Pharmacology Flashcards
Pharmacodynamics
Biochemical and physiological mechanisms of drug actions and relate to molecular interactions between body constituents and drugs
Effect of drugs based on the concept of drug receptor interactions in order to determine efficacy, potency and toxicity
Maximal efficacy
Emax
Largest effect that a drug can produce
ED50
Dose of drug required to produce a defined therapeutic effect in 50% of the population receiving drug
LD50
The dose that is lethal in 50% of animals treated
Demonstration of adverse drug responses.
Therapeutic index
TI
Ratio of LD50/ED50
Efficacy
Effectiveness.
Aspirin vs morphine.
Same ED50 but efficacy different at same dose.
Potency
Dosing difference. Efficacy is same.
Morphine vs meperidine.
LD50
Dose of drugs that produce adverse response.
Extent. Of drugs effect due to increase dose or idiosyncratic responses.
Therapeutic Index
Relative safetiness. Usually between 2 drugs.
LD50/ED50
Ligand
Agonist or antagonist chemical/dru that binds to a receptor
Receptor
Target/site of drug action
Affinity
Propensity/attraction of a drug to bind with a receptor
Selectivity
Specific affinity for certain receptors vs other receptors.
Agonist
Chemical that binds to a receptor and activates the receptor to produce a biological response
Antagonist
Blocks the action of the agonist at the same receptor.
Pharmacological agonists
Mimic actions of endogenous neurotransmitters at same site
Demonstrate high affinity binding and activate receptors with good specificity
Pharmacological antagonists
Block actions of neurotransmitter at same site
Competitive vs non competitive
Partial vs inverse
Competitive antagonists
Reduce potency of agonists but have no effect on overall efficacy. Their effects are able to be overcome by increasing concentration of agonist substrate concentration
Non competitive antagonist
Reduce agonist efficacy and their effects are not overcome by increasing agonist substrate concentration
Partial agonist
Act at same site as the full agonist but with lower maximal efficacy
Inverse agonist
Causes an action opposite to that of the agonist at same receptor
Physiological antagonists
Activate physiological responses that oppose agonist mediated physiological responses.
Enzyme receptor
Receptor is linked to kinase which leads to series of phosphorylation reactions
Insulin receptor
Ligand gated ion channel
Ligands bind to receptor which causes channel to open allowing ions to pass in/out of cell
Nicotinic acetylcholine receptor
G protein coupled receptor
Receptor is linked to family of G proteins which then cause biological response through secondary messenger systems
CAMP
Transcription factor
Receptor is intracellular and activation/inhibition affects gene transcription
Specificity
Alterations to drug’s chemical structure may influence potency
Many drugs have multiple sites of action resulting in side effects
Sensitivity
Upregulation
Presence of antagonist causes increased celllular build up of receptors.
Removal of antagonist produces increase physiological response to agonist due to increased receptor population
Tolerance
Down regulation
Long term exposure to an agonist reduces receptor population or receptor responsiveness thus reducing physiological response.
Additive
Effect of sub x and y together is equal to sum of ind effects
Aspirin and acetaminophen
Synergistic
Effect of sub x and sub y is greater than sum of ind effects
Clopidogrel with aspirin
Tachyphylaxis
Decreased drug response by many potential mechanisms
Acute decrease in response to drug after initial/repeat administration
Morphine
Pharmacokinetics
Study of how the body impacts the drug
Absorbed
Distributed
Eliminated
Standard drug dose
Based on trials in healthy individuals with average physicological processes.
Pharmacokinetics can be effected by
Age
Liver funciton
Renal function
Fat/lean tissue
What molecules can cross the cell membrane
Nonpolar molecules such as steroids cross easily
How do large polar molecules may enter cell through
Protein pores/channels
Facilitated / active carriers
Many drugs don’t need to enter cell but act where
At cell surface receptors via second messengers
Drug diffusion
Drugs able to enter cell do so through diffusion
Movement of these drugs is based upon Fick’s law.
Effect of charge on diffusion
Presence of charge will impede drug’s ability to cross cell membrane
Uncharged molecules are readily lipid soluble
Charged molecules are readily water soluble
Ph/ion trapping principle
Pka vs ph
Pka ph - uncharged drug form
Example of ph/ion trapping
Example of drug with Pka =4.4
Unchargedd drug diffuses through lipid bilayer at pH1.4
Charged drug is trapped in blood at pH 7.4
Acidic urine favors excretion of
Weak bases
Alkaline urine favors excretion of
Weak acids
Why can’t drugs pass into the BBB
Capillaries contain specialized tight junctions that prevent passive diffusion of most drugs
What sort of drugs act on the CNS
Must be hydrophobic.
Intrathecal administration
And function
Drug is injected directly into the CSF as way to bypass BBB
Absorption areas
Uptake of drug from GI tract- enteral Tissue/muscle - parenteral Mucous membranes Skin - transdermal
Enteral advantages
Simple Inexpensive Convenient Painless No infection
Enteral disadvantages
Drug exposed to harshGI environments
First pass metabolism
Requires GI absorption
Slow delivery to action site
Parenteral advantages
Rapid delivery to site of pharmacological action
High bioavailability
Skips 1st pass
Parenteral disadvantages
Irreversible
Infection
Pain
Mucous membrane advantages
Rapid delivery to action site.
Skips 1st pass
Usually painless
Low infection
Mucous membranes disadvantages
Few drugs have chemical characteristics/formulations that allow them to be administered this route.
Transdermal advantages
Simple Convenient Painless Excellent for continuous/prolonged administration Skips 1st pass
Transdermal disadvantages
Requires highly lipophilic drug
Slow delivery to site
May be irritating
Subcutaneous advantages
Slow onset
May be used to administer oil based drugs
Subcutaneous disadvantages
Slow onset
Small volumes
Intramuscular advantages
Intermediate onset
May be used to administer oil based drug
Intramuscular disadvantages
Can affect lab tests CK
Intramuscular hemorrhage
Painful
Intravenous advantages
Rapid onset
Controlled drug delivery
Intravenous disadvantages
Peak related drug toxicity
Intrathecal advantages
Bypasses BBB
Intrathecal disadvantages
Infection
Highly skilled personnel required
First pass metabolism
Oral drugs only
Drugs absorbed from GI are carried to liver via hepatic portal vein
May reduce amount of drug reaching target tissue by inactivating drug
Some cases results in activation of inert prodrug
Bioavailability
Fraction of unchanged drug reaching systemic circulation following administration by any route.
Bioavailability equation
Quantity of drug reaching systemic circulation / quantity of drug administered
Factors that affect bioavailability
Extent of absorption
First pass metabolism
Bioavailability of 100%
IV
Variable bioavailability examples
Oral
Rectal
Inhalation
Transdermal
Bioequivalence
Compare bioavailability of generic drug product to brand name product
Both drug products should contain the same amount of active ingredient.
Loading dose
Initial dose of drug administered to compensate for distribution into body tissues.
Loading dose dependent on
Volume of distribution
Without a loading dose how many elimination half lives to achieve steady state
3-5 elimination half lives
Steady state
Therapeutic dosing of drug maintained between peak and trough (high and lows)
How many half lives does it take to achieve steady state
3-5 half lives
Maintenance dose
Maintains steady state concentration
Subsequent doses needed to replace only amount of drug lost through metabolism and excretion
Maintenance dose dependent on what
Clearance of drug
Metabolism + excretion / plasma drug concentration
Where do water soluble drugs reside
Blood
Fat soluble drugs reside in
Cell membranes
Adipose tissue
Fat rich areas
Volume of distribution
Represents fluid volume required to contain total amount of absorbed drug in body at uniform concentration equivalent to plasma concentration at steady state.
Amount of drug in body/ plasma drug concentration
Drugs with small Vd retained where
Primarily retained in vascular compartment
Drugs with large vd reside
Extensively distributed to tissues (muscle, adipose and other non vascular compartments)
Has long duration of action
Vd of about 4L
Low
Present mainly in vascular compartment
Heparin
Vd about 10 L
Medium
Present in extracellular fluid but are unable to penetrate cells
Mannitol
Vd of about 42L
Medium high
Drugs about to pass most biologic barriers and are distributed in total body water (ICF and ECF)
Alcohol
Vd above 42
High
Drugs extensively stored within specific cells/ tissues
At low concentration in vascular compartment at steady state
Chloroquine
Azithromycin
Digoxin
Rate of accumulation into tissue compartments depends on
Blood flow to the organ
Chemistry of the drug
Plasma protein binding of drug
Drug protein binding
Usually reversible interaction of drugs with proteins in plasma
Drug protein bindings
Albumin
Alpha 1 acid glycoproteins
Lipoproteins
Albumin
Most abundant plasma protein
Responsible for most acidic drug binding
Alpha 1 acid glycoproteins
Responsible for most basic drug binding
Lipoproteins
Responsible for most lipophilic drug binding
Bound drugs
Pharmacologically inactive
Free unbound drug
Can act at target sites and elicit biological response
High protein drug binding
Leads to more drug present in the central blood compartment and therefore a lower vd.
Low protein binding
Leads to increased free rug and increased concentration in tissues and therefore results in high vd
Disease state or drug and protein binding
Disease state or drug can displace highly protein bound drug and increase free drug concentration and may lead to drug toxicity
Hypoalbuminemia and protein binding
May alter the level of free drug
Ceftriaxone and drug protein binding
In neonates with hyperbilirubinemia can exacerbate hyperbilirubinermia
When would you monitor low clearance drugs with a low therapeutic index
When coadministered with drug known to cause displacement interaction
Drugs known to cause displacement interactions
Warfarin
Phenytoin
Tolbutamide
Distribution
Pediatric considerations
Drug dosing calculated as mg/kg
Increase total body water and extracellular water, increase vd for hydrophilic drugs
Decrease plasma protein albumin, increase percentage of drug that is active
Decrease body fat, decrease for lipid soluble drugs
Distribution
Elderly considerations
Age associate changes in body composition can alter drug distribution
Decrease total body water- decrease vd for hydrophilic drugs > higher serum levels.
Increase fat stores increase vd for lipophilic drugs and prolongs half life
During acute illness what occurs
Decrease plasma protein > increases percentage of unbound drug
Increases alpha 1 acid glycoproteins > increase percentage of unbound drug
Where does drug metabolism/biotransformation occur
Predominately in liver
Some in other tissues: skin, lungs, GI, and kidneys
Endogenous enzyme systems for drug metabolism
Cytochrome p450 -95% of oxidative biotransformation
Alcohol dehydrogenase
Monoamine oxidase MAO, amine containing compounds such as catecholamines and tyramine
Drug metabolism outcomes
Active drug>inactive metabolite Unexcretable lipophilic drug> excretable metabolite Active drug> active metabolite Inactive prodrug>active drug Active drug> toxic metabolite
Metabolism reactions
Functions
Aim to reduce lipid solubility (increase hydrophilicity)
Often occur sequentially
Phase i reactions
Oxidation/reduction/ hydrolysis
Purpose to add polar to make more water soluble metabolites for renal elimination
Mediate by microsomal cytochrome p450.
Phase 1 enzyme activity decreases with patient’s age.
Phase ii reactions
Conjugation
Purpose to increase polarity to make polar inactive metabolites
Enhances drug’s solubility to be excreted in bile or bile
Phase ii conjugation reactions
Glucuronidation
Acetylation
Sulfation
Cytochrome p450 system
Heme protein mono oxygenase
Found in smooth ER of hepatocytes
Metabolizers hydrophobic drugs
Cytochrome p450 enzymes important for drug metabolism
Cyp3a4 Cyp2d6 Cyp2c19 Cyp2c9 Cyp2e1 Cyp1a2
Genetic variation in cytochrome p450
Can alter drug metabolism either by changing the rates of the reactions or eliminating.
Pharmacogenetics
Study of effects of genetic variability on drug metabolism
Rapid metabolizers
Ore enzyme present and increased drug metabolism
Induction of enzyme
Poor metabolizers
Less functional enzyme present and decreased drug metabolism
Inhibition of enzyme
Induction of P450 enzyme
Increase expression of enzyme, increases drug metabolism and increases drug clearance and decreases drug efficacy
Inhibition of p450 enzyme
Decrease expression of enzyme, decreases drug metabolism and increases drug toxicity
Competitive or irreversible inhibition by another drug or compound, decreases metabolism
Renal excretion
Major route of drug excretion
Kidneys receive about 25% total systemic blood flow
Rate of drug elimination through kidneys depends upon
Balance of
Drug filtered
Drug reabsorbed
Drug secreted
Elimination Kinetics first order
Constant fraction of drug elimination in unit time
Elimination is proportional to drug
Exponential decay of plasma concentration time curve
Most drugs 95%
Zero order elimination kinetics
Constant amount of drug elimination in unit time
Elimination saturates at higher
Alcohol, aspirin, warfarin, theophylline
half life
Amount of time over which the drug concentration in plasma decreases to one half
Why is half life important
Allows clinician to estimate frequency of dosing required to maintain therapeutic levels
