graphesthesia - tracing letter on skin. indicate sensory deficit pariatel lobe
five ways drugs alter target cells; alteration of body chem, antacids, mannitol; absorption
of toxins, electrolytes; questran, charcoal; imposition of a physical barrier, sulcrafate,
sunscreen; lubrication, talcum powder; alteration of surface tension, stool softeners.
agonist i - bind to very same receptor at site that natrual biomediator would epi, norepi, opiate;
agonist ii- bind to different site on recepter, but by binding to recepter enhance effect
of biomediator on its OWN receptor. i.e, they increase intrinsic activity of biomediator
examples are thyroid meds and benzos
antagonist- have affinity for receptors but lack intrinsic activity on them. they occupy receptor
preventing occupancy of natural endogenous biomediators.
antagonist i - bind to same site as natrual biomediator. i.e atropine, and h-2 receptor blockers
agonist ii - have different site but partially inhibit action of natural compound. CCB's
antagonist iii - translocate through the plasma membrane, inhibiting signal on inside of the cell
ex. primacor, phosphodiesterase inhibiters (theophylline), viagra
sustained administration of agonists results in down-regulation of receptors, and antagonists
result in up-regulation.
ED50 lies somewhere on the steep curve of the log dose-response curve.
four processes of pharmacokinetics; absorption, distribution, metabolism, excretion
determines 1. ABSORPTION: the solubility of the drug. Fastest to slowest
1. Liquids (elixirs, syrups, mists, aerosols)
2. Suspensions
3. Powders
4. Capsules
5. Tablets
6. Enteric-coated tablets
7. Sustained-release tablets
2. PHYSICAL PROPERTIES OF THE DRUG. Fat soluabl drugs can easily cross cell membranes lipid content.
Endothelial cells (blood vessel lining) holes are called aqueous pores and epithelial cells (mucosal cells)
are called tight junctions. If a drug molecular makeup has no net positive or negative charge and has
equal charges throughout the molecule then it is fat soluble (non-ionized, non-polarized). Hence, Water
soluble absorb more slowly.
weak acid drugs include phenobarbital, pentobarbital, acetaminophen, and aspirin (absorbed faster
in the stomach (pH 1.4 – 2))
weak bases include cocaine, ephedrine, chlordiazepoxide, and morphine. (absorbed at faster rate in
intestine pH 7.50 – 8)
3. area of absorptive surface – i.e lung and gi mucosa has large absorptive surface area so absorption is
very fast.
4. BLOOD SUPPLY AT ABSORPTIVE SURFACE – GOOD sources are intestinal tract, the lung, and skeletal
muscle
5. THE LENGTH OF TIME THE DRUG IS IN CONTACT WITH THE ABSORBING SURFACE –
Vomiting and diarrhea do not give drug very long contact with surface, thus poorly absorbing if at all.
Mouth PH 6.8
[Note: This accounts for the commonly noted marked differences in doses for the oral and I.V.
preparations of the same drug with the recommended dose for the oral formulations frequently being
ten times the dose recommended for the same drug administered I.V. (FIRST PASS EFFECT)
If rectal suppository is placed high in the rectum, the medication is absorbed into the superior
hemorrhoidal veins that drain into the portal system. These drugs may undergo significant first-pass
metabolism, decreasing their pharmacologic effect (see metabolism). If suppository is placed low in
the rectum, the drug is absorbed into the systemic venous system, by-passing the first-pass
metabolic effect.
Fat soluble drugs are typically highly protein bound, leaving less free drug circulating. Highly bound 80100 percent, weakly protein bound 20-30 percent
can reduce the availability of albumin-binding sites include hypoalbuminemia, hyperbilirubinemia,
excessive high serum fatty acid levels, and occasionally renal failure. [Note: In some patients with
renal failure, an unknown metabolic products accumulates in the blood and apparently attaches to
the albumin-binding sites, eliminating them from providing binding capability for highly protein-bound
drugs.]
There are two areas in the body that, despite being well-perfused, have special anatomic
configurations which prevent the free and equal distribution of drugs to the tissues and organs they
protect. These two areas are the brain (protected by the blood-brain-barrier) and the developing
fetus (protected by the placenta). Of these two, the most efficient is the blood-brain-barrier that
allows some fat-soluble drugs to pass but denies access to the brain of many water-soluble drugs.
The placenta is much less efficient in this regard; although drugs may be delayed in crossing,
eventually almost all drugs can get across the placenta.
Process for drug biotransformation:
a. Reduction in pharmacologic activity of the drug : In the absence of this three dimensional
relationship, affinity and intrinsic activity of a drug for its targets is radically altered. This, in
turn, results in marked reduction or even elimination of the normal pharmacologic
(pharmacodynamic) activity of the drug.
b. Enhancement of the pharmacologic activity of the drug: initially the drug is metabolized to
where the three dimensional structure changes in such a way as to make it more compatible
to target receptor or enzyme. This seems contrary to the usual purpose of metabolism (i.e.,
decreasing the drug-induced alterations) but this is not the complete story. This metabolite is
further metabolized (e.g. by phase II reactions); these additional changes in the drug's
structure do reduce the drug's pharmacological effects.
c. Activation of a prodrug: There are some medications called prodrugs that, in the form in
which they are administered, have no pharmacological activity (i.e. they lack both affinity and
intrinsic activity). Many of the drugs administered in clinical medicine are actually prodrugs.
The reasons for administering a drug as a prodrug include inability to administer the active
metabolite orally and insufficiently short shelf life of the active metabolite. Pharmaceutical
companies understand how the body will metabolize the parent prodrug and plan on using
these metabolic processes to convert their product into the active form of the drug.
d. Enhancement of excretion: The two components of drug clearance from the body are
metabolism and excretion. Both of these mechanisms work in concert to eliminate the
"unwanted foreign substance" (i.e., drug). Because most drugs are eliminated from the body
by way of renal excretion, any parent drug or metabolite which is fat soluble or minimally
water soluble can be restructured by either phase I or phase II enzyme reactions to become
more water soluble and more likely to be excreted in the water of the urine.
e. Detoxification of foreign substances:
Determinants of drug metabolism: physiologic status of liver, hepatic enzyme induction and inhibition,
first pass effect. Occasionally, diet factors will affect metabolic rates.
Excretion: The great majority of the drugs and the drug metabolites that result from
biotransformation are eliminated by renal excretory mechanisms. Other routes by which drugs are
excreted include the bile, the stool, breast milk, the lungs, saliva, and sweat. Mechanisms include
GFR, renal tubular secretion.
Gfr- Drugs and metabolites are filtered through the pores in Bowman's Capsule in the renal
glomerulus and enter the lumen of the nephron at this level. Only free drug and free metabolites are
capable of being filtered by this mechanism; any drug or metabolite that is bound to serum albumin
cannot be filtered because the albumin molecule is too large to fit through the pores in the capsule.
Therefore anything attached to the albumin will not pass. This process of filtration is a timed event
and the amount of drug (and metabolite) that is excreted in this way is dependent on the total
number of functioning glomeruli and, especially, the renal blood flow (i.e., the glomerular filtration
rate [GFR]).
(2) RENAL TUBULAR SECRETION - In the proximal convoluted tubule of the renal nephron there
are excretory channels capable of actively pumping drugs and metabolites from the blood against a
concentration gradient into the lumen of the nephron. This active process does require energy
expenditure on the part of the renal epithelial cells. The energy is in the form of ATP (adenosine
triphosphate). Drugs actually have to compete for these excretory pathways with waste products.
Free drug (i.e., not bound to protein) is excreted by this mechanism. Albumin bound drug is also
excreted by this pathway because the renal epithelial cell possesses enzyme systems which are
capable of cleaving drug molecules from the drug binding sites on the albumin molecule. The
amount and the rate by which drugs are excreted by this mechanism are not dependent on renal
blood flow but rather are determined by the drug's serum concentration.
Distal renal tubular reabsorption - Acidic drugs become less ionized (i.e., more fat soluble) in acid
urine but alkaline drugs become more ionized (i.e., more water soluble) in acid urine. The opposite is
true for alkaline drugs entering acid urine. If the urine is alkaline, then the converse is true (i.e.,
acidic drugs become more ionized in alkaline urine and alkaline drugs become less ionized in
alkaline urine). Therefore, the pH of the urine is a main determinant of drug reabsorption. Urinary pH
can be altered by other drugs. An example of this concept is the treatment of aspirin overdose. In
those patients who accidentally or intentionally take an overdose of aspirin, toxic effects from the
drug can be minimized by enhancing the rate of elimination of the drug from the blood. Aspirin is an
acidic drug. Administering to the patient sodium bicarbonate that is itself excreted in the urine can
increase its renal excretion. As the sodium bicarbonate enters the urine it changes the pH of the
urine to alkaline (or at least less acidic). The aspirin (acidic) drug becomes more ionized in the
alkaline urine; the now more ionized aspirin drug molecules become more water-soluble and pass
through the renal nephron without being reabsorbed. They are eliminated more quickly. This
accelerates the clearance of aspirin from the patient's blood. The more ionized the more water
soluble, the easier to pass through renal nephron bypassing absorption.
- Increased (Gastric) HCl Secretion - The normally increased serum levels of estrogen always
present in pregnancy are thought to be responsible for an increased secretion of HCl in the stomach.
This can result in a reduction in the pH of gastric juice that, in turn, alters the ionization of drug
molecules in the stomach. If drug molecules become more ionized in a more acid environment (as
occurs with alkaline drugs), they become more water-soluble and will be absorbed more slowly,
delaying their onset of action. If they become less ionized in an acid environment (as occurs with
acidic drugs), they will become more fat soluble, increasing the rate of absorption and possibly
speeding their onset of action.
Teratogenic effects can only occur during the period of fetal organogenesis. For the great majority of
organ systems this is day 18 (week 3) to day 55 (week 8) of gestation. [Note: Injury to palate, limbs,
and GU tract may occur as late as week 12-15.]
For example, barbiturates are weak acids, whereas amphetamines and opiates are weak bases
Changes in liver function- The phase I pathway of metabolism is often reduced in the elderly, which
may have the effect of decreasing clearance of certain drugs (certain benzodiazepines) and
prolonging the half-life of elimination. Although data are limited, drugs with high rates of first-pass
metabolism (calcium channel blockers, tricyclic antidepressants and major tranquilizers) should be
administered cautiously as lower doses may be sufficient to see therapeutic effects.
Between the ages of 20 and 90 renal function declines on average of 35%.
Unit 2
TYPE A: INTRINSIC ADVERSE DRUG REACTION - A direct (excessive) extension of the known
pharmacodynamic actions of the drug (or its metabolites).
TYPE B: IDIOSYNCRATIC ADVERSE DRUG REACTION - An uncommon, unpredictable ADR that
is not explained by the known pharmacodynamics of the drug or its metabolites.
Allergic reactions can be manifested on the skin only (hives, rashes, whelps, etc.) or they can cause
a severe systemic reactions (anaphylaxis, bronchospasm, hypotension, gastrointestinal
disturbances, etc.).
When the response is directly opposite to what is expected from the drug the reaction is called a
paradoxical response
7 step process: establishing a diagnosis – subjective, objective, lab and xrays
2. choosing a specific drug – interactions, pt compliance, etc.
3. deciding on a dose and form to be prescribed 4. determine whether dose will actualy be taken
5. what will be the drug concentration in plasma or tissue – drug absorption, distribution, metabolism,
excretion
6. what will be pharmacologic response – time of course of action, drug pharmacodynamics
7. what will be ultimate drug response – therapeutic response
pharmacodynamic drug-drug interactions, pharmacokinetic drug-drug interactions
(part of pharmacokinetic interactions). Alteration of Gastric pH - Drugs which alter gastric pH will
change the rate of dissolution of other orally administered solid medications, change the degree of
ionization of weakly acidic or weakly basic drug molecules, change the water/fat solubility of drug
molecules, and either enhance or inhibit absorption across intestinal absorptive surfaces. (Example:
antacids, H2 receptor blockers)
Hepatic enzyme inhibitors generally have an immediate effect as opposed to hepatic enzyme
inducers (see above).
As with the gastric pH, drugs which alter the pH of the urine will affect the degree of ionization (and
the water/fat solubility) of other drugs present in the urine. Drugs which are highly ionized (and water
soluble) at a given urinary pH will remain in the water of the urine and will be more readily excreted,
increasing their excretion and decreasing their clinical effects. Drugs which are less ionized (and
more fat soluble) at a given urinary pH will be more likely to be reabsorbed from the urine back into
the blood in the distal renal tubule, decreasing their excretion and increasing their clinical effects.
* (Example: URINE ALKALINIZERS - sodium bicarbonate, antacids, certain diuretics)
* (Example: URINE ACIDIFIERS - ammonium chloride, any drug causing metabolic
acidosis)
What are the physiologic determinants of each of these factors?
1. HEART RATE
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Circulating Catecholamines (especially norepinephrine, epinephrine, and dopamine)
Serum Calcium Ion Concentration
The Neurotransmitters of the Autonomic Nervous System (especially norepinephrine and
epinephrine)
2. STROKE VOLUME
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Myocardial Contractility (the muscular force with which the ventricle contracts)
Ventricular Preload (the force exerted on the ventricular wall by the contained volume of blood
inside)[Note: Ventricular preload is proportional to end-diastolic ventricular volume or the amount
of blood contained inside the ventricle at the end of ventricular diastole.]
Ventricular Afterload (the force that the ventricle must contract against) [Note: In the case of the
left ventricle, left ventricular afterload is proportional to systemic arterial blood pressure.]
Blood Volume (this refers to the total circulating blood volume)
Venous Tone (this refers to degree of contraction of the venous smooth muscles and the
diameter of the venous vasculature which is proportional to the amount of blood volume
"temporarily held" in the venous side of the circulation).
Serum Calcium Ions (this relates directly to the force of muscular contraction in both cardiac
muscle and vascular smooth muscle).
Serum Catecholamines
Neurotransmitters
Renal Function (as it relates to total circulating blood volume).
3. TOTAL PERIPHERAL RESISTANCE
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Arteriolar Smooth Muscle Tone (this relates to the degree of contraction of smooth muscles in
the wall of arterioles and the diameter of these vessels which is proportional to the amount of
resistance created by the peripheral arteries to the flow of blood out of the left ventricle).
Blood Viscosity (this relates to the thickness of blood which, in turn, is proportional to hematocrit
and to some extent to the amount of solutes (fat and protein) contained in the blood).
Arterial Elasticity (the amount of stretch allowed within the walls of the major arteries and aorta
to the sudden ejection of blood by the left ventricle).
Neurotransmitters
The adrenergic receptors are further divided into alpha 1, alpha 2, beta 1 and beta 2 receptors.
There are three main concepts relating to these receptors that will assist in understanding the
pharmacodynamics of the cardiovascular drugs. These are (1) their activation, (2) their function, and
(3) their location. These receptors are activated by both the naturally occurring catecholamines and
neurotransmitters and the agonist drugs of these naturally occurring substances. As a general rule, if
the receptor has a subscript of 1, when it is activated, the target cell upon which it is located will be
stimulated (e.g., if a muscle cell, the muscle cell will contract; if a nerve cell, its firing will increase). If,
on the other hand, the receptor has a subscript of 2, when activated, the target cell where it is
located will experience a decrease in its function (e.g., if it is a muscle cell, it will relax; if a nerve cell,
its firing will become less frequent).
1. Alpha 1 - located (1) on the vascular smooth muscle cells of the walls of arteries that supply blood
to the skin, mucous membranes, kidney and intestinal tract, (2) on the smooth muscle cells of the
walls of veins, and (3) on the radial muscles of the iris of the eye (i.e., the muscles that are
responsible for pupillary dilation).
2. Alpha 2 - located on the nerve cells of the cardiovascular control center in the brain stem.
3. Beta 1 - located (1) on the myocardial muscle cells and the cardiac conduction system cells in the
heart, (2) on neurons in the brain, and (3) on the intraocular fluid producing cells inside the eye.
4. Beta 2 - located (1) on the bronchial smooth muscle cells that line the bronchus and bronchioles,
(2) on the smooth muscle cells in the walls of the arteries that supply blood to the skeletal muscles,
and (3) on liver cells associated with the enzyme systems responsible for glycogen synthesis. [Note:
Activation of these receptors results in decreased entry of glucose into the liver and more glucose in
the blood.]
If ventricular preload increases too much, however, excess strain is placed on the wall of the left
ventricle and heart failure ensues with decreased stroke volume and decreased cardiac output.
Interaction and activation of alpha 2 receptors by hormones or endogenous drugs results in a sharp
reduction in sympathetic nervous system output to the heart and the vascular beds (arterial and
venous). Reduction in sympathetic stimulation of these organs results in decreased activation of
alpha 1, beta 1, and beta 2 receptors.
In addition, blockade of the beta 1 receptors in the eye will result in a decrease in the production of
intraocular fluid and will benefit patients with glaucoma.
List of Available Thiazide Diuretics in the Treatment of Hypertension distal renal tubules to block the
reabsorption of the filtered load of NaCl from the nephron back into the blood
- hydrochlorothiazide (HCTZ) (HydroDiuril)
- chlorothiazide (Diuril)
- chlorthalidone (Hygroton)
- indapamide (Lozol)
- metolazone (Zaroxolyn)
List of Available Loop Diuretics in the Treatment of Hypertension The loop diuretics exert their
effects in the loop of Henle of the renal nephron. Block reabsorption of nacl back into the blood and
increase renal blood flow (thus gfr). They are water soluble and highly protein-bound.
- furosemide (Lasix)
- bumetanide (Bumex)
- ethacrynic acid (Edecrin)
- torsemide (Demedex)
List of Available Potassium-Sparing Diuretics
spironolactone (Aldactone)
eplerenone (Inspra)
amiloride (Midamor)
tri they block the interaction of aldosterone with its receptor in the distal renal tubule and prevent the
excretion of potassium in exchange for sodium amterene (Dyrenium). Spironolactone is a prodrug,
requiring hepatic metabolism. Eplerenone has a shorter half-life than its predecessor spironolactone.
Triamterene is partially metabolized in the liver but amiloride is not metabolized at all. All are
excreted in the urine.
- Spironolactone has anti-androgenic effects and may cause gynecomastia. Eplerenone is less likely
to do so. Also - May cause bone marrow suppression (thrombocytopenia, agranulocytosis);
List of Available Centrally-Acting Alpha 2 Adrenergic Agonists
alpha - methyldopa
clonidine (Catapres)
guanfacine (Tenex)
Alpha-methyldopa is usually administered orally but can be given I.V. It is a prodrug and requires
hepatic metabolism for activation to its pharmacologically active form. It is excreted in the urine.
Clonidine and the others are not prodrugs, are administered orally, and are metabolized in the liver
and excreted in the urine. Clonidine is also available in a transdermal formulation.
Clonidine, especially in its transdermal formulation, is also used for the vasomotor symptoms of the
post-menopausal syndrome; - Clonidine reduces the tendency for reflex tachycardia Commonly
causes impotence and decreased libido beyond what is caused simply by a reduction in blood
pressure. - Associated with a rebound hypertension upon too rapid reduction in dose or
discontinuation of the drug. Patients on long-term therapy with this drug require gradual reduction in
dose (usually over 2-3 weeks) if the drug must be discontinued.
- Special disadvantages of alpha-methyldopa (Aldomet):
1. Drug-associated hepatitis (requiring discontinuation of the drug)
2. Bone marrow suppression
3. Delayed onset of action because of its required hepatic activation
List of Available Selective Alpha 1 Blockers
prazosin (Minipress)
doxazosin (Cardura)
terazosin
results in decreased peripheral resistance of the arterial system and decreased venous return from
the venous system. Decreasing arterial resistance is the most effective mechanism of reducing
blood pressure and the decreased cardiac output resulting from reduction in venous return is an
additive effect. Can significantly reduce left ventricular afterload as a peripheral vasodilator and can
be effective in the management of congestive heart failure. - May increase the sensitivity of insulin
receptors; this improves the efficacy of insulin, especially in diabetics and would be a good choice
for antihypertensive therapy in diabetics.
May increase the sensitivity of insulin receptors; this improves the efficacy of insulin, especially in
diabetics and would be a good choice for antihypertensive therapy in diabetics.
Has dual action for decreasing blood pressure; (decreases peripheral resistance and decreases
cardiac output). Having more than one mechanism to achieve correction of the same
pathophysiologic mechanism makes any drug more effective.
Relaxes bladder neck spasm; this improves urinary output and drainage from the prostate in patients
with benign prostatic hypertrophy (BPH). [Note: There are also alpha 1 receptors on the smooth
muscle cells of the bladder neck. Blocking them results in widening of the diameter of the bladder
neck at the level of the prostate.] In male hypertensive patients who also have BPH, it is a significant
advantage to be able to treat two different problems with one drug.
Commonly produces impotence in male hypertensive patients. Commonly produces nasal stuffiness;
by blocking alpha 1 receptors in the vascular smooth muscles of the arterioles of the nasal mucosa,
there is a vasodilatation of nasal arterioles and capillaries, promoting leakage of fluid into the
interstitial spaces of the nasal mucosa which swells and blocks nasal passages.
List of Available Adrenergic Neuron Blockers
Reserpine
These drugs lower blood pressure by either directly preventing the release of norepinephrine from
sympathetic nerve endings or by depleting the nerve endings of stored norepinephrine and
therefore, indirectly preventing its release. Reserpine depletes norepinephrine stores from
adrenergic nerve endings. By interfering with the actions of norepinephrine, the normal blood
pressure elevating mechanisms that are mediated by norepinephrine and the sympathetic nervous
system are prevented. Inexpensive. 1-2 weeks for med to reach peak effect. Common cause
dizziness and sedation. Contraindicated in pre-existing psychological depression, linked to suicide.
Nasal stuffiness/swelling
Beta Adrenergic Antagonists (Beta-blockers)
In this category, there are 3 subcategories of medications:
- Non-Selective Beta-blockers
- Combination non-selective Beta-blocker and selective Alpha 1 Blockers
- Selective Beta 1 Blockers
List of Available Non-Selective Beta-blockers
Drugs with Non-selective Beta-blocker action only:
propranolol (Inderal)
nadolol (Corgard)
pindolol
penbutalol (Levatol)
timolol
sotalol (Betapace)
pin tim nad with a PEN, so props
Combination Non-selective Beta-blockers and Selective Alpha 1 Blockers:
labetalol (Trandate)
carvedilol (Coreg)
The non-selective Beta-blockers are antagonists to the adrenergic neurotransmitters (i.e.,
norepinephrine and epinephrine) on both the Beta 1 and Beta 2 adrenergic receptors. The Beta 1
receptors are located on: 1) the cardiac electrical system and on the myocardial muscle cells, 2)
certain brain cells, 3) the ciliary body of the eye, and 4) renin-producing cells in the kidney. The Beta
2 receptors are located on 1) the vascular smooth muscle cells of the skeletal muscle arteries, 2) on
the smooth muscle cells that line the bronchioles, and 3) liver cells. By blocking the Beta 1 receptors
in the heart, heart rate slows and myocardial contractility decreases. Both of these actions decrease
cardiac output and blood pressure. These are the main therapeutic actions of the nonselective Betablockers when used in the therapy of hypertension. Blockade of the other Beta 1 receptors is
responsible for other pharmacologic or clinical indications, specifically glaucoma and psychological
anxiety states. When used in the therapy of glaucoma, the main action of beta 1 blockade is to
reduce the production of intraocular fluid from the ciliary body of the eye that decreases intraocular
pressure. This is therapeutic in patients with either open-angle or closed-angle glaucoma. By
blocking Beta 1 receptors in the brain, there results a generalized reduction in the activation of Beta
1-mediated CNS stimulation which is useful in the treatment of mild anxiety states such as stage
fright. Blockade of Beta 2 receptors in the lungs and in the peripheral muscular arteries is not a
therapeutic action of these drugs but is responsible for many of the adverse effects of these drugs
They prevent reflex tachycardia associated with lowering of blood pressure; by blocking Beta 1
receptors, any reflexive sympathetic stimulation of the heart to increase cardiac output triggered by a
sudden lowering of blood pressure is prevented. [Note: Blockade of reflex tachycardia is dangerous
in diabetics because this normal reflexive reaction (along with anxiety) is the diabetic's earliest
warning signal to alert him/her to hypoglycemia.] Renin release is a Beta 1 function in the kidney;
blockade of this Beta 1 receptor blocks any component of hypertension caused by elevated serum
levels of renin and, therefore, angiotensin II. Reduces potential for arrhythmias; blockade of Beta 1
receptors in the heart decreases the electrical system and reduces electrical excitability and the
potential for both tachycardia and tachyarrhythmias. Non-selective Beta-blockers can also be used
for angina, arrhythmia therapy, migraine headaches, and hyperthyroidism; the use of one drug for
multiple simultaneous therapeutic indications is a distinct advantage in favor of better compliance.
Some non-selective Beta-blockers are available with intrinsic sympathomimetic activity (ISA); these
drugs (pindolol, penbutolol) Betablockers with ISA are generally safer to use in diabetics (they do
not produce as much hypoglycemia), in patients with peripheral vascular disease (they do not
cause as much peripheral vasoconstriction), and in patients with hyperlipidemias (they do not
increase cholesterol and triglycerides as much). The ISA Beta-blockers do not cause as much
bradycardia and have less of an inhibitory effect on cardiac output. - Commonly results in Beta
receptor up-regulation and target cell hypersensitivity; this effect requires that Beta-blocker drugs
that have been used for any length of time be withdrawn slowly (over three weeks) to prevent
rebound tachycardia, angina, hypertension, etc.
List of Available Selective Beta 1 Blockers
metoprolol (Lopressor)
atenolol (Tenormin)
betaxolol (Kerlone)
acebutolol (Sectral) (has intrinsic sympathetic activity ISA)
bisoprolol (Zebeta)
esmolol (Brevibloc)
only blocks beta 1, spares beta 2 at normal doses.
Note: atenolol is not metabolized at all
BY NOT BLOCKING BETA 2, relatively safe for asthma, diabetics, and pt with PVD.
List of Available ACE Inhibitors
captopril
enalopril (Vasotec)
benazepril (Lotensin)
lisinopril (Prinivil) (Zestril)
fosinopril (Monopril)
moexipril (Univasc)
perindopril (Aceon)
quinapril (Accupril)
ramipril (Altace)
trandolapril (Mavik)
the normal actions of angiotensin II (peripheral arterial vasoconstriction and stimulation of
aldosterone secretion by the adrenal gland) are blocked. have multiple mechanisms by which they
lower blood pressure; they reduce peripheral arterial resistance, decrease aldosterone-stimulated
increase in blood volume, and increase vasodilation. Multiple mechanisms of action. Tends to
increase serum potassium. Can help offset hypokalemia of thiazides if taken together. Can help
delay diabetic nephropathy. May reduce complications in patients with chronic stable angina.
Very potent, especially with renal insufficiency. contraindicated in patients known to have bilateral
renal artery stenosis. teratogenic and toxic in pregnancy; ACE inhibitors are contraindicated in
pregnancy.
(only captopril is administered BID)
List of Available Calcium Channel Blockers
verapamil (Calan)
nifedipine (Procardia)
diltiazem (Cardizem)
amlodipine (Norvasc)
felodipine
isradipine
nicardipine (Cardene)
nisoldipine (Sular)
inhibiting the entry of calcium ions into muscle cells (especially arteriolar and venous smooth muscle
and cardiac muscle). In this way, these drugs decrease the force of contraction of these muscle cells
The result is a decrease in myocardial contraction, a decrease in cardiac output, a decrease in
peripheral vascular tone and peripheral resistance, and a decrease in blood pressure. The three
types of receptors that are blocked are the diphenylalkylamine-based and benzothiazepinebased (type 1) and dihydropyridine-based (type 2) receptors. ] They are highly protein-bound.
short serum half-life. oral bioavailability is limited due to extensive first-pass hepatic metabolism.
Some (especially verapamil and diltiazem) ease the strain on the heart by decreasing myocardial
oxygen consumption; this is an advantage for patients with ischemic heart disease also. are also
used for angina, arrhythmias, M.I., migraine headache
Verapamil (Calan) is most likely to cause this effect (bradycardia)
Amlodipine has half-life of 30-50 hours. Others may need sustained-release forumulas due to short
duration of action.
Arrythmias more likely with verapamil and nifedipine, bradyarrythmia most common.
Constipation from blocking cc in the gi tract, inhibiting peristalsis
Expensive. Can worsen GERD by relaxing esophageal smooth muscle. CCB not considered safe for
pregnancy. Drugs that inhibit cyp-450 system and grapefruit juice may increase free drug levels.
List of Available Direct-Acting Vasodilators
ORAL AGENTS:
- hydralazine
- minoxidil
PARENTERAL AGENTS:
- nitroprusside (Nitropress) (also produces vasodilatation)
Decreases peripheral vascular resistance.
The direct-acting vasodilators do not inhibit the sympathetic compensatory mechanisms that are
activated by a lowering of blood pressure. As a result, the pharmacologic effects of the direct-acting
vasodilators are accompanied by reflex tachycardia, renin release, aldosterone activation
(reninangiotensin- aldosterone system), sodium and water retention, and absence of orthostatic
hypotension.]
Minoxidil is also available as a topical agent (Rogaine)
Nitroprusside has a unique metabolite (thiocyanate) that can accumulate and cause thiocyanate
(cyanide) poisoning which is characterized by tinnitus, confusion, hyper-reflexia, metabolic acidosis,
arrhythmias, hypotension, and death. All direct-acting vasodilators are excreted in the urine.
Absence of orthostatic hypotension.
Apresoline produces a lupus-like syndrome; long-term therapy with oral Apresoline can cause
myalgia, arthralgia, fever, and rashes
Not first line drugs
List of Available Angiotensin II Receptor Antagonists (also called ARBs)
losartan (Cozaar)
valsartan (Diovan)
irbesartan (Avapro)
candesartan (Atacand)
eprosartan (Teveten)
azilsartan (Edarbi)
olmesartan (Benicar)
telmisartan (Micardis)
Common combinations with the thiazides:
losartan + HCTZ (Hyzaar)
eprosartan + HCTZ (Teveten HCT)
olmesartan + HCTZ (Tribenzor)
telmisartan + HCTZ (Micardis HCT)
azilsartan + chlorthalidone (Edarbyclor)
They block angiotensin II-stimulated vasoconstriction and angiotensin II-stimulated aldosterone
secretion.
Dual routes of excretion; drugs that have two routes of excretion do not generally require dosage
adjustments (i.e., reductions) in patients with renal insufficiency.
Glucose neutral; good drugs to use in diabetics.
Lipid neutral; good drugs to use in patients with hyperlipidemias.
Contraindicated in pregnancy; has caused an increased incidence of fetal death especially in the
second and third trimesters. Very expensive. Some report persistent nocturnal cough. h/a and
diarrhea sometimes reported.
In hypertensive patients aged 60 years of age or older who do not have diabetes or chronic kidney
disease, treat to a blood pressure goal of less than 150/90 mmHg. In all other hypertensive patients,
including patients aged 18 to 59 years of age, patients with diabetes, or patients with chronic kidney
disease (CKD), treat to a blood pressure goal of less than 140/90 mmHg.
In most patients with uncomplicated hypertension, initiate therapy with a thiazide diuretic, an ACE
inhibitor, an ARB, or a calcium channel blocker, either alone or in combination. Initial therapy in the
black hypertensive population, including those with diabetes, should include a thiazide diuretic or a
calcium channel blocker, alone or in combination. It is also recommended to initiate therapy with an
ACE inhibitor or ARB, alone or in combination with another drug class, in persons with CKD to
improve kidney outcomes. The new guidelines also introduce new recommendations designed to
promote safer use of ACE inhibitors and ARBs; it is recommended to avoid concomitant uses of
these drug classes.
If goal blood pressure cannot be reached using the recommended drug classes because of a
contraindication or the need to use more than 3 medications, medications from other drug classes
can be used
POTENTIAL FOR ADVERSE DRUG REACTIONS
1. Avoid drugs that alter blood glucose in the therapy of hypertensive patients with diabetes.
2. Avoid drugs that increase serum lipids in the therapy of hypertensive patients with hyperlipidemia.
3. Avoid non-selective Beta-blockers in patients with peripheral vascular disease.
4. Avoid drugs that induce sedation in the therapy of patients who must remain alert during the day.
5. Avoid drugs that induce impotence in the therapy of male hypertensive patients.
6. Avoid drugs that cause hyperkalemia in patients with renal insufficiency.
Cholesterol
CKD
Diabetes
PVD
hyperkalemia
Prostate
ARBs
ARBs
ARBs
Selective Beta
1 Blockers
ACE inhibitor
hyper
Selective
Alpha 1
Blockers
pindolol,
penbutolol
ACE inhibitor
ACE inhibitor
pindolol,
penbutolol
hypokalemia
increases the
risk of digoxin
toxicity
Thiazides
Selective Beta
1 Blockers
pindolol,
penbutolol
Non-selective
Beta-blockers
Selective Alpha
1 Blockers
Thiazides
(hyperglycemia)
Older people
CHF
avoid selective alpha
1 receptor blockers
and calcium channel
blockers
caution
precaution when using
diuretics
Isosorbide
dinitrate
and hydralazine in
combination may be
beneficial in African
American patients with
moderate to severe
CHF who are already
in using beta-blockers
and calcium channel
blockers
on beta blockers and
an ACE inhibitor.
CO-MORBID CONDITIONS
1. Pregnancy
2. Diabetes
3. Hyperlipidemia
4. Gout (hyperuricemia)
5. Migraine
6. Asthma (bronchospastic conditions)
7. Peripheral vascular disease
8. Coronary Artery Disease (angina)
In African-Americans, calcium channel blockers and thiazide diuretics are particularly effective, alone
or used in combination.
AGE-RELATED CONCERNS
- Older adults are more susceptible to orthostatic hypotension than other patients; avoid selective
alpha 1 receptor blockers and calcium channel blockers in this population if possible.
- Older adults are more susceptible to constipation than other patients; calcium channel blockers
may aggravate constipation if already present.
- Older adults are more likely to have CHF than other patients; exercise caution
in using beta-blockers and calcium channel blockers in them.
- Older adults already have a contracted blood volume; use precaution when using diuretics in them
(i.e., may have to use a lower than normal dose to begin therapy).
Most Expensive→ → →Least Expensive
1. Calcium channel blockers
2. Angiotensin II antagonists (ARBs)
3. ACE inhibitors
4. Selective alpha 1 receptor antagonists
5. Beta-blockers (non-generic)
6. Reserpine Large clinical trials have shown that combined treatment with reserpine plus a thiazide diuretic
reduces mortality of people with hypertension
7. Beta-blockers (generic)
8. Diuretics
Treatment of Heart Failure
The major categories used are angiotensin converting enzyme inhibitors (ACE-I), diuretics (loop and
thiazides), beta adrenergic receptor antagonists (beta blockers), cardiac glycosides and nitrates.
ACE inhibitors-all but perindopril (Aceon)
1) they reduce peripheral arterial resistance and, thereby, decrease left ventricular
afterload and 2) they decrease aldosterone-stimulated increase in blood volume
which lowers left ventricular preload and wall stress. These mechanisms achieve the
objectives of reduction in cardiac work load, reduction of blood volume, restriction of
sodium reabsorption, and improvement of cardiac ejection fraction (i.e., the
percentage of end-diastolic ventricular volume that is ejected into the aorta with each
systole). - Useful in patients with renal insufficiency; ACE inhibitors improve
intrarenal blood flow and are somewhat protective of the kidney. May provoke a
persistent, dry cough; the mechanism for this is due to interference with bradykinin
LOOP DIURETICS. Water soluble. highly protein bound. Though not a therapeutic effect of the loop
diuretics, the reabsorption of potassium and chloride ions is also blocked leading to hypokalemia and
hypochloremia.
When given IV, diuresis begins in about 5 minutes. 1) produces early reduction of left ventricular filling
pressure. This effect on the left ventricle begins even before diuresis begins and may be mediated
through the stimulation of a prostaglandin and 2) produces late reduction of left ventricular filling
pressure secondary to diuresis and reduction of blood volume. Excessive dosing may be needed in
patients with renal insufficiency .Diuretics have not been shown to improve mortality.
List
of
Thiazide
Diuretics
Used
in
Acute
Congestive
Heart
chlorothiazide
hydrochlorothiazide
Chlorthiazide (Diuril) is the only thiazide diuretic that can be administered I.V. and is useful
congestive heart failure for this reason
Failure
(Diuril)
(HCTZ)
in acute
Thiazides can increase cholesterol and cause hyperglycemia. Impairs release of insulin
List of Selective and Non-Selective Beta Blockers Used in Stable Congestive Heart Failure
NON-SELECTIVE
BETA
BLOCKERS
carvedilol
(Coreg)
SELECTIVE
BETA
BLOCKERS
metoprolol (Lopressor) (Toprol XL)
Over time, beta blockers can be beneficial to heart function by improving left ventricular ejection
fraction. The cardiac glycoside (digoxin) binds to and blocks the enzyme Na-K ATPase which is the
activator of the Na-K pump in excitable cells (i.e., cardiac muscle, cardiac electrical conductive cells,
and nerve cells in the central nervous system). By blocking this enzyme, it is prevented from activating
the pump that keeps sodium ions on the outside of these cells. As sodium ions accumulate inside
these cells, they in turn, trigger (through a sodium-calcium exchange port) the accumulation of calcium
ions in the cells. It is this increased influx of calcium that is responsible for the increased force of
contraction of myocardial cells and the increase in stroke volume, cardiac output, renal perfusion, and
decrease in left ventricular filling pressure and preload. Not protein bound, not metabolized. Short half
life. - Useful in patients with concomitant liver disease since it is not metabolized.
hypokalemia increases the risk of digoxin toxicity. concomitant use of St. John's wort (Hypericum
perforatum) may decrease plasma digoxin levels by up to 25%.
Isosorbide dinitrate and hydralazine in combination may be beneficial in African American patients
with moderate to severe CHF who are already on beta blockers and an ACE inhibitor.
Other Drugs that can
morphine
dobutamine
dopamine
milrinone
nitroprusside (Nipride)
be
used
in
managing
acute
CHF
in
hospitalized
patients
sulfate
(Dobutrex)
(Intropin)
(Primacor)
morphine It may have something to do with the release of histamine. The vasodilatation is more
prominent on the venous side of the circulation but also occurs on the arterial side. Venous
vasodilatation causes decreased venous return to the heart which results in decreased left ventricular
preload, decrease wall stress and decrease in heart size. This, in turn, results in improved cardiac
pumping
performance.
less than 10 min onset IV.
Pharmacodynamics of Dobutamine in the Management of Acute Congestive Heart Failure
Dobutamine is primarily an agonist on B 1 receptors but also has slight agonist activity on Beta 2
receptors and alpha 1 receptors. By activating Beta 1 receptors, dobutamine increases the force of
myocardial contraction. This action will result in an increase in cardiac stroke volume and cardiac
output and cardiac pumping performance. These effects put this drug in the category of a positive
inotrope. By having slight activity on alpha 1 receptors, dobutamine will increase peripheral resistance
slightly and will elevate blood pressure. Although activation of Beta 1 receptors normally increases
heart rate, this usually does not happen with dobutamine (except as an adverse effect). Note: An
increase in heart rate will produce an increase in the need for oxygen by the heart. Since most cases
of heart failure are the result of ischemic conditions in the myocardium, any increase in heart rate is
detrimental.] the addition of nitroglycerin or nitroprusside will improve the efficacy of dobutamine (i.e.,
a pharmacodynamic potentiative drug-drug interaction). Contraindicated in atrial fibrillation, the
improvement in A-V conduction can result in excessively fast ventricular response in atrial fib and lead
to ventricular tachycardia.
Pharmacodynamics of Dopamine in the Management of Acute Congestive Heart Failure
The
pharmacodynamics
of
dopamine
are
dose
dependent:
1. At low doses, dopamine activates special dopaminergic receptors located on renal, intestinal,
coronary, and cerebral arterial smooth muscle cells. Activation of these receptors results in
vasodilatation
and
improved
blood
flow
to
these
organs.
2. At moderate doses, dopamine activates Beta 1 receptors in the heart, improving myocardial
contractility, stroke volume, cardiac output, and cardiac pumping performance. Dopamine also
increases
heart
rate
by
this
mechanism.
3. At high doses, dopamine activates alpha 1 receptors on peripheral arteries resulting in
vasoconstriction, increased peripheral resistance, and elevation of blood pressure. myocardial oxygen
supply is increased. This is often needed in patients with acute CHF because acute CHF is often on
the basis of ischemic heart disease. ; the best results with dopamine in acute CHF are achieved only
with concurrent administration of nitroglycerin or nitroprusside. accidental administration of dopamine
subcutaneously will produce excessive alpha 1 receptor activation in the arteries of the skin. This
results in an ischemic infarct of skin and skin sloughing. iljrfgbifhvgbfvf
Milrinone is an antagonist of the enzyme phosphodiesterase. By blocking the actions of this enzyme
in the heart muscle, myocardial cells experience an increase in intracellular calcium which increases
the force of myocardial contraction.
The
three
types
Chronic
stable
angina
(also
Variant
angina
(also
called
Unstable
angina
(also
of
angina
called
effort
or
classic
vasospastic
or
Prinzmetal
called
pre-infarction
are:
angina)
angina)
angina)
Since coronary blood flow is greatest during diastole, coronary blood flow in increased which increases
myocardial oxygen supply.
Calcium channel blockers are administered orally; (some [verapamil and diltiazem] can be given I.V.).
Short duration of action; calcium channel blockers require TID or QID dosing to be effective.
ANTI-THROMBOTIC DRUGS
This group contains both antiplatelet drugs and anticoagulants.
List
of
aspirin
clopidogrel
dipyridamole
dipyridamole/aspirin
prasugrel
ticagrelor
ticlodipine
List
dabigatran
dalteparin
enoxaparin
heparin
rivaroxaban
warfarin (Coumadin)
the
Antiplatelet
Drugs
(Plavix)
(Persantine)
(Aggrenox)
(Effient)
(Brilinta)
(Ticlid)
of
the
sodium
Anticoagulants
(Pradaxa)
(Fragmin)
(Lovenox)
(Liquaemin)
(Xarelto)
Pharmacodynamics of the Anti-Thrombotic Drugs
PHARMACODYNAMICS of aspirin
- Aspirin binds to and blocks the synthesis of the enzymes cyclooxygenase I and II (COX I and COX
II). This action prevents the formation of the prostaglandin thromboxane A2 which promotes the
agglutination of platelets. By blocking the agglutination of platelets, blood clotting is markedly slowed
and the tendency for a patient to form a thrombus (on an ulcerated atherosclerotic plaque, for
instance) is prevented.
PHARMACODYNAMICS of clopidogrel, ticlodipine, prasugrel and ticagrelor
- Clopidogrel, ticlodipine, prasugrel and ticagrelor bind to surface proteins on platelets and block
platelet-to-platelet aggregation as well as attachment of platelets to exposed collagen. By preventing
the binding of platelets in this way, the potential for intravascular clotting (i.e., coronary thrombosis)
is reduced.
PHARMACODYNAMICS of dipyridamole
- Dipyridamole's mechanism of action is unknown but is believed to interfere with platelet
agglutination in some way. It also has some coronary artery vasodilating effect but, again, the
mechanism for this is unclear.
PHARMACODYNAMICS of heparin, dalteparin, and enoxaparin
- Heparin and its low molecular weight (LMW) fractions, dalteparin and enoxaparin, work by
accelerating the actions of a naturally occurring anticoagulant protein called antithrombin III.
Antithrombin III irreversibly binds to enzymatic proteins that trigger the clotting cascade. By binding
to these proteins, clotting is slowed. The heparin-type drugs increase the binding between
antithrombin III and the clotting proteins and intravascular clotting (i.e., thrombosis) is prevented. In
addition, the LMW fractions directly inhibit clotting factor Xa, one of the essential factors in the
formation of prothrombin.
PHARMACODYNAMICS OF rivaroxaban
Rivaroxaban is an orally active, direct factor Xa inhibitor. It inhibits the first step in the common
pathway similar to the LMW fractions.
PHARMACODYNAMICS dabigatran (Pradaxa)
Dabigatran is an orally active direct thrombin (factor IIa) inhibitor.
PHARMACODYNAMICS of warfarin
- Warfarin interferes with the liver synthesis of clotting factors X, IX, VII and prothrombin.
Pharmacokinetics of the Anti-Thrombotic Drugs
PHARMACOKINETICS of aspirin, clopidogrel, ticlodipine, prasugrel and ticagrelor
- These drugs are administered orally. All of them are metabolized in the liver. Aspirin is not highly
protein bound and is excreted in the urine. Clopidogrel, ticlodipine, prasugrel and ticagrelor are
highly protein bound, are extensively metabolized in the liver and are excreted both in the urine and
in the bile.
PHARMACOKINETICS of heparin, dalteparin, and enoxaparin
- The heparin-type drugs are only administered parenterally (I.V. or subcutaneously).
PHARMACOKINETICS
OF
rivaroxaban
Rivaroxaban is is administered orally. Rivaroxaban exhibits almost compete absorption and is highly
protein bound. It does go through some degree of hepatic metabolism and is primarily eliminated
renally.
PHARMACOKINETICS
dabigatran
(Pradaxa)
Dabigatran is administered orally. Bioavailability of dabigatran is low, but the capsule design aids in
absorption. The prodrug dabigatran etexilate is converted to dabigatran (active form) by hydrolysis.
Dabigatran is not a substrate, inhibitor, or inducer of CYP450 enzymes and is primarily eliminated
renally.
PHARMACOKINETICS
of
- Warfarin is administered orally, metabolized in the liver and excreted by the kidney.
warfarin
DISADVANTAGES OF ASPIRIN, CLOPIDOGREL, TICLODIPINE, PRASUGREL AND
TICAGRELOR
- Excessive bleeding; the actions of these drugs on the platelet are permanent and irreversible for the
life of the platelet with the exception of ticagrelor. Any excessive interference with platelet function with
this drug will last for a while (i.e. several days). Ticagrelor exhibits reversible binding with full recovery
of platelet upon withdrawal.
Aspirin causes GI distress (i.e., gastritis, ulceration, etc.); by blocking COX I, protective gastric mucus
production is inhibited and the stomach is damaged by its own acid. [Note: Ticlodipine and clopidogrel
do not have this problem.] concomitant use of aspirin and Ginkgo biloba may have an additive effect
on platelet inhibition and increase the risk for spontaneous bleeding. Ticlodipine may cause bone
marrow suppression including thrombocytopenia which may result in excessive bleeding; CBC and
platelet count must be monitored
Heparin Cannot be withdrawn abruptly; abrupt discontinuation of heparin will cause rebound
hypercoagulation and may provoke re-thrombosis.
DISADVANTAGES
OF
- Lag time of several days (range 36 - 72 hours) between initial dosing and effect
WARFARIN
concomitant use of St. John's wort (Hypericum perforatum) with warfarin may decrease the
anticoagulant effect of warfarin.