PK of Elim & PD Flashcards
Explain the derivation and clinical relevance of: 1ST ORDER AND 0 ORDER KINETICS
1ST ORDER: rate of elimination [mg/hr] is proportional to the concentration of the drug in the plasma [mg/L] (so if Cp is doubled, elimination is doubled)
This is because major biologic processes responsible for drug elimination are first order processes.
Has log slope because as Cp decreases, rate of elim decreases
ZERO ODER: rate of elimination of drug from the body is INDEPENDENT of the amount of drug in the body (so it’s constant, regardless)
• Most often occurs due to saturation of hepatic metabolic enzyme systems by drug administration
• Drugs eliminated by zero order kinetics do not have half-lives and can present dose adjustment
Explain the derivation and clinical relevance of: CLEARANCE
Clearance: volume of plasma (Vd) which is completely cleared of drug in a given period of time (metab + elim)
Can also think of it as a proportionality constant (k) that makes the average plasma concentration at steady state (Cpss) equal to the rate of administration
Measured in volume over time (L/hr)
Explain the derivation and clinical relevance of: HALF-LIFE
As drug is eliminated, rate of elimination dec
Half-life = Time to Cpss or removal from body (both take 4-5 half-lives)
Explain the derivation and clinical relevance of: Elimination rate constant (ke)
constant for any given drug; influences how fast the drug is eliminated (higher ke = faster elimination).
Describe the drug-receptor concept and its consequences for pharmacotherapy.
- Drug binds to a receptor (for which it specifically fits) and induces conformational change in receptor protein.
- Conformational change in the receptor leads to the transduction step that alters cellular function via effector molecules.
- Transduction is amplified via:
• Ligand-gated ion channels: A very fast response (msec) via opening (or closing) of ion channel that changes membrane potential
• G-protein-coupled receptors: A fast response (sec) via change in activity of G-protein linked enzyme system that produces effector molecules (2nd messengers) such as cyclic AMP, cyclic GMP, or inositol triphosphate (IP3)
• Kinase-linked receptors or hormone (nuclear) receptors: A slower response (hours) brought about by changes in gene transcription and protein synthesis - This ultimately leads to a physiological response, such as: muscle contraction or relaxation, neurotransmitter release, glandular secretory activity, etc.
Can be agonist (mimic natural molecule in body that would normally bind to receptor) or antagonist (block natural molecule) – which won’t work in absence of said natural molecule
**Theory allows determination of quantitative relation between dose or concentration of drug and its pharmacologic effects via use of dose-response curves.
Explain the theoretical aspects and therapeutic consequences of the hyperbolic shape of the dose-response curve.
Starts out linear, but then flattens out. This is because, per the theory, the response obtained by administration of any drug is proportional to the amount of receptors occupied by drug. When the dose of drug is high enough to occupy all of the receptors, no further increase in response can be obtained, i.e., Emax has been reached. Receptors are saturated
Describe the advantages of the log dose-response curve versus the dose-response curve.
Go from hyperbolic to sigmoidal shape
This allows a wide range of concentration values to be plotted in a small area.
This also allows the linear portion of the curve (the therapeutic dosage range) to be mapped out over a large portion of the x-axis.
Explain the terminology of log dose-response curves and their use to compare potency and efficacy of different drugs:
- Potency refers to the concentration (EC50) or dose (ED50) required to produce 50% of that drug’s individual maximal effect (NOT the 100% value of that system)
- Potency of a drug depends on affinity (Kd) of receptors and on the efficiency of this drug-receptor complex to generate a response
- The potency of a drug provides information on how much drug (dose) will be required to produce a given effect, the more potent a drug, the less that is needed for any given effect.
- Max Effect / Max Efficacy [Emax] indicates the relationship between binding to the receptor and the ability to initiate a response at the molecular, cellular, tissue or system level.
- The efficacy of a drug is the MOST IMPORTANT determinant of its clinical utility, as potency simply determines what dose is necessary to achieve the desired level of response
- Power is often used interchangeably with efficacy to describe the ability to initiate a response
- Efficacy is a pharm term. You can give a drug at nowhere near the Emax of that drug (i.e. lots of unbound receptors) with a complete clinical effect (ie no more pain).
Discuss agonist, partial agonist, and antagonist
Agonist: An agent that binds to a receptor to produce a biological response.
Full agonists: drugs that can achieve full Emax (all receptors occupied) at a certain dose.
Partial Agonists: Drugs that can’t achieve full Emax at any dose.
For example: smoking cessation aids that deliver nicotine at a much lower possible maximal effect (enough to decrease symptoms of withdrawal but not enough to prolong addiction).
Few drugs are partial agonists; most are full.
Antagonist: A drug molecule that combines with a receptor compound but does not bring about a response– effectively it prevents agonists from binding. See below for types and examples.
Distinguish between characteristics of the different types of antagonism (pharmacological [competitive reversible and noncompetitive irreversible], physiological, chemical) and provide examples.
PHARMACOLOGICAL
• Competitive shifts a dose-response curve to the RIGHT (same Emax, bigger EC50)
• Uncompetitive (i.e. irreversible) shifts a dose-response curve DOWN (lower Emax, same EC50)
PHYSIOLOGICAL
• one drug (the antagonist) produces an opposite effect to that of another drug (the agonist) by two SEPARATE pathways and receptor systems.
• Example: histamine binds to histamine receptors to promote bronchoconstriction; epinephrine acts as its physiological antagonist during treatment for anaphylactic shock by binding to adrenergic receptors to promote bronchodilation.
Another example: norepinephrine binds to adrenergic receptors in heart tissue to increase heart rate. Acetylcholine can act as a physiological antagonist by binding to muscarinic receptors in heart tissue to decrease it again.
CHEMICAL
• Does not involve receptor binding. The antagonism occurs via inactivation of the agonist itself by modifying it or sequestering it so it is no longer capable of binding to and activating the receptor.
Examples:
EDTA (a chelating agent) combining with lead ions
Antacid bases neutralizing excessive stomach acid
Osmotic diuretics
Protamine (positively charged molecule) countering effects of heparin (negatively charged molecule)
