Drug metabolism and excretion Flashcards
What is the main site of drug metabolism?
Liver
What is the main site of drug excretion?
Kidney
What are the two main processes of drug metabolism?
- Molecule is made more lipophilic to reduce the possibility of reabsorption in the renal tubules
- Conjugated to reduce its effects and aid excretion
What is a prodrug?
Inactive form of drug that becomes active through conversion in the body
Which reactions happen in phase I of metabolism?
Oxidation
Reduction
Hydrolysis
Glucyronidation
Glycosylation
Sulfanation
Methylation
Acetylation
Amino acid conjugation
Glutathione conjugation
Which phase I reactions are the most important?
The ones by the P450 system
What is required for reactions by the P450 system to take place?
Cytochrome P450 haem proteins
Molecular oxygen
cP450 reductase
NADPH
What reaction does P450 catalyse?
NADPH + oxidised cyto + H+ -> reduced cyto + NADP+
How can other drugs affect the P450 system?
Other drugs can increase/decrease the effect of P450
Some drugs can increase the effect of drugs through inhibiting the P450 system
What processes are involved in renal excretion?
Filtration at the glomerulus
Active tubular secretion
Reabsorption from the tubule
Describe how glomerular filtration helps to excrete drugs
Arterial blood pressure forces ultrafiltrate from the glomerular capillaries into Bowman’s capsule
Small drug molecules in both charged and uncharged states cross the glomerular membranes readily, achieving a concentration in the filtrate identical to their free concentration in plasma
Drug molecules bound to plasma proteins are not filtered
Describe how active tubular secretion helps to excrete drugs
Occurs at the PCR
Low-specificity carriers in the basolateral membrane transport endogenous substances and drugs from the plasma into the tubular cells from where they pass into the filtrate by facilitated diffusion
Tubular secretion of one drug may be competitively inhibited by another
Describe how reabsorption from the tubule affects drug excretion
Drugs within the tubules in the unionised and lipid form will be reabsorbed
A weak acid = more readily excreted in alkaline than acidic urine
Self-renewal of bile
Bile is produced at a daily rate of 0.5-1 litre
Describe the enterohepatic circulation and how that affects the bioavailability of drugs
Drugs may be reabsorbed from the bile back into the intestine to undergo further cycles of billiary excretion
This happens through active transport
This increases the drug’s half life
What determines the course of drug action?
The concentration of the drug at the site
An important exception - drugs that bind irreversibly, since the effect outlives the concentration
Describe the course of drug action in well and poorly perfused systems
Well perfused tissues can equilibrate with the plasma concentration quickly
Poorly perfused tissues will take up and release drugs slowly
What are ways drugs can enter cells?
Direct diffusion through the lipid bilayer
Carrier-mediated transport
Diffusion through aqueous pores
Pinocytosis
What determines the diffusion of a drug through membranes?
Concentration gradient
Diffusion coefficient
What is the Henderson Hasselback equation?
Determines the fractional ionisation of weak acids and bases
For a weak acid: log10 ci/cu = ph-pKa
For a weak base: log10 ci/cu = pKa – ph
What is lipid trapping?
In different pH, the level of ionisation is different
Lipid bilayer prevents the movement of ionised molecules
Therefore, we can say that lipid bilayers act as traps preventing the movement of ions
What is the importance of carriers for nutrition?
Carriers are important for membrane transport of essential nutrients that have low lipid solubility
Which transporters are effective for drug transport?
Transporters found in the kidney
Important in the elimination of drugs from the body
Example of a kidney transporter involved in the removal of drugs
P-glycoprotein
Involved in the removal of chemotherapeutic agents
What are features of activa transporters?
Uphill transport
Finite number of transporters - leads to saturation
What are the two main ways of drug administration?
Enteral administration
Factors controlling oral absorption
What is enteral administration?
Oral absorption from the stomach or gut following swallowing
Most convenient/acceptable route
What is an important consideration regarding enteral administration of drugs?
Oral absorption will deliver the drug directly to the liver, the major site of drug metabolism, via the portal circulation
This will lead to substantial first-pass elimination
What type of administration prevent first-pass metabolism from the liver?
Sublingual or buccal administration
Lower rectal administration
Example of drug given through the sublingual/buccal route
Glyceryl trinitrate absorbed quickly to relieve anginal pain
Which factors control oral absorption of drugs?
Lipid solubility and ionisation
Drug formulation
Gastrointestinal motility
Bioavailability
How does lipid solubility and ionisation affect the absorption of drug?
Weak acids will be mostly absorbed in the more alkaline intestine
Rapid passage of drug from the stomach to the intestine is likely to speed up drug absorption
Fill in the blank
Ionised form of drugs are more -
Water soluble
Fill in the blank
Unionised form of drugs are more -
Membrane permeable
How does gastrointestinal motility affect drug absorption?
Stasis can slow oral absorption
Diarrhoea may allow insufficient time for complete absorption
Causes of low bioavailability
Incomplete release of the dosage form
Destruction within the gut
Poor absorption
First-pass elimination
What is bioavailability?
Proportion of the administered dose that reached the systemic circulation
What are the uses of parenteral administration of drugs?
Rapid effects
Drugs that are poorly absorbed from the gut
Irritants
Localisation of action
Different types of parenteral administration
Intravenous
Inhalation
Intramuscular and subcutaneous
Topical
Advantage of intravenous administration
Most rapid route
Advantage of intramuscular and subcutaneous drug administration
Utility in providing long-term therapy
Describe the difference in drug distribution between small and large molecules
Large molecules cannot easily enter interstitial and intracellular spaces
Smaller, lipid-soluble molecules can spread rapidly throughout the whole body
What does volume of distribution mean?
The volume of fluid required to hold the amount of drug in the body at the measured plasma concentration
What is the equation for volume of distribution?
Vd = dose/cp
cp concentration of drug in the plasma after it has equilibrated in its distribution volume but before a significant fraction has been eliminated
What are different ways drugs can interact with body tissues once administered?
Can bind in to proteins and other tissue components
Can accumulate in lipids
Can penetrate into the brain
Which proteins bind to drugs?
Weak acids = albumin
Weak bases = a-acid glycoprotein
What is the consequence of protein binding?
The bound drug is usually inactivated
The reduction in free drug concentraiton may reduce elimination or protein binding may serve to deliver the drug to the kidney and liver to enhance elimination
One drug may prevent the binding of another, enahncing the pharmacological activity
What two aspects of the brain prevent drug entry?
Blood brain barrier - tight juncitons
Turnover of CSF - drugs that penetrate slowly will be removed by washout and achieve a steady-state concentration below the plasma concentration
