An agonist is a compound that binds to a re- where CLx is clearance of substance X in ml/

ceptor and produces the biological min

response.
U, is the urine concentration of substance X in
A partial agonist produces the biological re- mg/ml
sponse but cannot produce 100% of the
biological response even at very high doses. V is the urine flow rate in ml/min

Efficacy is the maximal response a drug can P, is the plasma concentration of substance X
produce. Potency is a measure of the in mg/ml
dose that is required to produce a response.
RENAL EXCRETION
Antagonists block or reverse the effect of ag- Renal elimination of drugs involves three phys-
onists. They have no effect of their iological processes: glomerular filtration, proxi-
ow mal tubular secretion, and distal tubular
reabsorption
FIRST-PASS EFFECT
The liver is a metabolic machine and often in-
activates drugs on their way from the Gitract to The autonomic nervous sys-
the body. This is called the first-pass effect.
tem
Drugs cross membranes by passive diffusion -is responsible for
or active transport. maintaining the internal environment of the
A drug tends to pass through membranes if it body (homeostasis).
is uncharged.
Within the autonomic nervous system, two
Uncharged drugs are more lipid soluble than neurons are required to reach a target organ, a
charged drugs. In addition many drugs are preganglionic neuron and a postganglionic
weak acids or weak bases. neuron.

Bioavailability is the amount of drug that is All preganglionic neurons release acetyl-
absorbed after administration by route X choline as their transmitter. The
compared with the amount of drug that is ab- acetylcholine binds to nicotinic receptors
sorbed after intravenous (IV) on the postganglionic cell.
administration.
X is any route of drug administration other than Epiniphrine- epi is above a, nephrite is ki-
IV. deney. Above the kidney which is adrenal
gland and epinephrine is called adrenergic
Bioavailability = AUC oral / AUC IV
Autonomic nervous system
Clearance is a term that indicates the rate at • Sympathetic
which a drug is cleared from the body. It is de- • Catabolic
fined as the volume of plasma from which all • Thoracolumbar
drug is removed in a given time. Thus the units • Long postganglionic
for clearance are given in volume per unit time. Parasympathetic
• Anabolic
Clearance = Rate of removal of drug (mg/min) • Craniosacral
/ Plasma concentration of drug (mg/min) • Short postganglionic
Total body clearance is the sum of the clear- All of the parasympathetic postganglionic
ances from the various fibers release acetylcholine. At the target
organs involved in drug metabolism and elimi- organ acetylcholine interacts with mus-
nation. carinic receptors.
CLx = Ux x V
Px Acetylcholine is synthesized from acetyl
coenzyme A (acetyl CoA) and choline. Its • EDROPHONIUM
action is terminated by • NEOSTIGMINE
acetylcholinesterase. • PYRIDOSTIGMINE
• ambenonium
There are two major classes of receptors • demecarium
for acetylcholine, muscarinic and nico- • physostigmine
tinic
Irreversible Inhibitors
• malathion
These muscarinic receptors are
• parathion
predominantly found in the viscera (GI
• sarin
tract).
• soman
Nicotinic receptors are found at the motor
PRALIDOXIME and ATROPINE are used
end plate, in all autonomic ganglia, and in
to treat poisoning with organophosphates
the adrenal medulla.
The prototypic muscarinic antagonist is
Activation of Muscarinic Recep- ATROPINE.
tors Results in the Following:
• Eye Miosis (constriction of pupil) All of the muscarinic antagonists are competi-
• Cardiovascular Decrease in heart rate tive antagonists for the binding of acetylcholine
to the muscarinic receptor
• Respiratory Bronchial constriction and
increased secretions
The effects and side effects of these drugs are the
• Gastrointestinal (Gl) Increased motility, opposite of the drugs considered in the previous
relaxation of sphincters chapter (the cholinomimetics)
• Genitourinary (GU) Relaxation of sphinc-
ters and bladder wall contraction • Eye Mydriasis, cycloplegia (blurred vision)
• Skin Reduced sweating, flushing
DIRECT CHOLINERGIC • Gastrointestinal (Gl) Reduced motility and se-
AGONISTS cretions
• Esters • Cardiovascular Increased heart rate (high
• BETHANECHOL doses)
• carbachol
• Respiratory Bronchial dilation and decreased
• Alkaloids
secretion
• muscarine
• pilocarpine • Genitourinary (GU) Urinary retention

BETHANECHOL is used in the treatment Muscarinic Antagonists

of urinary retention • ATROPINE
• benztropine
Carbachol administered ocularly to induce • IPRATROPIUM
miosis to reduce intraocular pressure in • SCOPOLAMINE
the treatment of glaucoma is also used to - Muscarinic antagonists are used preopera-
stimulate micturition by contraction of tively to reduce secretions.
detrusor muscle.
- SCOPOLAMINE is used to prevent motion
sickness.
Muscarine is a nonselective agonist of the
muscarinic acetylcholine receptors. - IPRATROPIUM is used in the treatment of
chronic obstructive pulmonary disease
Pilocarpine is a medication used to reduce (COPD) to produce bronchodilation.
pressure inside the eye and treat dry
The competitive neuromuscular blocking drugs
are used to produce skeletal muscle
CHOLINESTERASE INHIBITORS relaxation.
Reversible Inhibitors
SUCCINYLCHOLINE is a depolarizing neu-
romuscular blocker.

Nondepolarizing Blockers
• d-TUBOCURARINE mivacurium
• Lisatracurium pipecuronium gallamine
vecuronium
• atracurium PANCURONIUM
• doxacurium rocuronium

The neuromuscular junction (and other cholin-

ergic synapses) can also be blocked by drugs
that block the release of acetvlcholine.

Botulinum toxin blocks the release of acetyl-

choline at all cholinergic synapses.

We usually think of botulinum toxin as a very

potent poison that causes botulism.
However, it has found a therapeutic use in the
treatment of prolonged muscle spasm and for
excessive sweating. A small amount of the toxin
is injected directly into a muscle fiber paralyzing
the muscle, or in the skin blocking stimulation of
the sweat glands. Botulinum toxin

• Most of the sympathetic postganglionic

fibers release norepinephrine. At the tar-
get organ norepinephrine interacts with a va-
riety of receptors.

• The effect of NE is terminated predominantly

by reuptake into the neuron from which it
was released.
• Norepinephrine can also be inactivated by en- Only EPINEPHRINE and NOREPINEPH-
zymes in the liver (mostly) and brain (some). RINE activate both a and ß
receptors.

NOREPINEPHRINE has a relatively

low affinity for ß2 receptors
PHENYLEPHRINE a1 agonist Nasal
decongestant

The degradative enzymesare called COMT

(catechol-omethyltransferase) and MAO CLONIDINE a2 agonist Decreases blood pres-
(monoamine oxidase sure through a central action

The general catecholamine structure is DOBUTAMINE 31 agonist Increases heart rate

illustrated. The catechol group consists of a ben- and cardiac output
zene ring with two hydroxyl groups.
ISOPROTERENOL ß1 = ß2 agonist
Receptors for NE are divided into a and B re-
ceptors. These receptors are further ALBUTEROL, TERBUTALINE,
subdivided, into a1and a2, 1, B2, and B3 metaproterenol B2 agonist Relieve bronchocon-
striction
• a1 activation of a1 receptors causes contrac-
tion or constriction, mostlyvasoconstriction At low doses, DOPAMINE causes renal and
coronary vasodilation. It also activates ß1
• a2 activation of presynaptic a2receptors re- receptors in the heart.
sults in feedback inhibition of the release of A
norepinephrine. AMPHETAMINE and its relatives,
dexmethylphenidate and methylphenidate, are
• ß1 heart contains mostly , increases heart rate central nervous system stimulants used to treat
attention deficit hyperactivity disorder in
• B2 receptors are found in skeletal muscle children.
blood vessels and the bronchial smooth
• muscle, receptors relaxes smooth muscle Adrenergic Antagonists
• B3- adipose tissue
a2 Agonists reduce sympathetic nerve activity
and are used to treat
hypertension
Isoproterenol- for pregnant women given to re-
lax the uterus
a1 antagonists
• PRAZOSIN,
Adrenergic Agonists • Terazosin,
Remember that: • Doxazosin,
• a1 = most vascular smooth muscle; agonists • Trimazosin
contract
• ß1 = heart; agonists increase rate Most of the a antagonists allow vasodilation and,
thus, decrease blood
• ß2 = respiratory and uterine smooth muscle; pressure
agonists relax
TAMSULOSIN and silodosin are specific an- A. Thiazides
tagonists of the a1 A receptor and B. Loop diuretics
are used in the symptomatic treatment of benign C. Potassium (K+)-sparing diuretics
prostatic hypertrophy II. Drugs that interfere with the renin-an-
The "-azosins." such as PRAZOSIN, are used giotensin system
in the treatment of A. ACE inhibitors
hypertension. B. Angiotensin I receptor antagonists (ARBs)
C. Aldosterone antagonists
B BLOCKERS Remember that: D. Direct renin inhibitor (DRI)
• ß1= heart; antagonists decrease rate
• B2 = smooth muscle; antagonists contract Ill. Drugs that decrease peripheral vascular
resistance or cardiac output
This latter effect translates into bronchial con-
A. Direct vasodilators
striction, which may be dangerous in
1. Calcium channel blockers
asthmatics
2. Nitrates
B. Sympathetic nervous system depressants
The -blockers have widespread use in the man-
1. a- and B-Blockers
agement of cardiac arrhythmias, angina and
2. Clonidine
hypertension.
-Blockers should be used with caution in diabet-
ics. Thiazide Diuretics
• CHLOROTHIAZIDE
In response to hypoglycemia (low blood glucose) • HYDROCHLOROTHIAZIDE
the sympathetic nervous system • chlorthalidone
stimulates an increase in blood glucose through • metolazone
B receptors. Blocking this response with a ß-
blocker will cause the blood glucose to remain
• indapamide
low. In addition, the reflex increase in heart • hydroflumethiazide

Nonselective Loop Diuretics

PROPRANOLOL • FUROSEMIDE
• carteolol • bumetanide
• levobunolol • ethacrynic acid
• nadolol • torsemide
• penbutolol
• pindolol Potassium-Sparing Diuretics
• timolol • SPIRONOLACTONE
• amiloride
Beta1 Selective
• acebutolol
• triamterene
• atenolol • eplerenone
• betaxolol
• bisoprolol Spironolactone and eplerenone are antago-
• esmolol nists of aldosterone at the mineralocorticoid re-
• metoprolol ceptor and can be used to treat hypertension.

• Labetalol has both a- and -blocking activ- The renin-angiotensin-aldosterone system

ACE inhibitors block the synthesis of an-
ity.
giotensin II
• Carvedilol belongs to a class of drugs known
as alpha and beta-blockers.
• ACE Inhibitors
• CAPTOPRIL
Drugs That Affect the Cardiovascular • moexipril
System • ENALAPRIL
I. Diuretics • perindopril
• benazepril pindolol 31 and 32antagonist plus some sympa-
• quinapril thomimetic activity
• fosinopril
• ramipril
• lisinopril
• trandolapril

Angiotensin I Receptor blockers

• Candesartan Antiarrhythmic Drugs
• eprosartan Organization of Class
• Losartan • Class I Drugs (Sodium Channel Blockers)
• irbesartan • Class I Drugs (ß-Blockers)
• Olmesartan • Class Ill Drugs (Potassium Channel Blockers)
• telmisartan • Class IV Drugs (Calcium Channel Blockers)
• valsartan
Notice that, so far, the names of the drugs in the Class I Drugs (Sodium Channel Blockers)
preceding box all end Class IA Drugs
in “-sartan. However, this is no guarantee that • PROCAINAMIDE
new ones under development will • QUINIDINE
retain the • Disopyramide
Calcium channel blockers inhibit the entry of Class IB Drugs
calcium into cells. They cause • LIDOCAINE
a decrease in afterload.
The most common side effects of the calcium • mexiletine
channel blockers (headaches, • phenytoin
dizziness,hypotension, etc.) are related to vasodi- • Tocainide
lation.
NITRATES Class IC Drugs
• Nitrates • flecainide
• NITROGLYCERIN • propafenone
• amyl nitrite
• isosorbide dinitrate The class I antiarrhythmics are ß-blockers
CLASS III DRUGS POTASSIUM CHANNEL
• isosorbide mononitrate BLOCKERS
NITROGLYCERIN is the most commonly used
antianginal agent. It is the • BRETYLIUM
drug of choice for relieving acute coronary • AMIODARONE
spasm. • dronedarone
Hydralazine and minoxidil directly relax arteri- • dofetilide
oles. • inutilice
Summary CLASS IV DRUGS (CALCIUM CHANNEL
The a1antagonists, such as PRAZOSIN, tera- BLOCKERS)
zosin, and doxazosin, dilate arteries and veins.
-Blockers prevent sympathetic stimulation of the OTHER ANTIARRHYTHMIC DRUGS
heart. DIGOXIN is used to control the ventricular rate
Some -Blockers Used to Treat Hypertension in
atenolol B1antagonist atrial fibrillation or flutter.
metoprolol ß1 antagonist
carvedilol ß1antagonist with a-blocking activity
labetalol ß1antagonist with a-blocking activity Drugs That Affect Blood
nadolol ß1 and ß2antagonist Antiplatelet Drug- Nonsteroidal anti-inflam-
PROPRANOLOL B1and BZantagonist matory drugs (NSAIDs), including
timolol ß1and B2antagonist
aspirin, inhibit platelet aggregation and prolong • tenecteplase
bleeding time. • lanoteplase
• NSAIDs, including aspirin • Urokinase
• anagrelide
• clopidogrel -Anticoagulant and antiplatelet drugs are ad-
• dipyridamole ministered to prevent the formation or extension
• prasugrel of clots. Thrombolytic drugs are used to lyse al-
ready formed clots.
• ridogrel
• ticlopidine
IlB/IlIA receptor antagonists
• abciximab - thrombolytic drugs are plasminogen activa-
• eptifibatide tors
• tirofiban
- The main side effect of the thrombolytic
Platelet glycoprotein Ilb/Illa receptor antago- drugs is bleeding
nists prevent platelet
aggregation by blocking the binding of fibrino- - STREPTOKINASE is a foreign protein and is
gen and von Willebrand factor to the antigenic. t-PA is not antigenic.
glycoprotein Ilb/illa
receptor on the surface of the platelet.
Drugs Used to Treat Anemia
Anticoagulant Drugs • ERYTHROPOIETIN
Heparin and LMWH • IRON
• HEPARIN • cyanocobalamin (vitamin B12) l
• ardeparin • epoetin alfa, darbepoetin alfa
• tinzaparin • folic acid
• dalteparin danaparoid • Iron salts, such as ferrous sulfate, are used as
iron supplements to treat iron deficiency Ane-
• enoxaparin mia
Oral anticoagulants • Epoetin alfa and darbepoetin alfa are human
• Warfarin recombinant erythropoietins .Side effects peo-
• Dicumarol ple report most often are various types of gas-
trointestinal distress
• HEPARIN interferes with clotting factor acti-
vation in both the intrinsic and extrinsic Path- Lipid-Lowering Drugs
way Drugs
• LOVASTATIN
• PROTAMINE is a specific heparin antagonist • atorvastatin
that can be used to treat heparin-induced
Hemorrhage
• cerivastatin
• fluvastatin
• Warfarin, a vitamin K antagonist, is the oral • pitavastatin
anticoagulant of choice. Administration of vi- • pravastatin
tamin K can overcome the anticoagulant ef- • rosuvastatin
fects of the oral agents, • simvastatin
• Mechanism
THROMBOLYTIC DRUGS • Inhibit HMG-CoA reductase
• STREPTOKINASE
• reteplase Drugs
• alteplase • CHOLESTYRAMINE
• t-PA • colesevelam
• anistreplase • colestipol
• EZETIMIBE To be a useful antibiotic, a compound should in-
• niacin hibit the growth of bacteria
without harming the human host.
• bezafibrate
The drug should penetrate body tissues in order
• clofibrate to reach the bacteria
• fenofibrate
• gemfibrozil Spectrum-as in narrow, broad, and extended-is
Mechanism a term used to convey an
• Bile acid-binding resins impression of the range of bacteria that a drug is
• Inhibits absorption of cholesterol effective against.
• Increase lipoprotein lipase activity Resistance of bacteria to an antibiotic can occur
by mutation, adaptation, or
Drugs Used in Parkinson Disease gene transter
THERAPY FOR PARKINSON DISEASE
1. Dopamine replacement therapy Adverse effects can be allergic, toxic, idiosyn-
2. Dopamine agonist therapy cratic, or related to changes in
3. Anticholinergic therapy the normal body flora.
• LEVODOPA (L-dopa) is a metabolic precur-
sor of dopamine that crosses the blood-brain Combinations of antimicrobial agents can take
barrier advantage of the mechanisms
• CARBIDOPA is a dopamine decarboxylase of action to produce a synergistic effect.
inhibitor that does notcross the blood- brain Culture and sensitivity testing will determine the
barrier. It reduces the peripheral metabolis- MIC (minimum inhibitory
mof levodopa, thereby increasing the amount concentration) for the bacteria
of levodopa that reaches the brain.
• Tolcapone and entacapone are plasma Antimicrobial Drug Classes
catechol-o-methyltransferase (COMT) in- Inhibitors of Cell Wall Synthesis ß-Lactams
hibitors that prolong the half-life of levodopa • aztreonam
SELEGILINE (also known as deprenyl) is an in- • carbapenems
hibitor of monoamine oxidase (MAO)-B, the en-
zyme that metabolizes dopamine in the central
• cephalosporins
nervous system (CNS) • penicillins
Others bacitracin daptomycin fosfomycin
Amantadine is an antiviral drug effective in the vancomycin
treatment of influenza. It appears to enhance the
synthesis, release, or reuptake of dopamine from CLAVULANIC ACID and SULBACTAM are
the surviving nigral neurons, so it can also be B- lactamase inhibitors that are given together
used in Parkinson disease. with the ß-lactam drugs to increase their effec-
tiveness.
Dopamine agonists used in the treatment of
Parkinson disease include bromocriptine, Folate Antagonists
pergolide, pramipexole, ropinirole, and sulfonamides and trimethoprim
rotigotine

Activation of dopamine receptors in the

pituitary gland inhibits prolactin release. This
reduction in prolactin can alter reproductive
function.

Trihexyphenidyl, benztropine, and biperiden

are muscarinic antagonists used in
Parkinson disease.

Introduction to Chemotherapy