the interaction of chemical substances• the study of drug action at the biochemical or...
TRANSCRIPT
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The interaction of chemical substances (drugs) with living organisms (humans)
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Pharmacology• consists of (1) pharmacodynamics
and (2) pharmacokinetics
�pharmaco��= drugs
�dynamics� = dynamics
�kinetics� = movement
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• the study of drug action at the biochemical or physiological level
�mechanism of action�
Pharmacodynamics
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Pharmacokinetics• study of how drugs:
(1) enter the body
(2) reach site of action
(3) are eliminated from the body
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PHARMACODYNAMICS
A. Drugs that change the environment of cells
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B. Drugs which bind to receptors on cell membranes and alter cellular physiology --> drug receptor interaction (�lock-and- key� mechanism)
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example:
digoxin (Lanoxin)
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agonist - drug which binds to a specific receptor and produces a physiological effect by stimulating the receptor
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Norepinephrine (NE)
--> stimulates beta-1 receptors (SA node)
--> increases heart rate
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antagonist - drug which binds to a specific receptor and blocks other substances from stimulating the receptor
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antagonist (cont.)
Benadryl (diphenhydramine)
blocks histamine receptors --> blocks allergic reactions
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Inderal (propranolol)
--> blocks beta-1 receptors on SA node
--> decreases heart rate
antagonist (cont.)
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--> blocks narcotic receptors in respiratory center (medulla oblongata)
--> reverses respiratory depression due to heroin (narcotic overdose)
antagonist (cont.)
Narcan (naloxone)
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Receptor Binding Characteristics
a. affinity - drug�s ability to bind to a receptor
• agonist --> affinity • antagonist --> affinity
b. efficacy - drug�s ability to stimulate its receptor
• agonist --> efficacy
• antagonist --> no efficacy
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Competitive Inhibition
morphine (agonist)<--> Narcan (antagonist)
Valium (agonist) <--> Romazicon (antagonist)
ACh (agonist) <--> atropine (antagonist)
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Pharmacokinetics
• drug absorption
• drug distribution
• drug metabolism
• drug elimination
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Drug Absorption
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Oral (PO)
drug is ingested
absorbed from stomach/intestine
enters hepatic portal system
liver enters general circulation
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Oral (cont.)
• oral route is convenient and economical
• once absorbed into the bloodstream, the drug enters the liver, where it may be metabolized (�first-pass effect�)
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Sublingual
• drug is dissoloved and absorbed under the tongue
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Nitroglycerin (NTG) sublingual tablets
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ransderma l
T
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Transdermal (cont.) • drug patch provides continuous drug dosing
• local skin irritation may occur
• drug enters the general circulation before passing through the liver
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Habitrol (nicotine transdermal system)
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Duragesic Patch
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Androderm
(testosterone)
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Rectal (PR)
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Rectal (cont.) • rectal route is convenient in unconscious or
vomiting patients
• disadvantage: drug may be incompletely or erratically absorbed
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Inhalational
• drug is inhaled as a gas or aerosol into the lungs where it either exerts a localized effect on lungs (e.g., bronchodilation) or ....
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... the drug enters the bloodstream through the lungs
• inhaled drug produces a rapid onset since it circulates to the brain shortly after being inhaled
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Intranasal
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Intranasal route (cont.)
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Parenteral route (IV, IM, & SQ)
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Parenteral route (cont.)
• advantages: • drug response: IV >IM> SQ
• avoids unpredictable absorption processes of GI tract
• useful in unconscious or uncooperative patients
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Parenteral (cont.)
disadvantages: • requires sterile conditions to prevent infections
• more costly than other routes of administration
• once injected, a drug cannot be retrieved
• pain at injection site
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Drug Distribution
general rule: small and highly lipophilic drug molecules penetrate cell membranes, capillaries, and physiological barriers (i.e., placenta, blood-brain-barrier, etc...) more readily than larger, polar (non- lipophilic) drug molecules
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Characteristics of Drug Absorption (GI tract)
a. drugs must be relatively lipid-soluble to pass through the membranes of the GI tract
b. drugs either exist in lipid-soluble form or non-lipid soluble form depending on their pH environment
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pH environment changes along the GI tract:
i. stomach (highly acidic)
ii. small intestine (slightly alkaline)
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Bioavailability
• describes what proportion of the administered drug is available to produce a pharmacologic response
• factors influencing bioavailability:
i. drug dissolution
• inert ingredients (binders, disintegraters, lubricants, buffers, ect...)
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• factors influencing bioavailability (cont.):
ii. GI tract
• presence of food may affect dissolution and absorption of drugs
• Tetracycline (TCN) + dairy products
! TCN binds to calcium
! unabsorbed TCN excreted in feces
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ii. GI tract (cont.)
• achlorohydria
• deficiency in pancreatic and intestinal secretions
--> prevents dissolution of enteric-coated tablets
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Drug Distribution (cont.)
• the degree to drug distribution depends on the physical and chemical properties of a drug and its ability to penetrate cell membranes, capillaries, blood-brain barrier, placenta, etc....
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Blood-Brain-Barrier (BBB)
• only lipid- soluble drugs and very small molecules are capable of crossing the BBB to exert an effect on the brain
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Blood-Brain-Barrier (cont.)
• heroin crosses the BBB more readily than morphine because of its greater lipid solubility factor
Mexican �tar� Heroin
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Plasma Protein Binding • many drugs bind to plasma reversibly with plasma proteins (e.g., albumin)
a. only unbound or �free� drug may:
• diffuse through capillary walls
• produce a pharmacological effect
• be metabolized
• be excreted
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Plasma Protein Binding (cont.)
�free� drug <----> protein-bound drug
circulating drug reservoir
prolongs the action of drugs
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Plasma Protein Binding (cont.) Drug-Drug Interactions
displaces Coumadin from albumin binding site
increase in �free� warfarin drug levels
increases bleeding potential
Aspirin
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Tissue Trapping • certain tissues (e.g., adipose tissue) are capable of trapping or storing drugs temporarily or permanently, converting them into �inactive� form
• when drugs leave the tissue-binding site, they become active again
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Drug Biotransformation (Drug Metabolism)
• lipid-soluble drug --> water-soluble drug --> drug excreted by kidneys
• the liver is the major organ responsible for metabolizing drugs
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�First-Pass� Effect of the Liver
• the first-pass effect of the liver inactivates potentially harmful chemicals and drugs before being distributed throughout the body
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Induction / Inhibition of Drug Metabolism
i. induction of enzymes (metabolism)
(nicotine)
induces metabolism of
theophylline
theophylline blood levels wheezing
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ii. inhibition of enzymes (metabolism)
Tagamet (cimetidine)
inhibits the metabolism of
theophylline
theophylline blood levels
theophylline toxicity
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Drug Elimination (Kidneys)
• it has been estimated that kidney function decreases by 10% per decade of life after 20 years of age
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Elimination of Drugs in the Feces
(a) metabolized drug --> bile --> feces
(b) enterohepatic recirculation
• metabolized drug --> secreted in bile
--> small intestine
--> return to liver
--> secreted in bile
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Elimination by Kidneys after Drug Metabolism
Elimination by Kidneys Directly into Urine
Drug Elimination & Age Considerations
i. infants --> underdeveloped abilities to metabolize and excrete drugs
ii. elderly --> impaired abilities to metabolize and excrete drugs
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Geriatric Considerations
i. Absorption (cardiac output)
ii. Distribution (plasma proteins)
iii. Metabolism
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Disease & Drug Elimination Rates
liver / kidney diseases
ability to metabolize & excrete drugs
prolonged & toxic drug effects
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Summary
Pharmaco-dynamics
&
Pharmaco-kinetics
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Time Profile
(1) onset of action
(2) peak
(3) duration of action
(4) half-life
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Estimated Creatinine Clearance
(for drug dosing considerations)
CrCl = (140-Age) x IBW
sCr x 72
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CONCEPTS
• continuous vs intermittent dosing regimens
• peaks & troughs
• drug half-life
• drug steady-state concentrations
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DOSE-RESPONSE CURVES