week 7 Flashcards

(14 cards)

1
Q

drug excretion

A
  • The removal of drugs drom body fluids, occurs primarily through urine.
    o Low molecular weight polar compounds are primarily excreted in fluids such as urine, sweat, bile, tears, breast milk, etc.
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2
Q

renal excretion of drugs

A

Most drugs are excreted through the urine
The kidneys excrete drugs by undergoing the process of glomerular filtration, passive tubular reabsorption and active tubular secretion
- Glomerular filtration = free movement of fluid and small solutes from the glomerular capillaries into the tubular space.
- Reabsorption = most water in the glomerular filtrate and lipid soluble drugs are reabsorbed via diffusion
- Tubular secretion = active process, mediated by secretory transporters e.g. organic anionic transporters (OAT) and organic cationic transporters (OCT) on the basolateral and apical membranes for basic or acidic compounds

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3
Q

factors that modify drug excretion: pH - dependent ionisation and ion trapping effect

A

Drugs accumulating where its ionisation is greater = the ion trapping effect
Ion trapping is the process where a drug accumulates in a compartment where its ionisation is greater due to a pH difference across a membrane.
The non ionised form of the drug crosses the lipid cell membrane more easily than its ionised form.

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4
Q

application of ion trapping in renal elimination of drugs

A

Phenomenon of pH dependent ionisation and ion-trapping influences the elimination of weakly acidic or basic drugs depending on the pH or the urine.
Ion trapping effect can be used to accelerate the renal excretion of drugs.
Ions aren’t lipid soluble; drugs that are ionised at the H of tubular urine will stay in the tubule and be excreted.
Therefore, manipulating urinary pH in a way that promotes the ionisation of a drug, we can decrease passive absorption back into the blood and accelerate the drugs elimination.

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5
Q

biliary excretion and enterohepatic circulation

A

Many drugs are excreted in bile as the parent or metabolite.
Biliary excretion favours drugs with molecular weights greater than 300g/mol with both polar and lipophilic groups.
Conjugation increases biliary excretion as conjugation reactions lead to an increase in metabolite/drug size.

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6
Q

enterohepatic circulation

A

Enterohepatic circulation
Involves the interaction between the liver and GI tract, where the liver releases bile, bile acids, and other metabolites through the common bile duct.
Steps:
1. Liver cells transfer various substances, incl. drugs, from plasma to bile by means of transport systems (OCTs and OATs)
2. Various hydrophilic drug conjugates are concentrated in the bile and delivered to the intestine.
3. In the intestines, the conjugate is usually hydrolysed by bacterial enzymes, releasing the active drug again. The free drug can then be reabsorbed into systemic circulation, and the cycle is repeated.

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7
Q

clearance

A

Measure of drug elimination. Defined as the volume of plasma that is cleared of the drug per unit time.
Total clearance from the systemic circulation represents the total sum of all clearance processes relevant to the particular drug.
Systemic clearance (CLs) = CL (hepatic) + CL (renal) + CL (other)

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8
Q

importance of clearance

A

Measure of drug elimination. Defined as the volume of plasma that is cleared of the drug per unit time.
Total clearance from the systemic circulation represents the total sum of all clearance processes relevant to the particular drug.
Systemic clearance (CLs) = CL (hepatic) + CL (renal) + CL (other)

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9
Q

calculating clearance

A

Clearance relates the rate of elimination of a drug to the plasma concentration, Cp:
Rate of elimination (mg/h) = CL (L/h) x [Plasma conc] (mg/L)

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10
Q

hepatic clearance

A

The volume of blood that is cleared of the drug when it passes through the liver. Affected by blood flow to liver.
The fraction of the drug entering the liver in the blood that is irreversibly removed (extracted) during a single pass is called hepatic extraction ratio.

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11
Q

pharmacokinetic variations in individuals affecting ADME

A
  1. Age – drug response varies significantly. Drug elimination is less efficient in newborns and the elderly. Drugs produce greater effects in elderly.
  2. Pregnancy – increased cardiac output, stroke volume increase, >40% plasma vol. increase. Can increased the volume of distribution for drugs.
  3. Genetics – altering expression of proteins involved in drug absorption, distribution, metabolism, and excretion.
  4. Concurrent diseases – disease of major organs responsible for drug metabolism + excretion. Diseases predispose to toxicity by causing unexpectedly intense of prolonged drug effects.
  5. Drug/food interactions – drug, food, alcohol, in the presence of another drug can lead to interactions causing toxicity or reduced therapeutic effect.
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12
Q

genetic polymorphism and its influence on drug metabolism

A

Influences pharmacokinetics by affecting gene expression of proteins involved in ADME.
Genetic polymorphism refers to the presence of different allelic forms of a gene within a population. These DNA variations arise in nucleotides, leading to changes in nucleotide sequence. The change results in the formation of a variant allele.
Several drug metabolising enzymes exhibit genetic polymorphisms that influence drug response. E.g.:
- Cytochrome P450 (CYP) isoenzymes – CYP2D6, CYP1A2, CYP2A6, CYP2B6
o Cyp2d6 -> converts codeine into morphine
- N – acetyltransferase (NAT2)
- Thiopurine methyltransferase (TPMT)
- UDP – glucuronosyltransferases – such as UGT1A1, UGT1A4, UGT1A9
The genetic polymorphism of these enzymes causes decreased, increased or absent enzyme expression or activity. The presence of genetic polymorphisms in metabolising enzymes can have significant consequences for drugs metabolised by those enzymes. Incl.:
- Increased plasma drug concentration and duration of action
- Decreased plasma drug concentration and therapeutic failure
- Adverse drug reactions/toxicity
- Failure to activate a prodrug
- Drug metabolism via alternate pathways
- Exacerbation of drug interactions

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13
Q

drug interactions

A

When another substance alters a drugs efficacy, effects, or safety.
Common in polypharmacy
OTC drugs, herbal medicine, caffeine, nicotine, alcohol.
St. johns wort -> induces drug metabolising enzymes, also inhibits CYP3A4, CYP2C19
grapefruit juice -> inhibits CYP3A4 enzyme
When two substances interact, one of 3 outcomes:
- One drug intensifies the effects of the other
- One drug reduces the effects of the other
- The combination may produce a new or unexpected response not seen with either drug alone.

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14
Q

types of drug/drug interactions

A
  1. Behavioural – alters patient’s behaviour to modify compliance w/ another drug
  2. Pharmaceutic – when the formulation of one drug is altered by another before its administered.
  3. Pharmacodynamic – when interacting drugs have either additive effects, in which case the overall effect is increased, or opposing, in which the overall effect is decreased.
  4. Pharmacokinetic – one drug changes the system concentration of another drug, altering how much and for how long the drug is present.
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