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Introductory Pharmacology

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Terms

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Alpha 1 Agonists
α1
Phenylephrine
Methoxamine
Alpha 2 Agonists
α2
Clonidine
Beta 1 Agonists
β1
Isoproternol
Dobutamine
Beta 2 Agonists
β2
Terbutaline
Dopa Agonists
Dopamine (D1)
Fenoldopam (D1)
Bromocriptine (D2)
Quiniprol (D3)
Acts on uterine smooth muscle to relax, can be used to prevent preterm labor.
Terbutaline
Dopamine agonists used to treat Parkinson's
bromocriptine
cabergoline
pergolide
pramipexole
ropinirole
D1 agonist used to increase vasodilation
Fenoldopam
Adrenergic Antagonists mechanism of action
block adrenergic receptors
Alpha-adrenergic blockers (α1)
Phentolamine (+ α2)
Phenoxybenzamine (+ α2)
Doxazosin
Prazosin
Terazosin
Tamsulosin
Beta-adrenergic blockers (β1 + β2)
Carvedilol
Labetolol
Pindolol
Propranol
Beta-adrenergic blockers (β1 only)
Atenolol
Metoprolol
Dopamine Receptors act on?
Brain, viscera, renal vasculature
D1-like receptor actions?
smooth muscle relaxation
vasodilation in smooth muscle of vascular beds
D2-like receptor actions?
reduce adenylyl cyclase
open potassium channels
reduce calcium channel influx
ACE Inhibitors:
⬢ Captopril (Capoten)
⬢ Enalapril (Vasotec)
⬢ Fosinopril (Monopril)
⬢ Lisinopril
⬢ Ramipril
ACE Inhibitors: Captopril
– Clinical Uses
⬢ Hypertension; cardiac failure; diabetic
nephropathy; myocardial infarction
ACE Inhibitors: Captopril
– Mechanism
⬢ Inhibition of ACE, inhibition the production of angiotensin II
ACE Inhibitors: Captopril
⬢ Pharmacological Effects
– Decrease angiotensin
- stimulates aldosterone
secretion
– Decreases sodium retention (Less recovered)
– Decreases water reabsorption.
– Potassium retention increased
» Hyperkalemia
ACE Inhibitors - Adverse Effects
– Taste
• Altered taste sensation, metallic
– Hyperkalemia - rare
• Inhibition of aldosterone
– Renal Failure
• In patients with bilateral renal artery stenosis
• Patient is dependent on angiotensin II to maintain renal
blood flow & glomerular filteration.
– Contraindicated in Pregnancy
• Fetal & neonatal morbidity and mortality (2nd & 3rd)
ACE Inhibitors - Drug Interactions
• Lithium - Low therapeutic index/ratio
– Increase serum lithium levels.
• Provoke toxicity
• NSAIDs
– Inhibits the effects of ACE inhibitors
Angiotension I
RECEPTOR BLOCKER DRUGS
Losartan (Cozaar)
Valsartan (Diovan)
Irbersartan (Avapro)
Candesartan (Lotensin)
Competitive and selective
blocking of AT1 receptors
Angiotensin II Receptors Blockers
(ARBs)
• ARBs: Losartan
– Adverse Effects:
• No major adverse effects
• Low incidence of dizziness
– Contraindicated in
• Pregnancy - 2nd & 3rd trimester
• Renal diseases - renal artery stenosis
Calcium Channel Blocking Drugs (CCB)Clinical Uses:
– Cardiac arrhythmias
– Heart failure
– Hypertension
– Ischemic heart disease
– Migraine headache
• Group as a VASODILATOR
• Antiarrhythmics Class IV Drugs
– Verapamil and Diltiazem
Role of Calcium - Heart:
• Ca channels - β1-adrenergic coupling
– regulates myocardium; SA & AV node.
– Myocardium: a positive iontrophic effect.
• Increase the force of contraction
– SA Node: Ca regulates the pacemaker
activity.
• Opening of Ca channel - increase dischages of SA
node, HR increases
Calcium Channels
⬢ Location
– Plasma membrane of smooth muscle &
cardiac tissues.
– Ca+2 influx - Leads to membrane
depolarization, and initiates or strengthen
muscle contractions.
– CCB blocks calcium entry
• produce smooth muscle relaxation and suppress
cardiac activity.
Calcium Channels: Types
• L (long) Type calcium channels
– High voltage channels
– Slowly inactivated
– Calcium influx has a relatively long duration.
• T(transient) Type calcium channels
– low voltage channels
– rapidly inactivated
– Calcium influx is transient
Calcium Channels
⬢ Types of channels
• L-Type: SA and AV nodes; cardiac muscles
• T-Type: SA and AV nodes only
– Current CCB acts to selectively blocks L-type
channels.
Ca channels - β1-adrenergic
coupling
• Cardiac β1-adrenergic activation
– Enhance Ca+2 influx
– β-blockers, more specifically β1-blockers will block Ca
influx
– Thus they (β1-blockers and Ca Channels blockers) have
identical pharmacological effect of on the heart.
• Reduce force of contraction, reduced HR and suppress conduction of the AV node.
(Phenylalkylamine)
Verapamil (Isoptin): Actions
⬢ Direct Effects
– Blocks Ca channels in
heart and blood vessels
• Vasodilation of arterioles:
decrease arterial
pressure
• Vasodilation of arteries &
arterioles of heart:
increase coronary
perfusion
• Blockage of SA node:
decrease HR
• Blockage of AV node: AV
conduction decreased
• Blockage of myocardium:
force of contractions
decreased
(Phenylalkylamine)
Verapamil (Isoptin): Actions
⬢ Indirect Effects
– Decrease in BP, activates the baroreceptor reflex.
– Increases sympathetic firing to the heart
• increase HR,
• increase AV conduction,
• increase force of
contractions.
(Phenylalkylamine)
Verapamil (Isoptin): Actions
Overall effects:
Vasodilation
Decrease arterial pressure
increase coronary perfusion
Verapamil (Isoptin)
• Clinical uses:
– Angina pectoris; essential hypertension and
cardiac dysrhythmias
• Adverse effects:
• Constipation especially in the elderly
– Due to inhibition of Ca+2 in GI smooth muscle
• Dizziness, flushing, headache & edema
(ankles/feet)
– Secondary to vasodilation
• Gingival hyperplasia
Verapamil (Isoptin)
⬢ Drug Interactions:
• Digoxin
– Both drugs suppress AV node conduction
– Verapamil increase serum levels of digoxin (Serum
[digoxin] ↑ by 60-75% due to decreased renal tubular
secretion and nonrenal clearance mechanisms. Biliary
clearance of digoxin is reduced by 42-43% when
administered with verapamil)
– Secondary to vasodilation ???
• Beta-adrenergic blocking agents
– Both have similar actions
» decrease HR
» decrease AV node
» decrease contractility
(Benzothiazepine)
Diltiazem (Cardizem)
⬢ Actions and adverse effects
⬢ Actions and adverse effects are similar to verapamil
(Dihydropyridines)
Nifedipine (Adalat): Actions
⬢ Direct Effects
– Blocks Ca+2 channels in
blood vessels
• Vasodilation of arterioles:
decrease arterial
pressure
• Vasodilation of arteries &
arterioles of heart:
increase coronary
perfusion
(Dihydropyridines)
Nifedipine (Adalat): Actions
⬢ Indirect Effects
– Decrease in BP, activates
the baroreceptor reflex.
– Increases sympathetic firing
to the heart
• increase HR,
• increase AV conduction,
• increase force of
contractions.
Dihydropyridines)
Nifedipine (Adalat): Actions
Overall effects:
Vasodilation increase HR
decrease arterial pressure increase AV conduction,
increase coronary perfusion increase force of contractions.
Nifedipine (Adalat)
⬢ Adverse Effects
• similar to verapamil & diltiazem
– Flushing, dizziness, headache, peripheral edema,
gingival hyperplasia
• Different from verapamil & diltiazem
– Minimal constipation
– Do not exacerbate AV block, heart failure, bradycardia
– Causes reflex tachycardia,
» Increase oxygen demand, can increase pain in
angina patients. Co-administration with propranolol.
Nifedipine (Adalat)
⬢ Drug Interactions:
• Beta blockers
– Combination prevent reflex tachycardia
– NOTE: Beta blockers intensifies the effects of verapamil
or thiazides (avoid)
CCBs: Pharmacokinetics CCB -general
• Adverse Reactions
– Fatigue
– Vasodilator effect: Headache; dizziness,
flushing, edema,
– Hypotension
– Cardiovascular events
• Myocardial infarction, congestive heart failure;
deaths -immediate release formulation nifedipine
Calcium Channel Blockers
⬢ Antihypertensive actions
– Effect on cardiac tissue
• Dilitiazam & verapamil reduce HR in some patients
Calcium Channel Blockers
⬢ Clinical Uses for
– Migraine headache
• Verapamil
– Migraine prophylaxis
• Efficacy is questioned
• Probably acts by preventing the vasoconstrictive phase of
migraine headaches
β-Adrenergic Receptor
Blockers
• Acts on receptors:
– cardiac muscles (which have predominately β
1 receptors)
– Juxtaglomerular cells that releases renin
• Agents: Propranolol; metaprolol; etc
β-Adrenergic Receptor
Blockers
• Acts on receptors:
– cardiac muscles (which have predominately β
1 receptors)
– Juxtaglomerular cells that releases renin
• Agents: Propranolol; metaprolol; etc
β-Blockers
⬢ Non selective blockers
– Propranolol; nadolol; carteolol;
β-Blockers
⬢ Cardioselective (β1) blockers
– Metoprolol; atenolol; betaxolol; bisprolol
β-Blockers
⬢ Partial agonists
– β-blockers with intrinisc sympathomimetic
activity
– Pindolol; acebutolol; penbutolol
Propranolol
Clinical uses, mechanism:
• Mild to moderate hypertension
• Severe hypertension - combine with
vasodilators
– Vasodilators causes a reflex tachycardia
which is block by propranolol.
• Blocks β1 and β2 adrenoceptors
– Decrease BP by decreasing Cardiac Output
– Other β blockers decrease CO and varying
degrees of peripheral resistant
Propranolol
• Inhibit the stimulation of renin proudction
– (which is via β1 stimulation by catecholamines)
• Depress (partly) the renin-angiotensin-aldosterone
system
– may be formulated with other agents such as
HCTZ
β-Blockers
Metoprolol
• Cardioselective
– Blocks β1, sparing β2 receptors
– Effects similar to propranolol
– Advantage for hypertensive patients with
history of asthma, diabetes or peripheral
vascular diseases.
Licensed health practitioners expressly authorized to
prescribe federal legend drugs (within the scope of
practice permitted by their license) as a “prescriber” in
Michigan include:
Independent Prescribers
⬢ dentists
⬢ veterinarians
⬢ doctors of podiatric medicine and surgery
⬢ optometrists
⬢ doctors of medicine
⬢ doctors of osteopathic medicine and surgery.
Dependent Prescribing Authority
•Only Michigan licensed “doctors of medicine” (MDs) and
“doctors of osteopathic medicine and surgery” (DOs) are
allowed to delegate prescribing authority,
•They may delegate this authority only to another
“licensed health professional acting under the
delegation and using, recording or otherwise indicating
the name of the delegating licensed doctor of medicine
or doctor of osteopathic medicine and surgery.”
Prescribing...
Rx Format
• If a PA does prescribe a Non-Controlled federal
legend drug, the prescription must indicate both
the PA’s name and the supervising physician’s
name.
• Otherwise, the prescription may be treated as if
it originated with the MD or DO.
Prescribing Regulations
• (Medicine) and (Osteopathic) have
identical requirements for physicians who
elect to delegate the prescribing of
controlled substances to the physician’s
assistants, nurse practitioners, or nurse
midwives they supervise
Department of Community Health Opinion
•“Since the prescribing is accomplished through
delegation from the physician, a separate
Michigan Controlled Substance or DEA license
is not required.”
•“Physician’s assistants, nurse practitioners and
nurse midwives are not independently tracked.
Prescriptions are recorded under the individual
physician’s DEA number.”
Delegation of prescribing of controlled substances to
physician’s assistants; limitation.(1)
A physician may delegate the prescription of controlled
substances listed in Schedules 3 to 5 to a physician’s assistant if
the delegating physician establishes a written authorization that
contains all of the following information:
(a) The name, license number, and signature of the
supervising physician.
(b) The name, license number, and signature of the
physician’s assistant.
(c) The limitations or exceptions to the delegation.
(d) The effective date of the delegation.
Prescription definition
– “order for drugs or devices written and signed or
transmitted by other means of communication (fax,
verbal, email) by prescribers to be filled,
compounded or dispensed”.

Prescribing apply to all “drugs”, not just federal
legend drugs. Prescribers often prescribe overthe
counter (OTC) drugs example: Insulin
Rx Contents General
•Name, Professional Degree (MD, DO, etc) and
Address of the MD or DO or
–Name and address where PA is located
•Patient’s Name (and address for CS)
•Name of Drug: Brand or Generic name
•Dosage Form (capsules tablets, liquids)
•Quantity (numeric and alphabetical if CS)
•Directions for Use (“Sig” qd, bid,qid)
•Refills if any (“prn” caution)
•Signed by PA
Legal Categories of Drugs
⬢ Over-the-counter (OTC)
⬢ Prescription
⬢ Controlled drugs or controlled substances (CS
Legal Categories of Drugs
⬢ Over-the-counter (OTC)
– Safe and effective without professional guidance (cold remedies,
vitamins, non-opioid analgesics etc)
– Medications are manufactured under the same quality control standards
that apply to prescription drugs
– Safety and effectiveness monitored by the FDA
Legal Categories of Drugs
⬢ Prescription
– As determined by the Food and Drug Administration (FDA) a prescription or legend drug is one that requires a prescription in order to
be dispensed by a pharmacist
– The term Legend drug derives from the requirement that a prescription
drugs must be identified by the legend “ Caution: Federal law prohibits
dispensing without prescription.”
– Legend drugs are “dangerous” drugs meaning that they are not safe for use except under the supervision of a licensed practitioner (local
anesthetics, antibiotics, systemic corticosteroids)
Legal Categories of Drugs
⬢ Controlled drugs or controlled substances (CS)
– Drugs with an abuse potential and have additional restrictions
placed on their use
– Drug Enforcement Administration (DEA) of the Department of
Justice is responsible for identifying and regulating such drugs.
– OTC (Tylenol # 2, acetaminophen with small amount of codeine)
– Legend (morphine for medical use)
– No medical use (heroin)
– Most controlled substances have their principal site of action in
the central nervous systems (except anabolic steroids)
– Controlled substances dispensed for medical use must carry the
label “ Caution: Federal law prohibits the transfer of this drugto any person other than the patient for whom it was
prescribed”
⬢ 1997: Food and Drug Administration
Modernization Act
• Controlled Substance Laws
– Control of the distribution of abused drugs (e.g.
opioid, barbiturates, amphetamines) by the DEA is
regulated by the Controlled Substance Act.
– This Act divided abused drugs into five schedules
based on the drugs’ potential for abuse, their
medical use and the degree to which they may lead
to physical or psychologic dependence.
⬢ To prescribe controlled substances:
– The licensed practitioner must register with the DEA
– Registration must be renewed periodically
– Certificate of registration must be retained and
displayed by the practitioner
• Administer controlled drugs in the practitioner
office:
– Need special order form available from the DEA
– Record of the dates of acquisition & dispensing
must be kept
– Biennial inventory of controlled substances on hand
must be filed with the DEA
⬢ Schedule II
• Schedule II drug may not be refilled
– written on a regular prescription pad and the
prescription is good for 60 days
– Only 1 drug per prescription pad.
• State is electronically notified whenever a
schedule II is filled (pharmacy level)
• Schedule II prescription can not be given to
pharmacist over the phone
⬢ Schedule I
⬢ Schedule I drugs may not be prescribed and
are made available only for specific, approved
research projects
⬢ Schedule V
– Drugs in schedule V, which consist of preparations
containing limited quantities of certain opioid agents
may be sold without a prescription, assuming that
the drug is dispensed by a pharmacist to a
purchaser who is 18 years old and that a record of
the transaction is kept by the pharmacist
Controlled substances III, IV and V
– Can be refilled up to 5 times within 6 months
– Pharmacist is allowed to fill oral prescription for
schedule III, IV and V provided that they are
subsequently committed to writing with all the
required informations.
Suggestions for writing prescriptions for controlled
substances (CS)
– Keep prescription blanks in a safe place
– Prescribing controlled substance by phone is discouraged
– Write out the actual amount prescribed in addition to giving
an Arabic number or roman numeral, in order to discourage
the alteration of prescription orders
– Avoid writing prescription orders for large quantities of
controlled substance
– Maintain only a minimum stock of controlled drugs in the
office
– Keep all controlled drugs under lock
– Maintain an accurate record of controlled substance that
have been administered as required by the Controlled
Substance Act of 1970 and its regulation
Suggestions for writing prescriptions for controlled
substances (continued)
– Never sign prescription blank in advance
– Assist the pharmacist who telephones in verifying information
about a prescription order.
– Do not write the full DEA number on the prescription (leave the last
3-4 digit blank and ask pharmacist to call office)
– Be caution when patient says that another clinician has been
prescribing a specific controlled substance or claims only one
product “works” for him/her
– Make sure that the patient does not see different doctors. Call
pharmacy and ask for profile. If patient goes to different pharmacies
then the clinician should be more careful
Chemical equivalent:
drug products that contain
the same amounts of the same active ingredients in
the same dosage forms and meet current official
compendium standards are considered chemically
equivalents
⬢ Chemical equivalent drug may not share similar
bioavailability
» Amount of therapeutic ingredient may be the same in two
dosage forms, the preparations may contain different
binders, excipients, diluents, stabilizers, preservatives, and
other pharmacologically inactive ingredients
» Pressure used to compress mixture into tablets or capsule
forms may vary
» Suspension or solution method used to dissolve, disperse or
suspend the drug in a liquid formulation may be different
» quality control, age, purity, physical consistency all may differ
and will affect bioavailability
– Bioavailability:
refers to the extent and rate of
absorption of a dosage form as reflected by the
time-concentration curve of the administered drug in
the systemic circulation.
– Therapeutic equivalents:
are chemical equivalents
that when administered to the same individual in the
same dosage regimen, provide essentially the same
efficacy (and toxicity).
⬢ Demonstrated by control clinical human studies which are
expensive and time consuming.
⬢ In the absence of contradictory clinical evidence, those
drugs that are bioequivalent are assumed to be
therapeutically equivalent
– Bioequivalent:
Those are drugs that when
administered to the same individual in the same
dosage regimen, result in comparable
bioavailability.
Blood pressure definition
the pressure exerted by the
blood on the walls of the blood vessels. Unless
indicated otherwise, blood pressure is
understood to mean arterial blood pressure,
i.e., the pressure in the large arteries, such as
the brachial artery (in the arm). The pressure of
the blood in other vessels is lower than the
arterial pressure.
⬢ Baroreceptor Reflex
modulates the sympathetic
stimulation of CO and PVR and adjust BP in
response to postural changes and altered physical
activity.
– Provide short term regulation of blood pressure via the
sympathetic nervous system.
– Provides long-term control of blood pressure.
⬢ Kidney: regulation of plasma volume and the
renin-angiotensin-aldosterone axis.
Physiological regulation Blood Pressure
BP is tightly controlled by baroreceptor reflex mechanism and
the kidney.
– BP is adjusted appropriated in response to postural changes
and physical activity.
• Normatensive: Increase in BP, leads to a proportional
increase in sodium and water excretion by the
kidneys.
• Results in reduced blood volume and BP returns to normal “set point”
• Hypertensive
– The BP “set point” is higher.
– Increase in BP, is NOT followed by a proportional increase
in sodium and water excretion by the kidneys.
– Unclear if elevated PVR (peripheral vascular resistance) is the cause or the result of hypertension.
Diuretics: Overview
⬢ Diuretics acts at
various sites in the
nephorn to cause
diuresis (an increase
in urine flow).
⬢ Most diuretics inhibit
Na+ reabsorption from
the nephron into
circulation--- increase
natriuresis
(excretion of sodium in
urine).
⬢ Most diuretics causes
an increase in
Kaliuresis (excretion of
potassium in urine).
a new
group of drugs that
increase free water
excretion by blocking
receptors for antidiuretic
hormone (arginine
vasopressin receptors;
V2 receptors).
⬢ Aquaretics
Classes of Diuretic Agents
⬢ Thiazide & Thiazide-related Diuretics
– Hydrochlorothiazide (HCZT)
Classes of Diuretic Agents
⬢ High Ceiling (Loop) Diuretics
– Furosemide; Muzolimine; Bumetanide;
Classes of Diuretic Agents

⬢ Potassium-sparing Diuretics
– Aldosterone (Mineralocorticosteroid): Spironolactone
– Non-Aldosterone: Triamterene
Classes of Diuretic Agents
⬢ Carbonic anhydrase inhibitors
?
Classes of Diuretic Agents

⬢ Osmotic Diuretics
– Mannitol; Urea
Thiazide & Thiazide Related Diuretics
⬢ Thiazide Diuretics
– Hydrochlorothiazide (HCTZ)
• HCTZ; HCZT & Reserpine; HCTZ & Propranolol (Inderil)
– Chlorothiazide (Diuril)
• Chlorothiazide & Reserpine (Diupres20)
Thiazide & Thiazide Related Diuretics
⬢ Thiazide Related Diuretics
– Indapamide (Lozol)
– Chlorthalidone (Hygroton)
– Metolazone (Zaroxolyn)
Thiazide & Related Diuretics
⬢ Most commonly used diuretics.
⬢ Oral efficacious with moderate natriuretic effect
and few adverse effects in most patients.
⬢ Increase renal excretion of NaCl, K+ and water.
⬢ Elevate plasma levels of uric acid and glucose.
⬢ The maximum antihypertensive effects is often
achieved with doses of thiazides below the
maximum diuretic doses.
Thiazide
⬢ Pharmacokinetics
– Well absorbed but have individual difference.
– All of the thiazides are secreted by the
organic acid secretory systems and compete
to some extent with uric acid secretion
(proximal tubule).
• Uric acid secretory rate may be reduced.
• Concomitant elevation in serum uric acid level.
– Travel down the nephron to reach their site of
action (distal convoluted tubule).
Thiazide
⬢ Mechanism of action
Thiazide
• Increased excretion of
– Potassium; Magnesium
• Decrease excretion of
– Calcium - mechanism unclear
• Reduces excretion of calcium and may lead to mild
hypercalcemia
Thiazide
⬢ Antihypertensive effects
– Short term effects:
• Increase sodium and water excretion. The blood volume
decrease and thereby decrease cardiac output.
– Long term effects (after weeks of administration):
• Decrease PVR, may be due to reduced sodium content of
arteriolar smooth muscle cells.
– Decreased muscle contraction in response to vasopressor
agents - NE & angiotensin. This effect can be counter acted by
increased dietary sodium.
Thiazide
⬢ Hydrochlorothiazide: Clinical uses
• Essential hypertension
– Reduce blood volume: Decrease load, immediate antihypertensive
effect.
– Reduce arterial resistance: This effect develop over
time, mechanism unknown.
• Edema:
– Patients with heart failure (mild to moderate), renal or
hepatic disease (cirrhosis)
• Diabetes insipidus -excessive urine production
– A paradoxical effect; Mechanism unknown
Thiazide
⬢ Hydrochlorothiazide: Contraindications
– Hypersensitivity to thiazides or sulfonamides (sulfa
drugs).
⬢ Hydrochlorothiazide: Adverse Effects
• Hypokalemia (Excessive loss of K+);
– Particularly in patients with inadequate dietary K+ intake.
– dryness of mouth, increase thirst, irregular heart beat,
mood and mental changes; muscle cramps; nausea or
vomiting, weak pulse.
• Elevated Uric acid (hyperuricemia)
– Inhibit uric acid secretion from the proximal tubule
• Elevated lipid levels (hyperlipidemia)
– Altered serum lipids: HDL, LDL
• Elevated blood glucose (Hyperglycemia)
– In part due to hypokalemia, which reduces insulin
secretion by pancreatic beta cells
• Loss of sodium, chloride and water
– Leads to hyponatremia (confusion, convulsions, fatique,
irritability, muscle cramps); hypochloremia; dehydration.
• Pregnancy & Lactation
– Decrease placenta perfusion; Excreted in milk.
• Calcium: urinary excretion reduced
• Magnesium: excretion increased
» Muscle weakness; tremor, twitching and
dysrhythmias
Thiazide
⬢ HCZT: Drug Interactions
⬢ Lithium - serum levels increased
⬢ Loop diuretics (Potentiates diuretic effects)
⬢ Potassium sparing diuretics (Counter-acts effects
on K+)
⬢ ACE Inhibitors - hypotensive activity augmented
⬢ NSAIDs - drecrease its antihypertensive effects
Loop Diuretics
⬢ Furosemide (Lasix)
⬢ Butetanide
⬢ Torsemide
⬢ Ethacrynic acid
Loop Diuretics (High
ceiling)
• Furosemide (Lasix)
– Mechanism of action
⬢ Inhibits the Na+ ,K+,2Clsymporter
(cotransport)
in the ascending loop of
Henle.
⬢ resulting in the retention
of Na+, Cl- and water in
the tubule.
Inhibits the back-diffusion of K+
into the nephron lumen, decreases
the transepithelial electrical
potential that normally drives the
paracellular reabsorption of
magnesium and calcium.
Resulting in an increased Mg & Ca
excretion
– Most efficacious of the diuretics.
• Potent natriuretic effect, highly efficient.
– Produce kaliuresis by increasing sodium -
potassium exchange in the late distal tubule &
collecting ducts.
– Increase magnesium &am
⬢ Furosemide (Lasix)
⬢ Furosemide (Lasix): Adverse Effects
– Electrolyte abnormalities
• Hypokalemia
– Loss of potassium via increased secretion in the distal nephron
– Leads to dysrhythmias
• Hypocalcemia, Hypomagnesemia, Metabolic alkalosis
– Hyperglycemia & Hyperuricemia (similar to thiazides)
– Ototoxicity (reversible)
• tinnitus, ear pain, vertigo & hearing impairment
– Dehydration
• Which promote thrombosis and embolism
• Dry mouth; unusual thirst and scanty urine output.
– Hypotension: dizziness, lightheadedness, syncope
– Loss of fluid volume and relaxation of venous smooth
muscle
– Reduces venous return to the heart.
– Altered serum lipid levels
• Decrease HDL; increase LDL

– Pregnancy: Use Contraindicated
Loop (High ceiling) Diuretics

⬢ Furosemide (Lasix): Drug Interactions
– Digoxin induced ventricular dysrhythmias
• Only when serum potassium level is low
• Furosemide causes Hypokalemia !!
– Ototoxic drugs
• Aminoglycosides (increase ototoxicity)
– Lithium excretion reduced
• Increase serum lithium levels
– Potassium sparing diuretics (spironolactone,
triamterene)
• Counter effects of potassium wasting
– Antihypertensive drugs
• Additive effects, beneficial, need dose adjustments.
– ACE Inhibitors - hypotensive activity augmented
– Thiazide diuretics (enhanced diuretic effects)
– Nonsteroidal antiinflammatory drugs (NSAIDs)
• drecrease its diurectic effects
– NSAIDs inhibits prostaglandins (PGs) production
– PGs regulates renal blood flow and urine volume
– Thus decreased PGs, results in a decrease in renal blood flow
and decrease urine volume.
Loop (High ceiling) Diuretics
⬢ Clinical uses (when intensive diuresis is
required)
– Pulmonary edema
– Renal impairment
• Effective even when creatinine clearance drops
below 30 mL/min
– Congestive heart failure
– Cirrhosis
– Hypercalcemia
– Hypertension (2nd to thiazides)
Potassium-Sparing Diuretics
⬢ Two types
– 1. Epithelial sodium channel blockers
(amiloride; triamterene)
– 2. Aldosterone receptor antagonists
(Spironolactone; potassium canrenoate)
• They act on the late distal tubule and
collecting duct
Potassium-Sparing Diuretics
In general:
– They produced a modest
increase in urine
production. Not potent as a
stand-alone drug to
promote diuresis.
– They substantially
decrease K excretion.
Useful to ___
counteract
potassium loss induced
by thiazide and loop
diuretics
Potassium-Sparing Diuretics
Aldosterone:
Activates the Mineralocorticoid
receptor:
Then interacts with nuclear DNA, promote gene transcription of
proteins that encode epithelial sodium channel and related
compounds involved in the reabsorption of sodium and
secretion of potassium.
– Stimulate the synthesis of proteins required for
Na+/K+ exchange.
– Promoting Na+ uptake in exchange of K+ in the
distal nephron
Potassium-Sparing Diuretics
⬢ Spironolactone (Aldactone)
– blocks action of aldosterone
• decrease Na+ reuptake (more in lumen)
• Increase retention of K+ (more recovered)
– Delayed on set of action (24 to 48 h)
• Blocks synthesis of carrier protein, takes time
– Well absorbed from GI
– Long duration of action
– Short half life
Potassium-Sparing Diuretics
• Spironolactone (Aldactone)

– blocks action of aldosterone
– Clinical uses
⬢ Prevention & treatment of hypokalemia;
⬢ Primary hyperaldosteronism
⬢ Polycystic ovary disease (antiandrogen effect)
⬢ Hirsutism
Potassium-Sparing Diuretics
⬢ Spironolactone (Aldactone): Adverse Effects
– Hyperkalemia
– Endocrine effects
• Male: Gynecomastia; impotence;
• Female: menstrual irrgularities; hirsutism & deeping of
the voice.
⬢ Spironolactone (Aldactone): Drug Interactions
– Thiazide & Loop diuretics (beneficial)
– Drug that increases K+ levels
• No potassium supplements or ACE inhibitors
Potassium-Sparing Diuretics
• Triamterene & Amiloride
– Directly inhibit the Na/K
exchange mechanism
• Blocks Na+ reuptake
(more in lumen)
• Increase retention of K+
(more conserved)
– Quick on set of
⬢ Prevention & treatment of
hypokalemia
Potassium-Sparing Diuretics
• Triamterene & Amiloride :
– Adverse Effects
⬢ Hyperkalemia
⬢ Metabolic acidosis, because of decrease H+
secretion.
⬢ Others: nausea; vomiting; dizziness; blood
dycrasias (RARE)
Potassium-Sparing Diuretics
• Triamterene & Amiloride :
– Drug Interactions
• Drug that increases K+ levels
– No potassium supplements or ACE inhibitors
Carbonic Anhydrase Inhibitor
• Carbonic Anhydrase
– Present in many nephron sites -lumnial, basolateral
membranes and cytoplasm of the epithelial cells and
RBC.
• Lumnial membranes of proximal tubule - the dehydration of
H2CO3
• Critical step in bicarbonate reabsorption
• Carbonic Anhydrase Inhibitors
– Blocks sodium bicarbonate reabsorption, causing
sodium bicarbonate diuresis and a reduction in body
bicarbonate stores.
Carbonic Anhydrase Inhibitor
⬢ Clinical uses
– Glaucoma: Topical application of -
Dorzolamide or brizolamide
• Reduce IOP (intra occular pressure)
– Urinary alkalinization: Acetazolmide
• Increase urinary pH will enhance excretion of
Uric acid & ASA .
– Metabolic Alkalosis: Acetazolmide
• usually decrease total body K or high
mineralocorticoids levels
– Acute Mountain Sickness: Acetazolmide
• Occurs when rapid ascent above 3000 m (10,000 feet).
– Mild symptoms - dizziness, insomia, headche, nausea lasting a
few days.
– Serious cases - rapidly progressing pulmonary or cerebral
edema.
Osmotic Diuretics
• Freely filtered at the golmerulus and undergo
little (if any) reabsorption.
• Do not have a molecular target (no receptors).
• Act via their physiochemical properties
– Increase osmotic pressure of tub
⬢ Mannitol; urea; glycerol
Osmotic Diuretics
Mannitol
– IV administration,
– filtered at the glomerulus BUT NOT reabsorbed.
– Promote diuresis by creating an osmotic gradient within the lumen of the
nephron
• Water moves into the lumen of the nephron, diluting Na+
concentration in the lumen.
• Na+ is retained in the lumen (concentration gradient)
Osmotic Diuretics
Mannitol
⬢ Clinical uses:
– Oliguria (reduce urine volume) Patients are said to be
anuric
• Acute renal failure (maintain renal function)
– To promote the excretion of toxic substances
– Co-administered with cisplastin, to minimize the renal toxicity
antineoplastics platinum compounds.
Aquaretics
⬢ Examples:
Lithium; demeclocycline
– Blocks ADH action on the distal tubule and
collecting duct.
• Blocking ADH decreases water permeability.
• Water is not recovered (distal tubule), resulting in
an increase in water clearance
Polyuria
• Excessive production of dilute urine and is
usually accompanied by polydipsia (Increase
drinking)
• Main causes:
– Diabetes mellitus
– Diabetes insipudus
• Central diabetes insipudus: Insufficient production of
vasopressin
• Nephrogenic diabetes insipidus: collecting duct fails to
response to vasopressin
Vasopressin receptors & agonists
• Vasopressin
– Also known as 8-arginine vasopressin (AVP)
and Antiduiretic hormone (ADH)
– Released from the posterior pituitary in
response to
• an increase in plasma osmolarility
• reduction in blood volume and/or arterial blood
pressure
– Two types of receptors: V1 and V2
• They are G-protein linked receptors
Diuretics- clinical Implications
• NSAIDs may block the antihypertensive effect of
diuretics.
• Increase incidence of orthostatic hypotension.
• Transient but significant hypokalemia.
• Adrenal corticosteroids with mineralocorticoid
activity promotes hypokalemia
– hydrocortisone
• Patients most likely being treated with essential
hypertension.
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