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2013 Biosciences and intro to pharmacology > Pharmadynamics - in extra detail > Flashcards

Pharmadynamics - in extra detail Flashcards

1
Q

What does Parenteral mean?

A

Drugs given by routes other than the digestive tract.

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2
Q

What are the main enteral routes of drug administration?

A

oral, intrarumenal, rectal

Parenteral:
intravenous (IV), intramuscular (IM), subcutaneous (SQ), intraperitoneal (IP), inhalation, topical (local), oral transmucosal (OTM)

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3
Q

Delivering drugs via :

IV, dermal, SQ, IM, Reservoir

A
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4
Q

What 6 things determine the choice of the route of administration of a certain drug?

A
  • physicochemical properties of the drug
  • formulation to be used
  • therapeutic indications
  • pathophysiology of the disease
  • target species
  • manufacturer’s recommendations
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5
Q

How does the route of administration affect absorbance and clearance of the drug?

A

route of administration may influence the rate and extent of absorption, but it should not influence the distribution or clearance

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6
Q

How is the magnitude of pharmacologic response related to drug concentration at the tissue?

A

proportionately - higher concentration = higher response

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7
Q

How are drug concentrations at the tissue site approximated? Why is it approximated, rather than definitely measured?

A

measuring the plasma drug concentration (PDC)

tissue samples cannot be collected easily

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8
Q

What are the 4 major movements of drugs that affect plasma drug concentration? What do these movements largely depend on?

A
  • Absorption from the sit of administration to systemic circulation
  • Distribution from systemic concentration to tissues and back again
  • Metabolism
  • Excretion
    passive diffusion
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9
Q

Describe the major steps a drug takes after it is administered.

A
  1. absorbed into circulation
  2. free drugs not bound to plasma proteins is distributed into tissue.
  3. the drug will either bind to the tissues/plasma proteins or is distributed back into circulation
  4. drug is eliminated via hepatic metabolism and renal/biliary excretion of it or its metabolites
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10
Q

What is absorption? Which routes of administration need this to occur?

A

movement of drugs from the site of administration and across one or more membranes into the bloodstream

all EXCEPT IV, where the blood is delivered directly to circulation

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11
Q

What does the presence of heterogeneity in morphology and physiology of the GI tract lead to?

A

regional variants in drug absorption

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12
Q

Where are most drugs coming from when they reach systemic circulation?

A

small intestine (due to large surface area)

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13
Q

What 6 things affect the rate and extent of drug absorption in the GI tract?

A
  • GI pH
  • surface area
  • motility
  • concentration of drug
  • permeability and thickness of mucosal epithelium
  • intestinal blood flow
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14
Q

Where do drugs go after the GI tract absorbs them?

A

portal vein —> liver

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15
Q

What is first-pass metabolism?

A

phenomenon in which a drug gets metabolized at a specific location in the body that results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation (not sufficiently high enough to cause a response)

drugs absorbed in the intestine are metabolized in the liver as well, so it may not reach target tissue in sufficient amounts

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16
Q

What are the 2 main areas for GI absorption of drugs in the mouth?

A
  1. sublingual area - systemic drugs (nitroglycerin)
  2. buccal mucosa - polymer patches, feline oral sprays
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17
Q

Why is it difficult for drugs to be absorbed in the oesophagus and cranial stomach?

A

cornified epithelium is an effective barrier that decreases the chances for drug absorption

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18
Q

In what way is it easy for drugs to be absorbed in the stomach? In what 2 ways is it difficult?

A

simple mucosa
1. surface mucus may act as a barrier

  1. acidity and motility create a hostile environment for drugs and promote their absorption further down the track
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19
Q

What is the primary site for most drug absorption? Why?

A

small intestine

Why:

more alkaline pH
more simple epithelial lining
higher blood flow to the small intestine compared to the stomach
microvilli increase the surface area

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20
Q

What are the second and third first-pass effects that occur in the small intestine?

A

SECOND FIRST-PASS EFFECT: the epithelial cells of the intestine are endowed with the necessary enzymes for drug metabolism

THIRD FIRST-PASS EFFECT: resident microbial populations are capable of metabolizing specific drugs

(drugs are metabolized before they reach target tissue and may not cause a drug response)

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21
Q

What must occur before a drug can be absorbed across the intestinal mucosa? What are the 2 major steps?

A

Drug must first be dissolved in the aqueous mucosa

DISINTEGRATION: solid dosage (tablet) physically disperses so that its particles can be exposed to the GI fluid.

DISSOLUTION: drug molecules enter into solution (pharmaceutical phase)

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22
Q

What are 3 important practices used for parenteral route of administration?

A
  1. sterile preparations must be administered using aseptic techniques
  2. dose must be accurate
  3. painful reactions are a possibility
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23
Q

What are the 2 primary therapeutic parenteral routes of drug administration? What is the major benefit to these routes?

A
  1. molecular weight
  2. partition coeficient (PC)
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24
Q

Moderately irritating preparations can be injected IM, but what can be a possible consequence?

A

tissue reaction and necrosis

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25
Q

How does the duration of drug action for IM, IV, and SQ administration compare? Rate of absorption for SQ and IM?

A

SQ > IM > IV

IM > SQ

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26
Q

Why is intraperitoneal (IP) administration used? What 2 things make this route unique?

A

Peritoneal absorption is very efficient and there is a good mixing of the injection with the peritoneal fluid

  1. large volumes can be administered
  2. a majority of the drug absorbed after IP administration enters the portal vein and undergoes first-pass hepatic metabolism
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27
Q

Does intravenous administration involve an absorption phase? How much of the drug can be injected?

A

NO

a large fluid volume is able to be injected

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28
Q

Since IV administration is a more direct administration route, what will this result in? What types of solutions are preferred?

A

immediately high levels of the drug in the blood and rapid onset of action

aqueous
(irritating and nonisotonic solutions can be injected if done slowly and carefully)

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29
Q

Which of the following parenteral routes of administration is not recommended for large volumes of application?

a. intravenous (IV)
b. intraperitoneal (IP)
c. intramuscular (IM)

A

C

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30
Q

How does inhalation (pulmonary route) absorb drugs? How does the size of the partlcles affect the place of absorption?

A

gases, volatile agents, and fine particles are rapidly absorbed from the airway and alveoli into the pulmonary circulation

< 2μm (nebulization) = terminal ducts and alveoli
< 5μm = respiratory bronchioles
5-10μm = upper respiratory tract and larger airways

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31
Q

Why is response so rapid during inhalation? What happens to the drug after absorption?

A

the lungs have such a large surface area and blood supply
cells lining the alveoli are very thin and profusely bathed by capillaries

oxygenated pulmonary veins —> systemic arterial circulation

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32
Q

What are the main 2 ways used for topical administration? Some examples?

A
  1. applied to skin and adnexa
  2. variety of mucous membranes

sublingual, intravaginal, intranasal, intrauterine, rectal, preputial, ocular, aural (otic)

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33
Q

What is unique about drug concentration and topical administration?

A

achievement of an effective systemic concentrations is often not required for what is essentially a local therapeutic effect

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34
Q

What is oral transmucosal (OTM), or buccal, drug administration? What are 2 huge advantages to this route?

A

Drugs are given by mouth with the intent of absorption occurring through the mucosa of the mouth

  1. avoids first-pass metabolism
  2. bypasses the harsh GI environment
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35
Q

What is bioavailability (F)? How is it determined?

A

percentage of an administered dose of drug that reaches systemic circulation

comparing plasma levels of a drug after a particular route of administration with the levels achieved by IV administration

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36
Q

Why is IV a base for calculating bioavailability (F)?

A

F for IV will always = 1 since the drug is going directly into circulation without absorption necessary, which is where drugs tend to be lost

all other routes will have an F < 1

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37
Q

How is total absorption of a drug determined? What does it mean when bioavailability is high?

A

measuring the area under the concentration-time curve after drug concentrations in the blood are assayed

greater F = greater extent of absorption of a drug and anticipated pharmacologic response

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38
Q

What is bioavailability used to predict?

A

DRUG EFFICACY after different routes of administration

39
Q

What is drug distribution?

A

After the drug reaches systemic circulation following any route of administration, it must be distributed from the central compartment (blood) to peripheral tissues

40
Q

How are drugs typically distributed?

A
  • numerous tissues at once
  • stored in tissues and slowly released back into the systemic circulation (low blood flow/mass ratio)
41
Q

What are the 5 major factors that determine drug distribution to and from tissues?

A
  1. drug lipid solubility and its ability to penetrate cell membranes
  2. regional blood flow (flow/mass ratio)
  3. concentration gradient established between blood and tissue
  4. the degree to which the drug is bound to plasma or tissue proteins.
  5. presence of transport proteins
42
Q

What tissues typically have high blood flow/mass ratio? Intermediate? Low?

A

HIGH: brain, heart, liver, kidney, endocrine glands

INTERMEDIATE: muscle, skin

LOW: adipose tissue, bone

43
Q

How is blood distributed in the kidneys?

A

renal cortex receives about 25% of cardiac output
- renal medulla receives a small fraction of this blood flow

44
Q

What are 3 possible transporters of drugs once they enter the circulatory system?

A
  1. plasma proteins**
  2. red blood cells
  3. lymph
45
Q

How does the pH of drugs affect their binding to plasma proteins?

A

weakly acidic drugs tend to bind to albumin

weakly base drugs tend to bind to α1-glycoprotein

46
Q

Why are the bonds formed between therapeutic drugs and plasma proteins considered covalent?

A

the binding is reversible and the drug will likely be released once it gets to the desired location

47
Q

What is dissociation?

A

the affinity for another tissue component for the drug is greater than that for the plasma protein

(drugs bound to plasma proteins will move throughout circulation until it dissociates)

48
Q

How does plasma protein binding affect drug distribution? Ability of drug to reach site of action? Glomerular filtration? Metabolism/secretion?

A

only free drugs can cross membranes, so when drugs are still bound, they cannot cross into their site of action

doesn’t prevent it from reaching the site of action, but it does slow it down

limits glomerular filtration because the protein makes it too large to be filterable

slows down the rate of metabolism and/or secretion

49
Q

How is protein binding expressed? When does protein binding tend to fall?

A

in terms of a percentage of the drug bound

when the drug concentration exceeds the value that saturates the binding site - more drug than available protein leaves some drugs unbound and free, leaving it unable to move to its target and vulnerable

50
Q

What is displacement?

A

competition for the same site on plasma proteins between different drugs, especially important when one of the potential ligands has a very high affinity

51
Q

If drug A were bound 98% and 10% of it is displaced by drug B, how much does the amount of free drug increase?

A

2% free
10% of 98 = 9.8
2 + 9.8 = 11.8

goes from 2% to 12%

52
Q

Drug A with 30% binding and 10% displaced by drug B results in an increase of how much of free drug?

A

70% free
10% of 30 = 3
70 + 3 = 73

goes from 70% to 73%

53
Q

What is distribution equilibrium (DE)?

A

AKA steady-state
the amount of drug leaving plasma for tissues is equivalent to the amount of drug leaving tissues for plasma

DE is never truly reached because a drug is continually being eliminated

54
Q

What drugs are less likely to reach distribution equilibrium? More likely?

A

drugs with short half-lives, particularly when administered at a long dosing interval

drugs that accumulate (given at a dosing interval shorter than half-life)

55
Q

What type of barrier does the blood-brain barrier use to only allow certain molecules into the brain?

What does it use to send things out?

A

selective transport mechanisms that accumulate specific chemicals against their concentration gradients, like glucose, L-amino acid, and transferring transporters

drug efflux transport mechanisms that remove a drug from the protected sites, like MDR1 (P-glycoprotein)

56
Q

Metabolism

A

Metabolism

57
Q

What is drug metabolism?

What is it a defence mechanism against?

A

The biotransformation of pharmaceutical substances in the body so that they can be eliminated more easily

adverse effects of lipophilic xenobiotics (chemicals unnatural to the body)

58
Q

What 4 things would happen in biological systems without drug metabolism?

A
  1. absorbed compounds would stay in the body for a much longer time
  2. drugs would have a prolonged activity
  3. tissue drug accumulation
  4. potential toxicity
59
Q

What the the major organ for drug metabolism?

A

liver

60
Q

Drug metabolism in the liver depends on what 4 factors?

A
  1. biological properties of the liver (existence of major drug metabolism enzymes)
  2. hepatic volume/perfusion rate
  3. drug accessibility to and extraction by hepatic metabolic sites
  4. physiochemical properties of the drug (pKa, lipid solubility, molecular weight)
61
Q

How are drugs eliminated?

A

hepatic metabolism (breaking in down to easier excreted products like urea), renal excretion, or both

62
Q

What must happen to lipid-soluble drugs before the kidneys can eliminate them?

A

they must be converted into a water-soluble form

63
Q

Understand the terms metabolism and excretion and differentiate.

A

LO!!!!

64
Q

Recognise the clinical relevance of drug metabolism with particular reference to; inducers and inhibitors, pharmacogenomics, active metabolites, toxic metabolites and pro-drugs

A

LO!!!!

65
Q

Understand the concepts of first-pass metabolism and bioavailability.

A

LO!!!!

66
Q

Relate changes in physiological function such as age and disease to drug metabolism

A

LO!!!!

67
Q

Explain the fundamental processes involved in drug excretion via the kidneys.

A

LO!!!!

68
Q

Explain the fundamental processes involved in drug excretion via the kidneys.

A

LO!!!!

69
Q

Relate changes in physiological function such as pH, age and disease to drug excretion

A

LO!!!!

70
Q

Understand the nature of biliary excretion and the importance of enterohepatic recycling

A

LO!!!!

71
Q

Define the concept of half-life

A

LO!!!!

72
Q

Other than the liver, what are 4 other organs with substantial metabolic capacity?

A
  1. kidney
  2. lungs
  3. skin
  4. gastrointestinal tract
73
Q

Where are most metabolizing enzymes located in the hepatocytes (liver cells)?

A

in the smooth endoplasmic reticulum

74
Q

Excretion on other cards

A
75
Q

LOs:

  • Describe the mechanisms used by drugs to cross cell membranes.
  • Understand the terms absorption and distribution and differentiate between them.
  • Relate changes in physiological function; such as pH, disease and age to drug absorption and distribution
  • Understand the nature of plasma protein binding and illustrate the effect of drug distribution with clinical examples
A
76
Q

How does the Rate of gastric emptying affect drug absorption?

A

Fast - Results in faster delivery to gut where most absorption occurs

Slow – results in slower delivery to the gut

77
Q

How does Disease affect drug absorption?

A

Surface area of bowel may be reduced leading to reduced absorption

78
Q

How does Transit time through gut affect drug absorption?

A

Surface area of bowel may be reduced leading to reduced absorption

79
Q

How does Blood flow affect drug absorption?

A

In hypotension, blood flow may be restricted reducing IM absorption

80
Q

How does Age affect drug absorption?

A

In the older person, gastric transit time is slowed.

81
Q

What is the role of Metabolism?

A

The role of metabolism is to make drugs more water soluble so that they can be excreted via urine (lipophilic drugs are metabolised to more polar products (hydrophilic)

82
Q

Drug metabolism:

What happens in phase 1?

Catabolic - using enzymes

A

Phase I reactions are catabolic (breaks down chemicals) and the products can be more chemically reactive (catalysed by CYP450 enzymes)

83
Q

Drug metabolism:

What happens in phase 2?

Conjugating something to a drug for excertion

A

Phase II reactions involve conjugation – the attachment of a chemical group (glucuronyl, sulphate, methyl, acetyl and glutathione).

84
Q

What phase will excrete inactive metabolites? (faeces/bile)

A

Phase 2

85
Q

What phases will excrete active metabolites? (urine)

A

Phase 1 and 2

86
Q

Drugs being inducers and drugs being inhibitors. These affect the enzymes affecting drug metabolism - the CYP450 enzyme. these enzymes are genetically determined.

A
87
Q

Give examples of drugs that are inducers

A

Rifampicin
Carbamazepine
Ethanol
Phenytoin

88
Q

Give examples of drugs that are inhibitors

A

Cimetidine
erythromycin
ciprofloxacin
Ritonavir
Fluconazole

89
Q

What is the role of Drug inducers of CYP450 enzmes in drug metabolism, activity and the therapeutic effect

A

Drug metabolism increases.
Drug activity decreases.
The therapeutic effect decreases.

90
Q

What is the role of Drug inhibitors of CYP450 enzmes in drug metabolism, activity and the therapeutic effect

A

Drug metabolism decreases.
Drug activity increases.
Side effects and toxicity increases

91
Q

Define polymorphism

A
92
Q

Explain first-pass metabolism

A
93
Q

Define Half-life

A

Time taken for the peak concentration of the drug in the plasma to decrease by 50%

94
Q

What does half-life depend on?

A

Dosing intervals
Residual effects

Depends on clearance by metabolism and renal elimination.

2013 Biosciences and intro to pharmacology (14 decks)

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