Lecture 1/23/23 Flashcards
Drug effect relates to
number of bound receptors
Ion bonding
electrovalent => oppositely charged ions
Hydrogen Bonding
to a very electronegative atom
Van der Waals interaction
the sum of attractive or repulsive forces; creates orbital shift
Competitive antagonism shifts the dose response sure to the __________
Right, more drug is needed to get the same response
What are some examples of how the number of receptors are not static
- Tolerance [tachyphylaxis => rapid tolerance => ephedrine]
- Albuterol treatment for asthma => downregulation of receptors due to repetition
- Pheochromocytoma => decreased β receptors in response to catecholamines
What types of receptors (classified by location) do we have?
What is a drug that binds to each of those types of receptors?
Lipid bilayer:
* Common for anesthesia drugs
* Membrane bound
* Opioids, bzd [benzos], b-blockers, catecholamines, NMBD
Intracellular proteins:
* Insulin, steroids, milrinone
Circulating proteins:
* Anticoagulants
* Age decreases proteins
* => more unbound drug => free drug
* => more anticoagulant [drug] effects
* => Bleeding
Central compartment
What dilutes the drug in the first minute following injection
Venous blood in arm, inferior vena cava, right heart, pulmonary vessels, lungs, left heart, aorta
movement based on CO and vessel-rich groups
Plasma proteins bind most drugs in 2 categories
- Acidic drugs primarily to albumin
- Alkalotic drugs primarily to a1-acid glycoprotein
Only ________ can determine the concentration available to the receptor (potency)
free drug
What conditions cause decreased proteins?
Age, Hepatic disease, Renal disease, Pregnancy, Burns, sepsis
If the normal free fraction of the drug is 5% but this. the patient has lost 50% of their plasma proteins what free drug concentration will this pt have?
10%
If a drug is poorly protein bound and lipophilic if will have a __________ Vd
high, ie Thiopental
What is phase 1 in metabolism
- Increase polarity and prepare for Phase II reactions
- Oxidation
- Reduction
- Hydrolysis
What is phase 2 in metabolism
- Covalently link with a highly polar molecule to become water soluble
- Conjugation
how many isoform of CYP450
10
CYP450 participate in what phase of metabolism and more specifically what subcategory
Phase 1, oxidation and reduction
most common CYP enzyme
- CYP3A4:
- Most common for anesthetic drugs
- Up to 60% of CYP450 activity
- Metabolizes > 50% of drugs: opioids, BZP, LA, immunosuppressants, antihistamines
Phenobarbital ___________ enzymes => _____________ metabolism of drugs, causing __________effectivness of other drugs
Induces, increases, decreased
What is a well-known CYP inhibitor and what effect does it have on other drugs?
Grapefruit juice => increases the concentration of drugs/toxicity levels by inhibiting their metabolism
* More drug left around, might cause OD
Rate of drug metabolism
- Rate is proportional to the concentration
- More drug/more clearance
R = Q (C inflow – C outflow)
Q= flow so low CO will affect Rare of metabolism
Three Methods of Renal Clearance
Glomerular filtration
* GFR and amount of protein bound drug controls amount of drug entering tubule
Active tubular secretion
* From peritubular capillaries
* Active transport process
* PCNs
Passive tubular reabsorption
* Increased if drug lipid soluble
* ie. thiopental
* Almost zero for water-soluble drugs => excreted in urine
Elimination ½ Time
- Time necessary to eliminate 50% of the drug from PLASMA after a bolus dose. Measured by peak and troughs and random blood draws.
What is Context Sensitive Half-Time
- Time to a 50% decrease after infusion discontinued
- Assumes a constant concentration
- Roughly relates to ½ life
- Increases the longer the infusion increases
- Accumulation in peripheral tissues
- Propofolfalls to 50% quickly even with long infusion times when you discontinue the drug
- Fentanyl takes a little longer with a longer infusion
- Need to stop early to get breathing back in time for the patient to wake up
https://www.youtube.com/watch?v=Asf97N69rME&ab_channel=MikeLoughren
Are local anesthetics weak bases or acids
bases
Acids are ionized in __________ pH
Alkaline pH
Bases are ionized at __________pH
Acidic
Non-ionized => ____________ and will cross cell membranes
lipid soluble
To be renal excreted you want the drug to be _________.
ionized
How can you tell if a weak acid will be ionized in a given pH
pH - pK = …
Aaaaacids pK go AAAfter pH
if the number is positive then it will be ionized
if the number is negative it will be unionized
How can you tell a weak base will be ionized in a given pH?
pK - pH = …..
Bbbbbbases pK go Before pH
if the number is positive then it will be ionized
if the number is negative it will be unionized
What is ion trapping?
When a drug enters an isolated environment and becomes ionized based on its surroundings and then can not get back to its original environment.
ie: fetal ion trapping
ie: urine ion trapping. Ion trapping alters the urine pH to inhibit the reabsorption of toxins across the renal tubular membranes. The principle behind this approach is to “trap” the toxin in its ionized form in the urine where it can be excreted.
the more acidic the environment the _________ a local anesthetic will work
Less. weak Base
* In ischemic tissue 8.0 (lido pK) – 6.6 (pH) = +1.4 (very ionized)
What is pharmacodynamics and what is a drug that has different pharmacodynamics at different concentrations
“What the drug does to the body,” Dopamine
What is potency?
Concentration vs response, Less drug with more effect = more potent
What is efficacy?
The ability of a drug to produce a clinical effect
* “How much of the effect can I get?”
Why is it important to understand the time to drug effect?
- Lag time between administration (plasma concentration) and effect
- So we don’t re-dose inappropriately
ie: fentanil has a 5 min delay from when you administer in plasma to when we see a tissue effect. Alfentanil has almost an immediate effect and no lag between administration and effect
Therapeutic index
LD50 / ED50
* ED50 : Dose required to produce effect in 50% of patients
* LD50 : Dose required to produce death in 50% of patients
The Wider the ratio the safer the medication
* Less side effects
* Gives area for caution
Chiral compounds
- Molecules with asymmetric centers [Center carbon]
- Usually related to way carbon molecules are bonded
Stereochemistry
How drug molecules are structured in 3 dimensions
What is an enantiomer?
- Chemically identical
- Mirror images
- Can’t be superimposed
- Can’t be placed on top of each other
Enantiomers that rotate light to the right are called
Dextrorotary
Rectur
Enantiomers that rotate light to the Left are called
Levorotatary
Sinister
What is a 50/50 mixture called?
Racemic,
each enantiomer can exibit different ADME
* One enantiomer is active => other inactive or side effects
* Albuterol vs. Xopenex
* Xopenex has the same effect as albuterol, but no tachycardia
* 1/3 of drugs are racemic => should decrease in future
the ____ enantiomer of ketamine more potent with less delirium
S- enantiomer
- Cisatracurium, the isomer of atracurium, lacks _______ effects
histamine
* Histamine => inflammation, vasodilation => hypotension
