Chp. 19: General Pharmacology Flashcards
+ Miller's Chp. 16
Pharmacokinetics
Relationship between drug administration and drug concentration at the site of action
Pharmacodynamics
Relationship between drug concentration and pharmacologic effect
Volume of distribution
Apparent size of the tank in which a known amount of drug distributes to produce a measured drug concentration once the drug has had enough time to thoroughly mix within the tank
Volume of distribution equation
Vd = [Amount (t)] / [Concentration (t)]
Clearance
Describes the rate of drug removal from the plasma/blood. Two processes contribute: systemic (removal from the tank) and intercompartmental (between tanks).
Defined in units of flow: volume completely cleared of a drug per unit of time (eg., L/min).
Systemic clearance
Removes drug from the body either by eliminating the parent molecule or by transforming it into metabolites
Intercompartmental clearance
Moves drug between plasma and peripheral tissue compartments
Clearance equation
Clearance = Dose / AUC
Zero-order kinetics
Drug is eliminated at a constant rate
Formula for straight line can be used
First-order kinetics
Drug is eliminated at a rate proportional to the amount of drug present at that time
Exponential function is appropriate
Affinity
Refers to how strongly a drug binds to a specific receptor (essentially it’s “attraction” to the receptor). A drug with high affinity for a receptor with have a high Ka (number of unbound ligand molecules at equilibrium is low).
Selectivity
Determines capacity of a ligand to produce a particular effect. Highly selective drugs will only produce one effect through activity at only one class or subclass of receptor.
Specificity
Describes a ligand’s capacity to associate with only one specific type of receptor. Effects of a highly specific ligand can be numerous but are due to only one type of receptor-ligand interaction.
Agonist
Ligand that binds to the receptor and activates it the same way that endogenous molecules would.
Full: Fully activates the receptor
Partial: Does not fully activate the receptor and produces a less intense maximal effect
Neutral antagonist
Ligand will bind to the receptor but be unable to activate it. No action will be seen following association of ligand with receptor.
Reverse agonist
Ligand will activate the receptor but will induce opposite effects compared to the agonist ligands. (Receptor has a baseline agonist effect; reverse agonist will decrease baseline effect).
Classical Receptor Theory
Receptor is, by default, in a nonactivated form and needs an agonist ligand in order to be activated.
Receptor State Theory
Role of a ligand is not to activate the receptor but to stabilize the receptor’s activated form. Permits possibility of “baseline activity” and allows existence of “inverse agonists.” Most suited to describing activity of gated channels.
GABA(A) Receptors
- Ligand-gated anion channels that allow passage of chloride ions into the cell
- Hyperpolarization inhibits subsequent neuronal depolarization
- Most of the drugs that bind GABA(A) do not directly activate the receptor. They induce an allosteric change (change of quaternary structure) of the conformation of the receptor–“allosteric modulators.”
- Barbiturates, benzos, propofol, etomidate, alfaxalone, inhalant anesthetics, ethanol are “positive allosteric modulators”
- Flumazenil is a “negative allosteric modulator” and decreases the efficiency of the channel
AMPA Receptors
- Ligand-gated ionotropic receptor
- Allows entrance of Na+ and exit of K+
- Association with agonist ligand induces a conformational change allowing the channel to open
- Amount of glutamate will dictate amount of cation transfer and degree of depolarization of the postsynaptic neuron
NMDA Receptor
- Ligand-gated and voltage-gated ionotropic receptor
- Allows entrance of Na+ and Ca2+ and exit of K+
- Molecule of Mg2+ keeps channel closed until strong enough depolarization of postsynaptic membrane occurs
- Glutamate and aspartate are main endogenous agonists
- Glycine is a required co-agonist
- Amantadine, gabapentin, ketamine, ethanol, xenon, nitrous oxide, and methadone and tramadol are NMDA receptor antagonists
- Magnesium, sodium, calcium, potassium, zinc, and copper are modulators of the receptor
Beta-adrenergic receptors
- Linked to AC enzyme system through G-proteins
- Activated by endogenous EPI and NE
- Stimulatory G protein (Gs or Galphas)
- Alpha subunit is associated with GDP and switched off
- Conformation changes when activated and GTP replaces GDP to switch on
- AC > inc. cAMP > activate PKA
ACE2 Receptor
Abundantly present in lung and SI epithelia and in most organs’ arterial and venous endothelial cells and arterial smooth muscle cells
Hormesis
Dose-response relationships characterized by stimulatory effects at low doses and inhibitory effects at higher doses (inverted U-shape dose-response curve)
E.g. naloxone
Efficacy
Represents the maximal pharmacological effect of a drug of ligand
Potency
Characterizes concentration of drug needed to obtain a pharmacological effect that equals 50% of Emax
ED50
Effective dose 50
Dose of drug necessary to induce the desired effect in 50% of animals
LD50
Dose of drug necessary to induce death in 50% of animals to which the drug is administered
TD50
Dose of drug necessary to induce toxic effects in 50% of the patients to whom it is administered
Therapeutic Index
LD50/ED50 or TD50/ED50
The higher the therapeutic index, the safer the drug
Not a useful measure of a drug’s clinical safety due to slope of concentration-response curve
ADME
Absorption
Distribution
Metabolism
Excretion
Body exerts effects on the drug–pharmacokinetics
Plasma elimination half-life
Time interval needed for the plasma concentration to be reduced to 50% of its initial value
The time one must wait after administering a drug or changing a drug dose rate before attaining a new steady-state plasma concentration, or before attaining complete elimination of a drug, is a function solely of what?
The half-life of that drug
How many half-lives must pass before a change in dose achieves a new steady-state plasma concentration? How many half-lives must pass after cessation of administration before all drug is effectively eliminated?
4-5 half-lives
What are the individual factors that affect the volume of distribution?
State of hydration, age and gender, body weight and body composition, protein content of serum, presence of plasma expanders (e.g. lipids after a meal), drug interactions
Total Body Clearance
Volume of blood from which drug is completely removed per unit of time
Measure of efficiency of drug elimination
What is intrinsic clearance of the liver?
Innate capacity of the liver to clear drug.
The liver in each animal has a maximum capacity for removing a drug from the blood when there are no blood flow constraints. It is a function of liver mass and the amount and activity of the enzymes of drug metabolism present in that individual’s hepatocytes.
High hepatic clearance drugs (hepatic clearance is very much greater than hepatic blood flow)
- Hepatic clearance is proportional to the faction of drug unbound
- Alterations in plasma protein binding of the drug can significantly affect the rate of that drug’s excretion
Low hepatic clearance drugs (hepatic clearance is very much less than hepatic blood flow)
- Alterations in hepatic blood flow will profoundly influence the rate of hepatic clearance
- Rate of elimination of many common anesthetic drugs can differ from that predicted due to changes in hepatic blood flow
First-pass effect
Drugs with a high intrinsic hepatic clearance have high elimination rates and therefore have low bioavailability when administered orally
Renal Clearance
Clearance of drug from the plasma by the kidneys is achieved by the summation of renal filtration and active renal tubular secretion of drug into the urinary ultrafiltrate. Renal clearance is diminished from this sum by any tubular resorption that may occur
Rate of renal filtration is a function of GFR and plasma concentration of UNBOUND drug
If renal clearance is greater than fu x GFR, renal secretion must be occuring; if renal clearance is less than fu x GFR, renal resorption must be occurring
Absorption
Absorption across membranes is proportional to the difference in concentration across the membrane, the area of the membrane, and its permeability to the drug. Concentration of drug in the formulation will partially determine the steepness of the diffusion gradient for drug absorption.
Bioavailability
Fraction of dose given which finds its way into the systemic circulation. Not necessarily equal to the fraction of the dose which is absorbed.
Principle of Superposition
Response to any combination of inputs must equal the sum of the responses when input separately. For pharmacokinetics, input is dose and response is the sample’s drug concentration.
Intermittent Boluses
After injection of a loading dose, effect can be maintained by repeated injections.
- Drug plasma concentration tends to oscillate between peaks of relative excess and troughs of ineffective amounts.
- Can result in administration of a large total drug dose
CRI
- Results in better quality of effect and decrease in total drug dose delivered
- Plasma drug concentration achieved is not controlled
- Not appropriate for drugs with relatively long elimination half-lives because [plasma] will be low at the beginning
- To avoid this, a loading dose may be administered
- Changing infusion rate based on patient results in rate-controlled infusion
TCI
Computer programmed with a set of PK parameters (specific for species and drug) and coupled with a syringe driver. If target kept constant, infusion rate will exponentially decrease over time to match the cumulative characteristic of the agent.
Context-sensitive half-time
“Context” is the variation of the duration of the infusion
CSHT is the time from the end of the infusion necessary for the plasma’s drug concentration to decrease by 50%
- For short-term infusions, CSHT dependent on redistribution.
- For moderate-term infusions, CSHT will depend on the drug’s distribution and elimination.
- For long-term infusions, CSHT will approach the true elimination half-life of the drug.
What is the effect of displacement of drugs from protein binding?
Does not markedly alter the unbound fraction in circulation, and therefore affects elimination rate more than efficacy.
What category of drugs has the most frequently reported adverse drug events?
NSAIDs
Phase I Biotransformation
Aim to convert fat-soluble compounds into water-soluble compounds read for immediate renal clearance, or to add chemically reactive sites to a relatively chemically inert molecule so as to allow further biotransformation.
Performed by the cytochrome P450 isoenzymes (CYPs) in liver but also GI, skin, brain, lung, kidney, other tissues. Located in endoplasmic reticulum. Oxidation, reduction, hydrolysis, and hydration reactions.
Phase II Biotransformation Reactions
Conjugation reactions attach the exogenous compound covalently to a substrate, which both increases the molecular weight and the water solubility of the complex.
Excreted in bile if of high molecular weight or urine if low MW and high water solubility.
Glucuronidation, sulfating, methylation, acetylation, amino acid conjugation, glutathione conjugation, fatty acid conjugation.
Phase III Biotransformation Reactions
Transcellular transport processes
In liver, transporters found on the canalicular membrane where they are involved in biliary excretion, and on the sinusoidal membrane, where they uptake drugs from blood into hepatocytes.
In kidney, transport systems found on brush border and basolateral membranes of the tubular epithelial cells and secrete drugs into urine.
What factors affect drug metabolism?
Species, gender, genetics, age, hormone and disease status, drug-drug interactions, diet, environment
What is slower: enzyme induction or inhibition?
Induction (days to weeks).
Chiral stereoisomers
Major consideration pharmacologically. Enantiomers are chorally active stereoisomers, which have planar symmetry (one form is the mirror of the other)
What are the two naming systems for stereoisomers?
R-S
Clockwise = R
Counterclockwise = S
Dextrorotary (+) when polarized light rotates to right
Levorotary (-) image of above
