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243 Cards in this Set

  • Front
  • Back
What are the sponsor responsibilities of FDA?
1. File an INVESTIGATIONAL NEW DRUG APPLICATION (INDA) prior to phase 1 testing
2. Reporting any serious and unexpected adverse effects in 10 days
3. Bioavailability studies
4. Seek final approval
What are legend drugs?
by prescription only
What are the steps of development of new drugs?(8)
1. ID chemical compound (invitro testing)
2. Preclinical research animal testing
3. INDA
4. Phase I
5. Phase II
6. Phase III
7. NDA
8. Post Marketing Surveillance
What is clinical testing?
Phase 1-3
What is Phase 1?
Is it safe? pharmacokinetics?....20-100 subjects
Phase 2?
Does it work in patients (100-200 subjects)
Phase 3
Does it really work? double blind. 1000-6000 patients
Phase 4....
Post marketing surveillance
The orphan drug act of 1983
provides incentives for developmnet of drugs for treatment of rare diseases/conditions....any disease that effects less than 200,000 ppl in US OR affects more than 200,000 but no expectation of making money from the drug
Blue book
bioequivalence
Orange book
Therapeutic equivalence
TO be therapeutic equivalent must meet the following criteria
1. safe and effective
2. identical quantities of same active ingredients
3. Same standards of strength, quality and purity
4. Bioequivalent
5. Adequate labeling
6. compliance with FDA regulations
Therapeutic equivalent example
Prevacid and prilosec
What is the GOLD Standard in clinical testing
Randomized, Double-blind placebo controlled trial (RCT)
US pharmacopeia (1820)
first compendium of standard drugs for the US
Pure Food and Drug act of 1906
prohibited mislabeling and adulteration of drugs
Federal Food and Drug and cosmetic act of 1938
Required that new drugs be safe and pure (does not require proof of efficacy)
Durham-Humphrey act of 1952
FDA the power to determine which products could be sold without prescription
Kefauver-Harris Ammendments (1962)
Required proof of efficacy as well as safety for new drugs; guidelines for reporting of adverse reactions, clinical testing and ad of new drugs
Comprehensive drug abuse prevention and control act
strict controls in manufacture, distribution and RX of habit forming drugs; est drug schedules and programs to prevent and treat drug addiction
Dietary supplement health and education act
Est. standards for dietary supplements but no full FDA review of supplements. Required specific ingredient and nutrition labeling....classifies as part of the food supply but allows unregulated advertising.
Thalidomide leads to
Phocomelia- a condition involving shortening or complete absence of the limbs
Which MD refused FDA approval of Thalidomide
Frances Oldham Kelsey
What is the misconception of ASA?
Prevents heart attach in men more; prevents stroke in women more
What does post market research do?
Subgroup analysis (sex, race/ethnicity, age, co-morbidity), new indications for existing drugs, drug combinations
When is a black box warning issued by black box warning
1. Drug presents a unique risk/benefit concern compared to other drugs in the same class
2. Potential adverse reaction is extremely significant above the drug's benefit
3. When such adverse reaction can be prevented or reduced by limited used or defined cautions
With black box this needs to be
1. prescribers are obligated to provide patients with info on treatment risks, benefits and warnings
2. Should be documented in the record
What is pharmacology
defeined as the study of substances that interact with living systems through chemical processes esp by binding to regulatory molecules
What is pharmacokinetics?
the absorption, distribution, and elimination of drugs.
WHAT THE BODY DOES TO THE DRUG
What is pharmacodynamics
the actions of the chemical on the organism. WHAT THE DRUG DOES TO THE BODY
What is toxicology
branch of pharmacology that deals with undesirable effects of chemicals on living systmes...ALL SUBSTANCES HAVE A POTENTIAL FOR toxicity
Pharmacogenomics
genetic variations that cause differences in drug response among individuals or populations
Pharmacologic agonist
agent binds to and activates the receptor - directly or indirectly causing an effect (FULL OR PARTIAL agonists)
PHARMAcologic antagonist
agent binds to a receptor - competing with other molecules and preventing binding by other molecules - inhibitor
Pro-drug
an inactive precursor chemical - must be absorbed and distributed and converted to the active form of the drug by biologic processes
What makes an IDEAL DRUG? (5)
1. Dec mortality and morbidity
2. improves quality of life
3. Effective
4. Low cost
5. Simple administration and dosing
Therapeutic goal -
to obtain and maintain concentrations within the therapeutic window for desired response and minimal toxicity
What are the fundamental pathways of drugs? (PHARMACOKINETICS)
ADME: Absorption, distribution, metabolism, and elimination
absorption -
entry of the pharmacologic agent into plasma
distribution
agent leaves bloodstream and distributes to interstitial and intracellular fluids
Metabolism
agent must be metabolized via liver, kidney, or other tissue
elimination
agent metabolities must be elminated from the body (urine, bile, feces)
Enteral drug administration...
easily self-administered. complicated drug aborption.
First pass metabolism affects
influenced by food and other drugs
Parenteral drug administration
IV, IM, SC. More control over dose of drug. bypass first pass.
CANT TAKE it back, infection risk
Inhalation
rapid delivery, large surface area (good for gases)
Rectal
(50% of circulatory drainage bypasses portal circulation)
Drug transport GI (3)
Passive diffusion, active transport, and endocytosis
Passive diffusion
concentration gradient across a membrane
Active transport
energy dependent, able to move drug from lower to higher concentration
Endocytosis
Transport of large size molecules. Englfment of drug molecule by cell membrane and transport into cell.
Drug abosrption...
drugs are typically weak acids or weak bases. Acidic release an H. Drug passes readily when uncharged.
Size and molecular weight of drugs
play a role in drug absorption. Lithium (7) to thrombolytic enzymes (50000). Smaller...easier to cross membranes
Concentration of drug depends upon
pH of the drug.
pH at the compartment site
pka of the drug.
Only the non-ionized
form of the drug can diffuse across membranes
the pKa of drug=
pH of tissue or fluid when 50% ionization occurs (equalization of ions and non-ionized molecules)
Factors in absorption and distribution
Chemical Properties (solubility: hydrophilic vs lipophilic); chemical nature - pH and pKa. Molecular weight, partition coeffient
Lipid: aqueous partition coefficient
of a drug determines how easily the molecule moves between aqueous and lipid media
pKa is the pH at which
the concentrations of the ionized and non-ionized forms are equal
Partition coefficient
ratio of lipid solubility to aqueous solubility....
The higher the partition coefficient the more membrane soluble is the substance
Factors influencing GI absorption
blood flow (intestinal>stomach)
pH - esp with H2 receptor blocker or PPI
Surface area - intestinal surface microvilli
Contact time with absorp surface
Contact time with absorptive surface
- rapid versus slow GI transport.
- parasympathetic input - inc rate of gastric emptying
-sympathetic input - delayed gastric emptying
-food
Bioavailability
-Fraction of chemically unchanged drug that reaches systemic circulation
Factors influencing bioavailability
- first pass metabolism
- solubility
-chemical instability (like insulin in the GI tract)
-Nature of the drug formation (chemistry, particle size, coatings, binders, etc)
First pass hepatic metabolism and bioavailability
-drug absorbed across GI tract - enters portal circulation prior to systemic circulation
-If drug undergoes rapid metabolism by the liver, dec amount of unchanged drug enters systemic circulation
Solubility of drugs and bioavailaility
hydrophilic drugs poorly absorbed (cant cross membrane)
IDEAL drug for absorption
- largely hydrophobic, but with some solubility in aqueous solution
-some highly lipid-soluble drugs are transported in aqueous solutions in the body via carrier proteins like albumin
Bioequivalence
Comparable bioavailability and similar time to achieve peak plasma concentration; Related drugs that do not demonstrate comparable bioavailability are BIOINEAUIVALENT
Therapeutic equivalence
Similar drugs deemed therapeutically equivalent if comparable efficacy and safety
***Clinical effectivess is dependent on serum drug concentrations and the time it takes to reach peak drug concentrations

THEREFORE. two drugs that are bioequivalent may not be therapeutically equivalent
Drug distribution
process in which drug reversibly leaves blood stream and enters interstitium and/or cells
Drug delivery is dependent upon
1. blood flow
2. capillary permeability
3. Plasma protein binding
4. drug structure - hydrophobicity
Wide varience in drug distribution r/t
unequal distribution of cardiac output
1. highest in organs,
2. lower in skeletal muscle
3. still lower in adipose tissue
drug distribution in capillary permeability
governed by capillary structure and chemical nature of the drug
Variance in capillary structure:
slit junctions btw endothelial cells
- largely present in liver and spleen. allows passage of plasma proteins and thus drug molecules
ABSENT IN THE BRAIN. (blood brain barrier)
in the blood brain barrier
drugs must pass through endothelial cells of the CNS capillaries or be actively transported.
Lipid-soluble drugs penetrate the CNS by
dissolving in the membrane of the endothelial cells
What is the basic calculation for IBW for women
100+5 # for ever inch over 60 inches
What is the basic calculation for IBW for men
100+6# for every inch over 60 inches
Concentration of drug depends on
pH of drug, pH at compartment site
What form of drug can diffuse across cell membranes?
non-ionized form of drug
The pKa of a drug=
pH of tissue or fluid when 50% ionization occurs (equalization of ions and non-ionized molecules)
pKa is the pH where
50% of the drug is ionized and 50% is not
The higher the partition coefficient t
then more membrane soluble is the substance
Chemical nature of the drug
largely determines its ability to cross cell membranes
Hydrophobic drugs
no net charge, uniform electron distribution. Able to dissolve in lipid membranes - permeate cell surface.
IMPACTED BY blood flood to region
Hydrophillic drugs
-positively or negatively chargd
-do not easily pass through cell membranes
-need slit junctions for passage
Plasma protein binding generally
reversible and non-selective: drugs bind where other compounds - such as bilirubin would normally attach
Plasma albumin
major drug binding protein
What may act as a drug reservoir?
Plasma albumin. As free drug concentration decreases protein bound drug dissociates from the protein. Maintains free-drug concentration as constant fracture of total drug in plasma
Volume of distribution
hypothetical volume of fluid into which the drug is dispersed
Large volume of distribution
impacts half-life
Drug elimination is dependent on
-amount of drug delivered to kidney or liver (wherever metabolism occurs)...which depends on blood flow and fraction of drug in plasma
If Volume of distribution is large
-majority of drug is not in the plasma and is not available to excretory organs
Factors that inc volume of distribution
also
increase half-life
extend duration of action
Very large Vd suggests
DRUG SEQUESTration in organ/compartment
Plasma protein binding
binding capacity of albumin
competition for binding
ClassI drugs protein binding
MAJORITY of agents.
-dose< albumin binding capacity
-low dose/capacity ratio
Class II drugs protein binding
MINORITY of agents
-High dose/capacity ratio
-Highly protein bound -> less 'free drug' ex Warfarin
drug displacement from albumin
substantial source of drug interactions
Class I drug - warfarin
highly protein bound - small fraction of free drug in plasma
Class II drug given - sulfa
-displaces warfarin from albumin;
- rapid rise in free drug concentration. Inc therapeutic effect - toxic effect
Large volume distribution
displaced drug may distribute to periphery; insignificant change in free-drug concentration
Small volume distribution
displaced drug less likely to distribute to tissues -> more significant change in free drug available in plasma
Therapeutic index
if therapeutic index is narrow -> small increase in drug concentration may have substantial clinical impact
First order kinetics (majority of drugs)
- metabolic transformation of drugs by enzymes
-rate of drug metabolism is directly proportional to the concentration of free drug, so constant fraction of drug per unit of time
linear elimination pattern -
reflected by the 1/2 life of the drug
each half life cuts the drug concentration by
50%
-at 2 half-lives - drug has been 75% removed
-at 5 half-lives - drug is essentially removed from the body
Zero order kinetics (minority of drugs)
- ASA, ETOH, phenytoin
-rate of metabolism is constant over time, therefore a constant amount of drug metabolized per unit of time
Processes of drug metabolism (Phase I)
involves oxidation, reduction and hydrolysis to inc polarity and water solubility of the drug
Processes of drug metabolism (Phase II)
involves conjugation - reaction in which a large chemical group is attached to the molecule to inc solubility and facilitate excretion of the metabolite from the body
Following phase I,
the drug may be activated, unchanged or most often, inactivated
Phase II
Some drugs directly enter phase II metabolism. Following Phase II conjugated drug is usually inactive
Kidney and lipophilic drugs
kidney is typically unable to effectively eliminate lipophilic drugs (can cross cell membranes and reabsorb into distal tubule)
Phase 1 metabolism and p450 system
serves to convert lipophilic molecule into more plar molecules. Phase I metabolism can inc, dec or leave drug pharmacologic activity unchanged
Lipid soluble agents must be metabolized
in the liver. - phase I/Phase iI.

Phase I reactions - involve CYP450 system
Cytochrome P 450 System
-Comprised of many families of isoenzymes. (found in most cells, much higher amounts in liver & GI tract) Various mutations result in INCREASED or DECREASED ability to metabolize certain drugs.
Inducers - which increase enzyme synthesis
drugs can be inducers of certain CYP isozymes
Inducers results in increased biotransformation of drug
-dec blood concentrations
-dec drug activity if metabolite is inactive
-inc drug activity if metabolite is active
-dec therapeutic drug effect
Ex of Inducer
rimfampin dec Haart therapy - dec suppression of HIV virus
Inhibitors- dec enzyme synthesis
inhibitor of CYP isozyme activity is also important. Most through competition for isoenzyme
Many drugs inhibit one or more biotransformation pathways of warfarin
EXample omeprazole inhibits 3 pathways.
-warfarin + omeprazole => warfarin level
due to inhibitors....inc drug levels can occur over time leads to
prolonged drug effects, inc drug toxicities

EX: grapefruit juice inhibits CYP3A4
Phase II reactions result in
more polar and water soluble therapeutically inacitve substances which are then able to be eliminated by the kidneys.

NEONATES are deficient in this conjugating system
Extraction ratio
decline of drug concentration in the plasma from the arterial side to the venous side of the kidney
Drug concentration entering kidney=C1
exit kidney=c2
Extraction ratio = C2/C1
Excretion rate=
clearance* plasma concentration
Drug half -life increased
1. Diminished renal plasma flow or hepatic blood flow (shock)
2. Dec extraction ratio
3. Dec metabolism (concomittant drug inhibitiation of biotrans). Hepatic insuff
Drug half-life decreased
1. inc hepatic blood flow
2. Dec protein binding
3. Inc drug metabolism
What do you assum in pharmacokinetics of continuous iv infusion?
1. rate of infusion constant, first order kinetics
2. Constant fraction of agent is cleared per unit of time
Rate of excretion increases proportionately as the
plasma concentration rises
Steady-state
achieved when the plasma concentration remains constant
Drug input rate=
drug elimination rate
steady state plasma concentration is directly proportional to
infusion rate
Steady state concentration is inversely proportional to
drug clearance
Any factor increasing drug metabolism will
dec the steady state concentration
Rate of drug concentration decline when
drug infusion is terminated. plasma drug concentrations dec to zero at the same time rate as when approaching steady state
Loading dose
used when more rapid attainment of desired plasma drug level is clinically important
cost benefit analysis
eval impact of intervention/program on population
Principles of pharmacoeconomics
all scarce items have a cost.
Ppl want what they want at a lower cost
Adverse drug reactions that are both serious and unexpected must be reported to FDA
within 15 days
all addictive drugs activate the
mesolimbic dopamine system
Schedule I (CI):
The drug or other substance has a high potential for
abuse ***never RX
• has no currently accepted medical use in treatment in the United States
• has no accepted safe use under medical supervision.
• Examples: heroin, marijuana
Schedule II (CII):
The drug or other substance has a high potential for
Abuse
• has a currently accepted medical use in treatment in the United States, or
• has a currently accepted medical use but with severe restrictions, and
• abuse of the drug or other substances may lead to severe psychological or
physical dependence.
• Examples: OPIOD
Schedule III (CIII):
The drug or other substance has a potential for abuse less
than the drugs or other substances in schedules I and II,
• has a currently accepted medical use in treatment in the United States
• abuse of the drug or other substance may lead to moderate or low physical
dependence or high psychological dependence.
• Examples: hydrocodone, codeine
Schedule IV (CIV):
The drug or other substance has a low potential for abuse
relative to the drugs or other substances in schedule III,
• has a currently accepted medical use in treatment in the United States
• abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in schedule III.
• Examples: benzodiazepines
• Schedule V (CV):
The drug or other substance:
• has a low potential for abuse relative to the drugs or other substances in schedule IV,
• has a currently accepted medical use the U.S.
• abuse of the drug or other substance may lead to limited physical dependence or psychological
dependence relative to the drugs or other substances
Psychomotor Stimulants
Methylxanthines
• include theophylline, (found in tea)
• theobromine (found in cocoa)
• caffeine
Methylxanthines stimulate secretion of
hydrochloric acid from the gastric mucosa
• PUD: people w/ peptic ulcers should avoid beverages containing methylxanthines.
A high dose of caffeine has what effect on cardiovascular
positive inotropic and chronotropic effects on the heart.
• Increased contractility can be harmful to patients with angina pectoris.
• In others, an accelerated heart rate can trigger premature ventricular contractions
• Diuretic action: Caffeine has a mild diuretic action that increases urinary output of sodium, chloride, and potassium.
Therapeutic uses: Caffeine
relax the smooth muscles of the
bronchioles. (Previously the mainstay of asthma Rx)
Pharmacokineticsof caffeine
well absorbed orally
• Caffeine distributes throughout the body, (including the brain)
• cross the placenta to the fetus and is secreted into the mother's milk
• All methylxanthines metabolized in the liver
• metabolites excreted in urine
Nicotine enters brain Stimulation of
nicotine receptors
Dopamine release
Dopamine Reward Pathway
Prefrontal
cortex
Nucleus accumbens
Ventral tegmental
area
pharmacokinetics of nicotine
Highly lipid soluble, absorption readily occurs via the oral mucosa, lungs, gastrointestinal mucosa, and skin
• Crosses placenta and secreted in breast milk
• Average smoker takes in 1 to 2 mg of nicotine per cigarette
• (most cigarettes contain 6 to 8 mg of nicotine)
• > 90% of the nicotine inhaled in smoke is absorbed
nicotine receptors
Receptors sites in the CNS- part of stimulant properties of nicotine
• Actions:
• CNS: Nicotine- highly lipid soluble, readily crosses BBB
• Smoking cessation:
combining pharmacologic and
behavioral therapy most successful to stop smoking
Bupropion
(antidepressant) can reduce the craving for cigarettes.
Partial nicotinic receptor agonist
Varenicline (competes with the nicotine receptors)
Partial agonist
produces less euphoric effects than nicotine itself (nicotine is a full agonist at these receptors)
VARENICLINE:
Mechanism of Action
Competitively inhibits binding of nicotine...Patients should begin therapy 1 week PRIOR to quit date.
BUPROPION SR: Mechanism of Action
Atypical antidepressant thought to affect levels of various brain neurotransmitters:
Dopamine, Norepinephrine
Drugs of Abuse: Cocaine
• Mechanism of action:
• Primary mechanism causing central and peripheral effects of cocaine is blockade of reuptake of the monoamines (norepinephrine, serotonin, and dopamine) into the presynaptic terminals
• Prolongation of dopaminergic effects in the brain's pleasure system (limbic system) produces intense euphoria that cocaine causes
• Chronic intake of cocaine depletes dopamine.
• depletion triggers vicious cycle of craving for cocaine
that temporarily relieves severe depression
Drugs of Abuse: Cocaine
• Actions: CNS
Behavioral effects d/t stimulation of the cortex and brainstem
• Acutely increased mental awareness, produces feeling of well-being and euphoria (similar to amphetamine)
Drugs of Abuse: Cocaine
• Sympathetic nervous system:
Peripherally, cocaine potentiates the action of norepinephrine, and it produces the “fight or flight” syndrome
• tachycardia, hypertension, pupillary dilation, peripheral vasoconstriction
• ability of baroreceptor reflexes to buffer the hypertensive effect may be impaired
• Hyperthermia: Unique aspect of Cocaine - death can result
secondary to dose but also d/t propensity to cause
hyperthermia.
Amphetamine:
noncatecholaminergic sympathetic amine that shows neurologic and clinical effects similar to cocaine
• Amphetamine achieves effect by
releasing intracellular stores of catecholamines
• behavioral effects of amphetamine are similar to cocaine
Elimination of THC
via biliary route
Oxidation of acetaldehyde inhibited by disulfiram
Drug used to deter drinking in alcohol dependent patients
• If ethanol consumed in the presence of disulfiram:
• acetaldehyde accumulates - causes facial flushing, nausea, vomiting, dizziness, h/a
Naltrexone, relatively long-acting opioid receptor antagonist, FOR ETOH
→ blocks the effects at opioid receptors
• dose-dependent hepatotoxicity
• caution w/ elevated LFTs
• Also causes opiate withdrawl
best overall index of kidney function
Glomerular filtration rate (GFR)
• Variables due to pharmacokinetics include:
impaired renal and liver clearance, circulatory impairment or failure, altered drug binding to plasma proteins, impaired GI absorption, and pharmacokinetic drug interactions
Therapeutic Index
Expression of relative safety of a drug.
• The closer the ratio is to 1, the less safe the drug (Digoxin)
• Calculated as the toxic dose for 50% of people
(TD50) divided by the Effective dose for 50%
Chronotherapy considerations
statins more effective taken at night
Additive effect
(drug A + drug B = effects A+B)
• When 2 drugs w/ similar action taken together and combined effect is summative (1+1=2)
Synergistic effect
Result of 2 drugs that when combined have > results than the sum of both drugs given alone (1+1=3) GREATER EFFECT
Drug Efficacy
• Efficacy -
determined by the number of receptor-drug couplings formed and the efficiency of these activations to produce a cellular response.
Agonists
fit into the lock and key and ACTIVATES it
antagonist
fit into the lock and key and breaks off the key….DOESNT ACTIVAT
Down regulation:
• constant stimulation of receptor → leads to ↓ responsiveness
• (Receptors move intracellularly because the receptor gets tired
• Refractoriness:
• severe down regulation leading to lack of response to drug
Up regulation:
occurs following period of down regulation, → then absence of stimulation (by the drug), → followed by hypersensitivity to the drug…..because the receptor hasn’t seen the drug in awhile
• (Receptors return to cell surface)
ligand
Any chemical that will react with or bind to a receptor site
• Receptors:
protein molecules embedded in cell membranes with ligand binding sites located on the outer surface of cells
Flomax – BPH –
alpha blocker, relaxes smooth muscle in urinary tract. Also causes syncope…due to dilated vessels in legs
htn result of
increased peripheral vascular smooth muscle tone
baroreflexes
sense changes in BP
Arterial Blood Pressure=
= Cardiac output * Peripheral Resistance
Angiotensin II is a POTENT circulating vasoconstrictor-so if we suppress this,
we can REALLY decrease BP
first line treatment for mild htn
Thiazide Diuretics
How do thiazide diuretics work?
inhibit Na reabsorption in distal tubules, excrete NA, water, K and H
Adverse effects of Thiazides
o Electrolyte disturbances (hypokalemia & hypomagnesemia)
o Hyperuricemia
o Hyperglycemia
o Photosensitivity
....• Avoid With severe renal disease & liver dysfunction….
• Drug interactions: Digoxin, lithium, cyclosporine
Side effects to monitor with thiazides
orthostatic hypotension, weight change, I/O, electrolytes, renal function ….TAKE In AM
• Mechanism of action of Beta blockers
dec CO through
o Neg chronotropic (dec HR) and inotropic effects (dec contractility)
• Use in HTN, CHF, glaucoma, etcetc
Side effects of beta blockers
• AV conduction abnormality! (heart block), acute heart failure, and bradycardia...Sweating. Hyperglycemia.
side effect of blockage with others are bronchospasm and dec peripheral blood flow (arteriolar)
Whats another use for beta blockers
liver patients
When do you never initiate therapy of beta blockers
acute decompensated heart failure
What are the benefits of ACE inhibitors
slow progression of heart failure, Post MI, slows diabetic nephropathy
What are side effects of ace inhibitor
! Small bump in creatinine, cough, rash (spotty, macular, papillary), angioedema. Start low and go slow
diff between hypertensive urgency and emergency?
urgency - no end organ damage
What are the 3 's of Sodium Nitro?
Closely monitor >3 micro grams per kilo per min.
No longer than 3 days.
Not with creatinine greater than 3
What test for statins?
baseline liver function and continuuous monitor
What are the 3 approved Beta blockers for HF?
carvedilol, metoprolol succinate (Toprol XL) and bisoprolol
What is the best drug for HF pt with arrythmias?
Digoxin
Angiotensin converting enzyme (ACE) converts angiotensin I to
angiotensin II. POTENT circulating vasconstrictor. SOOOO we really want to block this!
Why use thiazide diuretics?
mild to mod HTN.
Treatment of edema and nephrotic syndrome.
examples of thiazide diuretics
HCTZ & metolazone
What are the uses of beta blockers
HTN, CHF, glaucoma, hyperthyroidism, angina pectoris, & post MI therapy
Beta 1 receptors stimulation
*heart, kidney*
contractility, conduction velocity, renin release,
Blockade of beta 1 leads to reduction in
CO, renin release, sympathetic activity, workload, and oxygen demand....SE of blockade= AV conduction abnormality, acute heart failure, and bradycardia
Stimulation of beta 2 receptors
*lungs, liver, pancreas, smooth muscle*
vasodilation, bronchodilation, smooth muscle relaxation.
SE of blockade of Beta 2
bronchospasm and dec peripheral blood flow
SE of beta blsockers
fatigue, dizzy, hypotension, bradycardia, inc sweating, hyperglycemia....can mask signs of hypoglycemia
All the side effects of Ace inhibitors
1. hypotesn
2. inc K
3. cough
4. rash
5. renal dys
6. angioedema
7. neutropenia, agranulocytosis, proteinuria
mechanism of action with angiotensin receptor blockers
block the AT-1 receptors, preventing the activity of angiotensin II. Produce arterial and venous dilation and blocks the aldosterone sec
uses of angiotensin receptor blockers
alternative to ACE inhibitor or with ACE inhibitor in heart failure. Treat HTN with diabetic nephropathy, 2ndary stroke prevent, and left ventricular hypertrophy
What are the advantages over ace inhibitors for angiotenin recept. blockers
no inc in bradykinin. so no cough. dec angioedema risk
Side effects of angiotensin receptor blockers
renal insufficiency, hyperkalemia, angioedema. contraindicated in preg
Mechanism of action of selective renin inhibitors
directly inhibits renin....as effective as ACE inhibitors and ARB at BP control
What are the SE of Selective renin inhibitors?
cough, angioedema, diarrhea,
Mechanism of action of Ca Channel blockers
dec the force of contraction of the myocardium, slows the conduction of electrical activity, relax cardiac and smooth muscle
Dihydropyridines
Nifedipine, Amlodipine
Use
Reduce systemic vascular
resistance and arterial
pressure
Chronic stable angina
Side effects of ca channel blockers
Side effects
Peripheral edema,
bradycardia, gingival
hyperplasia, reflex
tachycardia, constipation,
dizziness, headache, flushing
selective alpha 1 blockers mechanism of acction
Inhibit catecholamine uptake in the smooth muscle
cells of the periphery resulting in vasodilation
use and benefit of alpha 1 blockers
In combination with other therapies for HTN
All equally effective; differ in duration
Benefits
Use in benign prostatic hyperplasia (BPH)
No effects on glucose or lipids
Clonidine
Mechanism of action
α2-receptor agonism to diminish central
adrenergic outflow
Uses
HTN therapy if two or more drugs are failing
Monitoring
Can cause sodium and water retention
Compliance – rebound hypertension
Side effects
Sedation, drying of mucous membranes
Methyldopa
Mechanism of action
Prodrug converted to methylnorepinephrine
centrally to diminish outfrom from the CNS
Uses
HTN therapy with one or more agents in
patients with renal insufficiency
HTN in pregnancy
Side effects
Sedation, drowsiness
Hydralazine (vasodilator)
Side effects
Headache, tachycardia, nausea, sweating
Arrhythmia with risk of angina precipitation
Dose-dependent lupus-like syndrome
Reversible on discontinuation of drug
Concerns
Can lose hypotensive effectiveness over time
unless given with beta blocker and diuretic
Minoxidil
Mechanism of action
Dilation of arterioles
Uses
Treatment of severe to malignant HTN that is
refractory to other drugs
Side effects
Reflex tachycardia, sodium and water retention
(volume overload, edema, CHF)
Hypertrichosis
Sodium Nitroprusside
Mechanism of action
Causes prompt arterial and venous dilation with
reflex tachycardia
Uses
Hypertensive emergency as continuous IV
infusion
Side effects
Hypotension
Nitroprusside metabolized into cyanide ions
Treated with infusion of sodium thiosulfate
Nitroglycerin
Mechanism of action
Nitrate resulting in vasodilation
Uses
Hypertensive emergency as continuous IV
infusion
Side effects
Headache, lightheadedness
Hypotension
Fenoldopam
Mechanism of action
Peripheral dopamine-1 receptor agonist that
lowers BP while maintaining renal perfusion
Uses
Hypertensive emergency as continuous IV
infusion
Side effects
Headache, flushing, dizziness
Hypotension
Cardiac dysrhythmia
Carbonic Anhydrase Inhibitors
Mechanism of action
Inhibits intracellular carbonic anhydrase on the
apical membrane of the proximal tubule
Decreases ability to exchange Na+ for H+,
resulting in a mild diuresis
Uses
Glaucoma, mountain sickness, contraction
alkalosis (↑ HCO3
-, ↓ Cl-)
Available agent
Acetazolamide
Carbonic Anhydrase Inhibitors
Side effects
metabolic acidosis
Hypokalemia
Renal stone formation
Drowsiness
Paresthesia
Decreased excretion of NH4
+ in liver failure
Nitroprusside (Nipride)
Actions
Nitric oxide mediated vascular smooth muscle
relaxation
Potent arterial and venous vasodilator
Indications
Hypertensive urgencies or emergencies
Congestive heart failure (increased afterload)
Aortic dissection or trauma
Pulmonary edema (with severe hypertension)
Perioperative blood pressure control
Hemodynamic Effects of NItroprusside
Reduces arteriolar smooth muscle tone
Reduces venous return
Dose range of 0.5 - 10 mcg/kg/min
CoA reducatase inhibitors
Adverse effects
Liver abnormalities
Evaluate liver function through serum transaminase levels
(baseline, @ 3 mos., Q 6 mos.)
Myopathy and rhabdomyolysis (destruction of muscle)
Rare but dangerous
Unexplained muscle weakness
Monitor plasma creatine kinase levels
Contraindicated in pregnancy and nursing mothers
Bile Acid-Binding Resins
Mechanism
Inhibition of bile acid reabsorption
Clinical efficacy
Reduces LDL 15-30%
Increases HDL 3-5%
May increase triglycerides 10-15%
Bile Acid-Binding Resins adverse effects
Gastrointestinal disturbances
Nausea, vomiting, diarrhea, constipation
Impaired absorption of fat-soluble vitamins
Many drug-drug interactions
Contraindications
Hypertriglyceridemia
Cholesterol Absorption Inhibitors: mechanism
Mechanism
Inhibition of intestinal absorption of dietary
and biliary cholesterol in small intestine
No effect on fat-soluble vitamins
Pharmacology
Enterohepatic circulation
Intestinal wall localization
Minimal systemic exposure
Available agents
Ezetimibe (Zetia)
Niacin (Nicotinic Acid) mechanism of action
Mechanism
Inhibition of lipolysis in adipose tissue
Clinical efficacy
Reduces triglycerides 30-60%
Reduces LDL 15-25%
Raises HDL 20-35%
Most effective agent for raising HDL
Dosage orally (immediate
Fibric Acid Derivitaves (Fibrates)
Mechanism
Increases lipoprotein lipase activity
Increases VLDL clearance
ASA
Targets inhibition of thromboxane A2
synthesis
Irreversible binding
Effects last 7-10 days
Indications
Prophylaxis of cerebral ischemia, reduction
of recurrent MI, decrease mortality in pre
and post MI patients
Thienopyridines (plavix, ticlid)
Block platelet aggregation by irreversibly
inhibiting the binding of ADP to its receptors on
platelets—thus preventing activation of GP
IIb/IIIa receptors
GP IIb/IIIa Inhibitors
Used in patients with ACS
Block binding of fibrinogen and von Willebrand
factor
Major side effect = bleeding
vitamin K antagonist
warfarin
Adenosine (Adenocard)
Inhibits SA nodal, atrial, and AV nodal conduction
More sensitive to effects on AV node
Inhibits cAMP-induced Ca2+ influx, suppressing Ca2+
dependent action potentials
Uses:
Narrow complex paroxysmal supraventricular tachycardia
(PSVT)– 90% effective
WPW
NOT for Afib, Aflutter, ventricular tachycardia