Lecture 2 Pharmacodynamics and Pharmacokinetics Test 1 Flashcards by Ebrima Jobe

Activation of protein receptors causes a ________________.

Conformational change

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What is the drug effect related to?

The number of bound receptors.

Ie: Paralytics Paralytics should be based on weight.

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What are 3 reversible bonds? (both agonists and antagonists)

What bond is irreversible?

Ion (opposite charges), Hydrogen (electronegative atoms), and Van der Waals interaction (repulsive attraction)

Covalent bonds (strongest bond)

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Increasing amounts progressively inhibit the agonist and shift the dose-response curve to the right.

Competitive antagonism

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Even high concentrations of agonist can’t cause the agonist event.

Noncompetitive antagonism

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Binding to a receptor (usually at agonist site).
Causes less response than the agonist even at a supramaximal dose.

Partial Agonist

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Compete for the same site as the agonist but produces the opposite effect.

Inverse Agonist. (can be called antagonist)

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Even high concentrations of agonists can’t cause the agonist event.

Noncompetitive antagonism

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The number of receptors are not __________.

Static

Receptors can increase or decrease depending on comorbidity and drug therapy

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What is tachyphylaxis?

Quick tolerance, down-regulation of receptors.

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In pheochromocytoma, there is a ___________ in beta receptors in response to an increase in ____________.

decrease; catecholamines

Tolerance builds up

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Receptors are classified by _____________.

Location

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What 3 areas can receptors be located?

Lipid Bilayer (most)
Intracellular Proteins
Circulating Proteins

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Most of the anesthetic drugs that we give have receptors located in the _____________.

Examples?

Lipid Bilayer (Membrane Bound)

Opioids, BZDs, Beta-blockers, catecholamines, NMBD.

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What are examples of drugs that bind to intracellular proteins?

Insulin, Steroids, Milrinone

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What are examples of drugs that bind to circulating proteins?

Anticoagulants

Anticoagulants that are free or unbound will cause drug effect

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Pharmacokinetics determines the concentration of the drug in the ____________ and at the _______________. This varies significantly from patient to patient.

Plasma and Effector Site

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What is the one-compartment model?

Immediately after drug injection, the concentration of the drug is diluted by plasma in a central compartment, resulting in a small volume of distribution, and excreted immediately.

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What is the vessel-rich group?

A small percentage of the body mass (brain, kidney, heart, lungs) that makes up a large percentage of cardiac output.

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What is the two-compartment model?

The drug goes into a central compartment and then peripheral compartments (muscles, fats, tendons, ligaments).

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For plasma protein receptors, what do acidic drugs bind to?

What do alkalotic drugs bind to?

Acidic drugs bind to albumin.

Alkalotic drugs bind to Alpha 1- Acid Glycoprotein.

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Only __________ drug can cross cell membrane (distribution) and can determine the concentration available to receptor (potency)

(Protein binding)

Free unbound drug

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Name factors that can decrease plasma protein.

Age (malnutrition)
Acidosis
Hepatic Disease (liver failure)
Renal Failure
Pregnancy
Burns
Sepsis

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If the normal free fraction of the drug is 2% and half the plasma proteins are lost, then the free fraction of the drug is _______%.

4%, it doubles. (can be an issue)

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Poor protein binding and lipophilic drugs have a ____________. Examples

Greater Volume of Distribution (escapes plasma) Examples: Thiopental and Diazepam

Highly protein-bound drugs to plasma protein will result in a ____________. Examples

Smaller Volume of Distribution (stays in plasma) Example: Warfarin

What is metabolism?

Usually conversion of an active drug to an inactive drug from lipid-soluble drugs to water-soluble and inactive metabolites (usually). Then kidneys pee it off.

What are some active metabolites?

Diazepam (Valium) Propanolol (Inderal) Morphine Prodrugs such as Codeine

How are most anesthetic drugs metabolized? What are three other ways drugs are metabolized?

Through the **Hepatic Microsomal Enzymes**. Plasma (Hoffman Elimination, ester hydrolysis) Kidney Tissue Esterase (GI Tract, Placenta)

What does phase 1 metabolism involve? What does phase 2 metabolism involve?

Phase 1: Increase polarity and prepare for phase II reactions *Oxidation* *Reduction* *Hydrolysis* Phase 2: Covalently link with a high polar molecule to become water soluble *Conjugation*

What is the large family of hepatic microsomal enzyme called consisting of 10 isoforms that are membrane-bound and contain a heme cofactor?

CYP 450

What specific enzyme makes up 60% of CYP 450 activity and metabolizes over half of the drugs?

CYP3A4

What drug will induce hepatic microsomal enzymes?

Phenobarbital *Drugs like opioids and BZD will have less effect*

What food will inhibit hepatic microsomal enzymes?

Grapefruit Juice *Increases concentration of drug/ toxicity levels*

Acute ingestion of alcohol will require the patient to receive ____________ anesthetics. Chronic use of marijuana will require the patient o receive _____________ anesthetics.

Less (acute EtOH intake) *Dr. Kane correction email* More (chronic marijuana)

For most anesthetic drugs, the hepatic clearance is __________. The rate is proportional to ____________.

Constant Concentration (*More Drug/More Clearance to a certain point since the liver capability is not unlimited*)

What is the rate of drug metabolism equation? What are the two limitations to this equation?

Rate = Cardiac Output (Concentration Inflow - Concentration Outflow) Flow limitation (Cardiac output) and capacity limitation (liver's metabolizing ability)

What are the three things involved in Renal Clearance?

1. GFR 2. Active Tubular Secretion 3. Passibe Tubular Reabsorption

Differentiate between Elimination Half Time vs Elimination Half-Life.

Elimination half-time is the time necessary to eliminate 50% of the drug from **PLASMA** after a bolus dose. Elimination half-life is the time necessary to eliminate 50% of the drug from **BODY** after a bolus dose.

You give 100 mcg of drug A. E 1/2 is 10 minutes. In 20 minutes what will plasma concentration be? If you reinject 100 mcg of drug A, 20 minutes later what will the plasma concentration be?

25 mcg 31 mcg

What is the time to a 50% decrease after **infusion** is discontinued?

Context Sensitive Half-Time

What drugs have a short context-sensitive half-time?

Sufentanil Alfentanil Propofol

What drugs have a long context-sensitive half-time?

Fentanyl Thiopental

What does it mean when the pK (dissociation constant) and pH are identical?

50% of the drug is ionized and 50% of the drug is non-ionized.

What drug is a weak acid? What drug is a weak base?

Weak acid: Barbituates, Thiopental Weak bases: Local Anesthetics, Opioids

Acids ionized in an _____________ environment. Bases ionized in an _____________ environment.

Alkalotic Acidic

Describe non-ionized drug molecules in terms of their Pharmacological Effect: Solubility: Cross lipid barriers: Renal Excretion: Hepatic metabolism:

Describe non-ionized drug molecules in terms of their Pharmacological Effect: Active Solubility: Lipids Cross lipid barriers: Yes Renal Excretion: No Hepatic metabolism: Yes

Describe ionized drug molecules in terms of their Pharmacological Effect: Solubility: Cross lipid barriers: Renal Excretion: Hepatic metabolism:

Describe ionized drug molecules in terms of their Pharmacological Effect: Inactive Solubility: Water Cross lipid barriers: No Renal Excretion: Yes Hepatic metabolism: No

Weak acid (pK 7.6) is put in a basic pH (blood 7.8). Ionized or non-ionized?

Ionized Because it is a weak acid, pK will go after the pH. pH - pK 7.8 - 7.6 = +0.2

Weak base (pK 8.0) is put in basic pH (blood 7.2) Ionized of non-ionized?

Ionized Because it is a weak base, pK will go before the pH. pK - pH 8.0 - 7.2 = +0.8

Spinal Anesthetic is a weak base (pK 7.3), fetal pH is 6.8, and the mother's pH is 7.4. Will the drug be ionized or non-ionized in the fetus and mom?

The anesthetic will be ionized in the baby, the drug will be trapped in the fetus. The anesthetic will be non-ionized in the mom, the drug will be active. Because spinal anesthetic is a weak base pK will go before pH pK - pH Fetus: 7.3 - 6.8 = +0.5 Mom: 7.3 - 7.4 = -0.1

Pt with an ischemic foot requested an ankle block. Will surgical anesthetic work? An opioid is a weak base with a pK of 8.0. Normal Tissue pH = 7.4 Ischemic Tissue pH = 6.6

No, a surgical anesthetic will not work. The drug will be ionized in normal tissue and ischemic tissue. With a weak base, pK is before pH. Normal Tissue: 8.0 - 7.4 = +0,6 (ionized) Ischemic Tissue: 8.0 - 6.6 = +1.4 (very ionized)

What the drug does the to the body. This is figured out by measuring concentrations at different pharmacological responses.

Pharmacodynamics

There is individual variability in pharmacodynamics in the elderly due to what 3 factors?

Decrease Cardiac Output to the Brain and Liver Decrease Protein Binding Increase Body Fat

Individual variability in pharmacodynamics includes _______ and ___________.

Enzyme activity Genetic Disorders

Concentration vs Response.

Potency Less Drugs with more effect = more potent

The ability of a drug to produce a clinical effect.

Efficacy

Time to drug effect, the lag time between administration (plasma concentration) and effect.

Relative Potency

Molecules with an asymmetric center, usually related to the way carbon molecules are bonded.

Chiral compounds

These structures are chemically identical that are mirror images of each other and can not be superimposed.

Enantiomers

In terms of rotation of light in solution, what is the right rotation called? Left Rotation?

Right rotation: Dextrorotary or R (Rectus) Left rotation: Levorotary or S (Sinister)

Drug mixture with optical activity of equal compounds that can exhibit different ADME. One enantiomer is active and the other is inactive or has more side effects.

Racemic Mixtures

What fraction of drugs are racemic?

1/3

___ - Enantiomer of Ketamine is more potent had has less delirium.

L-Bupivacaine has less _____________ .

Cardiac Toxicity

What isomer of atracurium lacks histamine effects?

Cistracurium

What is the isomer of albuterol that does not cause tachycardia?

Xopenex (*But not as efficacious as albuterol*)

With pharmacogenetic testing, we look for variants in genes that code for _______, ________, and ________.

Drug-metabolizing enzymes Drug targets Immune Proteins