Pharmacology Flashcards
What does ADME process stand for?
A: Absorption, how does the drug get into the blood?
D: Distribution, where does it go?
M: Metabolism, what happens to it?
E: Excretion, how does the drug get out?
What is absorption?
Movement of drug from the site of administration into the blood; passive diffusion
What influences drug absorption?
Concentration gradient
Drug size
Lipid solubility/ionization/pH
Henderson Hasselbach equation
pH-pKa = log ([A-]/[HA])
Which form of the drug can passively diffuse across lipid membranes?
Uncharged
What factors influence drug distribution?
Concentration gradient
Drug size
Lipid solubility/ionization/pH
(same as absorption)
ALSO
Tissue perfusion (>blood flow = first and most amount of drug)
Protein binding (large plasma pr- trap drugs in blood stream)
Define volume of distribution (Vd)
Amount of drug in the body : [drug] in the blood
[drug] in blood = dose given/Vd
Vd = dose given/[drug] in blood
Each drug has a unique Vd identified during clinical development
Large Vd (>42L)
Tells us the drug distributes outside blood and body fluids into tissues/fats.
Small Vd (</=42L)
Tells us the drug has limited distribution, typically restricted to blood or other physiological fluid compartments.
What is responsible for Phase 1 metabolism of a drug?
P450 enzymes.
P450 activity can be induced or inhibited.
What is metabolism of a drug?
Irreversible drug biotransformation.
Increases polarity to promote renal excretion.
What is responsible for Phase 2 metabolism of a drug?
Conjugative enzymes.
These are rarely able to be induced or inhibited.
What is excretion of a drug?
The irreversible loss of drug from the body.
In what ways are small and large or ionized drugs excreted in the kidney?
Small drugs = passive diffusion.
Large/ionized drugs = active transport.
What can happen to non-ionized drugs and what can be used to manipulate this?
Non-ionized drugs can be passively reabsorped.
Urine pH can be manipulated to determine if a drug is reabsorbed or not.
MEC
Minimal effective concentration.
The concentration below which there is not therapeutic effect.
MTC
Minimum toxic concentration.
The concentration above which significant side effects can be observed.
What is the objective of drug dosing?
To obtain the therapeutic range between the MTC and MEC.
Cmax
The peak drug concentration achieved at time, tmax, following a single dose.
For IV administration, Cmax and tmax occur at time 0.
C vs T equation for a single IV dose
Ct = C0e^(-kt)
Ct = drug concentration at a given time (t)
C0 = drug concentration at time 0
e = base natural log (2.718)
k = first order elimination rate constant (fraction of drug eliminated per time)
Relationship of k (1st order elimination rate) : CL (clearance) : Vd
The hypothetical volume of blood from which drug is completely removed per unit of time (mL/min).
CL = Vd k
What routes of elimination are represented by CL?
ALL routes; hepatic, renal, biliary, etc.
What does a high CL value indicate?
Low CL value?
High CL value = drug is rapidly removed from the body.
Low CL value = drug is removed slowly from the body.
When is CL used?
To calculate maintenance doses and infusion rates.
What is the relationship between the elimination rate (k) and half-life (t1/2)?
t1/2 = ln2/k = 0.693/k
Inversely proportional.
Describe using t1/2 to estimate the drug washout period and when this would be used.
Used to estimate clearance of a drug prior to surgery or when switching meds.
Washout period = 5 half-lives
eg. acetaminophen t1/2 is 3 hours, so the complete washout would be 5 half-lives x 3 hours = 15 hours.
Describe using t1/2 to maintain therapeutic levels of a drug in the body.
If the time period is a factor of the half-life, can do mental math to determine the concentration left in the body. T1x1/2 = 1/2 dose, T2x1/2 = 1/4 dose, etc.
If time period is not a factor of the half-life then need to use full equation:
Ct = C0 e^(-kt)
What is Steady State (Css)?
Plateau that is reached when the rate of administration = rate of elimination.
Takes about 5 x t1/2 to reach steady state.
What must you keep in consideration for Css?
Css can occur at ANY concentration (toxic, therapeutic, or sub-therapeutic)
Large doses or frequent small dosing results in higher concentration ~ toxic.
Small doses or doses spaced too far apart result in lower concentration ~ sub-therapeutic.
What are the 2 approaches used to achieve Css?
- Passively - give repeated doses over 5 x t1/2.
- Actively - give a loading dose.
What is the simplest way to achieve Css?
Give repeated doses at intervals close to the drug’s t1/2.
5 x t1/2 = Css
When would you use a loading dose to get to Css?
If the t1/2 is very long or the situation is very urgent.
Loading Dose (LD) equation
LD = (Ctarget x Vd)/F
Ctarget = desired Css
F = bioavailability
Maintenance Dose (MD) equation
MD = (Ctarget x CL x T)/F
T = dosing frequency
How are LD and MD calculated?
Same as LD and MD equations, except that F=1 because bioavailability is not a consideration.
How is Css achieved for drugs with a narrow therapeutic index where the peaks and trough fluctuations are not tolerable?
Continuous IV infusion.
Steady state is still achieved after 5 x t1/2.
Concentration that is attained is determined by the infusion rate where faster rate = [higher] and slower rate = [lower]
Infusion rate equation
R0 = CL x Css = Vd x k x Css
What are two important concepts for drugs eliminated via first order kinetics?
- A constant fraction of the drug is eliminated per unit of time (ie 50%/hr = gives us a t1/2). F=F First order = fraction.
- Double dose = double plasma concentration.
What drugs are eliminated via Zero order kinetics?
PEA
Phenytoin (anti-seizure)
Ethanol
Aspirin
How are zero order kinetic elimination processes different?
They become saturated and are unable to increase when concentrations rise.
A constant amount of drug is excreted/unit of time - no t1/2.
Dose:concentration is not proportional, increases risk for toxicity/overdose.
What are the benefits of therapeutic drug monitoring?
Provides patient specific dosing information.
Measures the patient’s actual plasma concentration.
Useful for drugs with a narrow therapeutic index and for special pops (geriatric, pregnancy, pediatrics).
Therapeutic Drug Monitoring equation
Dose new/Dose previous = Css target/Css measured
What are some ways to reduce ADRs?
Decrease drug burden.
Report suspected ADRs.
Which enzymes are most likely to be involved in drug interactions when their expression and activity changes?
- Cip 3A4 then,
- Cip 2D6 then,
- both Cip 2C9/19
What is primary compliance?
The act of filling a prescription.
>95% for acute problems.
60-70% for chronic.
Cost can be a barrier as well.
What is secondary compliance?
Not taking medication as directed.
Convenience contributes: more frequent dosing = less compliance.
Side effects also affect compliance.
How does appearance of a drug affect compliance?
Colour associations
Size, diameter >8mm
Changes in colour or shape of a drug can decrease compliance.
How does the stomach acid content differ in infant and geriatric pops compareed to adults?
Infants & geriatric pH = 4
Adult pH = 2
Therefore acid labile drugs will have a higher plasma concentration in infants and geriatric pops.
This will also affect the way that drugs are absorbed in the stomach.
How does body composition affect drug distribution and plasma concentration?
Total body water higher in peds, lower in geriatrics; affects hydrophilic drug concentrations.
Fat lower in peds, higher in geriatrics; affects lipophilic drug concentrations.
Plasma proteins lower in both peds and geriatrics; leads to increased fraction of free drug.
How does metabolism affect drug distribution/availability?
Both peds and geriatrics have decreased Phase 1 enzymes - longer t1/2, need lower dose or increased dosing interval.
Peds take several months for Phase 2 enzymes to be expressed.
Both peds and geriatrics have decreased liver mass and blood flow.
How does the decreased kidney function in peds/geriatrics affect drug excretion?
Increases t1/2; must lower dose or increase dosing frequency.
Summarize the factors affecting drug response.
- Compliance
- Drug interactions
- Disease
- Genetics
- Age (young & old)
Local anesthetics
Drugs that block the generation and propagation of action potentials along nerve fibres.
What types of tissues do local anesthetics work on?
All types excitable tissues.
What are the two chemical groups of clinically used local anesthetics?
Aminoesters.
Aminoamides.
Weak bases with an aromatic head and a amine tail with either ester or amide linkage/
What is the principal action of local anesthetics?
Blockade of voltage gated Na+ channels.
What are the 4 common local anesthetics?
Lidocaine (zylocaine)
Bupivacaine
Mepivacaine
Ropivacaine
All are aminoamides.
What is the polarity of local anesthetics?
Amphoteric.
Dissociate to form equilibrium between base and cation.
What form of the LA can penetrate through lipid membranes and what form is responsible for the blocking action at the voltage gated Na+ channel?
Penetrates: base
Blocking action: cation
Which LA only exists as a base and blocks the channel via a lipophilic pathway?
Benzocaine.
What is the consequence of the higher pKa of Bupivacaine and Procaine?
Low percentage of total drug in base form.
Slower onset of effects.
What are the 3 functional states of Na+ channels and which one so LA’s stabilize?
Resting
Activated (open)
Inactivated
LA’s stabilize the inactivated state which means the channel must have been active for the drug to be effective.
Discuss the differential sensitivity of nerve fibres to LAs.
LAs block small diameter fibres first.
Three consecutive nodes of Ranvier need to be blocked.
Define differential block
Preferential blockade of sympathetic & pain fibres while minimizing impairment of motor function (eg walking epidural).
Routes of administration for LAs
Topical
Infiltration
Peripheral nerve blockade
Central blockade
IV regional anesthesia
Systemic (IV)
Which LA is particularly good for differential blocks?
Bupivacaine
Rpoivacaine (even more motor-sparing thean Bupivacaine)
Which of the 4 LAs discussed has the longest duration of action?
Shortest?
Longest = Bupivicaine (180-600 minutes)
Shortest = Lidocaine (90-200 minutes)
What helps determine the potency of an LA?
Lipid solubility - positive correlation
What determines the onset of action of an LA?
pKa: lower = faster
What influences duration of action of an LA?
Increases with lipid solubility and protein binding.
How are aminoesters metabolized?
Aminoamides?
Aminoesters = plasma cholinesterases
Aminoamines = hydrolysis in the liver
How are LA’s excreted?
Mainly in urine.
What effects do added vasoconstrictors have on LAs?
Delay absorption
Prolong effect
Reduce system toxicity
What is the contraindication for vasoconstrictors with LAs?
Do not inject into peripheral body parts - can cause tissue necrosis and gangrene.
No toes, fingers, ears, nose, penis!!
Discuss local tissue toxicity of LAs
Both neurotoxicity and myotoxicity.
Neurotoxicity - concentration dependent. Most severe can lead to paraplegia or cauda equina syndrome.
Discuss systemic toxicity of LAs
Dose and concentration dependent continuum.
CNS vs CV effects.
Increased by rapid injection, hypoxia, increase PaCO2, decreased pH, decreased K+, pregnancy.
Must be individualized, observed, monitored and frequent aspiration.
Discuss the presentation of systemic CNS LA toxicity
Initially - Inhibition; sedation, numbness, tinnitus, blurred vision.
Then - Excitation; tremor, tonic-clonic seizures.
Then - Generalized Depression; coma, cardiorespiratory arrest, death.
Discuss the toxicity of Bupivacaine.
High propensity to accumulate in the heart causing ventricular arrhythmias and severe myocardial depression.
Lipid rescue can help reverse.
Discuss the toxicity of Benzocaine.
Cyanosis
Discuss the toxicity of Cocaine.
Inhibits Norepi and epi reuptake leading to euphoria, agitation, seizures, vasoconstriction, HTN, MI, tachycardia, death.
MOA of Alteplase
Tissue plasminogen activator (TPA).
converts plasminogen to plasmin.
Most common indication for Alteplase (TPA)
Ischemic stroke
Dosing/route of administration for Alteplase (TPA)
0.9 mg/Kg (max 90 mg)
10% bolus over 1 minute, then 90% infusion over 1 hour.
Risks of Alteplase (TPA)
6% risk of intracranial hemorrhage
<1% risk of systemic hemorrhage
2-5% risk of angioedema (increases w/ACEi)
MOA of Tenecteplase (TNK)
Thrombolysis with greater fibrin selectivity than TPA.
Most common indication of Tenecteplase (TNK)
Ischemic stroke
Benefit of Tenecteplase (TNK) vs TPA
Can be given as a bolus.
Makes it easier for transport.
MOA of Apixaban (Eliquis)
Direct oral anti-coagulant.
Inhibits Factor X - preventing prothrombin to thrombin.
Most common indication of Apixaban (Eliquis)
Prevention of stroke with Afib.
Tx and prevention of DVT/PE.
Prevention of DVT/PE after surgery.
Dosing/route of administration for Apixaban (Eliquis)
5 mg BID
Oral
MOA of ASA (Aspirin)
Inhibits COX enzyme.
Antiplatelet action d/t irreversible acetylation of COX-1 in platelets.
Most common indication of ASA (Aspirin)
Ischemic heart disease:
Acute MI
MI prevention
Angina
CV disease:
Acute stroke
Stroke prevention
General:
Analgesic
Anti-pyretic
Anti-inflammatory
Dosing/route of administration for ASA (Aspirin)
Oral
80 mg daily for prophylaxis
Pain:
325-650 mg q 4-6 hours, max 4g/day
