -> LDL (Apo B)
o 75% of plasma LDL cleared by liver through LDL
receptors

Lipoprotein particle structure:

Apoprotein ligand for receptors
Hydrophobic core TAGs and cholesteryl esters

Outer layer phospholipids & free cholesterol

HDL = 20% cholesterol

LDL = 60% cholesterol
Hyperlipidemia
Risk factors for CV dz:
o High LDL, total cholesterol, total cholesterol/HDL, high 1/HDL
Macrophages take up LDL and form foam cells and

atherosclerotic lesions
HDL picks up cholesterol from cells and takes it back to liver
(reverse cholesterol transport)
o High HDL Protective, low HDL is atherogenic

Synthesis and Metabolism of Cholesterol

Made from Acetyl-CoA -> HMG-CoA and HMG-CoA reductase > mevalonate -> Cholesterol

Drugs:

Cholesterol incorporated into bile acids and into GI and

reabsorbed (enterohepatic recycling)
Also used for hormone synthesis

Statins
o Most effective and best tolerated for hyperlipidemia
Except when LDL receptor is dysfunctional
o Inhibits HMG-CoA reductase (helps with cholesterol
synthesis)
Reducing cholesterol and VLDL (and subsequent LDL) in
the liver
o Ex: Atorvastatin, simvastatin
o Statins inhibit cholestrol synthesis, but liver needs it so
it increases LDL receptors and picks up more
cholesterol reducing its plasma levels
o other protective effects:
increase NO
plaque stability

anti-inflammatory
decrease LDL oxidation (form macrophages take
up)
reduce plt aggregation
Given at bedtime (most cholesterol made b/w midnight
and 2am), not with bile-acid binding resins
Do not use during pregnancy/breastfeeding
Extensive first pass metabolism
Work better in combo with bile-acid binding resins,

o
o
o
o

fibrates or niacin
o Side effects:
Hepatotoxicity check ALT (alanine
aminotransferase)
Myopathy when other drugs metabolized by CYP3A4
are given (erythromycin, azole antifungals,
cyclosporine)

Fibrates (Gemfibrozil, Bezafibrate)

o Work via transcription factor receptor (Peroxisomal
proliferation activated receptor; PPAR-a)
Increase LPL activity, decrease TAG/VLDL synthesis,
etc
o Primarily in liver and adipose tissue
o Better absorbed with meals
o Fibrates + statins = myopathy (so monitor with CK,
myoglobin)
o Not for kids, pregos, and breast-feeders; renal failure or liver
disease

Niacin (Nicotinic acid)

o Water soluable B-complex vitamin
o Cofactor for many rxns
o Best agent to increase HDL (30-40%)
Also reduces TAGs and LDL
o Lots of side effects that decrease pt compliance
Flushing (give ASA)
Dyspepsia/indigestion (take after meals)
Hepatotoxicity
Not for pregos -> birth defects; or pts with peptic ulcer
or gout
o Binds receptor in adipose, reduces breakdown of TAGs
and release of FFA to liver, thereby reducing TAG/VLDL
synthesis in liver. Also decreases HDL clearance in liver
o Statins + niacin = myopathy (monitor)

Bile Acid Binding Resins (Cholestyramine, colestipol)

o Decrease reabsorption of bile acids
o Positively charged molecules that bind neg charged bile
acids
o Liver has to make new ones, therefore lowers plasma
cholesterol by increasing LDL receptors
o Safe b/c not absorbed (stays in GI lumen)
o Only one recommended for children

o Not used in patients with hyper-TAG-emia

o Side effects:
Inhibits absorption of lipid soluable vitamins (AEDK)
and drugs
Bulk of resins = discomfort bloating and dyspepsia
Suspend resin in liquid before ingestion

Ezetimibe
o Prevents absorption of dietary cholesterol from the
intestines
o Not a bile acid bind resin

Obesity
BMI = kg/m^2 (N 20-25, obese > 30)
Waists: Male > 100cm or female > 90cm
Higher risk of DM, MI and HTN
Anti-Obesity Drugs
Orlistat (xenical)

o OTC drug, for Tx of obesity, not to decrease cholesterol

o Inhibits pancreatic and intestinal lipases in GI lumen
(safe)
Inhibits breakdown of dietary fat
Prevents FA absorption by 30%
o Side effects:
Bloating, oily spotting, fecal urgency
Vitamin deficiencies (AEDK)
Sibutramine
o Anorectic decreases appetite
o Inhibits reuptake NA, 5-HT, and dopamine; increasing
their concentrations in the brain
Activates sympathetic system, higher
metabolism?
o Side effects:
Dry mouth, headache, constipation, increased HR and
BP (related to dose)

Rimonabant
o Anorectic, not approved here yet
Symlin (Pramlintide)
o Analogue of Amylin, secreted by pancreas after eating
Delays gastric emptying and causes satiety
o Given to DM pts
Leptin
o From adipocytes as they stores fat (also placenta, stomach)
o Release also stimulated by insulin
Leptin receptors in hypothalamus
Decreases neuropeptide Y, causing decrease
hunger and food intake
Results in higher energy expenditure
and lower energy intake (weight loss)
Also reduces size and # of adipocytes
Also increases GnRH secretion (increased LH/FSH)
Explains why anorexics can get infertile
o Most obese patients are resistant to leptin

Module 8 Antibiotics & Antifungals

4/21/2011 8:38:00 AM

Ideal Drug
Selective toxicity
o High LD50, vs MIC and/or low MBC
Bactericidal/Bacteriostatic
Favorable pharmacokinetics
o Reach target site with effective concentration
Spectrum of activity
o Broad vs narrow
Lack of side-effects
o Therapeutic Index = LD50/ED50; therefore higher is better

Little resistance development

Antibiotic
Product produced by a microorganism or by chemical synthesis,
which in low concentrations inhibits the growth of other
microorganisms
o Old antibiotics were not chemical/synthetic, only products of
microorganisms
Mechanism of Action
Inhibit/Damage cell wall (Penicillins, Cephalosporins,
Carbapenems, monobactams, bacitracin, vancomycin)
Inhibit/damage cell membrane (Polymyxins, amphotericin
B)
Disrupt nucleic acid synthesis/metabolism (quinolones,
rifampin, nitrofurantoins)
Disrupt protein synthesis (Macrolide, Tetracyclines,
Chloramphenicol, Aminoglycosides, Clindamycin, linezolid)

Disrupt energy metabolism (ex: Folic Acid TMP-SMX;

dapsone, isoniazid)

Bacteriostatic

Bactericidal

Sulfonamides
Trimethoprum
Choramphenicol
Tetracycline
Macrolides/Erythromycin

Quinolones
Penicillins
Cephalosporins
Most Aminoglycosides

Fluoroquinolones and aminoglycosides have more killing at higher []

and have a post-antibiotic inhibitory effect (beyond the MIC)
o Means their action continues past their -life; they can be
administered less frequently
Beta-lactams dont have concentration-dependent killing or postantibiotic effect

MIC Minimal inhibitory concentration

Use un uncomplicated infection where host immunity can help
eliminate the microorganism
Peak [ ] of the drug at the site of infections should be at least 4X
the MIC
MBC Minimal bactericidal concentration
Neutropenic patients

Infection is in an area protected from host immunity (CSF, brain,

eye prostate)

Pharmacokinetic Factors in IV-administered drugs (determine the amount of

antimicrobial that reaches the extravascular tissues or fluids where the
infection is):

Concentration (gradient b/c plasma and target tissues)

Degree of drug binding to plasma and tissue proteins
Molecular size

Ionization
Lipid soluability
Rate of elimination/metabolism of drug

Special Cases:
These require usually higher concentration antibiotics for
longer periods:
o Abscesses

o Endocarditis
o Osteomyelitis
o Mycobacterium infection
Host Factors:
Allergy
Age
o Ex: Tetracyclines stain growing teeth and bone
o Declining renal function in elderly
o Sulfonamides in newborns CNS disorder

Renal Function adjust dosage for aminoglycosides, vanco,

penicillins, cephalosporins, carbapenems, quinolones
Hepatic Function adjust dosing of chloramphenicol, macrolides,
rifampin
Pregnancy
o Almost all antimicrobials cross the placenta to some
degree; greatest risk in first trimester
Genetic/Metabolic Factors
Host defenses
o Bacteriostatic agents in often ineffective in
neutropenic/immunosuppressed hosts

Reasons

for using >1 antimicrobial agent in a patient:

Life-threatening infection
Polymicrobial infection
Achieve synergy
Prevent resistant strains
Permit lower dose of one of the antimicrobial agents

Synergistic effects have been documented for 3 combos of antibiotics:

Ampicillin + Gentamicin (cell wall inhibitor + aminoglycoside
protein synthesis inhibitor)
Trimethoprim + Suflamethoxazole (sequential steps of a
metabolic pathway)
Amoxicillin + Clavulanate (b-lactam + lactamase inhibitor)

Antibiotic Resistance
Intrinsic or acquired
o Intrinsic ex: Pseudomonas aeruginosa intrinsically resistant
to many b/c they cant cross outer membrane or bind target
sites
o Acquired
Mutation
New genes
Exchange of genetic information b/w bacteria
Mechanisms of Resistance:
Altered receptors/targets drugs cant bind
Decreased rate of entry or increased rate of removal of drug
Enhanced destruction/inactivation of drug
Resistant metabolic pathways
Antibiotics
Bacterial Cell Wall Inhibitors

B-lactams (bactericidal)
o Penicillins (amoxillicin, cloxacillin, penicillin, oxacillin,
methacillin)
o Cephalosporins
o Carbapenems
o Monobactams
o Glycopeptides

B-lactamase inhibitors
o Often given with penicillins
Clavulanate
Tazobactam
Cephalosporins
o 1st do not enter CSF
Cefazolin moderate spectrum
o 2nd

Cefuroxime greater gram spectrum + some

gram + cocci
o 3nd enter CSF
Cefatriaxone broad spectrum, some gram o 4th - many cross into CSF
Cefepime similar to 1st
Carbapenems
o Highly resistant to B-lactamases
Imipenem broad spectrum
Monobactams

o Azetreonam
Glycopeptides
o Vancomycin gram +
o Bacitracine topical gram +

Inhibitors of Protein Synthesis

Tetracyclines
o Tetracycine
o Doxycycline

Macrolides
o Erythromycin
o Ketolides
o Azithromycin
Aminoglycosides
o Streptomycin
o Gentamicin
Clindamycin
Chloramphenicol (serious side-effect = aplastic anemia)
Mechanisms of Protein Synthesis Inhibition
o Blocking amino-acyl-tRNA binding to ribosome
o Inhibit formation of ribosomes
o Block peptide bond formation
o Block translocation step of ribosome
o Misread mRNA to add wrong aminoacid
o Prevent release of growing peptide from ribosome

Inhibition of Metabolism
Folic acid synthesis
o Sulfonamides
Sulfamethoxazole
o Trimethoprim
o Synergistic effect:
Trimethoprim/Sulfamethoxazole
Sulfa inhibits synthesis of dihydropteric
acid by competing with PABA (Para

aminobenzoic acid)
Trimeth blocks production of THF by
inhibiting dihydrofolate reductase
This combo blocks 2 consecutive steps and
usually bactericidal

Inhibiting/Damaging Nucleic Acids/DNA

Fluoroquinolones inhibit DNA topoisomerases (DNA gyrase
and Topoisomerase IV)

o Ciprofloxacin (2nd)
o Norfloxacin (2nd)
o Levofloxacin (3rd)
o Gatifloxacin (4th)
o Moxifloxacin (4th)
Nitrofurans (banned in Canada)

Inhibiting/Damage Cell Membrane

Colistin (Polymyxin E)

Polymyxin B poke holes in membrane and cause leakage

Actinobacteria
Mycobacterium is a class of actinobacteria
o TB (always treated with multi-drug b/c of risk of
resistance
1st Line Drugs for TB

Isoniazid (INH) inhibit mycolic acid/waxy

synthesis
Rifampin inhibits RNA Polymerase
Pyrazinamide (PZA) disrupt plasma
membrane
Ethambutol
2nd Line
Fluoroquinolones
Streptomycine (Aminoglycoside)
o Leprosy

Rifampin inhibits RNA polymerase

Dapsone inhibits dihyrdopteric acid (Like SMX)
in folic acid synthesis
Clofazimine

Anti-Fungals
Fungi more complex b/c:
o Different ribosomes
o Different cell wall

o Discrete nuclear membrane

Principle antifungals:
o Inhibits Cell wall
Capsofungin
o Inhibit Cell membranes
Polyenes
Amphotericin B (most widely used
antifungal)
Messes with ergosterol and causes ion leak
Nystatin
Azoles inhibit synthesis of ergosterol
Allylamines inhibit synthesis of ergosterol
o Inhibit nuclear division
Griseofulvin inhibits microtubule function
therefore inhibits mitosis
o Inhibit DNA synthesis
Flucytosine pyrimidine analogue

Module 9 Antivirals, AntiCancer

4/21/2011 8:38:00 AM

Viruses
Nucleic acid core surrounded by a protein capsid; some have an
envelope
Attach then enter cell (endocytosis or penetration)
SS or DS RNA or DNA genomes
Viral Infection
Lytic, latent or chronic
Is characterized by an incubation period
Is prevented primarily by cell-mediated immunity
Overview for Tx:
Block virus attachment
Block uncoating of virus
Inhibit viral DNA/RNA synthesis
Inhibit viral protein synthesis
Inhibit viral enzymes
Inhibit viral assembly
Inhibit viral release

Stimulate host immune system

Respiratory Virus Infection

Influenza A and B and RSV
Viral Uncoating Inhibitors (Amatadine and rimantadine)
o For Influenza A ONLY
Immunization is the preferred approach
Neuraminadase Inhibitors (Oseltamivir [oral] and Zanamivir
[inhaled])

o Prevents attachment
o For Influenza A and B
Ribavirin Guanosine analog
o In RSV and HCV

Hepatic Viral Infections

Hepatitis B and C most common for chronic hepatitis,
cirrhosis and HCC

Hepatitis B
o IFN-a inhibit viral RNA translation, degrades it and
stimulates host immune system
o Lamivudine inhibit HBV DNA polymerase and HIV
reverse transcriptase
Hepatitis C
o IFN-a + ribavirin

Herpes Infections
HSV 1 and 2 (Oral and genital)

VZV
Acyclovir
o Analog of endogenous substrate deoxyguanosine;
premature termination of viral DNA
o Choice drug for HSV1, HSV2 and VZV
o Most commonly used for genital herpes infections
Valacyclovir (oral)
Famiciclovir acyclovir analog w/ longer duration of action
Peniciclovir (topical)
Ganciclovir
o Guanosine analog
o Good vs HSV, VZV, EBV, CMV
o 100x better for CMV than acyclovir
Foscarnet
o Pyrophosphate derivative
Inhibits viral DNA and RNA polymerases
o For CMV retinitis, acyclovir-resistant HSV

Retroviral Infections
HTLV-1, HTLV-2
Lentiviruses (HIV-1, HIV-2)
o Attach to CD4+ cells
o Has a reverse transcriptase (RNA->DNA)
o Inactivates CD4+ cells -> deficient cell-mediated
immunity
o Therapeutic Regimen:

HAART (Highly active anti-retroviral therapy)

Use combination (3 or more) to suppress HIV
replication and restore immuno-competency
NRTIs (Nucleoside/tide reverse transcriptase Inhibitors)
o Prodrugs, and analogs of native nucleosides/tides
o Incorporated into viral DNA and prematurely
terminates elongation
Zidovudine (AZT- Azidodeoxythymidine)
Decreases viral load and increases CD4+
cells

Introduced into viral DNA by reverse

transcriptase
Metabolized by liver and excreted in urine
Didanosine (ddI, dideoxyinosine)
Pancreatitis (monitor amylase)
Zalcitabine (ddC, didoxycytosine)
Peripheral neuropathy (major toxicity)
Lamivudine (3TC, deoxy-thiacytidine)
Used with AZT, but not ddC

Terminiates synthesis of proviral DNA and inhibits

reverse transcriptase
For HCV and HIV
NNRTIs (Non-nucleoside/tide reverse transcriptase inhibitors)
o Lack affinity for HIV-2
o Dont need activation by cellular enzymes (like NRTIs
do)
Nevirapine
Substitute for AZT

Inducer of CYP3A4 of cytochrome p450

(drug interactions!)
Increases metabolism of: OCPs,
ketoconazole, methadone,
metronidazole, warfarin, theophylline
Delavirdine
Inhibitor of cytochrome p450 metabolism
(drug interactions!)

Protease Inhibitors
o Inhibit HIV aspartyl protease (formation of reverse
transcriptase, protease, integrase and other structural
proteins) and block viral maturation
o Synergistic with NRTIs + NNRTIs
o Substrates and inhibitors of cyp3A4 of p450
Rx interactions are common and problematic
Midazolam/Triazolam etc excessive
sedation
Warfarin bleeding

Fentanyl resp distress

Inducers of cytochrome p450 (rifampin,
barbituates, carbamazepine) failure of
protease inhibitor

o Saquinavir
Poor bioavailability, need to be taken with meals
(absorption increases with high fat meals and
grapefruit juice)
o Ritonavir
Inhibits p450 (drug interactions)
Pharmacokinetic enhancer for other protease
inhibitors
o Indinavir
Nephrolithiasis can occur

Viral Fusion Inhibitor Enfuvirtide

Binds gp41 and prevents conformational changes that occur
with HIV tries to fuse with host membrane

Combines with other antivirals

Given SC

2 New Drugs for HIV:

Raltegravir
o Inhibits Integrase (prevents viral DNA integrating with host
DNA)
o Active against HIV resistance to other anti-retrovirals

Miraviroc
o CCR5 (CC chemokine receptor 5) antagonist
Only for adults with CCR5-tropic HIV-1 (R5 Virus)
CCR5 is major receptor involved in viral entry
o Binds CCR5 preventing entry
o Active against HIV resistance to other anti-retrovirals

Anti-Cancer Drugs
4 Features of Cancer/Neoplasm

uncontrolled cell prolif

impaired apoptosis
loss of normal functions
metastasis

Goals of Cancer Tx
Primary Goal Cure (long term disease free survival) eradicate all
neoplastic cells
Secondary Goal palliation, reduce Sxs, delay tumor growth,
preserve normal function
Treatment Modalities
Surgery
Radiation
Chemotherapy
o Indications:
Cancer disseminated and not amenable to surgery
Tumor close to vital organ and other modalites

not feasible
Vs micrometastasis following surgery and
radiation Tx

Tumor Susceptibility & Growth Cycle

Cancer cells have more cells in replicating cycle
Normal cells tend to be in G0 (resting phase)

Solid tumors in vivo initially grow rapidly but slow down b/c
O2 and nutrients cant keep up
Recruitment:
o Reducing tumor burden via surgery/radiation,
promoting recruitment of remaining cancer cells into
active replication thereby increasing their susceptibility
to chemotherapeutic agents
Significance of a 1g Tumor Mass
o 10^9 cells is the smallest tumor burden that is
physically detectable
o Clinical Sxs usually first appear at this stage
1 Kg tumor burden, usually death

Treatment Regimens & Scheduling

Log Kill
o Chemotherapeutic agents follow 1st order kinetics:
A given dose of drugs destroys a constant
FRACTION of cells
Pharmacologic Sanctuaries

o Tumor cells can find sanctuaries in tissues like CNS

May need radiation to craniospinal axis or
intrathecal Rx administration to eliminate tumors
there
Drugs may be unable to penetrate certain areas of
solid tumors (usually cells at the center)
Treatment protocols
o Cytotoxic agents are usually combined at full doses
o Advantages of combinations:
Maximal cell killing within range of tolerated
toxicity
Effective against broader cell lines in
heterogenous tumor population
Delay or prevent development of resistant cancer
cell lines
o Usually identified by acronym (ex: POMP: Prednisone,
oncovin, methotrexate, purinethol)

o Examples:
Hodgekins Disease
MOPP (Mechlorethamine, oncovin,
procarbazine, prednisone)
ABVD (adriamycin, bleomycin, vinblastine,
dacarbazine)
Problems with Chemotherapy
Resistance minimized by short-term intensive intermittent
tx with combo of drugs

Multi-drug resistance expression of P-glycoprotein

(permerability glycoprotein) pumping drugs out of the
cancer cells
Toxicity
o Common adverse effects:
Bone marrow pancytopenia
GI tract ulceration, diarrhea
Hair alopecia
Gonads menstrual irregularity, impaired
spermatogensis
Wounds impaired healing
Fetus teratogenesis (esp 1st trimester)
o Many of these are due to drug effects on non-tumor
cells that are usually growing (GI tract, gonads, hair,
bone marrow, etc)
Treatment-induced tumors
o Anti-neoplastic agents are mutagens and new cancers
may arise years after chemoTx
o Esp with alkylating agents that can X-link DNA

Anti-Cancer mechanisms
Impair nucleic acid synthesis
Impair DNA function
Impair protein synthesis
Inhibit mitosis
Stimulate immune system

Impair endogenous cell growth regulating mechanisms

Inhibit angiogensis and metastasis

Cell-cycle specificity of Drugs:

Cell-cycle specific only effective vs replicating cells
Cell-cycle non-specific useful vs tumors with low % of
replicating cells also vs replicating cells
Antimetabolites
Struct. Related to normal compounds in the cell

Interfere with availability of pyrimidines/purines by

inhibiting synthesis or competing with them
Maximal cytotoxic effects in S-phase and are Cell-cycle
Specific
o Methotrexate (MTX)
Structurally related to folic acid; inhibits
dihydrofolate reductase (converts folic acid to active
THF)
Decreases synthesis of nucleic acid precursors
Usually used in combo with other cancer Rx
Low dose MTX is anti-inflammatory and
immunosuppressive (ex: Crohns Disease, SLE )
o 6-Mercaptopurine (6-MP) + 6-Thioguanine (6-TG)
Purine analogs and inhibit purine synthesis
o 5-Fluorouracil (5-FU)
pyrimidine analog

Antibiotics

Cell-cycle specific
Interact with DNA, leading to disruptions in DNA function
o Doxorubicin (Adriamycin)
Belongs to anthracycline family of abx
Used in drug combos
Blocks DNA and RNA synthesis, binds to cell
membranes and generates O2 radicals (causing
breaks in DNA)

Tumors and heart tissue low in supraoxide

dismutase
Cardiotoxicity
o Dactinomycin (actinomycin D)
1st abx to find application in cancer Tx
Forms complex with DNA
Also immunosuppressive
o Bleomycin
Mixture of copper-chelating glycopeptides causing
scission of DNA via oxidative processes (like

doxorubicin)
Cell-cycle specific
Pulmonary toxicity (Fibrosis)

Alkylating Agents
Alkylating DNA (covalent binding) lethal to tumor cells
Cell-cycle non-specific
Mutagenic + carcinogenic and can cause secondary
malignancy
o Mechlorethamine
Mustard gas in WW1
Causes lymphocytopenia
Alkylates guanine and causes x-linking b/w
guanines in DNA
o Cyclophosphamide
Most commonly used alkylating agent
Transformed by body into active phosphoramide
mustard, which alkylates DNA
Microtubule Inhibitors
Mitotic spindle needed for moving organelles during cell
division
o Vincristine (VX, oncovin), vinblastine (VBL)
From plant Vinca rosea
Cell-cycle specific and phase-specific

Bind to Tubulin blocking the polymerization to

microtubules
o Paclitaxel (Taxol)
Promote polymerization and hyper-stabilizes the
microtubules and blocks the ability to use
cytoskeleton in a flexible manner
Chromosomes dont segregate and cell death occurs

Steroid hormones & Their Antagonists

Some tumors are steroid hormone sensitive, hormoneresponsive, hormone-dependent or both.
o Tamoxifen
Estrogen antagonist
Blocks estrogen stimulation of breast cancer
growth
o Prednisone
Potent synthetic anti-inflammatory steroid, with
less mineralocorticoid activity than cortisol
For Lymphoma and ALL
Antibodies
Polyclonal, monoclonal (mAbs), humanized and chimeric antibodies
o Monoclonal Antibodies (mAbs)
Naming:
zu in the name = humanized
muro = murine antibody
xi = chimeric antibody
Identify malignant cells as targets for attack by
complement-dependent cytotoxicity and antibodydependent cell-mediated cytotoxicity
Trastuzumab
Targets human epidermal growth factor
(hEGF) receptor protein 2 (HER2) and
inhibits prolif of HER2 expressing cells
o For regression of breast cancer
Others:

Rituximab - (anti-CD20) for malignant

B-cells
Bevacizumab anti-VEGF
Cetuximab anti-EGFR

Antivirals
Influenza A & B
o Uncoating inhibitors (only for A)
Amatadine, rimantidine
o Neuraminidase inhibitors (block attachment) A & B

Osteltamivir

RSV
o Ribavirin (guanosine analog)
RSV, HCV

Hepatic
HBV & HCV most common for chronic hepatitis, cirrhosis and HPCC
o HBV IFN-a and lamiduvine
o HCV IFN-a and ribavirin
Herpes Viruses
HSV 1 and HSV 2
o Acyclovir choice for HSV and VZV
o Valcyclovir - oral
o Ganciclovir better for CMV and EBV
o Famiciclovir longer duration that acyclovir
o Foscarnet pyrophosphate derivative
For CMV retinitis and acyclovir-resistant HSV
Retroviral
HTLV 1 and HTLV 2
HIV1 and HIV2
o NRTIs
Zidovudine/AZT
Lamiduvine
Didanosine - pancreatitis

 Zalcitabine peripheral neuropathy

o NNRTIs
Nevirapine
Substitute for AZT
Inducer of CYP3A4 p450
Delavirdine
Inhibitor of p450
o Protease Inhibitors (substrates and inducers of p450)
Saquinovir
Ritonavir inhibitor of p450

Indinavir nephrolithiasis
Viral Fusion Inhibitor
o Enfuvirtide
Binds gp41 and prevents conformational changes
that occur with HIV tries to fuse with host
membrane
New HIV Drugs
o Raltegravir
Inhibits integrase
o Miraviroc
CCR5 receptor antagonist prevents viral entry
For resistant HIV

Anti-Cancer
Antimetabolites
o Methotrexate messes with folate
o 5-mercaptopurine + 6-thioguanine purine synthesis
o 5-fluorouracil pyridimine

Antibiotics
o Doxorubicin
o Dactinomycin
o Bleomycin
Akylating Agents
o Cyclophosphamide
o Mechlorethamine
Microtubule Inhibitors

o Vincristine, Vinblastine
o Paclitaxel
Antibodies
o Trastuzumab
o Ritixumab
o

CNS Pharmacology

4/21/2011 8:38:00 AM

Functional Neuroanatomy
Spinal cord
o Relays info b/w brain and rest of body
PONS/Medulla
o Crucial physiological reflexes
o CO2 centers for breathing
o CTZ reduces absorption of toxic compounds from GI tract
Hypothalamus
o Thermoregulation and autonomic NS
o Controls pituitary

Basal Ganglia
o Extrapyramidal system
o Smooth coordinated muscle activity
o Removes unwanted movement
Limbic System
o Amygdala, hippocampus, habenula, septal area
o Memory, emotions
o Focusing by inhibiting irrelevant sensory and cognitive activity
o Judgement, evaluation, inhibition of inappropriate thoughts
and behaviours
Cortex
o Sensory and motor activity
o Language, concept manipulation
o Thoughts, ideas, consciousness
o Long-term memory storage

Chemical Neurotransmission
In PNS its ACh and Norepi

In brain theres much more

o Neurotransmittiers - released from nerve terminal and acts on
receptor near site of release
Dopamine
Extrapyramidal system
Parkinsons Disease
Limbic, hypothalamus, CTZ
Norepi

Reticular activating system

Arousal, alertness, wakefulness
Limbic, hypothalamus, pons/medulla

Epi
Pons/medulla CV control
Serotonin
Limbic, hypothalamus
ACh
Limbic
Extrapyramidal

Glutamate/glutamic acid
Everywhere - main excitatory NT
GABA
Everywhere main inhibitoryNT
Endorphin, enkephalin, dynorphin
Limbic, Spinal cord, thalamus
Addiction, analgesia
Substance P
Pain

Capsaicin in chili peppers stimulates these

receptors
Histamine
RAS - arousal
Neuromodulator chemical that alters neuron activity by acting on
a receptor located some distance away from site of release

Steps in Neurotransmission
DNA/RNA/Protein synthesis

Axo-plasmic transport
AP tetrodotoxin
NT Synthesis
NT Storage
NT Release
NT Receptor coupling/binding
NT Removal
o Reuptake or breakdown

CNS Pharmacokinetics
Blood Brain Barrier
o Physical brain capillaries have different structure
Lack fenestrae + intercellular clefts
Tight junctions
Surrounded by astrocytic endfeet (more layers of lipid)
o Chemical enzymes
Capillary endothelium has more mitochondria w/
enzymes (MAO to break down neuroactie monoamines)

o Physiochemical plasma protein binding

Keeps neurotoxic lipid soluable compounds (bilirubin)
out
Nutrients enter brain by active transport (Glucose, AA, FFAs)
For a drug to enter brain it must be lipophilic or carried by active
transport across BBB

Neuropsychiatry
Neurosis

o Maladaptive learned behaviour

Ex: fears/phobias
Psychosis
o Loss of contact w/ reality
o Disrupted brain function
o Neurochemical imbalance
Induced by:
Drugs/chemicals
Neurodegeneration

Genetic abNs

Schizophrenia
o Symptoms
Negative
Affective flattening
Alogia (poverty of speech)
Avolition-apathy
Anhedonia-asociality

Reduced attention
Positive
Hallucinations
Delusions
Bizzare behaviour
Positive formal thought disorder
Most common
Unchanging facial expression
Persecutory delusions
Lack of persistence at work/school

Impaired grooming/hygiene
Few recreational interests
Few relationships w/ friends/family
o Dopamine Hypothesis
Anti-schizoprenia drugs are D2 (dopamine) antagonists
DA receptor overstimulation mimics schizophrenia
Amphetamine psychosis
Schizo an adverse effect of Tx in Parkinsons Dz
DA antagonists reduce + Sxs

5HT antagonists reduce Sxs

Neuroleptics
Phenothiazines
o Not all of them are neuroleptics
Chlorpromazine
o DA antagonist
o A-adrenergic antagonist
o Muscarinic antagonist

o Histamine antagonist
Thioxanthenes
o Structural analogues of phenothiazines
Main effect and side effects are similar
o Flupenthixol
o Flupenthixol decanoate
Depot IM injection, maintain therapeutic levels for 2-4
weeks

Butyrophenones
o Differ from phenothiazines in structure and side effect profile
o Block dopamine receptors, no affinity for others
o Haloperidol
Only butyrophenone used as a neuroleptic
D1 and D2 receptor blocker
Has only dopamine related SEs
Extrapyramidal symptoms, hyperprolactinemia,
anti-emetic, tardive dyskinesia

Atypical Neuroleptics
Clozapine
o D1, D2, 5HT2 antagonist
For + and Sxs
o Little or no EPS?
o SEs
Bone marrow suppression -> agranulocytosis + death
Weekly blood tests
Respiridone

o D2 +

Olanzapine
o D2 +

o Halts
o SEs

5HT2 antagonist
+ & - Sxs
little or not EPS or SEs
5HT antagonist
+ and Sxs
progression of schizo
Weight gain, dizziness, dry mouth

Quetiapine
o D1, D2, 5HT1a, 5HT2 antagonist
Similar to respiridone and olanzapine but cheaper
o Neuroprotective actions

Depressants, Anti-depressants, Stimulants

Anxiety
o Is good for you

o Is a negative enforcer
o Keeps us out of danger (escape and avoidance)
o Crucial for learning and memory
o Has a bell-shaped effect on performance
Anxiety Disorders
o Panic disocer w/ or w/o agoraphobia
o Agoraphobia
o Social phobia
o Specific phobias
o OCD
o Post-traumatic Stress Disorder
o Substance-Induced

Axiolytics
Benzodiazepines
o Pharmacological Effects
Anxiolytic, hypnotic, anticonvulsant, muscle relaxant
o Neurochemical Effects
Increased GABA
Down-regulated benzodiazepine receptors
Up-regulated downstread receptors for noreepi, 5HT,
etc
Increasing GABA induces release of the same,
which upregulates receptors, and so on
Overdose of benzodiazepines is not lethal but can
potentiate the actions of other depressants like EtOH
and narcotics
o Anxiolytics

Alprazolam (high potency)

Chlordiazepoxide
Diazepam
Oxazepam
o Hypnotics
Triazolam (high potency)
Flurazepam
Temazepam

Tolerance and Addiction

o Due to altered receptor density neural system goes back to
pre-drug functioning level
o Effects of withdrawal is exact opposite of direct drug effects
o Withdrawal syndrome lasts until enough receptors have
returned to previous pre-drug state to maintain normal nerve
impulse traffic
o Withdrawal syndrome is more severe with short halflife drugs
All active drug mocules eliminated before receptors can
return to pre-drug densities
o Benzodiazepine withdrawal
Severe with short half-life drugs (Triazolam)
Not a problem with long half-life (Diazepam)
To discontinue a short half-life drug, switch patient to a
comparable dose of a long half-life drug and reduce the
amount of a drug given by 10% a week

Atypical Anxiolytics
o Buspirone

Not a benzo
Partial agonist at 5HT inhibitory presynaptic
autoreceptors
A selective anti-anxiety drug
Lacks hypnotic, anti-convulsant or muscle relaxant
effects
Does not potentiate the resp depressant actions of
alcohol, narcotics, etc
Little, or no withdrawal syndrome

But takes 2-3 weeks for its effects

Sleep Disorders
Insomnia
o Less sleep needed for daily activities
o Excessive daytime sleepiness
Sleep is an active brain process
Chemically induced sleep is not normal

Many drugs suppress REM sleep

Hypnotic drugs are rarely needed but help in: but use only for 2-3
nights
o Jet lag
o Shift work
o Bereavement
Ideal sleeping pill
o Short half-life, drug gone by morning
o Rapid onset (sleep w/in an hour)
o Little effect on brain activity during sleep

Hypnotic Agents
Benzodiazepines
o Triazolam (1/2 t = 2-3 h)
o Temazepam (1/2 t = 8-10 h)
Atypical
o Zopiclone (5 h)
o Zolpidem (2 h)
o Less sleep effects than benzos but still not normal sleep
Sleep Hygiene
To get bed at same time each night
Get up at same time each morning
Dont do other things in bed, just sleep
Dont nap; if you do, it counts toward total sleep time
No caffeine before bed
Analgesics if sleep disturbed by pain
Major depressive Disorder
Heterogenic genetic disorders
10% of population
Symptoms
o Emotional (sad, frustrated, hopeless, apathetic)
o Cognitive (negative thoughts and ideas, impaired
concentration, pseudo-dementia)

o Neurovegetative (loss of apetite, libido, motivation, interest in

anything)
Antidepressant Interventions
Electroconvulsive Therapy
o Currently safe and effective
MAO Inhibitors
o MAO
Mito enzyme helps to maintain neural activity be
preventing buildup of neuroactive amines

Chemical part of Blood brain barrier

2 forms
MAO-A
Highest affinity for 5HT
Less for NE, dopamine, trace amines like
tyramine
MAO-B
Highest affinity for dopamine
Less for NE and tyramine

Wine-Cheese Reaction
Contain tyramine and MAO inhibitors will cause
buildup of tyramine and displaces NE from
sympathetic nerve terminals
o Tranylcypromine
Irreversibly binds MAO
Inihibts MAO A and B
o Moclobemide
Reversible binding and selective for MAO-A

Not usually a problem b/c short half-life and reversible

NT Reuptake Inhibitors
o Nonselective Reuptake Inhibitors (NSRIs)
Inhibit NE and 5HT reuptake (broad-spectrum)
o Selective Serotonin Reuptake Inhibitors (SSRIs)
Inhibit only 5HT
Fluoxetine
Inhibits p450 enzymes

Fluvoaxamine
Paroxetine
o Selective NE Reuptake Inhibitors
Desipramine
Nortriptyline
Active part of amitriptyline
Maprotiline
Neurotransmitter Release Enhancers
o Increase NE and 5HT release
Mirtazapine

Antidepressant Mechanism
Uptake blockade maximal w/in a few hours
Clinical improvement not seen for 2-6 weeks
o Therefore acute drug reaction is not the theapeutic action of
antidepressants
Down-regulation of b-adrenergic receptorcs common to all
antidepressant interventions
Other uses for Anti-depressants/Mood Stabilizer
Panid disorder
OCD
General anxiety disorder
Stimulants/Sympathomimetics
Caffeine
o Blocks adenosine receptors (an inhibitory NT)
Cocaine

o Blocks reuptake of NE and dopamine

Amphetamine
o Stimulates release of NE,dopamine and serotonin
Methylphenidate
o Similar to amphetamine
Adverse Effects
o High doses stimulates dopamine reward pathways
o Amphetamine psychosis

o Appetite suppression
o Suppression of growth hormone
Narcolepsy
Patient enters REM sleep instantly
Methylphenidate
o Drug of choice
Bipolar Disorder (Manic Depression)
Higher in professionals and entertainers

Mood swings b/w depression and mania

Genetic
Drugs useful as Mood Stabilizers
o Lithium
Reduce neuronal inositol 2nd messenger system
o Carbamazepine
Anticonvulsant (reduce excitatory NTs)
o Clonazepam
Anticonvulsant (Benzo therefore increase GABA)
o Valproate
Anticonvulsant (increase GABA)

Glutamate
o Main excitatory NT
o 4 receptors
NMDA opens Ca2+ channel
Over-stimulation of NMDA causes massive
increase in intracellular Ca2+ killing neuron

Epilepsy
Abnormal synchronous APs of groups of neurons in various parts of
brain
Many casues (infection, fever, tumors, injury, lyte imbalance, etc)
Therapy aimed to reduce excitability of neurons
o Increasing GABA
Benzodiazepines (Clonazepam, Diazepam)

o Alter

Diazepam used for status epilepticus

Barbiturates (Phenobarbital)
Benzos and Barbituates increase GABA channel
hyperpolarization of neurons
Gabapentin
Increases gaba release
Valproic acid
Increases GABA, also blocks Na+ and Ca2+
channels, and increase K+ conductance
transmembrane flow of ions
Phenytoin
Blocks Na+ channels
Carbamazepine
Blocks Na+ channels and potentiates postsynaptic effect of GABA
Ethosuximde
Blocks Ca2+ channels
Iamotrigine
Blocks Na+ channels

o Decrease glutamate excitatory tone

Glutamate antagonists have too many side effects and
none are on the market as anticonvulstants yet
Pain Sensory System
Endogenous opiod preptides (EOP) modulate pain sensory
transmission
o Also modulate GI function
Stimulation of opiod receptors in intestine causes
contractions of GI muscle and blocks propulsive
transport of GI contents = Constipation
EOPs

Products of 3 separate genes:

o Pro-opiomelanocortin
B-endorphin, ACTH and MSH
o Prepro-enkaphalin

 Met-enkephalin, leu-enkephalin
o Prepro-dynorphin
Dynorphin
EOP Receptors
3 classes (mu, kappa, and delta)
Mu has highest affinity for B-endorphin
o Mu stimulation:
In brain and spinal cord produces analgesia
In GI constipation

Limbic system euphoria

Kappa highest for dynorphin
o Kappa stimulation
Brain and spine analgesia
Selective kappa agonists are underdevelopment as Non
addicting analgesics
Deta highest for met-enkephalin and leu-enkephalin
o Brain and spine analgesia

Pharmacological Actions of Opiod Analgesics

Dose-dependent
Mood changes (mellow, pleasant, euphoria, etc)
Analgesia w/o sedation
Constipation (reduced GI propulsive motility)
N+V, drowsiness
Respiratory Depression
o Reduced responsiveness to CO2 in brain stem
The cause of death in opiod overdose

Tolerance includes down-regulated EOP receptors and up-reg

downstream receptors
Withdrawal has exact opposite symptoms
o More severe with short half-life (ex: morphine and heroin vs
methadone)
EOPs released from acupuncture
o Also physical activity (running, ex: second wind during long
run)

EOP Receptor Agonists (Opiod Analgesics)

Morphine
o Constituent of opium
o Mu agonist
Codeine
o Also from opium
o Less potent than morphine at mu receptors
o Converted to morphine by Cyp 2D6
o Good cough suppressant

Meperidine
o Synthetic mu agonist
o Less resp depression than morphine
Methadone
o Synthetic mu agonist
o Used in addiction treatment programs
o Good analgesic profile, and for chronic pain syndrome

Non-Opiod Analgesics

NSAIDs (inhibit COX I and II)

o Aspirin/ASA
o Ibuprofen
Selective COX II inhibitors (dont mess with GI or plts)
o Celecoxib
o Rofecoxib
BUT increased clots and MIs in patients with CV risk
factors
Due to thromboxane A2 made from COX I causing plt
aggregation
Other analgesics
o Acetominophen (Tylenol)
Weak inhibition of PG synthesis
Lacks anti-inflamm actions
Analgesic and anti-pyretic actions same as ASA
N-acetylcysteine is antidote for overdose

Addiction to Opiod Analgesics

Drugs potentially addictive if:
o Pleasant enjoyable drug action (euphoria, pain relief)
o Rapid onset (IV gets to brain in 20 sec)
o Short half-life (morphine)
Once tolerance to morphine occurs, (down-reg EOP receptors)
withdrawal is quick in onset and severe
Taking drug to avoid withdrawal is final step in addiction
EOP Receptor Antagonists

Naloxone
o Blocks all EOP receptors
o Used in opiod overdose
Naltrexone
o Blocks all EOP receptors
o For narcotic addiction
o Reduces craving of EtOH in alcoholics

Parkinsons Disease
Motor
o Akinesia
o Bradykinesia
o Muscle rigidity
o Tremor at rest
o Mask-like facies
o Cog-wheel locomotion
Other

o Dementia + depression
Pathology
o Due to degeneration of Parkinsons Disease
o Death of dopamine cell bodies in substantia nigra

Extra-pyramidal System (EPS)

Regulation of fine motor activity
For smooth and coordinated movement

When dopamine inhibition b/c deficient, acetylcholine excitation is

unchecked and GABA output becomes excessive
Dopamine/ACh balance can be restored by augmenting dopamine
inhibition or by reducing acetylcholine excitation

Treatment of Parkinsons
Dopamine Replacement Therapy
o Dopamine cant cross BBB
o Levodopa
Precursor of dopamine can cross
Restores dopamine/ACh balance and normal output of
EPS
Adverse Effects
Peripheral HTN, tachycardia, arrhythmia, N+V
Central psychosis, dyskinesias

o Selegiline MAO-B inhibitor, inhibits braindown of dopamine

Dopmaine Receptor Agonists
o Bromocriptine

o Pramipexole, Ropinirole
Anticholinergic Therapy
o Benzotropine muscarininc ACh antagonist
Antioxidant Therapy

Alzheimers Disease
Dementia
o Memory loss, impaired judgement and evaluation, labile and
inappropriate emotions
o Motor functions intact until late stages
o Pathology
Plaques and tangles in brain
Treatment of Alzheimers
ACh Replacement Therapy
o AChE inhibitors
Donepezil, Galantamine, Rivastigmine

Antioxidant Therapy
o Block neurotoxicity of B-amyloid
o Vitamin E, C, blue berries, strawberries, ethanol

The Alcohols
Methanol
o Metabolized to formaldehyde
o Metabolites are harmful to living tissue blindness, acidosis,
death
o Methanol poisoning treatment
Saturate alcohol dehydrogenase with ethanol and bicarb
to reduce acidosis
Initate hemodialysis
Also Fomepizole alcohol dehydrogenase inhibitor
Ethanol (beverage alcohol)
o Suppresses neuronal excitability in concentration dependent
manner
o Moderate consumption has health benefits due to antioxidant
effects

Ethylene Glycol (anti-freeze)

o Severe metabolic acidosis, if they survive go on to get
hypocalcemia and renal failure -> death
o Treatment is ethanol, fomepizole, bicarb and dialysis
o Also fluids and calcium

Calculation of Blood Alcohol Concentration (BAC)

Grams of ethanol consumed form time Y to X (minus) grams of
ethnol metabolized (average metabolism = 124mg EtOH / kg
weight/hour) from time Y to X (divided by) WIdmark Factor (WF)
o WF = kg body weight x (.55 for females) or (.68 for males)

Smooth Muscle & Migraines

4/21/2011 8:38:00 AM

Emetics & Anti-emetics

Vomiting
Physiological protective anti-peristaltic response in a forceful
expulsion of GI contents
Sequence of Events in Vomiting:
Nausea increased salivation, sweating, pallor, etc
Wretching abd muscles contract + antiperistalsis
Vomiting contraction of diaphragm and expulsion through mouth
Causes

of Vomiting
Drug Induced
Infectious GI disorders
Non-infectious
Early pregnancy
CNS related

Emetic Center

In medulla
Receptors for:
o Dopamine
o Acetylcholine (muscarinic)
o Histamine
o 5-hydroxytryptamine (5-HT/serotonin)

Anti-emetics
Antihistamine

o Dimenhydrinate (Gravol)
o Most effective in Motion sickness and inner ear dysfunction
(Meniers disease excess fluid in ear; and Labrynthitis)
o SE
Drowsiness, sedation, dry + blurred vision (block
muscarinic receptors)
Anticholinergics
o Scopalamine

o Used in motion sickness

o Same SE as above + tachycardia (blocks muscarinic)
Dopamine Antagonists
o Non-selective dopamine antagonist (Phenothiazines)
Decrease vomiting caused by gastric irritants
SEs
Dystonic reactions, extrapyramidal side effects
o D2 Selective antagonists (Metoclopramide, domperidone)
During cancer chemotherapy to control nausea and
vomiting
Benzodiazepines
o Lorazepam, Alprazolam
o Prevent central cortical induced vomiting
o For anxiety and anticipatory emesis (ex: Chemotherapy)
5-HT3 Selective Antagonist
o 1st gen (Ondasetron, Granisetron)
o 2nd gen (Palonoseron) more potent and longer acting
used for vomiting from chemotherapy
Cannabinoids
o Tetrahydrocannabinol, nabilone
o Control of vomiting when all other agents fail
o SEs
Hallucinations, bulimia
Corticosteroids
o Dexamethasone
o Motion sickness, mountaineering
o Effective when combined with dopramine and 5-HT
antagonists
o SEs
Osteoporosis, cushingoid features, adrenal suppression,
susceptibility to infection
Substance P Antagonist (NK-1 antagonist)
o Aprepitant

Combination Treatment for Chemotherapy-Induced Nausea-Vomiting (CINV)

When cisplatin and oher anti-cancer drugs are used there is severe
intractable N+V
o Combination with Palonosetron + Aprepitant + corticosteroid
Long lasting relief in adv cancer patients with severe
pain and N+V

Migraine
Unilateral pulsating or throbbing headache associated with N+V,
photophobia, phonophobia, osmophobia
Common migraine (w/o aura) 85%

Classical migraine (w/ aura) 15%

o Visual scotomas, hemianopias, or speech abnormalities
Triggers
o Stress, sleep deprivation, bright light, diet changes, menses
and food (chocolate and cheese)
Pathophysiology
o Vascular hypothesis
Increased venous draining causes inadequate perfusion
causes vessels in anoxic regions to dilate and stretch
perivascular nerve fibers and cause pain
Goal selective vasoconstrict vessels using 5HT
agonists and dihydroergotamine (a1 and 5HTreceptors)
o Neurogenic Hypothesis
Pain transmitted by serotoninergic nerve fibers
When 5-HT agonists fiven, it cuz down the pain
tranmission by acting on an interneuron

Treatment
o Symptomatic (for acute attack)
Mild non-narcotic analgesics
Acetominophen, aspirin
Moderate
NSAIDS + dichlorophenazone
Triptans
Ergotamine (Ergot alkaloids)

 Butorphanol
Severe
Ergot or Triptan + antiemetic
Narcotic of meperidine if above fail
o Prophylactic (if >3 attacks/month)
BBs (Propanalol)
CCBs (verapamil)
Tricyclic antidepressants (Amitriptyline)
Anti-epileptics (Valproic acid)
Cyproheptadine (5HT and histmine antagonist
Ergotamine
Constricts vessels, redistributing flow and no pain generation
No for pregnant women, PVD CAD, HTN or sepsis
Can cause N+V as SE
Triptans
5-HT selective agonists
Activate 5HT1b receptors to reduce rapid draining to the venous

side by vasoconstriction of unwanted collaterals

o redistribution of blood to anoxic underperfused regions and
reduces vasodilation and pain
Triptans also act on 5HT1d receptors and cuts down level of
endogenous 5HT release which is required for activation of pain
sensitive fibers.
Contraindicated in angina and PVD (Peripheral vascular disease)

GI Tract Pharmacology

4/21/2011 8:38:00 AM

Physiology of Gastric Acid Secretion

Regulated by neural (ACh muscarinic), endocrine (Gastrin) and
paracrine (Histamine) secretory factors
o Gastrin and ACh work through ECL secretion of histamine
causing Parietal cell secretion of acid
Secreted products:
o HCl
o Pepsin
o Mucus
o HCO3

Aggressive Factors
o HCl, Pepsin, H. pylori infection
Protective Factors
o Mucus, HCO3, PGEs (PGE1 and PGE2)

Pharmacology of Anti-Ulcer Agents

Agents that Neutralize Acid
o Antacids
Weak bases that form salts with HCl causing chemical

neutralization to buffer the acid

Advantage immediate relieve
Disadvantage short duration, rebound acid secretion
Compounds
NaHCO3
CaCO3
Al(OH)3
Agents that reduce acid secretion
o H2 receptor antagonists
Ranitidine
Good for gastric/duodenal ulcers and in Zollinger-Ellison
Syndrome
Cimetidine
Many side effects (CNS, Immune, Gondal, inhibits
Cyp450
o Proton Pump Inhibitors (PPIs)
Inhibit H+/K+ ATPase

 Omeprazole
o Cytoprotective Mucosal Defensive Agents
Sucralfate: Sucrose Octasulfate Aluminum Hydroxide
Gives a protective coating over ulcerated region
and prevents erosion
Also stimulates PGE1 production, absorbs pepsin
SE dry mouth + constipiation
Misoprostol
PGE1 analog
Enhances mucus and HCO3 production

Good for ulcers from NSAIDs

Not for pregnancy
Bismuth chelate
Protective coating
Increases mucus and PGE
Kills H. Pylori

Management of H. Pylori Infection

Gram rod

Causes erosion of protective epithelial cells -> gastritis or peptic

ulcer
H2 antagonist or PPI + Abx
o Metronidazole or amoxicillin/clarithromycin
PPI + 2 or 3 antimicrobials is standard
Ex: Ranitidine + Peptobismol + Clarithromycin +
Amoxicillin 7-14 days
Add bismuth if resistant H. pylori
o Ex: PPI + BMT (Bismuth + Metronidazole + tetracycline) 7
days

Treatment for ZE Syndrome

Gastrinoma of the duodenum or pancreas
Elevated gastrin levels
o Peptic/gastric ulcers
Treatment

o High dose PPI until resorting to surgery or chemotherapy for

tumor removal
Drugs that Promote Upper GI Motility (Prokinetic Agents)
Increase gastric emptying, relieve gastric stasis
Prevent reflux esophagitis/heart burn/GERD
Decrease N+V

Modulate ACh release to promote opening of gastroduodenal

sphincter and selectively increase duodenal motility to promote
gastric emptying
o Metoclopramide (D2 blocker), Cisapride (5-HT agonist),
Erythromycin (Motilin agonist) are prokinetics via
increasing ACh release
Cholinomimetics (Bethanachol) and Anti-AChE
(Neostigmine) also promite GI motility but the effects are
non-specific and many side-effects
o Therefore use selective D2 (Dopamine) blockers, 5-HT
(serotonin) and Motilin agonists as prokinetics

Metoclopramide
D2 antagonist/blocker
Crosses BBB
Prokinetic and also anti-emetic
CNS SEs
o Parkinsonian Sxs (Extrapyramidal) +
hyperprolactinemia
Domperidone
D2 antagonist
Doesnt cross BBB
Prokinetic and moderate anti-emetic effects
o Therefore few CNS effects
Can cause hyperprolactinemia (b/c pituitary is outside BBB)
Erythromycin

Macrolide abx
Also activates motilin receptors
Not an anti-emetic
Also causes diarrhea (effect on lower GI motility)
o Can help with constipation

Cisapride
5-HT agonist
Not an anti-emetic
Not used now b/c blocks K+ channels and can cause long QT

syndrome (TdP)
Cardiotoxicity when comboed with clarithromycin (which is
a CYP3A4 inhibitor and decreases metabolism of cisapride
toxicity)

Smooth Muscle Pharmacology

4/21/2011 8:38:00 AM

Drugs Affective Uterine Motility

Oxytocics
o Uterine stimulants
Oxytocin
From Post. Pituitary
Targets
Cervix (Opens)
Myometrium (Contracts)
Myoepithelial cells of breast (Milk let down)
Stimulus

Uses

Risks

Positive feedback mechanism

Afferent info from target tissues
At term induce labor
Preterm augment incomplete abortion
Postpartum control hemorrhage
Postpartum to enhance milk let down
At high doses: H2O intoxication and
hyponatremia (OT similar to ADH, can can
activate renal ADH receptors)

Prostaglandins
PGF2a and PGE2 (intravaginal, IV)
To ripen and dilate cervix and increase
uterine contraction at term
Given with OT to induce labor intravaginally
With mifepristone to terminate pregnancy in
1st trimester (con contraction to clear fetus)
SE N+V
Ergot alkaloids
Ergonovine, Egometrine (IV or IM)
Stimulate pregnant/non-pregnant uteri
Activates adrenergic A1 receptors in
myometrium

Used to control post-partum

hemorrhage/uterine atony
SE Angina
NOT USED IN CANADA

Tocolytics
o Uterine Relaxants
Ca2+ Channel Blockers
Nifedipine
COX Inhibitors
NSAIDs (Diclofenac, ketorolac)
B2 Selective Agonists
Terbualine, ritodrine
Oxytocin Antagonists
atosiban
MgSO4 IV (Mg2+)
17-a hydroxyprogesterone caproate
o Order in management:
CCBs>>NSAIDs>>B2 selective agonists > OT
antagonists> MG2+ IV > Progesterone

o In Canada we use NSAIDs, Corticosteroid (for lung maturation

of fetus) and MgSO4 (Mg2+)
o Mg2+ prevents neurological defects in neonates if premature
labor occurs, decreases seizures and neurological symptoms
in patients with pre-eclampsia
Urinary Pharmacology
Ach -> M3 muscarinic receptors promotes micturition
o Contraction of the Detrusor

o Relaxation of trigone + urethral sphincter

Sympathetics do the opposite of above

Stress Urinary Incontinence (urine voiding w/o control)

Antimuscarininc like Oxybutynin to reduce micturition
Duloxetine
SSNRI (Selective Serotonin-Norepi Reuptake Inhibitor
o Antidepressant

Increases Epi and closes urethra (but increases BP)

Bladder Neck Obstruction/Benign Prostatic Hypertrophy (BNP)

Selective A1 antagonist to relieve spasm and relaxation of urethra
o Tamsulsoin/Flowmax or Prazosin problem w/ postural
hypotension
Selective A1 antagonist + 5-a reductase inhibitor (Finasteride)
A1 blocker + anticholinergic (Oxybutynin-ditropan)
Nocturnal Enuresis in Children/Elderly

Desmopressin
o V2 selective agonist to reabsorb water
Tricyclic antidepressant (amitryptiline)
o Antimuscarinic and norepi uptake inhibition effects
o Decrease micturition

Diabetes Insipidus (DI)

Lack of reabsorption of water in renal collecting ducts
o Lack of ADH

Desmopressin acetate
o More potent V2 agonist than ADH
o Good for neurogenic DI (no ADH)
But not nephrogenic DI (ADH insensitivity)
o Also used for hemophilia and Von Willebrands Disease

Renal Colic
1st line
o Opiod analgesics (Meperidine) then NSAIDs

Opiod for pain and for anticholinergic, NSAIDs to

decrease motility and pain

2nd line
o besides opiods give A1 blocker (Tamsulosin/Flowmax)
expulsive therapy to promote urine flow
o Or CCB (Nifedipine) to relax smooth muscle
o Combo treatment
Analgesic + NSAID + A1 antagonist + nifedipine

Toxicology

4/21/2011 8:38:00 AM

Toxidromes
Agitated delirium
o Sympathimometic or anti-cholinergic
o HR, BP, Temp, RR elevated
o pupils dilated
o Skin sweaty or dry
Sedative hypnotic
o Opiod or benzos or EtOH
o Above depressed
o Pinpoint pupils or small pupils

Fluids out of every orifice

o Cholinergic
Slow HR
N or increased RR
DUMBELS
Diarrhea
Urination
Miosis
Bradycardia, bronchospasm, bronchorrhea (Killer

Bs)
Emesis
Lacrimation
Salivation

Two main toxidromes you will encounter:

Sedatative hypnotic
o By far most common toxicologic cause is EtOH
o Also benzos, opiods, anti-depressants
o Also trauma (ICH), infectious, or metabolic (hypoglycema,
hyponatremia) can cause coma
o DONT forget to reverse a coma mnemonic:
Dextrose 1amp or 50ml D50W
Oxygen (maintain SaO2 > 92%)
Naloxone 0.1-0.4mg IV, repeat PRN (opiod antagonist)
Thiamine 100mg IV or IM
o Actual approach to coma should be:

1) Assess ACBDs and vital signs

2) Get IV access, give O2 and connect cardiac monitors
3) Give glucose if hypoglycemic; thiamine first is
pt has normal glucose
4) Naloxone if pinpoint pupils and RR <12
Agitated delirium
o Most common toxicologic cause is EtOH (from disinhibition)
o Also sympathimometic (cocaine, ecstacy, crystal meth)
o Anticholinergics (gravol, mushrooms, Jimsonweed, etc)
o Also Psychosis (Schizoprhenia), traumatic (ICH), infectious

(meningitis, encephalitis) and metabolic (Thyroid storm)

o If certain its a psych cause (known psych Hx with N vitals)
consider using neuroleptic (Haloperidol)
o In most cases sedate with high dose benzos:
Lorazepam (Ativan)
Diazepam (Valium)
o Sympathimometics work by increasing circulating
catecholamines
Youd think to give BBs but if u block all the Bs, then
catecholamines flood the A receptors and cause HTN
crisis
Give benzodiazepines, effetive in countering Sx of
sympathimometic toxicity.
o Anticholinergics treat by increasing amount of ACh to
overcome the blockade
Cholinesterase inhibitors like physostigmine rsk of
causing cholinergic syndrome (DUMBELS) and the killer
Bs therefore used infrequently

Most managed supportively w/o antidotal therapy

Cholinergic (fluids out of every orifice)
o Infrequent and hard to miss clinically
Ex: farmer who works with pesticides presents with
DUMBELS and killer Bs you should suspect cholinergic
toxicity
o Antidote = Atropine, blocks ACh activity; dose is 1mg, PRN

Decontamination
2 main methods
o Activated Charcoal
1g/kg up to 50g/dose, 1st one given with sorbitol
if aspirated can cause pneumonitis, so pt must be
awake, alert and stay that way
Indications
Toxic ingestion w/in 1-2 hours of presentation or
longer if enteric coated preparation
Potentially lethal injestion with any suspicion of

Rx still in GI tract
Contraindications
Rx that dont bind charcoal (PHAILS)
Pesticides
Hydrocarbons (chloral hydrate)
Alcohols
Iron
Lithium
Solvents

Pt is drowsy (risk of aspiration) unless airway

protected by endotracheal tube
Non-intact GI tract (caustic ingestion, kid with TE
fistula)
Bowel obstruction
o Whole Bowel Irrigation (Polyethylene Glycol or Go-lytely)
Dose 25-50ml/kg/hour up t 1L/hour
Usually used when substance cant bind charcoal
(Iron/lithium) and body packers (Human drug

trafficking)
o Induced vomiting
Ipecac and gastric lavage (stomach pump) not routinely
used
Investigations
Some tests are routine for poisoned patient work-up and others
used selectively

Remember, most blood/urine tests take 1-2 hours to get back and
decisions often need to be made well before results get back
Routine Tests
o CBC, INR/PTT
o Lytes, Urea, Creatinine
o Liver enzymes
o CK, Troponin
o Lipase
o Acetominophen level
o Salicylate level
o EtOH level
o Serum osmolarity
o ECG
Tricyclic anti-depressant (TCA) toxicity shows up nicely
as ECG changes b/c blocking of Na channels
Earliest finding is terminal R wave in aVR > 3mm
in height
The > the QRS widening, the > the
potential for seizure and arrhythmia

Treatment for wide QRS = NaHCO3 (1mp or

50mEq) IV bolus repeatedly until QRS narrows

Antidotes
Toxin : Antidote:
o Acetominophen : N-acetylcysteine
o Cholinergic (Organophosphates) : Atropine
o Methanol or Ethylene Glycol : Ethanol or fomepizole
o Benzodiazepines : Flumazenil (compet. Inhibitor of
GABA receptor)
Not routinely used unless you give benzos to someone
who has never had them before and you over-sedate
them (respiratory depression), flumazenil will reverse it
Not routinely used b/c in people who take benzos
regularly or with mixed-overdose the removal of the
benzo effect may cause the patient to seize
o Opiod : Naloxone (opiod inhibitor)

o Anticholinergic : Physostigmine
o TCA : Sodium bicarbonate (NaHCO3)
Elimination
Some meds can have their rate of elimination enhanced
o Alkalination of urine/serum
Helps keep meds in ionized state and in the blood and
out of the tissues so they cant exert their effects
Also helps kidney enhance elmination of certain drugs
Salicylate, ethylene glycol, phenobarbitol,
methotrexate
o Dialysis
Methanol, ethylene glycol, salicylate, litium
These need to have a fairly LOW volume of distribution
With meds with HIGH Vd, most of the drugs is in the
tissues and dialysis cant remove those
Ex: Digoxin (high Vd)
Summar y Approach to the Poisoned Patient

1) Resuscitation
2) History use all potential sources
3) Physical exam search for a TOXIDROME
4) Supportive Care and Management of Agitation, consider
antidotes
4) Decontamination consider charcoal if indicated
5) Investigations almost all patients need to be tested for
Acetaminophen
6) Antidote if indicated

7) Enhance elimination if indicated

Acetominophen (Tylenol) Toxicity

N-acetyl-para-aminopheno (APAP)
APAP overdose is #1 cause of liver failure in US
Many formuations (Tylenol, Nyquil, Percocet, etc)
Actions:
o Centrally analgesic (inhibits prostaglandins)

o Peripherally analgesic (blocks pain impulse generation)

o Antypyretic inhibiton @ hypothalamus
90% APAP metabolized to non-toxic metabolites by the liver and
excreted in urine
10% metabolized to N-acetyl-para-amino=benzoquinomeimine
(NAPQI)
o reduced by glutathione into non-toxic mercapturic acid
o when glutathione stores depleted, NAPQI binds to liver
proteins causing dysfunction and cell death (liver toxicity)
o Inducers of CP450 have increased risk b/c increased
production of NAPQI
Ex: Smoking, barbituates, phenytoin, ING, chronic
EtOH, Carbamezapine

Clinical stages of Toxicity

o Stage I: 0-24 hours
minimal symptoms, but may have nausea, vomiting and
anorexia
for this reason Acetaminophen is considered a Toxic
Time Bombby the time you manifest real symptoms,
it is too late to reverse the toxicity
- for this reason it is crucial that all suspected
overdose patients get an APAP level!
Stage II: 24-48 hours
o RUQ pain, elevation of liver enzymes (usually in the
thousands), elevated INR/PTT and bilirubin
Stage III: 48-96 hours
o hepatic dysfunction: acidosis, bleeding, cerebral
edema/coma, death
5% of patients with APAP levels above the treatment
threshold who do not receive N-acetlycysteine within 8
hours will die of liver failure without a transplant
Stage IV: 96 hours to 2 weeks
o resolution of hepatic dysfunction
Testing

o Acetaminophen is potentially toxic at 150mg/kg

o A toxic 4 hour level would be 1300 umol/L
o A Toxic 8 hour level would be 800 umol/L
Treatment
o Decontaminiation
Activated charcoal if indicated
o Antidote
N-acetylcysteine (NAC/mucomyst)
In Canada given IV
Loading dose over 60 min, then 2 infusions

(4 and 16 hours) so total duration is 21

hours
Glutathione precursor
Converts NAPQI to non-toxic metabolite
Crucial to start within 8 hours
If > 8 hours, start anyway b/c it will reduce
chance of liver failure and death

Endocrine Drugs

4/21/2011 8:38:00 AM

Insulin & Anti-DM Agents

Diabetes Mellitus
o Impaired glucose homeostasis characterized by elevated
blood glucose
o Due to inadequate insulin production or impaired action or
both
Insulin secreted from islet B-cells in pancreas
o Glucose (or AAs or FAs) stimulate B cell receptors and are
broken down into ATP, causing closing of K+ channels
Depolarization from increase in K+ opens V-G Ca2+
channels and the release of insulin containing vesicles
o Catecholamines also regulate insulin release
A receptors on B-cells decrease insulin release
B receptors on A-cells increase glucagon release
o Actions
Increase glucose uptake of cells
In Liver via Glut2
In muscle and fat via Glut4
Glycogen, lipid and protein synthesis

Mitogenesis

Classification of DM
T1DM (10% of DM)
o Childhood or puberty onset
o Moderate genetic predisposition
o AI destruction of B-islet cells
o Often undernourished at onset of dz
o Ketonemia and ketoacidosis common

T2DM (90% of DM)

o Adult onset (>35)
o Very strong genetic predisposition
o Insulin resistance, reduced insulin secretion
o Obseity common

Complications of DM
o Retinopathy blindness

o Nephropathy dialysis or renal transplant

o Neuropathy neuropathic pain, ulcers, impotence
o CV CAD, HTN, Stroke
DM Treament
T1DM insulin, intensive therapy, Edmonton protocol
Insulin delivery system standard is SC injection
Drugs for T1DM
In increasing time of onset and duration of action:

Lispo-> Regular insulin -> NPH -> Lente -> Ultralente

All these preparations contain zinc and the ratio of zinc : insulin
influences rate of release and duration

Insulin Lispro
o Enters circ twice as fast as regular
Ultra-rapid onset and very short duration (3-4 hours)
Suitable to use immediately before meals
More drug only increases intensity, not duration

Regular insulin
o Rapid onset and short action (5-7 hours)
o Used IV in emergencies
Intermediate-acting insulin
o Includes:
Isophane insulin suspension (Netural Protamine
Hegadorn or NPH insulin)
Lente insulin (18-24 hours)
o Both SC, not for IV

Ultralente insulin
o To provide basal insulin level (>30 hours)
o Usually given in the morning only or morning and evening to
provide basal level for 12-24 hours
o Can be supplemented with injection of lispro or regular to
meet requirement of carb intake

Hazards of Insulin Use

Hypoglycemia / insulin shock

o Treatment with glucose (sugar or candy by mouth, glucose
IV) or glucagon IM
Insulin induced immunologic complication
o Insulin antibodies form -> insulin resistance

T2DM Management
Weight reduction/Exercise
o Increases insulin sensitivity and lowers blood glucose
o Central obesity = waist circumference >88 or >102 cm in

women or men, respectively

Dietary control
Oral antidiabetic agents (monotherapy)
Combination therapy

Oral Antidiabetic Drugs

Insulin secretalogues
o Sulfonylureas
Stimulate release of endogenous insulin
2nd gen:
Glyburide (Diabeta)
Inhibit Katp channels causing release of insulin
Decrease glucagon, and may increase insulin
receptors in peripheral tissues
SEs hypoglycemia, rash, allergy
o Repaglinide
Stimulate release of insulin by same mechanism
No effect in pts who lack working B-cells

Different from sulfonylureas b/c faster onset and short

action take just before meals

Biguanides
o Metformin
Unclear mech
Decrease liver gluconeogenesis, stimulate tissue
glycolysis, decrease GI absorption of glucose
Does NOT stimulate insulin release

Therefore doesnt cause hypoglycemia

SE GI distress (N+D), lactic acidosis in renal or liver
dz
Thiazolidinediones (TZD)
o Ex: Rosiglitazone
Mech
Activates PPAR-y regulating transcription of genes
of proteins for carb and lipid metabolism
Causing increased insulin sensitivity, glucose
uptake, deceased liver gluconeogenesis

Reduces fasting and postprandial glucose

Monotherapy or combo wih insulin or other anti-DM
drugs
SEs edema, anemia, induces CP450 3A4 can affect
concentrations of OCPs and cyclosporine
a-Glucosidase Inhibitors
o acarbose (Prandase)
inhibits enzyme in gut that converts starches to smaller
sugars for absorption
reduces post-prandial glucose and no effect on fasting
sugar
o Mono or combo therapy
o SEs are gas, diarrhea and cramping

Thyroid
Thyroid Hormone Synthesis
o Uptake of iodide ion
o Iodination

MIT, DIT
o Coupling
DIT+DIT = T4
MIT+DIT = T3
Thyroid hormone release
o Thyroglobulin is endocytosed and cleaved to release T3/T4
o T3/T4 bound to Thyroid-binding globulin (TBG) transport
protein in blood

o TSH and TRH stimulate release of hormones

o 80% is T4, 20% is T3
T3 5-10x more potent than T4
T4 converted to T3 in target cells, liver and kidney
Effect of Thyroid hormone
o Growth & Development
Absence of thyroid hormone Cretinism
o Calorigenic effect heat production
Increased O2 consumption
o CV effects
Augments sympathetic NS function
Thyroid Disorders
o Hypothyroidism low T4, high TSH
o Hyperthyroidism high T4, low TSH
Hypothyroidism
o Primary Hypothyroidism
Hashimotos Disease (most common)
AI attack on thyroid cells
Thyroid surgery
Dietary Iodine deficiency
Thyroid hypoplasia or enzume defects
o Secondary hypothyroidism
Pituitary or hypothalamus dysfunction
o In kids cretinism
Due to iodine deficiency or failed thyroid development
o In adults impaired physical and mental activity, slowing of
CV, GI and NM function
Lethargy, cold intolerance, weight gain, constipation,
skin-coarse and dry and cold
In severe hypothyroidism clinical syndrome called
Myxedema occurs
Dry and waxy swelling of skin (non-pitting
edema)
o Treatment
For all forms: T3/T4 replacement therapy

Synthetic Levothyroxine (T4) is the form of choice

Careful when giving it to older patients, more sensitive
to effects of thyroid hormones on their heart
Drug Interactions:
Anticoags thyroid hormones increase catabolism
of vit.K clotting factors, they potentiate effects of
warfarin bleeding
Anti-DM Rx may require more insulin or more
anti-DM rx b/c thyroid hormone will return BMR to
normal

Female hormones increases circulating TBG

therefore pts on OCP or pregnant may need more
thyroid hormone

Hyperthyroidism
o Graves Disease (most common)
abN production of Thyroid-stimulating immunoglobulin
(TSI)
goiter common
o also TSH secreting tumors, toxic nodular goiter, overdose for
hypothyroid treatment
o Manifestations of hyperthyroidism or thyrotoxicosis
Nervousness, emotional lability, weight loss, heat
intolerance, proximal muscle weakness, increased freq
of BMs, irregular menses
Acute thyrotoxicosis/aka Thyroid Storm
Usually provoked by infection, surg, trauma in
hyperthyroid pts
Life-threatening emergency
o Treatment
Anti-thyroid agents to inhibit synthesis and secretion of
T3/T4
Thiourea drugs
Propylthiouracil (PTU)
o Inhibits synthesis and conversion of
T4->T3
o For Graves disease

o SE rash (common), immune

reaction rare
o Caution in pregnant and nursing
women; can cross placenta and breast
milk (can cause Cretinism)

Iodide Salts
Lugols solution (iodine and potassium iodine)
Inhibit iodination of tyrosine
Used for short-term to treat thyroid storm
Rapid onset but transiet effects (thyroid
escapes the block)
Iodinated Radiocontrast media
Ex: Ipodate
Prevent conversion of T4->T3
Radioactive Iodine (RAI) Therapy
Taken up and concentrated in thyroid gland and
emits beta particales that destroy thyroid tissue
w/o damaging other tissues
Iodide salts used to inhibit iodine release after
Not in pregnant or nursing women
Surgery
Thyroidectomy
Reduce functional thyroid mass
Beta-blockers
Propranolol
Controlling tachycardia and other cardiac abN of
thyroid storm
Thyroid hormone and sympathetic NS work
synergistically on CV function, so increased
thyroid hormones can cause tachycardia and
arrhythmia

Bone

25% organic/cells
75% inorganic (hydroxyapatite)
o 99% calcium in body is stored in skeleton

Bone Mineral Homestasis

Involves 2 elements
o Ca2+ and Phosphate
3 Organs (intestines, bone, kidney)
4 Hormones
o PTH, Vit. D, calcitonin, and estrogen
Vitamin D
Vit.D converted to active form by hydroxylation in liver and kidney

o 1,25-(OH)2-D3
Osteomalacia/Rickets due to Vit. D Deficiency
Vit. D functions like a hormone (circulates and acts at different
places)
o Ultimately causing increased circulating Ca2+ and Phosphates
GI increased absorption
Kidney increased reabsorption
Bone increased bone resorption

Parathyroid Hormone
Acts on G-protein coupled receptors to increase cAMP in bone and
renal tubules
o Net effect is increase levels of Ca2+ and decreased PO4- and
increased osteoclast activity
Release inhibited by high Ca2+ and enhanced by low Ca2+ or high
Phosphate
o b/c phosphate can complex with ionized Ca2+
A major stimulus for synthesis of active Vit. D

o Negative Feedback to decrease PTH

No clinical use as a drug
o Vit. D and calcium supplement substitute for PTH replacement

Calcitonin
Secreted by C cells of thyroid in response to plasma Ca2+ lelvels
o Kidney decreases Ca2+ and PO4- reabsorption
o Bone opposite of PTH and Vit. D

Inhibits osteoclasts and decreases bone resorption

Protects against Ca2+ los during pregnancy or lactation
Good for management of hypercalcemia and Pagets Disease of
Bone where there is increased resorption of bone -> bone pain and
deformity
Injection or nasal spray

Estrogens
Estrogens and Selective Estrogen Receptor Modulators (SERMsraloxifene) can prevent or delay bone loss post-menopause
o Inhibition of PTH stimulated bone resorption
Decreases osteoclast differentiation/activation by
inhibiting IL-1 and TNF
Osteoporosis
Most common bone disorder
o Gradual reduction in bone masss weaknening bone and ->
fracture
Most common in post-menopausal women

o Most rapid BMD loss in 1st 5 years of onset of menopause

(generally at age 50)
Treatment
o Vit. D, Calcium
o Estrogen Replacement Tx
First line drug in post-menopausal women
o Raloxifene (SERMs)
Prevents osteoporosis w/o increasing risk for
endometrial cancer and estrogen positive breast cancer
o Alendronate (used in place of or in addition to estrogen) a
bisphosphonate

Pagets

Disease of Bone
2nd most common bone dz
bone deformities, bone pain and fractures
unknown cause

Treatment
o Calcitonin (intranasal)
o Bisphosphonates
Alendronate, Risedronate
Adsorb to hydroxyapatite and become permanent part
of bone structure
Reduce bone resorption by inhibiting osteoclast
activity

Osteomalacia/Rickets

AbN mineralization of bone matrix due to vit. D deficieincy and

osteoblast dysfunction
In kids = Rickets
Treatment
o Vit. D or Cacitriol

Bisphosphonates
Indications
o Osteoporosis

o
o
SEs
o
o

Pagets Disease
Hypercalcemia and osteolytic bone lesions (cancer)
Esophageal ulceration (if PO)
Mild nausea, dyspepsia, constipation/diarrhea

Bone Anabolic Agents

Fluoride
o A mitogen for osteoblasts

o Increases bone mass

o But leads to hydroxyapatite -> fluoroapatite which is denser
but more brittle
PTH (1-34)
1-34 fragment of PTH shown to be powerful anabolic agent to make
new bone
SC injection
Increased osteoclast activity (continuous PTH)

Increased osteoBLAST activity (one-daily PTH)

Steroids
Hypothalamo-pituitary axis with regard to CRH->ACTH -> Cortisol,
Aldosterone and androgens (DHEA)
Synthesized from Cholesterol
Glucocorticoids
Enter cell and nucleus and alter gene transcription and protein

synthesis
Effects of Nutrient Metabolism (Generally, increase circulating
nutrients)
o Stimulate gluconeogenesis (anti-insulin) and lipogenesis
o Activate protein catabolism
o Excessive glucocorticoid may lead to abN fat distribution,
muscle wasting
Anti-inflammatory Effects
o Inhibit macrophage cytokine release
o Inhibit T cell activiation and cytokine production
o Prevent mast cells and eosinophils from releasing inflamm
mediators
o Cause vasoconstriction and decrease capillary permeability
Other Effects
o Increase bone catabolism -> SE is osteoporosis
o Behavioral changes, peptic ulcers

Corticosteroids

Cortisol (Hydrocortisone)
o Major natural glucocorticoid
o Circadian rhythm (peak in am, and trough around midnight)
o 95% bound to corticosteroid-binding-globin in plasma
o small mineralcorticoid effect salt-retaining
o Important cause of HTN in patient with cortisol secreting
tumor or pituitary ACTH-secreting tumor (Cushings
Syndrome)

Aldosterone
o Major natural mineralcorticoid
o Important in regulating blood volume and BP
Synthetic Glucocorticoids and Mineralcorticoids
o Glucocorticoids
Triamcinolone
Dexamethasone
Prednisone
o Mineralcorticoids
Fludrocortisone

Glucocorticoids
Indications
o Adrenal insufficiency
Primary Adrenal Cortical Insufficency (Addisons
Disease)
All regions of cortex destroyed
Deficiencies in cortisol, aldosterone and
androgens

Hypoglycemia, fatigue, hypotension,

hyperpigmentation
Hydrocortisone used orraly in a manner that
mimics circadian rhythm or cortisol
Secondary Adrenal Insufficiency
Caused by prolonged use of exogenous
glucocorticoid
Therefore, chronic glucocorticoid Tx should
whenever possible, be tapered slowly; decreasing

doses
o Congenital Adrenal hyperplasia
Specific enzy,e deficiencies that impair synthesis of
cortisol and aldosterone
o Diagnosis of Cushings Syndrome
o Nonadrenal Disorders
Inflammatory or immunologic in nature (Asthma, organ
transplant rejection, collagen Dz)

Cushings Syndrome
Caused by hypersecretion of glucocorticoids
o Excessive ACTH (pituitary adenoma most common) or Adrenal
adenomas
Dx often based on:
o Free cortisol level in urine
o Results of dexamethasone suppression test (not for adrenal
adenoma)
Given dexamethasone PO and measure serum cortisol

over 4 days
If plasma [cortisol] decrease to less than 50% of
baseline, pituitary adenoma indicated
b/c giving glucocorticoid will
If not, adrenal tumor or ectopic ACTH-producing tumor
is indicated
Clinical Features
o Moon face
o Buffalo hump
o Weight gain
o Hirsutism
o Muscle wasting
o Thinning of skin
Treatment
o Surgical excision
o Adrenal steroid inhibitors

Corticosteroid Antagonists

Receptor Antagonists
o Spironolactone
Aldosterone receptor antagonist
o Mifepristone
Glucocorticoid and progesterone receptor antagonist
Used in Tx for Cushings
Synthesis Inhibitors
o In Tx of adrenal cancer, if surgery impractical or mets

o Ketoconazole (antifungal)
Inhibits p450 enzymes, therefore inhibiting synthesis of
all steroids
For adrenal carcinoma, hirsutism, breast cancer
o Aminoglutethimide
Blocks cholesterol -> pregnenolone
o Metyrapone
Inhibits cortisol synthesis
Dx test of adrenal function
Gonadotropic and Gonadal Hormones
GnRH
FSH
o Ovarian follicle development
o Secretion of estrogen
o spermatogenesis
LH
o Estrogen and progesterone synthesis in ovaries
o Testerone synthesis in testes
Ovarian Hormones
Estrogens (Estradiol, major in women)
o Indication
Primary hypogonadism
HRT in menopause
Compnent of OCPs
o SEs
When used as HRT, risk of endometrial cancer

(Prevention w/ Progestin)
Progestins (Progesterone, major in humans)
o Indications
Component of OCPs and implantable contraception
In HRT to prevent endometrial cancer
Suppress ovarian function in Tx of dysmenorrheal,
endometriosis, uterine bleeding

Hormonal Contraceptives
OCPS
o 3 types
Monophasic constant dosage
Biphasic & Triphasic
Progestin doses rise during the month (mimics
natural cycle)
Progestin only
Prevents LH surge that simulated ovulation
o Cause feedback inhibition of gonadotropin release from

pituitary (LH, FSH)

Post-coital
o Prevent pregnancy if used w/in 72 hours after unprotected
intercourse
Adverse Effects
o Thromboembolism
Major toxic effect
Increased blood coag, -> MI, stroke, DVT and PE
o Breast Cancer

Selective Estrogen Receptor Modulators (SERMs)

Mixed estrogen agonists that have estrogen agonist effects in some
tissues and act as partial agonists or antagonists of estrogen in
other tissues
o Tamoxifen & Raloxifene
Estrogen receptor antagonists in breast tissue to
prevent or treat Breast Cancer
Agonist effect in bone prevent osteoporosis in postmenopause
But tamoxifen is an agonist at endometrium ->
risk of cancer
Ramoxifene no effect on endometrium
Estrogen and Progesterone
Clomiphene
o Non-steroid

o Increases FSH and LH

o Block estrogen receptors in puiitary, reducing negative
feedback
o Used to induce ovulation
Mifepristone
o Synthetic steroid
o Progesterone antagonist, used in medical abortion

Androgens
Testosterone & Methyltestosterone

o Indications
HRT in hypogonadism
Anabolic steroids used illicitly by athletes to increase
body mass, strength and performance
o SEs
Male decrease testicular size and function, impotence
Female hirsutism, masculinization
Anti-androgens
o Leuprolide GnRH analog
o Ketoconazole, Spironolactone inhibit steroid synthesis
o Finasteride
5a-reductase inhibitor
o Flutamide, cyproterone receptor inhibitors

Oral Contraception
Mechanism of action
o Gross inactivity of ovarian functions: Inhibition of ovulation or
ovum production by decreased release of pituitary

gonadotropins (FSH, LH) NO OVULATION high dose

estrogen and progestin combined effect
o Cervical mucus and Decreased uterine motility: Makes the
mucus thick and viscous, which inhibits the penetration of
sperms- progesterone effect
Contraindications
o CHF
o Vascular disease

HTN
Liver dz, Cholestatic Jaundice, severe depression
Reactions
OCP with anticonvulsants (barbiturates, Phenytoin) reduce
the efficiency of the former due to increased hepatic
metabolism of OCP due to induction of p450.
o OCP with antibiotics (eg. Ampicillin/amoxcillin) reduce the
OCP efficacy due to increased intestinal excretion and reduced
enterohepatic reabsorption of estrogens.

o
o
Drug
o

Mifepristone
o A steroid antagonist that competes with progesterone
and cortisol at their receptors and block their effects.
o It is Helpful in the termination of pregnancy (during the first
53 days only).
o It is also useful in the Pharmacological management of
Cushings Syndrome (Excess Cortisol or Tumor of the Adrenal
Cortex) and Endometriosis.

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