Pharmacodynamics/kinetics (Test 1) Flashcards
What are receptors?
Usually proteins
How are receptors activated?
Conformational shape changes (bound vs unbound)
Thermodynamically more/less active
How do receptors relate to the drug effect?
Drug effect depends on the number of receptors bound
greatest effect all receptors are bound
If you give a full weight based dose of a paralytic how many receptors are bound?
Should attach to many receptors and produce its full effect
What is an agonist?
Activates receptor by binding to receptor
How do agonists undergo binding to receptors?
Ion (or electrocovalent): oppositely charged ions–electron transfer
Hydrogen: binds to electronegative atom
Van der Waals interaction: weal fluctuating bonds
What bonds are not reversible?
Covalent–electrons are shared
What is an antagonist?
Binds to a receptor but does not activate the receptor
They “get in the way” of the agonist
Which bonds between receptor and antagonist and reversible?
Ion
Hydrogen
Van Der Waals
What is competitive antagonism?
Increasing amounts progressively inhibit the agonist
Shifts dose response curves to the right
What is non-competitive antagonism?
Even high concentrations of agonist cannot cause the agonist effect
Partial Agonist:
Binding to a receptor (usually at agonist site)
causes less response than the agonist even at supramaximal doses
Inverse Agonist:
Compete for the same site as the agonist but produce the opposite effect
Were categorized as antagonists
Lower constitutive activity below baseline
What are examples of inverse agonists?
Propranolol
Metoprolol
Cetirizine
Loratadine
Prazosin
Naloxone
What causes changes in receptor numbers in the body?
Numbers of receptors are not static
Can increase and decrease depending on comorbidity, drug therapy,
Can be up-regulated until tired of being used
What happens to receptors that are up-regualted?
Receptors become less responsive= tolerance/ tachyphylaxis
What are examples of common drugs/ conditions that develop receptor tolerance?
1) Albuterol–down-regulation of receptors due to repetition (less effective each time its used consecutively)
2) Ephedrine–mixed beta agonist develops tolerance very quickly
3) Pheochromocytoma–decreased B receptors in response to catecholamines
How are receptors classified?
Classified by location
What are common locations for receptors?
Lipid Bilayer
Intracellular proteins
Circulating proteins
Where are receptors located that are common for anesthesia drugs?
Lipid bilayer: membrane bound
opioids, beta blockers, BZD, catecholamines, NMBD
What are some drugs that have intracellular receptors?
insulin, steroids, milrinone
What are some drugs that have circulating protein receptors?
Anticoagulants (warfarin)
Pharmacokinetics:
What the body does teh the drug
ADME
Determines the concentration of the drug in the plasma and at effector site
How was the 1st compartment model of absorption described?
Drug is injected and concentration of drug is diluted by plasma (Small volume of distribution)
Central compartment (distribution):
Then drug goes through vessel rich groups
Then blood absorbs into muscle then fat
What is the central compartment distribution?
What dilutes the drug in the first minute following injection
What influences drugs blood flow to the muscle and fat?
Blood flow is less to these areas and drug properties influence drugs leaving the vessel and going to the tissue
What areas are considered vessel rich groups?
Parts of the body that have high cardiac output
Brain, heart, lungs, kidney, liver
How did the 2nd compartment model describe metabolism?
Inject drug into blood and goes into the central compartment of plasma-some eliminated but some goes into the periphery
periphery is everything except vessel rich group–then back to the plasma then eliminated
In 2nd compartment model what things leave the central compartment to go to the peripheral compartment?
Drugs that are fat soluble
How do fat soluble drugs Vd compare to water soluble Vd?
Fat soluble drugs have a larger Vd than water soluble drugs
water soluble drugs will not be able to get across lipid bilayer
What drugs are taken up in the lungs >65% during 1st pass?
Licocaine, Propranolol, Meperidine, Fentanyl, Sufentanyl, Alfentanyl
Volume of distribution is affected by anything that changes ________ _________.
blood volume
What plasma protein do acidic drugs bind to?
Albumin
What plasma protein do alkolotic drugs bind to?
A1- acid glycoprotein
Can drugs cross membranes when bound to proteins?
No, only free unbound drug can cross cell membranes
only free drugs determine concentration available to receptor (potency)
Do anesthetic drugs bind to proteins?
Almost all anesthetic drugs are somewhat bound to plasma proteins–some up to 98%
What can cause decrease plasma protein levels?
Age
Hepatic disease
Renal failure
Pregnancy
Acidosis
Burns
Poor nutrition
If a drug has a normal free fraction of 2%, then 50% of the plasma proteins are lost. How much of the drug is free?
4% free fraction–doubles when albumin is cut in half
What type of drugs have a large volume of distribution?
Drugs that have poor protein binding and lipophilic
Access to blood, fat
What are examples of drugs that have high Vd?
Propofol, Thiopental, Diazepam
This is the reason why these drugs cause you to be drowsy for so long–drug goes into fat, muscle brain tissue–causes concentration gradient from these areas back into the blood later when the drug in the blood has been metabolized
What type of drugs have a small Vd?
Drugs that are highly bound to plasma proteins
We want small Vd–when its metabolizes we know it will stay that way (not stocked up in fat)
Decrease intravascular volume causes ________ Vd.
Lower
Increased intravascular volume causes ______ Vd.
Increased
What is the function of drug metabolism?
Convert active, lipid soluble drugs into water soluble for excretion
metabolites are usually inactive
Examples of active metabolites:
Diazepam
Propranolol
Morphine (2)
Prodrugs (codeine)
What are the different ways drugs can be metabolized?
Hepatic Microsomal Enzymes
Plasma-Hoffman Elimination and ester hydrolysis
Kidneys
Tissue esterases (GI, placenta)
What is the function of phase 1 vs phase 2 in drug metabolism?
Phase 1: increase polarity and prepare for phase 2
Phase 2: Covalently link with polar molecule to become water soluble (conjugation)
What are the different phase 1 reactions?
Oxidation: Lose electrons
Reduction: remove O2 or add H+
Hydrolysis: Use water to break bonds
What is the most common enzyme for metabolism of anesthesia drugs?
CYP3A4
How are paralytics metabolized?
Hoffman elimination and ester hydrolysis
How many isoforms of CYP450 are there?
10 isoforms
Membrane bound
Contains a heme cofactor
Involves oxidation and reduction
What phase are CYP450 enzymes?
Phase 1 reactions
-REDOX
How are CYP isoforms grouped?
The more similar the CYP enzymes (homologous), the smaller group they are in
longer name of enzyme= more closely related isoforms
CYP450 enzymes metabolize more that ___% of drugs (opioids, BZD, LA, immunosuppressants, antihistamines
50%
What happens if something induces CYP enzyme?
Increased amount of enzyme
EX:Phenobarbital induces enzymes… increases metabolism of drugs—break down drug faster
What happens if something inhibits CYP enzymes?
Decreased activity of enzyme
EX: Grapefruit juice…increases concentration of drugs/toxicity levels
How are anesthetic drugs processes by the liver?
most anesthetic drugs hepatic clearance is constant
Rate is proportional to concentration–flow limited (more coming in more coming out, less coming in less coming out)
What happens if liver has maxed out its clearance capacity?
Metabolism is exceeded since liver capability is not unlimited
Capacity limited: livers ability to metabolize is the limiting factor–causes build up of the drug
What 3 mechanisms are involved in renal clearance?
1) Glomerular filtration: controls amount of drug entering tubule
2) Active tubular secretion: from PT caps (PCN)
3) Passive tubular reabsorption: increased if drug is lipid soluble (0 for water soluble drugs-excreted in urine)
Elimination half time
Time necessary to eliminate 50% of drug from plasma after bolus dose
Easier to draw blood and do peak/trough than to calculate half life (samples from areas all over the body)
What would the the % of initial drug eliminated with half time is 10 min?
Context sensitive half time:
Time to a 50% decrease after infusion discontinued
Increases the longer the infusion increases
Accumulation in peripheral tissues
When is 50% of the drug ionized and 50% of the drug unionized?
When the pK and pH are the same
What drugs are weak acids?
Barbiturates
What drugs are weak bases?
Local anesthetics, opioids
When are acids ionized?
Acids are ionized in alkaline pH
When are bases ionized?
Bases are ionized in acid pH
What form of ionization is active?
Non-ionized: more lipid soluble
Which form of drug ionization is more water soluble?
Ionized–not active
Formula for weak Acids:
pK After pH
(pH- pK)
Formula for weak bases:
pK Before pH
(pK- pH)
Negative numbers are __________.
Non-ionized
Nicely Negative Numbers are Non-ionized
Pharmacodynamics:
What the drug does to the body
“the sensitivity of the body to the drug”
Measure plasma concentrations at different pharmacologic responses
How does pharmacodynamics vary between people?
Elderly:
Decreased cardiac output to brain and liver (slower response takes longer to go down and longer to wake up)
Decreased protein binding
Increased body fat
Enzyme activity:
Acute vs chronic alcohol ingestion (chronic upregulated receptors)
Genetic disorders:
Atypical cholinesterase activity
Malignant hyperthermia
Potency:
concentration vs response
less drug with more effect = more potent
Efficacy:
the ability of a drug to produce a clinical effect
Effective dose vs Lethal dose:
ED50 : dose required to produce effect in 50% of patients
LD50 : Dose required to produce death in 50% of patients
Therapeutic index:
Therapeutic index: ratio between (LD50/ED50 )
What is the structural basis of enantiomers?
Chemically identical
Mirror images
Can’t be superimposed
“optical isomers”
How can the rotation of light in solution be described (R vs L)?
Right: Dextrorotatory
Left: Levorotatory
Molecule sequence
R: Rectus
S: Sinister
What is a 50/50 mixture of isomers?
racemix mixture
optical activity it equal
can have different ADME
One enantiomer is active, the other is inactive or side effects
How many drugs are racemic?
1/3 (should decrease in the future)
Enantiomer examples:
S-enantiomer of ketamine more potent with less delirium
L-bupivicaine less cardiac toxicity: 3-4x less cardiac toxicity
Cisatracurium, the isomer of atracurium, lacks histamine effects
Albuterol and Xopenex (isomer)
What is the purpose of pharmacogenetic testing?
Look for variants in genes that code for:
Drug-metabolizing enzymes
Drug targets
Immune proteins
