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CPPS 304 > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

Define Pharmacokinetics

A

The study of the processes of absorption, distribution, metabolism, and excretion of drugs. (How does the body handle the drug - what does the body do to the drug)

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2
Q

Give 2 examples of drugs that don’t bind receptors.

A

Anti-Acids
Laxatives

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3
Q

Make sure you know this

A

Absorbtion: Drug Reaching Systemic Circulation
Distribution: To different organs
- Site of Action (Receptors): Switch between bound and free - Bound for only a few seconds before unbinding.
- Tissue Reservoirs - Muscle, Adipose Tissue
Biotransformation(Metabolism): Liver - Transforms drugs to metabolites.
Excretion: Through the kidneys - Excretes Metabolites and Free drugs.
Free Drug: Only Active Form - In Circulation but unbound
Bound Drug: Remain in circulation bound to plasma proteins, storage form, remain in the system longer before excreted, in equilibrium with free drug.

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4
Q

What are the Enteral Routes of Drug Administration?

A

Enteral - GI Tract

  • Oral
  • Sublingual - Under Tongue - Bypasses Liver right to Superior Vena Cava
  • Rectal

Barriers: Liver Epithelium is Natural Drug Killer

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5
Q

What are the Parenteral routes of drug administration?

A

Parenteral - Route other then GI Tract

  • Intravenous - 100% Absorbtion
  • Intramuscular
  • Subcutaneous - Fat Under Skin - Little Bloodflow and Circulation - Gradual and Slow
  • Intra- arterial: Not common - Used for Anti-Liver Cancer
  • Intrathecal: fluid filled space between the thin layers of tissue that cover the brain and spinal cord
  • INtraperitoneal: Large Quantities of Fluid
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6
Q

What mode of transport plays a major role in many capillary beds?

A

Paracellular transport - Major role in organs such as liver and kidney capillary beds - Allows all molecules to enter.

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7
Q

What is the most common mode of transport of a drug?

A

Diffusion through cell membranes. Facilitated and Not
- Lipid Soluble and Non Ionized Drugs

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8
Q

What type of Drug treatment should you use for cancer?

A

Multi Drug Treatment

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9
Q

Explain Primary active transport and give 2 examples?

A

Active Transport - used energy to transport against a concentration gradient.

  1. Sodium Potassium Pump transports Digoxin used for heart failure.
  2. P - Glycoprotein transports anticancer drugs out of cells - Anticancer drugs create resistance - Use multi drug treatment
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10
Q

Explain and provide examples of Secondary active Transport.

A

Secondary Active Transport - Uses energy stored in concentration gradient.

2 Types

  1. Antiporters - Sodium Calcium Exchanger(SLC8)
  2. Symporters - Sodium pumps in neurons which transport neurotransmitters. - (DET Dopamine, NET Noraepinephrine, SERT Serotonin)
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11
Q

Define Drug Absorbtion

A

Drug absorption refers to the passage of drug from the site of administration into general circulation.

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12
Q

What are the Factors affecting drug absorption?

A

Polarness
Size of Molelcules
Lipid Soluble

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13
Q

Where does the factors of drug absorbtion and distribution, have the most effect?

A

Factors take most effect where an uninterrupted cell membrane like the brain capillaries creates a barrier.

  • Interrupted Cell membranes or capillaries have fenestrations that allow all molecules through - found in liver and Kidney(Glomerulus).
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14
Q

What factors effect oral absorbtion of a drug?

A
  1. Stomach Acid and Digestive Enzymes - Most Drugs are destroyed (peptide-based drugs, Penicillin G, Insulin).
  2. Bind to food to form Insoluble Complexes - Drugs need to be taken on an empty stomach to prevent. (Tetraglycerines)
  3. Too Polar to cross membranes - Cannot give these drugs orally - (Streptomycin for Turburculosis, Gentamycin for Gram Neg infection of Brain)
  4. Undergo Extensive Metabolism
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15
Q

What does the pka of a drug mean?

A

The pH at which half the drug is in its ionized form.

  • Most drugs are weak acids or bases
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16
Q

What is Ion Trapping

A

At a steady state - an acidic drug would accumulate on the more basic side of a membrane and a basic drug on the more acidic side.

  • Acidic Drug in Basic Medium would be ionized - more likely excreted and not absorbed and Vice Versa

If it is the opposite pH medium It becomes trapped in that organ because cannot diffuse out.

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17
Q

Give 2 clinical examples of Ion trapping?

A

Fetal Blood and Breast Milk are both Acidic compared to Mothers Plasma - If basic drugs are taken by the Mom it can enter the fetal circulation and have many effects.

Poisoning - Drugs that have reached toxic concentrations

  • Excretion of Toxic Acidic Drugs - Basic compounds given (Sodium Bicarbonate, salicylates, phenobarbital)
  • Excretion of Toxic Basic Drugs -
    Acidic compounds are given
    ( amphetamine, ammonium chloride or ascorbic acid)
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18
Q

What is the First Pass effect? (First Pass Metabolism)

A

Metabolizing enzymes in the intestinal wall and liver metabolize drug and don’t let it reach circulation.

This is why some drugs cannot be given orally. - Insulin

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19
Q

Explain the link between the First Pass effect and the Cheese Wine Reaction

A

Tyramine in found in foods such as cheese and wine. Normally metabolized by first pass effect by metabolizing enzyme Monoamine Oxidase.

MAO inhibitor leaders to Tyrmanie to reach circulation and nerves where it will release NE and cause Tachycardia and Vasoconstriciton through Alpha Andregenic Receptors.

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20
Q

Remember

A

Selective MAO inhibitors do not cause the cheese wine reaction.

Reversible MAO inhibitors have low risk of causing the cheese wine reaction.

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21
Q

What is Bioavailability?

A

It is the fraction of an orally given drug that reaches the circulation

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22
Q

What are factors effecting drug distribution?

A

Factors affecting drug distribution from circulation to tissue.
- Ionization
- Lipid Solubility - Imp for Blood Brain Barrier
- Capillary Permeability
- Blood Flow - Skin has low blood flow
- Plasma Protein Binding

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23
Q

What plasma proteins to acidic and basic drugs bind to.

A

Acidic drugs bind to Albumin
Basic drugs bind to A1 Acid Glycoprotein

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24
Q

What are the only drugs that can diffuse through the brain capillaries?

A

Lipophilic

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25
Q

When does the blood-brain barrier let in polar molecules?

A

Areas have infection of injury.

26
Q

What is the Volume of distribution?

A

Theoretical volume in which the toal amount of administered drug should be uniformly distributed to account for its plasma concentration.

Assume Concentration is the same everywhere in the body.

Use a two-compartment model of body: intravascular, and extravascular.

Volume of Distribution = Dose Administered / Plasma Concentration

27
Q

What do high and low vd values tell you?

A

High VD - Indicates most of the drug is in a extravascular compartment - Lipid Soluble drug concentrates is adipose tissue

Low VD - Most of the drug is in the vascular compartment bound to plasma proteins

28
Q

Definition of Drug Metabolism

A

Chemical modification of drugs by enzymes, to make them more polar, and therefore readily excretable by the kidneys.

29
Q

What reactions to oxidation, reduction and hydrolytic reactions fall under? (Reactions that increase polarity of drug, not always inactivate)

A

Phase 1 functionalization reaction

30
Q

What reactions do conjugation(sulfation, acetylation) fall under? Results in Drug Inactivation

A

Phase 2 conjugation reaction

31
Q

What are the Phase 1 Functionalization Enzymes?

A

Microhunter cytochrome P450 monooxyenase(CYP) Enzymes

  • Mainly Oxidize Drugs

Others: Esterases and Epoxide Hydrolase.

Act on many unrelated drugs. Some very specific for hormones.

Most cases they inactivate drug. But sometimes produce active metabolites.

The same enzymes bind many drugs - competes for binding - the biggest reason for drug-to-drug interaction.

32
Q

How are CYP enzymes named?

A
33
Q

What is the enzyme that metabolizes half of all drugs?

A

CYP3A4 - This causes many drug to Drug Interactions

34
Q

What are the factors affecting drug metabolism?

A

Induction - The drug stimulates the expression of some metabolizing enzyme, (CYP). - Drug is metabolized at a faster rate - more likely to reach therapeutic failure.

Inhibition - Drug inhibits the expression of enzymes - Drug is metabolized at a slower rate - more likely to reach toxicity.

Lipid Solubility
Rate of Metabolism
Blood flow to live rand kidney
MAturation of enzymes
Gene polymorphisms
Diseases of Liver and Kidney

35
Q

What is an important inducer(helps induction)?

A

St Johns Wort

36
Q

What are some important inhibitors( Helps inhibition)?

A

Grapefruit juice.

37
Q

WHat is the most common example of CYP Polymorphism?

A

CYp2D6 Mutation - lack expression of this enzyme

Need this enzyme to metabolize codiene into morphine for Analgesic effect.
Codeine does not need to be converted to morphine to treat coughs.

38
Q

What is an example of gene polymorphism for Phase 2 reactions?

A

50% americans, 60-70% Europeans have reduced expression of acetylating Enzyme ( N- acteyl Trasnferase)

Slowly metabolize

39
Q

What is a prodrug?

A

A prodrug is an inactive precursor with favourable pharmacokinetics, which is metabolized into an active drug in the body.

40
Q

What are 2 examples of Prodrugs?

A
  1. Proton Pump Inhibitors
  2. Levo Dopa - Converted to Dopamine - Used for Parkinson’s
41
Q

What are the features of P - Glycoprotein?

A
  1. It is an Efflux Pump
  2. It used ATP
  3. It has broad substrate specificity
  4. It is located at many sites in the body
  5. It can also be induced or inhibited
42
Q

Explain Enterohepatic Recirculation

A

Increases the half-life of a drug

Affects hormones as well - assuming it is happening when given a contraceptive dose

43
Q

How does Antibiotics effect contraceptives

A

Antibiotics kill the flora which removes conjugation(Enterohepatic Recirculation) - Drug excretion is increased - Contraceptive failure

Also is inducer of CYP enzymes. Increases drug metabolism.

44
Q

d

Explain how Enterohepatic circulation affects body cholesterol concentration.

d

d

A

Cholesterol is metabolized in the liver to bile acids which are conjugated to taurine and glycine and excreted in the intestine where they are deconjugated. 95 percent of bile acids are reabsorbed and used in cholesterol synhthesis for the body

d

d

45
Q

How can you treat hypercholesterolemia?

A

If a bile acid binding resin such as cholestyramine is given the enterohepatic recyling of bile salts is interrupted leading to reduced cholesterol synthesis.

46
Q

What does clearance rate refer to?

A

The net effect of the excretion rates of all the body organs. Reflected as a decrease in plasma concentration of a drug.

Volume of blood from which a drug is irreversibly removed per unit time.

Make sure when talking about clearance rate it refers to plasma concentration.

47
Q

Drug Elimination Kinetics

What type of kinetic rate are most drugs eliminated by?

A

First Order Rate Process

48
Q

What does a First-Order rate process mean?

A

A constant fraction of the drug is being eliminated per unit time

Constant Slope

49
Q

What does the slope represent in a first order reaction.

A

The amount of drug exposed to enzyme.

50
Q

What is a zero-order rate process?

A

A constant amount of drug is eliminated per unit time. Because Drug metabolism becomes saturated

51
Q

What is a key feature of a First Order Rate Process?

A

Enzymes and Rate of Metabolism do not saturate. Enzymatic rate is faster than the drug. Therapeutic dose range is on the lower side.

52
Q

What are some examples of some drugs that become saturated?

A

Phenytoin, Aspirin

53
Q

What is the clinical application of Zero Order Elimination of Drugs?

A

A small increase in dose can lead to an large increase in plasma concentration causing toxicity.

Must wait until some of the drug is metabolized to give more.

Plasma concentrations monitored closesly.

54
Q

Can first order elimations become zero order?

A

Yes - If you keep increasing the dose

55
Q

What is usefule to calculate from the clearance values?

A

Maintenance Dose
Rate of Administration(Maintenance) = Rate of Elimination
Maintenance Dose = Cp(Plasma concentration) X Cl (Clearance)

56
Q

What are the factors affecting drug exretion.

A
  • Lipid Solubiity - Lipid soluble gets reabsorbed in the nephron
  • First order or Zero Order Elimination
  • GFR - Varies in age groups
  • Diseases of the Liver and Kidney
  • Maturation of Enzymes
  • Ion Trapping
  • Plasma protein binding
  • Competition for transporters in the nephron.
57
Q

Is drug binded to plasma proteins filtered in the Glomerulus.

A

No, only free drug filtered.

58
Q

Where do Strong Acid and Base drugs get secreted in the nephron?

A

Proximal Tubule

59
Q

What is a steady state?

A

Relatively Constant Plasma - Drug Concentration

60
Q

What is a half life?

A

Time required for the blood concentration of a drug to be reduced by 50%

61
Q

How many half lifes does it take to reach a steady state?(97%)

A

5 half lifes

Also takes 5 to effectively eliminate drug from body

62
Q

How does half life relate to VD and Cl?

A

CPPS 304 (6 decks)

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