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131 Cards in this Set
- Front
- Back
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
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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 |
– Vasodilation
– Blocks vasoconstriction, – Mainly arterioles, less on veins. – Decrease PVR - decrease in BP. • Both arterial and venous pressure DECREASE • Preload and afterload BOTH DECREASE |
|
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
|
• Relatively well tolerated drugs
– First-dose hypertension • Due to wide spread vasodilation – Cough, • Persistent, dry irritating, non-productive cough, • Up to 20%, Reversible • Due to accumulation of bradykinin. – Pruritic rash • 10% of patients |
|
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
|
• Loop & Thiazide Diuretics
– Augmented hypotension and renal insufficiency – Caution when used in combinations . • Anti-hypertensives – Combine hypotension • Drugs that increases Potassium levels – K supplements – Potassium-sparing diuretics. |
|
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) |
• Mechanism of Action:
– Blocks angiotensin II from activating the AT1 receptors. • Vascular smooth muscles: dilation of arterioles and to veins (less) • Adrenal glands: – Causing vasodilation & decrease aldosterone secretions. » Increase Na and water excretion » BUT no significant effect on K levels and do not cause cough or angioedema. • The net effect is similar to ACE inhibitors. |
|
Angiotensin II Receptors Blockers
(ARBs) |
• ARBs: Losartan
– Adverse Effects: • No major adverse effects • Low incidence of dizziness • (DO NOT increase serum glucose; uric acid or alter serum lipid levels) – Contraindicated in • Pregnancy - 2nd & 3rd trimester • Renal diseases - renal artery stenosis |
|
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:
|
– AV Node:
• is a conduit between SA node & the ventricles. – Critical role in coordinating the contractions of the Ventricles and Atria • AV nodes excitability is regulated by Ca+2. – When Ca+2 channel opens, more discharges from AV node – Thus Ca+2 Channel blockers, suppresses discharges from AV nodal cells |
|
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. |
|
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 |
|
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. |
|
CCB- site of action @ clinical dose
|
• Nifedipine (Dihydropyridines)
– Arterioles • Verapamil (Phenylalkylamine) – Arterioles and the heart • Diltiazem (Benzothiazepine) – Arterioles and the heart Note: ALL cause cardiac suppression @ high doses |
|
(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 |
– Vasodilation
• Smooth muscle relaxation • Greater effect on arteriole smooth muscle • Decrease BP via a decrease in PVR with little impact on venous capacitance, cardiac filling pressure and cardiac output |
|
Calcium Channel Blockers
• Antihypertensive actions |
– Effect on cardiac tissue
• Dilitiazam & verapamil reduce HR in some patients |
|
Calcium Channel Blockers
• Clinical Uses for |
– Hypertension
• Except Bepridil and nimodipine – Cardiac arrhythmias • Diltiazem & verapamil – Ischemic heart disease – Migraine headache – Subarachnoid hemorrhage (one of the causes of stroke) • Nimodipine - dilate small cerebral vessels, increase collateral circulation, may reduce neuronal damage |
|
Calcium Channel Blockers
• Clinical Uses for |
– Ischemic heart disease
• Amlodipine; nicardipine and nifedipine, bepridil, diltiazem, verapamil |
|
Calcium Channel Blockers
• Clinical Uses for |
– Antiarrhythmic
• diltiazem, verapamil • Decrease AV node conduction velocity • Smaller effect on SA node and heart rate. • Little effect on the ventricular conduction velocity and refractory period. |
|
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 in ______________ |
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 |
– Blocks reabsorption of
sodium and chloride • Early segment of the distal convoluted tubule • Water retention in nephron • Increase urine flow – (but less than furosemide) – Effectiveness is dependent on kidney function A small amount of potassium is secreted into the urine in the tubules. Thus, thiazides have a kaliuretic effect that leads to hypokalemia in some patients. Na+ Cl- Symporter |
|
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 & calcium excretion. |
• Furosemide (Lasix)
|
|
• Furosemide (Lasix): Adverse Effects
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– 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 |
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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. |
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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) |
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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 |
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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 |
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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 |
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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 |
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Potassium-Sparing Diuretics
• Spironolactone (Aldactone) – blocks action of aldosterone – Clinical uses |
• Prevention & treatment of hypokalemia;
• Primary hyperaldosteronism • Polycystic ovary disease (antiandrogen effect) • Hirsutism |
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Potassium-Sparing Diuretics
• Spironolactone (Aldactone): Adverse Effects |
– Hyperkalemia
– Endocrine effects • Male: Gynecomastia; impotence; • Female: menstrual irrgularities; hirsutism & deeping of the voice. |
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• Spironolactone (Aldactone): Drug Interactions
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– Thiazide & Loop diuretics (beneficial)
– Drug that increases K+ levels • No potassium supplements or ACE inhibitors |
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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 action • Direct effect on carrier protein – Clinical uses |
• Prevention & treatment of
hypokalemia |
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Potassium-Sparing Diuretics
• Triamterene & Amiloride : – Adverse Effects |
• Hyperkalemia
• Metabolic acidosis, because of decrease H+ secretion. • Others: nausea; vomiting; dizziness; blood dycrasias (RARE) |
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Potassium-Sparing Diuretics
• Triamterene & Amiloride : – Drug Interactions |
• Drug that increases K+ levels
– No potassium supplements or ACE inhibitors |
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Carbonic Anhydrase Inhibitor
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• 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. |
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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. |
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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 tubular fluid, reducing water reabsorption |
• Mannitol; urea; glycerol
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Osmotic Diuretics
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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) |
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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. |
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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 |
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Vasopressin receptors & agonists
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• 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 |
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Diuretics- clinical Implications
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• 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. |