Body compartment in which the receptor sites reside Concentration of drug in biophase cannot be directly measured Usually inaccessible in humans Drug concentration in microscopic environment at receptors will not be same as in other measurable areas (e.g., blood, urine, CSF)

PK lecture Flashcards by Iris Jonnah Simbulan

Definition: Steady State Concentration

The constant serum concentrations that is achieved when rate of drug administration equals rate of drug metabolism and excretion
Usually used to assess patient response and used to make new decisions

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Definition: Liner pharmacokinetics

Also known as first-order or non-saturable kinetcs
Steady state concentrations increase or decrease proportionally according to dose.

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Definition: Non-liner pharmacokinetcs

Steady stated concentrations change in a disproportionate fashion after dose is changed.

i.e : valproic acid, carbamazepine, phenytoin

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Definition: Half-life (t1/2)

Time required for serum concentrations to decrease by 50% during elimination phase after absorption and distribution are complete.

takes 3- 5 half-lives to reach steady-state concentrations during continuous/ routine dosing

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Definition: Bioavailability

The fraction of the administered that is delivered to the systemic circulation

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Definition: Multi (two) compartment model

Classic drugs for two-compartment model

Represents the body as centrral compartment into which drugs us administered and as a peripheral compartment into which a drug distributes; used for drugs that slowly equilibriate with tissue compartment.

I.E VANCO, DIG

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Definition: Context-Sensitive Half time

Time for plasma concentration to decrease by 50% after discontinuing infusion
Context sensitive half time increase with longer duration of infusion
- Short context sensitive half-life: remifentanil
- Variable context sensitive half-life: fentanyl

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Definition: Biophase

Body compartment in which the receptor sites reside
Concentration of drug in biophase cannot be directly measured
- Usually inaccessible in humans
- Drug concentration in microscopic environment at receptors will not be same as in other measurable areas (e.g., blood, urine, CSF)

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Definition: Absorption

What are the factors that affect absorption

Factors that affect absorption

GI perfusion (GI absorption, transdermal/SC/IM absorption, vasopressor effect)
Intestinal atrophy
GI dysmotility/delayed gastric emptying
Intestinal drug transporters (p-glycoprotein, cytochrome P450)
Physical incompatibilities (drug/enteral nutrition binding, pH changes)

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What is the effect of Hypothermia on transdermal drugs?

vasoconstriction = less absorption

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Definition: Volume of Distribution

Vd = Dose ÷ Concentration

Indicates the extent of drug distribution into tissues and areas of the body
Physiologic determinants include actual volume of blood and size of various tissues and organs.

Larger person –> higher Vd

Smaller person –> smaller Vd

Larger loading doses are needed to achieve a therapeutic concentration if volume of distribution is large.

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Tissue perfusion

concept

Cardiac output is primary determinant of drug exposure speed to organs
- Brain, heart, lung, kidneys get highest relative cardiac output and reach equilibrium faster with blood
Shock states –> decreased perfusion to muscle, skin, splanchnic organs
Decreased delivery of hydrophilic drugs to areas of decreased perfusion
- Drugs (hydrophilic) with smaller Vd remain more in plasma water volume

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Redistribution Concept

Drug will distribute from the organ back to blood once concentration in the organ exceeds the blood. Once in the blood, the drug will redistribute to other tissues that are still uptaking drug
Single bolus doses of highly lipophilic drug leads to rapid decrease in brain concentrations and redistribution to muscle
Eventually, the adipose tissue will contain the majority of the lipophilic drug that has not been metabolized or eliminated [trapped in adipose tissue]

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Protein Binding

Albumin and AAG in Critical illness state

Critical illness state: –> Albumin decreases –> fraction unbound drug (Fu) increases Vd
AAG increases –> Fu decreases –> decreased Vd

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Drugs bound to both Albumin and AAG

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Carbamazepine

Midazolam

Verapamil

Propofol

*P**ropanolol
*D**iltiazem

Drugs bound to AAG

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Carbamazepine, Midazolam, Verapamil, Propofol, Propanolol, Diltiazem

Lidocaine and Fentanyl

If your patient has one of the following:

What will happen to your lipophilic drugs?

what will happen with your hydrophilic drugs?

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No change in Vd for lipophilic drugs
Increased Vd for hydrophilic drugs –> decrereased serum concentration
- – interstitial concentrations may be low due to larger interstitial space [dilution]

What is Phase I reaction

CYP450

CYP3A4 accounts for 40-45% of all CYP mediated drug metabolism

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Oxidation, hydrolysis, and reduction

CYP3A4 metabolism

Alfentanil
Diazepam
Fentanyl
Lidocaine
Midozalam
Warfarin

drugs that are CYP3A4 inducers

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St. John’s Wort

Rifampin

Phenytoin

Carbamazepine

Phenobarbital

CYP inhibitors

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Amiodarone
Cimetidine
Clarithromycin
Diltiazem
Erythromycin
Fluconazole
Grapefruit juice
Isoniazid
Ritonavir
Verapamil

Phase II: Conjugation

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Often occurs outside CYP450 system
Glucuronosyltrasferases, glutathione-S-transferases, N-acetyl-transferases, sulfo-transferases
- Propofol, morphine, midazolam
Transforms hydrophobic molecules –> water-soluble molecules through addition of polar groups –> excretion via kidney or hepatobiliary system
Involve reactions that form glucuronides, acetates, or sulfates

Changes in intrinsic clearance

What causes decrease CYP enzymes

in turn increasing drug concentration

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Drug interactions

CYP enzymes – phase 1 metabolism
- CYP enzyme inhibitor –> increased serum concentration
- CYP enzyme inducer –> decreased serum concentration
Genetic variations
Inflammation
- Interluekin (IL)-1α, IL-6, tumor necrosis factor (TNF)α decreases expression and activity of CYP activity
- Time course unknown
Hypothermia
- Decreased metabolism through CYP system
  - Midazolam, fentanyl, remifentanil, pentobarbital, vecuronium –> decreased hepatic clearance
Kidney injury
- Decreased metabolism through CYP system
  - Midazolam + kidney injury –> increased concentration

What is the effect of TBI in intrinsic clearance?

What should be the proper intervention in dosing ?

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Traumatic brain injury

Increased clearance of some drugs
- Example: increased phenytoin metabolism during first 7- 14 days
Enhanced phase II enzyme activity
- Example: increased lorazepam clearance
rapid metabolism and rapid clearance of the drugs in TBI

What can increase hepatic blood flow?

* Hyperdynamic phase of sepsis * Increased cardiac output

What can **decrease hepatic blood flow?**

* Hypovolemic shock * Hemorrhagic shock * Hypodynamic phase of sepsis * Myocardial infarction * Cardiogenic shock * Acute heart failure exacerbation * Increased intrathoracic pressure * Spinal anesthesia

Defition: Hepatic Extraction ratio and metabolism

* Hepatic extraction ratio * Fraction of drug removed during one pass through liver * Ranges from 0 to 1 * 0 = Liver does not metabolize drug * 1 = hepatic metabolism entirely dependent on blood flow * Low (\<0.3) * Intermediate (0.3-0.7) * High (\>0.7

**Low hepatic extraction ratio drugs** ## Footnote characteristics

* Clearance varies with changes in intrinsic enzyme activity * **Clearance is independent of hepatic blood flow** * **\<0.3 will be dependent on enzyme activity**

Hepatic extraction ratios of drugs used in anesthesia

Drugs that underfo significant renal clearance in anesthesia

What is **Pharmacodynamics?**

* Relationship between drug concentration and biochemical and physiologic effect on the body including intensity of therapeutic effect and adverse effects * Determined by the drug receptor binding * What the drugs will do to the body

Receptor Theory

What is Potency?

What is the definition of **effective dose?**

* *ED 50** - -\> Dose required for desired effect in 50% of population exposed to it * ED50 --\> can be used to compare various drug effects for a single drug * Fentanyl EC50 for analgesia (2 ng/mL), ventilatory depression (4ng/mL), loss of response to laryngoscopy (15 ng/mL), changes to electroencephalogram (20 ng/mL) **Minimal effective dose (MED)** --\> Lowest dose level of a drug that provides a clinically significant response **Maximal tolerated dose (MTD)** --\> Highest possible, while still tolerable, dose that provides a clinically significant response **Large range between MED and MTD** --\> large therapeutic window

Drug interactions: **In Vitro**

**In vitro** pharmaceutical interactions * **Can significantly change bioavailability** * Formation of insoluble salts * Acidic drugs (e.g., thiopental) + basic drugs (e.g., opioids, muscle relaxants) with insufficient fluid rate * **Can produce unintended toxic effects** * Soda lime or Baralyme used in modern anesthesia machines to removed carbon dioxide + sevoflurane = production of Compound A

Drug interactions: In ViVo

In vivo pharmaceutical interactions * Decrease or increase in concentrations **within the body** * Sugammadex irreversibly binding to rocuronium molecules --\> decreases free concentration of rocuronium and causes redistribution from neuromuscular junction into intravascular space

**Drug Interactions** **Pharmacokinetics interactions**

* **Alteration in absorption, distribution, elimination** * Absorption (uptake) * Altering delivery of drug to site of drug absorption or altering local blood flow to site of drug administration * Ranitidine changing pH or metoclopramide decrease GI transit time --\> changes absorption from GI tract * Vasopressors decrease local blood flow --\> prolong effect of local anesthetics when added as an adjunct agent * Vasopressor decrease absorption of drugs administered intramuscular or subcutaneous

Definition: **Time dependent antibiotics**

Time dependent antibiotics * Percentage of dosing interval concentration of antibiotic is above the MIC * Ideal T\>MIC is 100% but often not achievable in clinical practice * Example **β- lactams (e.g, carbapenems, penicillins, cephalosporins, monobactam)**

Definition**: Concentration dependent antibiotics**

* Higher maximum drug concentrations above the MIC lead to better killing * Example: **aminoglycosides** * Cmax:MIC of 8-10 --\> 90% clinical response * **Once-daily aminoglycosides** can be used to attain ideal peak:MIC ratios in appropriate patients

PK lecture Flashcards

(39 cards)