Test 1 Flashcards
The study of intrinsic sensitivity or responsiveness of the body to a drug and the mechanisms by which it occurs. What drug does to body. Effect site concentration and clinical effect
Pharmacodynamics
Study of absorption, distribution, metabolism (biotransformation), and excretion of a drug. What body does to a drug.
Pharmacokinetics
A protein or other substance that bind to an endogenous chemical or drug
Receptor
Properties of receptors
Sensitivity
Selectivity
Specificity
Receptor Sensitivity
Responsiveness or reactivity of a receptor to a particular ligand or substance
Receptor Selectivity
Preference of a ligand for a specific type of subtype of receptor
Receptor Specificity
The degree to which a receptor recognizes and binds to a particular ligand over other substances
Drug receptor classification
Generic characterization, similarity of structure and function
Examples of receptor classifications
G protein coupled, ligand gated ion channels, ion channels, catalytic receptors, nuclear receptors, transporters, enzymes
Receptor locations
Lipid bilayer of cell membrane
Intracellular proteins
Circulating proteins
Also there are drugs that do not interact with proteins at all
One of many mechanisms that contribute to variability in drug response
Changing number of receptors aka upregulation or downregulation
Signal transduction
Process by which a cell converts one kind of signal or stimulus into another
Ordered sequences or cascades of biochemical reactions inside the cell
ex. second messenger pathways
Drug response equation
Drug + Receptor⇆ (Drug Receptor Complex)⇄ Tissue Response
Fundamental to pharmalogic principles and derived from the law of mass action
Affinity and Efficacy
Describe the degree of drug receptor interaction for a given drug and receptor protein population
Affinity
Potency. Strength of binding to receptors. Weak affinity can be bumped off by something with strong affinity. Ex Aspirin has STRONG affinity
Efficacy
The ability of a drug to produce the desired effect or maximum response. The magnitude of a response with respect to a given dose. (dilaudid vs. morphine)
Pure antagonists
Have receptor affinity BUT lack intrinsic efficacy or activity. Similar in structure to corresponding agonist.
Competitive antagonists
Have a weak affinity for the same receptor protein and may be displaced by an agonist
Ex. Atropine and esmolol
Noncompetitive antagonists
Have a strong affinity for the receptor protein and cannot be displaced by the agonist
Ex. Aspirin
Agonist Antagonist
Second major type of antagonist drugs. Have receptor protein affinity and intrinsic activity, but often only a fraction of the potency of the full agonist.
Ex. Nalbuphine
Physiological antagonism
two AGONIST drugs that bind to different receptors. Both drugs bind to specific unrelated receptor proteins, initiate a protein conformational shift, illicit individual tissue responses. Responses generate opposing forces.
Ex. Isopreteronol vasodilation and NE induced vasoconstriction. Net effect is less than if either drug were used alone.
Chemical antagonism
When a drug’s action is blocked and no receptor activity is involved.
Ex. protamine forms an ionic bond with heparin and renders it inactive
Full agonist
Binds to a receptor site and turns on response, mimics endogenous ligand, produces maximal effect.
Ex. Dopamine, propofol
Down regulation is continued stimulation of cells with
AGONISTS. Results in states of desensitization. The effects of same amounts of drug are diminished (because now there’s not as many receptors) and more drug is required.
Up-regulation happens with chronic administration of
ANTAGONISTS. The number and sensitivity of the receptors increases as response to chronic blockade. Pt develops tolerance and requires higher doses of antagonists.
Drug interaction
Alteration in the therapeutic action of a drug by concurrent administration of another drug or substance
Types of drug interaction
Addition
Synergism
Potentiation
Antagonism
Addition
1+1=2
Synergism
1+1=3
Potentiation
1+0=3
Antagonism
1+1=0
The drug interaction between most anesthetics is
Syngergism
Properties influencing pharmacokinetics
Molecular size
Transporters
Lipid solubility and degree of ionization
Ion trapping
Protein binding
Molecular Size
The smaller the agent, the easier it crosses lipid membranes and membranes of tissues
Transporters
Control entry and exit molecules. Can affect bioavailability, clearance, volume of distribution, and half life for orally dosed drugs
Drive their substrates out of the cell
Efflux transporters.
Transfer their substrates into cells
Uptake transporters
Water soluble form of a drug
Ionized (charged).
Not absorbed well orally and not metabolized by the liver.
Excreted via the renal system.
Lipid soluble form of drug
Nonionized (uncharged)
Able to cross membranes easily.
Cannot be excreted by the kidneys so it gets reabsorbed for metabolism by the liver.
Degree of ionization is determined by
the dissociated constant or pKa
pH of surrounding fluid
When pH and pKa are identical
50% of drug is ionized and 50% is unionized
Acids are proton
Donors
Bases are proton
Acceptors
Acidic drugs (barbiturates) are highly ionized at a
alkaline pH
Acidic drugs are nonionized in a
acidic pH
Basic drugs (opioids and LA) are highly ionized in a
Acidic pH
Basic drugs are nonionized in a
alkaline pH
Ion trapping
occurs when an ionized drug (WEAK acids or bases) gets trapped on one side of a membrane that divides compartments of two different pHs. Ex mom gets lidocaine (weak base), crosses placenta easily in unionized form, becomes ionized in acidic fetal environment, gets trapped and cannot cross back over
Plasma Proteins
Albumin: favors Acidic compounds (but will also bind with basic and neutral)
A1 Acid Glycoprotein: favors basic compounds
B Globulin: Favors basic drugs
Protein binding affects
Distribution: Free or unbound fraction readily crosses membranes
Potency: The free fraction is able to bind to a receptor site
Degree of protein binding is proportional to the drug’s:
Lipid solubility
Most drugs are cleared via what order kinetics
First order kinetics
Drugs cleared via zero order kinetics
Phenytoin, ETOH, Aspirin, warfarin, heparin
What is constant in First order kinetics
Fraction of the drug eliminated. Half Life.
What is constant in Zero order Kinetics
Amount of drug eliminated regardless of plasma concentration
When is the greatest amount of drug eliminated per unit time in first order kinetics
When the drug concentration is highest
First order kinetics graph is
CURVED
Zero order kinetics graph is
LINEAR
Population variability
Range of responses to a given drug
Affected by age, sex, body weight, bsa, basal metabolic rate, pathologic state, and genetic profile
Therapeutic dose
ED50. Average dose of a “normal” population of people
Therapeutic index
The distance between the LD50 and TD50
LD50/TD50
Drug Response equation
Derived from law of mass action.
The magnitude of a drug’s effect is directly proportional to number of receptors occupied
The arithmetic average of the range of doses that produce a given response
Mean
The middle. Half of responses occur on either side
Median
The dose representing the greatest percentage of responses. Shows up most frequently.
Mode
Provides information regarding actual responses measured and their difference from the calculated mean
Standard deviation
The mean reflects the central tendency of responses LESS when the SD is
greater
Describes the variance of the mean
Standard error of the mean
A proportional expression that relates the amount of drug in the body to the serum concentration.
Volume of distribution
The apparent volume into which the drug has been distributed after being introduced to the body
Vd=
dose of drug/plasma concentration
Large Vd implies
widely distributed, highly lipid soluble, unionized
Small Vd implies
largely contained in plasma, water soluble, ionized
Steady State
Drug elimination = drug administration
Stable plasma concentration is achieved and all body compartments equilibrate
Elimination of the drug by the GI system before the drug reaches systemic circulation
Presystemic elimination
Mechanisms of presystemic elimination
- Stomach acids hydrolyze the drug
- Enzymes in the GI wall deactivate the drug
- Liver biotransforms the ingested drug before it reaches the effect site (First pass effect)
Best med route for prevention of emesis caused by irritation of GI mucosa
Rectal
Proximal rectal undergoes first pass
Distal rectal does not
Systemic absorption of IM and SQ routes is dependent on:
Capillary blood flow to the area and lipid solubility of the agent
Transdermal route drugs must have what solubility
Water soluble: penetrate hair follicles and sweat ducts
AND
Lipid soluble: traverse skin and exert effect at the receptors
Converts pharmacologically active, lipid-soluble drugs into water-soluble inactive metabolites
Metabolism
Main organ of metabolism
Liver
Phase 1 Metabolism
Modification
Phase 2 Metabolism
Conjugation
Phase 3 Metabolism
Elimination
Phase 1 Reactions
Increase the polarity of the molecule, transforming a lipid-soluble compound to a water-soluble one:
Oxidation
Reduction
Hydrolysis
Oxidation
Phase 1: adds an O2 molecule to a compound. Catalyzed by enzymes of the P450 system
Reduction
Phase 1: Adds electrons to a compound. Using P450 system
Hydrolysis
Phase 1: adds H2O to a compound to split it apart
Conjugation
Phase 2: Adds on an endogenous, highly polar, water-soluble substrate.
Results in a biologically inactive molecule to prepare for elimination.
Common substrates for conjugation
Glucuronic acid, sulfuric acid, glycine, acetic acid, or a methyl group
Increased enzyme activity by stimulating enzymes over a period of time
Enzyme induction
Increased capacity to clear drug =
Reduction in half-lives. Important for dosing intervals
Common enzymes inducers
Tobacco, barbiturates, ethanol, phenytoin, rifampin, carbamazepine
Increased clearance, decreased drug plasma levels, dose increase may be required
Common enzyme inhibitors
Grapefruit juice, cimetidine, omeprazole, SSRIs, erythromycin, ketoconazole, isoniazid
Decreased clearance, increased plasma drug levels, dose decrease may be required
Elimination
Phase 3: Half-life - time necessary for the plasma content of a drug to drop to half of its prevailing concentration after rapid bolus injection.
When is drug regarded as being fully eliminated
When 95% has been eliminated OR 4-5 half lives
An independent value governed by the properties of the drug and the body’s capacity to eliminate it
Clearance
Clearance is directly proportional to
The dose
Clearance is inversely related to
the Half-Life and the concentration in the central compartment
Drugs with a high extraction ratio 0.7 or greater
Perfusion-dependent elimination. Rely heavily on the perfusion of the liver to be cleared
Drugs with low extraction ratio 0.3 or less
Capacity-dependent elimination.
Clearance depends on hepatic enzymes and the degree of protein binding
Other factors effecting metabolism
Age, Gender, Temperature (hypothermia impairs metabolism), disease states
