Pharmacology
“study of properties and effects of drugs on living systems”
Nomenclature (naming)
Chemical: acetyl salicylic acid
Generic: aspirin
Trade: Bayer
Drug
Agonist vs Antagonist
“chemical that interacts with specific molecule and exerts biological effect”
Agonist: stimulates response
Antagonist: inhibit response
Drug receptor
“functional macromoelcule to which drug binds and produces measureable effect”
Ligand-gated ion channel receptors
bind and open gate (ms)
Ex. ACH open Na channel (nicotinic receptors)
G-protein-coupled receptors
G protein load GTP and release alpha/beta second messengers (also gamma subunit)
Ex. AcH muscarinic receptors
Kinase linked receptors
Mebrane bind, conformational change activates a kinase which phosphorlyates 2nd messengers-
amino acids tyrosine, serine, threonine (cascade amplification)
Ex. Cytokine, insulin
**Nuclear receptors **
DNA coupled intracellular receptors–> stimulate gene transcriptio–> protein/enzyme synthesis
Ligand lipiphilic to cross membrane
Ex. Steroid hormones (estrogen, progesterone, cortisol, thyroid hormone)
Mechanism of Action
“specific cellular change mediated by a drug that cause clinically evident response”
Ex. Aspirin–>decrease CoX enzyme->decrease prostaglandin synthesis->decrease inflammation, edema, pain
Receptor occupancy
=number of receptors bound to drug
depends on concentration of drug and its affinity for a given receptor
(specificity and selectivity)
**Intrinsic activity **
how much effect does drug have on receptor action
**Sensitivity **
Up-regulation= more sensitive to drug due to increase # of receptors
Down-regulation= less sensitive due to less # of receptors or more tolerant to drug
Agonist
Antagonist
bind to receptor to trigger response
Can be competitive and bind depending on afinity and concentration
block receptor and access of drug to block flow of ions into and out of cell
Efficacy
Emax
“magnitude of drug response”
How well it does what its supposed to?
Emax= maximal drug response
**Potency **
ED50
“concentration of drug necessary for an effect”
ED50- effective dose to get 50% max response
desired response in 50% individuals
Competitive antagonist
Noncompetitive antagonist
=decrease ED50 but not Emax
=decrease Emax but not ED50
(agonist no longer induce same effect, not competing for same site so decrease overall magnitude of drug response)
Grade dose response curves
Quantal dose curves
% response over drug concentration
yes or no of individual responses
(# responding vs log10 dose)
Exampine descrete outcomes versus gradation of responses
Toxicology
side-effect
adverse effect
toxic effect
“undesired effect of drugs and chemicals”
- minor, uncomfortable
- compromising or potentially harmful
- major or life threatening at high dose
TD50 or LD50
toxic or lethal dose
toxicity or death in 50% of animals tested
**Therapeutic Index **
margin of safety
=TD50/ED50
Acetominophen=30 (30xs recommended dose get toxic)
Cancer drugs= 1
Safety Margin
LD1/ED99
distance betweeb quantal dose-response curves for desired effect undesired effect
More concervative measure (how safe, risk vs benefit)
_Biological variability _
Hyper-reactivity
Hypo-reactivity
Tolerance
Tachyphylaxis
Idiosyncrasy
Number-needed-to-treat (NNT)
=people respond differently to different medications
- response at low dose
- no response until high dose
- hyporeactivity results from repeate administration
- rapid onset of tolerance
- unexpected deviation from normal
unexpected drug response
:# patients who must be expose to drug for 1 patient the deisred effect (takes into consideration individual variations among patients wieght, age, genetics)
_Pharmodynamics _
Pharmokinetics
=biological, chemcial, physiological effects of drug
=dealing with absorption, distribution, metabolism, exretion of a drug
“rate at which drug concentration accumulates in and are broken down and eliminated from organs of body”
**Bioavailability **
fraction of unchanged drug reaching systemic circulation
degrees to which drug reaches site of action
intravenously versus orally
_Absorption _
=drug entry into systemic circulation from site of administration
rate influenced by route of administration
oral, sublingual, subcutaneous, topical, intravenously, intramuscular, inhalation
Biological membranes
Simple diffusion
Facilitated diffusion
Active transport
=lipid soluble, water-filled channels, carrier proteins
- small/nonpolar- with electrochemical gradient
- big/charged- with electrochemical gradient
- need ATP- against electrochemical gradient
Absorption
Compatibility and blood flow
**Ionization **
depends on size, charge, ionization
Oral->GI lumen->GI epithemlium->mesenteric vessels-> blood flow
weak acids non-ionized (no charge) in acid solutions
weak based non-ionized basic solutions
= better diffusable/absorbed in like solutions
Iontophoresis
-transcutaneous drug diffusion occurs via electrical repulsion push drug across membrane
(electicity may vasoconstrict holding drug in area- most drug passive diffusion)
Absorption
**Disease effects **
GI disease decrease absorption
(digoxin blood levels decrease, malabsorption)
Inflammation decrease absorption
change ionization state of drug HA<->H+ + A-
Stomach pH 1-3
Small intestine pH 5-7
Absorption
Drug/Food effects
Iron sulfate- form complex with many agents and decrease absorption (thyroxine, methyldopa, penicill)
Calcium can inhibit iron absorption
Neomycin and phenytoin cause malabsorption as side effect
Food/liquid can slow transit time (pop pH<3)
Absorption
PT effects
Age effects
Exercise->decrease GI blood flow->decrease GI absorption
Intense exercise–>change GI pH->change drug solubility
Heat, massage, exercise–>increase local drug absorption administered transdermally
Secondary to cutaneous ateriodilation
-impaired GI (active) transport and decrease bioavailibility
Distribution
“transfer drug from blood to extracellular fluids and tissues”
Interstitial=12 L
Intracellular= 24 L
Vascular= 5 L
**Volume of distribution **
VD= dose/Co (plasma concentration at time 0)
Small= most drug stay in blood
Large= not concentrated in blood compartment (dilute)
Factors of distribution
Tissue permeability
Blood flow
Drug bind plasma proteins
Bind subcellular components
Albumin: drug bind, not as bioavailable
Drug storage: Adipose- fat soluble drugs
Bone- heavy metals
Muscle- mefloquine-antimalarial drug
Organ- streptomycin in renal proximal tubule
1st pass effect
drugs given orally are absorbed by small intestine through portal system to liver (limits bioavailibility)
Distribution
Disease effects
Drug effects
Hypoalbuminemia- renal/hepatic disease
decrease bind drup typically bind to albumin–> increasing availability free drug (increase toxicity)
Chronic renal failure-
uremia decrease drug bound to protein–>
unbound phenytoin levels–>
increase toxic levels even when total blood levels normal
-protein bound drugs can be displaced at binding sites by other drugs
Ex. Warfarin displaced from binding protein by metronidazole= may result in hemorrhage
Distribution
PT effects
Age-related
Redistribution by exercise, massage, heat, ultrasound
2ndary to increase blood flow
Exercise change blood pH and may change drug’s ability to cross tissue membrane
Increase body fat–>retention lipid soluble drugs
Decrease water content-> water soluble drugs more concetrated
Decrease serum albumin->increase biolavailbility albumin bound drugs
Metabolism
Make drug hydrophilic
Make drug less active
Prodrugs
-Necessary for excretion in renal tubes
Enzyme increase regulatioin occur with repeated admin
-metabolite not as effective as parent drug
Exception: prodrugs
Metabolites more active- converted into more active
Ex. L-dopa->dopamine
Codeine-> morphine
Metabolism
Inactivation, detoxification, or bioactivation
Phase 1
Phase 2
- Transform drug into more polar molecule- oxidations (cytochrome P-450s) , reduction, hydrolysis
- Nonpolar drug–>polar via conjugation with transferase
Ex. Glucaronide, glutathione
Morphine (prodrug)–> morphine glutathione
Metabolism
Disease effects
Drug effects
Hepatic disease- impaired metabolism
Chronic heart failure alter hepatic perfusion (alter metabolism lidocaine, propanol)
Induction/Inhibition of metabolizing enzymes can increase or decrease 1/2 life of drug
Barbiturate/rifampin=increase metab oral anitcoagulants
Lovastatin/simvastatin+ketconozole/grapfruit=decr
Disulfirom (antabuse)= inhibit aldehyde dehydrogenase (alcoholism- alde dehydr help detox/digest ethanol)
_Metabolism _
PT effects
Age-effects
