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Toxicology > Lecture 4 > Flashcards

Lecture 4 Flashcards

1
Q

What is excretion

A

Excretion is the elimination of the substances from the body unchanged or as a metabolite

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2
Q

Drugs after metabolism gets excreted via different organs, they are categorized as follows…

A

Renal channel:
* Through Kidney - Urine

Non-renal channels:
* Liver – Bile
* Skin (Sweat)
* Lungs
* Intestine
* Milk
* Hair
* Nail
* Saliva

Artificial excretion

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3
Q

Most drugs leave the body in…

A

urine as the unchanged molecule or as a broken-down metabolite of the original drug

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4
Q

What is lumen

A

Breast Milk

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5
Q

Passage of the drugs into breast milk occurs generally by…

A

simple passive diffusion

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6
Q

Drugs can be concentrated in milk according to…

A

the ion trapping phenomenon.

Because the breast milk is more acidic than plasma, especially basic drugs tend to concentrate in breast milk.

Milk / plasma ratios of a drug can be used as an indicator of the passage of some drugs into the breast milk.

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7
Q

Milk / plasma ratios for some drugs

A
  • Iodide: 65
  • Propyltiouracil: 12
  • Aspirin: 0.6 – 1.0
  • Penicillin: 0.1 – 0.25
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8
Q

What is pulmonary excretion

A

Lungs
* Important in excretion of general anesthetic drug
* Gaseous or the volatile substances can pass from the blood circulation into the alveoli by passing across the endothelium and epithelium of the alveolar membrane.
* Simple passive diffusion is the main mechanism for this transport. (non-polar)
* After passing into the alveoli, these substances can be excreted by expiration.

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9
Q

Hair and nails

A
  • Drugs and metabolites excreted through hair may be deposited from the capillaries, which supply blood to the follicles, or they may be excreted in the sebum, oil, or sweats that coat the hair shafts.
  • Arsenic is getting accumulated on hair follicle after prolonged use. Hair is used to detect arsenic poisoning
  • Illicit substances become trapped in the keratin fibres of the nail and can be identified via laboratory testing.
  • Nail tests provide a simple and non-invasive way to test for drug use for up to a 12-month period prior to the samples being collected.
  • The detection of alcohol abuse using fingernails provides a reliable alternative to head or body hair. The EtG (Ethyl Glucuronide) - metabolite of ethanol - are trapped in the fingernail as it grows.
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10
Q

Tears

A
  • Important in drug information services to patients
  • Tears Example: Rifampicin (medications to treat tuberculosis)
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11
Q

Rifampin

A

Its is a medication to treat tuberculosis.

It is excreted in urine, tears,
sweat, and other body fluids (reddish-
orange to reddish-brown color). In 80% of
recipients, body fluids and contact lenses
are discolored orange during consumption
of rifampin.

Discoloration of body fluids
can be a useful indicator of adherence to
therapy.

Fatal acute overdoses in adults have been
reported with doses ranging from 14-60 g

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12
Q

Sweat and Saliva

A
  • Drugs or drug metabolites
  • Passive diffusion
  • Salivary recycling: Drug excreted in saliva is probably swallowed
  • Saliva example: Metronidazole, Lithium, Caffeine, Potassium Iodide (treat overactive thyroid)
  • Side reaction of the skin
  • Small amounts of a few drugs can pass through the skin and be excreted in sweat.
  • Sweat Smelly
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13
Q

Biliary excretion

A

*These substances are generally secreted into
the biliary ducts from the hepatocytes by
active transport and finally they are drained
into the intestines.
* Especially, highly ionized polar compounds
(conjugation products) can be secreted into
the bile in remarkable amounts.
* The most suitable molecular weight for the
drugs to be secreted into the bile is
approximately 500 Daltons

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14
Q

The common bile duct empties into the…

A

duodenum

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15
Q

Bile primarily consists of…

A

water, bile salts, bile pigments, electrolytes, & to a lesser extent, cholesterol & fatty acids

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16
Q

Drugs excreted into bile are…

A

metabolites (very often glucuronide conjugates)

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17
Q

Phenobarbital

A

may stimulate the billiary excretion of drug.

In contrast, compounds that decrease bile flow or pathophysiologic conditions that cause cholestasis will decrease billiary drug excretion

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18
Q

Formation of a glucuronide increases the…

A

Molecular weight by the nearly 200, as well as increasing the polarity

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19
Q

Enterohepatic circulation

A
  • After biotransformation, metabolites are drained into the small intestine by
    biliary duct.
  • Drug metabolites in the small intestine are broken down again in the small intestine and reabsorbed back reaching the liver by portal vein again.
  • This cycle between the liver and small intestine is called the enterohepatic cycle.
  • Especially the drugs which are metabolized by the conjugation reactions go under enterohepatic cycle.
  • This is important, because enterohepatic cycle prolongs the duration of stay of the drugs in our body which leads an increase in the duration of their effect.
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20
Q

Drug examples that go under the enterohepatic cycle in remarkable amounts include…

A
  • Chlorpromazine (antipsychotic medication)
  • Digitoxin (control the rate and rhythm of the heartbeat)
  • Indomethacin (NSAID; used to treat mild to moderate acute pain)
  • Chloramphenicol (antibiotic)
  • Other examples can be hormones, opioids, warfarin, etc
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21
Q

What is activated charcoal

A

Activated charcoal is charcoal that has been treated with oxygen at very high temperatures to make it more porous. It is neither absorbed in the gastrointestinal tract nor metabolized and excreted in the feces.

Activated charcoal adsorbs many noxious substances—medical drugs, phytotoxins and poisonous chemicals—onto its surface, preventing their absorption from the gastrointestinal tract.

As a secondary decontamination mechanism, it interrupts a potential enterohepatic circulation.

22
Q

Antibiotics may block enterohepatic circulation by…

A

suppressing the intestinal flora and thereby reducing the levels of deconjugating
enzymes.

23
Q

Renal excretion

A
  • Kidneys are main excretory organ for removal of metabolite waste
  • Plays major role in maintaining the normal fluid & composition (about 180 L fluid/day is filtered through kidneys)
  • Maintain salt & water balance (kidneys excretes electrolytes, water, waste product)
  • Located almost in our peritoneal cavity (retroperitoneal)
  • Nephrons are basic functional units in kidneys
24
Q

Examples of psychoactive substances

A

*Alcohol
*Caffeine
*Nicotine
*Marijuana
*Certain pain medicines

Many illegal drugs, such as heroin, LSD, cocaine, and amphetamines are also psychoactive substances.

25
Q

Psychoactive drugs are often…

A

Reabsorbed out of the kidneys, so the liver has to enzymatically transform the drugs so with minimal reabsorption they can exit in urine.

26
Q

Drugs and metabolites are excreted from
the kidneys by 2 ways

A
  1. Glomerular filtration
  2. Tubular secretion
27
Q

Glomerular filtration

A
  • Simple passive diffusion play role in glomerular filtration.
  • The filtration rate (GFR) is 110-130 ml/min.
  • They are filtered from the glomerulus into proximal tubules except the bound fraction of drug molecules to the plasma proteins. Because albumin cannot be filtered from the glomerulus, the drugs cannot pass through into the proximal tubules.
  • Non-ionized & ionized drugs
  • Hydrostatic pressure
28
Q

Tubular secretion

A

There are 3 important points about the tubular secretion mechanism of the drugs:

  1. Tubular secretion occurs mainly in the proximal tubules.
  2. Active transport is the main mechanism for tubular secretion.
  3. The efficiency (performance) of the excretion by tubular secretion is higher than glomerular filtration route. Clearance maximum in glomerular filtration is approximately 120 ml/min, whereas the clearance maximum of tubular secretion is about 600 ml/min.
  • Active renal secretion that uses a carrier-mediated system, requires energy input, because the drug is transported against a concentration gradient
  • Carrier system is capacity limited & may be saturated
  • Drugs with similar structures may compete for the same carrier system
29
Q

Tubular reabsorption

A
  • This mechanism works in an opposite (counter) way by reducing the drug or
    metabolite excretion.
  • Tubular reabsorption occurs mainly in distal tubules and partially in proximal tubules.
  • It occurs by simple passive diffusion generally (but it can also be active)
  • Changing the pH value of the urine (making the urine acidic or basic) is going to
    change the ionization degree and the simple passive diffusion of the drug or the
    metabolite and lastly affect the excretion from the kidney.
  • If we make the urine acidic, the reabsorption of the weak acid drug from the renal tubules into the blood will increase, thus the excretion will decrease.
  • In the opposite way, making the urine basic will cause an increase in the excretion of
    weak acid drugs.
30
Q

The variation of the Ph of urine depends on…

A

1.Diet
2.Pathophysiology
3.Drug intake

  • Higher urine pH caused by: Vegetable diets
  • Lower urinary pH caused by: Diets rich in carbohydrates & Diets rich in protein
  • Example: Ascorbic acid may decrease the urine pH; Antacid may increase the urinary pH.
  • Amphetamine is a weak base; it will be reabsorbed if the urine pH is made alkaline as
    more non-ionized species are formed.
    more ionization - more secretion
31
Q

Artificial Excretion

A

*Hemodialysis is one of the options among the artificial excretion way for the drugs.
* It is used especially for the treatment of acute drug intoxications to eliminate the drug
from the body.
* Dialyzer = artificial kidney
* It is done 3 times a week, with each session usually lasting about 4 hours

32
Q

What are the three types of semipermeable membranes currently used to manufacture dialyzers

A
  1. Cellulose
  2. Substituted cellulose
  3. Synthetic noncellulose.

These membranes allow only low-molecular-weight molecules, such as sodium, potassium, urea, and creatinine, to pass through while blocking proteins, such as albumin, and other larger molecules.

33
Q

Requirements of artificial excretion

A
  1. Plasma protein binding of the drug should be low (bound fraction should be low).
  2. Drug should not be stored in tissues (apparent volume of the drug should be low)
  3. The main elimination route of the drug should be from kidneys in unchanged
    (without biotransformation) form
34
Q

Current hemodialysis techniques fail to efficiently remove the…

A

protein-bound uremic toxins p-cresyl sulfate and indoxyl sulfate due to their high degree of albumin binding.

  • Uremic toxins are defined as substances, organic or inorganic, that accumulate in the
    body fluids of subjects with acute or chronic kidney disease and impaired kidney function. Renal dysfunction can increase the prevalence of renal cancer.
  • Indoxyl sulfate is also associated with coronary artery calcification (coronary
    atherosclerosis).
35
Q

What is an artificial kidney

A
  • An artificial kidney to sustainably support a culture of human kidney cells without provoking an immune response.
  • It includes a hemofilter made up of silicon semiconductor membranes (based on silicon nanoparticles) that remove waste products from blood and a bioreactor containing renal tubule cells that regulate water volume, electrolyte balance and other metabolic functions. These membranes also protect cells from being rejected by the patient’s
    immune system.
  • The bioartifical kidney implant works without the need for the immune-
    suppressing drugs or blood thinners typically required with transplants
36
Q

What is clearance

A

It can be described as the volume of plasma cleared from the drug per unit time (ml/min).

37
Q

What is total body clearance

A

It is the plasma volume cleared from the drug per unit time via the elimination of the drug from all biotransformation and excretion mechanisms in the body.

38
Q

What is renal clearance

A

It can be described as the rate of the excretion of a drug from kidneys. So in other words, renal clearance is the volume of plasma cleared from the non-metabolized (unchanged) drug via the excretion by kidneys per minute.

39
Q

What are the four important factors that affect the renal clearance of the drugs

A
  1. Plasma protein binding of the drug.
  2. Tubular reabsorption ratio of the drug.
  3. Tubular secretion ratio of the drug.
  4. Glomerular filtration ratio of the drug.
40
Q

Elimination rate (half-life)

A
  • It is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50% via different elimination mechanisms.
41
Q

Patient-specific variables that may affect half-life

A
  • Age
  • Blood circulation
  • Diet (eg, grapefruit juice and several drugs, green vegetables, and warfarin)
  • Excessive fluid (such as in people with heart failure or edema) or low fluid levels (dehydration)
  • Gender
  • History of previous drug use
  • Kidney function (for drugs that are cleared via the kidneys)
  • Liver function (for drugs that are metabolized through the liver)
  • Obesity
  • Pre-existing conditions (such as heart failure, gastrointestinal disorders, pregnancy)
  • Presence of drugs that compete for binding sites or interact in other ways
  • Race/ethnicity or genetics (this can influence the metabolism of a drug)
  • Smoking
  • Other variables, such as if the person is on hemodialysis.
42
Q

Drug-specific variables that may affect half-life

A
  • Drug formulation (ie, modified or controlled release preparations extend half-life)
  • How the drug behaves in the body (ie, zero-order, first-order, or multi-compartmental
    pharmacokinetics)
  • How the drug is administered (half-life may be different with IV administration, compared to
    intranasal or oral administration)
  • How the drug is cleared from the body (eg, kidneys, liver, lungs)
  • If the drug accumulates in fat or other types of tissue
  • If the drug binds to proteins or not
  • Presence of metabolites or other drugs that may interact
  • Properties of the drug, including molecule size, charge, and pKa
  • The volume of distribution of a drug
  • Other variables, such as if the drug is actively transported, is self-induced, or has saturation
    pharmacokinetics.
43
Q

Short versus long half-lives

A
  • Drugs or substances that have a shorter half-life tend to act very quickly, but their effects wear off rapidly, meaning that they usually need to be taken several times a day to have the same effect. Drugs with a longer half-life may take longer to start working, but their effects persist for longer, and they may only need to be dosed once a day, once a week, once a month, or even less frequently.
  • When considering drugs with a high addiction or dependence potential, those with a short half-life are typically harder to withdraw from than those with a long half-life. For this reason, drug treatment programs will often switch a person from a short-acting drug to a long-acting equivalent from the same class, in order to improve the withdrawal process.
44
Q

What is accumulation

A
  • Accumulation is often wrongly associated with toxicity, thus it is often spoken of in the context of toxicokinetic analysis.
  • Accumulation is simply a reflection of how much drug is being added to the body relative to how much is being eliminated from the body during a defined period of time. And that ratio can be controlled by changing the dosing frequency.
45
Q

What is Steady-State

A
  • Following repeated administration of a drug, a steady-state is reached when the quantity of drug eliminated in the unit of time equals the quantity of the drug that reaches the systemic circulation in the unit of time.
  • Steady-state occurs after a drug has been given for approximately four/five elimination half-lives.
  • At steady-state the rate of drug administration equals the rate of elimination and plasma concentration - time curves found after each dose should be approximately superimposable.
  • Important when interpreting drug concentrations in time- dependent manner or assessing clinical response
46
Q

What is zero-order elimination

A

Implies rate of elimination is constant, regardless of drug concentration
* constant amount of drug is eliminated per unit time

  • drug concentration in plasma (Cp) decreases linearly with time
  • e.g., phenytoin, aspirin
  • aspirin is zero-order drug at high therapeutic or toxic concentrations
47
Q

What is first-order elimination

A
  • implies rate of elimination is proportional to drug concentration
  • constant fraction of drug is eliminated per unit time
  • drug concentration in plasma (Cp) decreases exponentially with time
  • first-order drugs have a characteristic, constant half-life of elimination
48
Q

What is Michaelis-Menten elimination

A
  • If there is some limit on how much enzyme activity there can be, then the system is said to be saturable, i.e. it is possible to saturate the enzymes to a point where increases in concentration can no longer produce
    increases in enzyme activity. This gives rise to non-linear elimination kinetics, known by the uninformatively eponymous term “Michaelis-Menten elimination”.
  • It tells us that at very lower concentrations, the rate of the enzyme is directly proportional to the concentration of substrate; at low concentrations, the more substrate
    you give the faster the reaction rate. At high
    concentrations, the rate of reaction remains the same because all the enzyme molecules are “busy”, i.e. the system is saturated.
49
Q

What are lipids

A

lipid, any of a diverse group of organic compounds including fats, oils, hormones, and certain components of membranes that are grouped together because they do not interact appreciably with water.

The different varieties of lipids have different structures, and correspondingly diverse roles in organisms. For instance, lipids store energy, provide insulation, make up cell membranes, form water-repellent layers on leaves, and provide building blocks for hormones like testosterone.

Some of the most important types of lipids includes- fats and oils, waxes, phospholipids, and steroids.

50
Q

What are phospholipids

A

Cells are surrounded by a structure called the plasma membrane, which serves as a barrier between the inside of the cell and its surroundings.
Specialized lipids called phospholipids are major components of the plasma membrane. Like fats, they are typically composed of fatty acid chains attached to a backbone of glycerol. Instead having three fatty acid tails, however, phospholipids generally have just two, and the third carbon of the glycerol backbone is occupied by a modified phosphate group. Different phospholipids have different modifiers on the phosphate group, with choline (a nitrogen-containing compound) and serine (an amino acid) being common examples. Different modifiers give phospholipids different properties and roles in a cell.
A phospholipid is an amphipathic molecule, meaning it has a hydrophobic part and a hydrophilic part. The fatty acid chains are hydrophobic and do not interact with water, whereas the phosphate-containing group is hydrophilic (because of its charge) and interacts readily with water. In a membrane, phospholipids are arranged into a structure called a bilayer, with their phosphate heads facing the water and their tails pointing towards the inside. This organization prevents the hydrophobic tails from coming into contact with the water, making it a low-energy, stable arrangement.
If a drop of phospholipids is placed in water, it may spontaneously form a sphere-shaped structure known as a micelle, in which the hydrophilic phosphate heads face the outside and the fatty acids face the interior of this structure. Formation of micelle is an energetically favored because it sequesters the hydrophobic fatty acid tails, allowing the hydrophilic phosphate head group to instead interact with the surrounding water.

51
Q

What are steroids

A

Steroids are another class of lipid molecules, identifiable by their structure of four fused rings. Although they do not resemble the other lipids structurally, steroids are included in lipid category because they are also hydrophobic and insoluble in water. All steroids have four linked carbon rings and several of them, like cholesterol, also have a short tail. Many steroids also have an –OH functional group attached at a particular site, as shown for cholesterol below; such steroids are also classified as alcohols, and are thus called sterols.

52
Q

What is cholesterol

A

Cholesterol, the most common steroid, is mainly synthesized in the liver and is the precursor to many steroid hormones. These include the sex hormones testosterone and estradiol, which are secreted by the gonads (testes and ovaries). Cholesterol also serves as the starting material for other important molecules in the body, including vitamin D and bile acids, which aid in the digestion and absorption of fats from dietary sources. It’s also a key component of cell membranes, altering their fluidity and dynamics.
Of course, cholesterol is also found in the bloodstream, and blood levels of cholesterol are what we often hear about at the doctor’s office or in news reports. Cholesterol in the blood can have both protective effects (in its high-density, or HDL, form) and negative effects (in its low-density, or LDL, form) on cardiovascular health.

Toxicology (8 decks)

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