Lecture 4 - The Pharmaceutical, Pharmacokinetic and Pharmacodynamic Phases Flashcards
(25 cards)
What is the effectiveness of a drug dependent on? Which pharma phase are each of these things in? (5 things)
- Route of administration (pharmaceutical phase)
- Disposition/distribution (pharmacokinetic phase)
- Metabolism (pharmacokinetic phase)
- Excretion (pharmacokinetic phase)
- Efficacy at drug target (pharmacodynamic phase)
What are the 6 main routes of drug administration? Describe when and why these routes are used and examples of drugs administered this way.
- Sublingual: drug absorbed through oral cavity. Used when rapid response required and when drug is unstable in gut/overtly metabolised (e.g. glyceryl trinitrate)
- Oral: most drugs administered this way. Absorption occurs largely in intestine. Particle size and formulation have major effects on absorption. Term ‘bioavailability’ used to indicate proportion of drug that passes into systemic circulation following administration. Bioavailability reduced if drug incompletely absorbed from gut/inactivated in liver (first-pass effect). Drugs with low bioavailability need to be administered in higher doses/via alternative route.
- Rectal: Drugs required to produce local effect
- Cutaneous: Used mainly when effect on skin required. Drugs absorbed through skin require high lipid solubility (e.g. oestrogen for hormone replacement)
- Inhalation: Used for volatile gases (e.g. anaesthetics). Drugs used to treat asthma can be inhaled as aerosol (e.g. salbutamol).
- Injection (subcutaneous, intramuscular, intravenous, intrathecal): avoid first pass metabolism. IV = fastest and most certain route (e.g. diazepam). Subcutaneous/IM faster than oral but rate-limiting factors include diffusion through muscle/skin and local blood flow.
What are the 2 classes of administration?
- Parenteral: Avoiding GI tract e.g. injections, dermal delivery systems and inhalers
- Enteral: Absorbed through alimentary canal e.g. oral
What are the 3 factors that need to be considered when designing a drug?
- Extent of transport across membranes (absorption)
- Transit to the site of action (distribution)
- Nature of compliance, age and physical ability of the patient
What is a dosing regimen?
- How a drug is administered
- Vary from single dose to regular daily doses
- Designed to maintain concentration of drug within therapeutic window (between therapeutic failure and toxic overdose) at site of action for period of time required for therapeutic effect
What is drug absorption?
- Passage of drug from site of administration into plasma after administration
- Involves passage of drug through biological membranes
What is distribution and which binding proteins are involved?
- Transport of drug from point of administration/absorption to site of action
- Very rapid process that mainly occurs through blood
- Drugs transported either in free form or reversibly bound to protein
- Most important protein is albumin which binds many acidic drugs (e.g. diclofenac 99.5% bound & phenytoin 90% bound)
- Other plasma proteins include beta globulin and acid glycoprotein which bind certain basic drugs e.g. quinine
- Amount of bound drug depends on free drug concentration, its affinity for binding sites and protein conc.
What is volume of distribution (give units)? Give examples in substances.
- Volume of plasma that would contain total body content of a drug equal to that found in plasma
- Vd litres / kg body weight
- e.g. heparin –? highly protein bound –? Vd < 0.1
- e.g. ethanol –> lipid soluble, readily crosses plasma membranes –> Vd = 1-2
What are the 2 ways drugs move around the body (translocate) and how do they differ?
- Bulk flow transfer (in blood)
- Independent of chemical characteristics
- Cardiovascular system supports continuous movement - Diffusional transfer (across non-aqueous cell membranes)
- Dependent on chemical characteristics
- Most drugs have similar molecular weight (200-1000)
- Thus variations in aqueous diffusion have only a small effect on overall diffusion rate
What are the 4 ways by which drugs pass across cell membranes? Which 2 are the most important for drug transport? What is rate of transport determined by?
- Diffusion through lipid
- Diffusion across aqueous pores that travel across/through the lipid
- Combination with a carrier molecule (ferry boat)
- Via pinocytosis (ingestion of liquid into cell by budding of small vesicles from cell membrane)
Diffusion through lipid and diffusion across aqueous pores are the most important as non-polar/uncharged drugs tend to dissolve readily in lipid and pass freely through cell membranes (and vice versa with charged drugs).
Rate of transport determined by solubility in membrane (often expressed as partition coefficient).
Where does the majority of drug metabolism occur? What does metabolism do to a drug?
In the liver, although most cells are capable of metabolising drug. Metabolism usually abolishes drug’s pharmacological activity (with the exception of pro-drugs).
What are the 2 kinds of reaction involved in metabolism and what do they involve? Compare and contrast.
Phase I reactions:
Generate (usually) more reactive products/more toxic. Often introduce functional group (e.g. hydroxyl, thiol or amino group). Serves point of attack for conjugation of larger substituent (e.g. glucuronyl, sulphate or acetyl group - Phase II)
- Oxidation
- Reduction
- Elimination
Phase II reactions:
- Conjugation
Both stages:
- Decrease pharmacological activity
- Decrease lipid solubility (increased rate of excretion in urine/bile)
- Increase molecular weight
What are some examples of Phase I reactions? (oxidative)
- N and O dealkylation
e.g. RNHCH2CH3 –> RNH2 + CH3CHO
e.g. ROCH3 –> ROH + CH2O - Aliphatic and aromatic hydroxylation
e.g. RCH2CH3 –> RCH(OH)CH3
R-Bn –> R-Bn-OH - N-hydroxylation (oxidation)
e.g. R3N –> R3N=O
RNHR’ –> RN(OH)R’ - Sulphoxide formation
e.g. RSR’ –> RS(=O)R’ - Deamination of amines
e.g. RCH2NH2 –> RCHO + NH3 - Desulphuration
e.g. RSH –> ROH
What are some examples of Phase II reactions?
- Glucuronidation
e.g. R’-UDP + HOR –> R’-OR + UDP - Acetylation
e.g. RNH3 + CH2C(=O)SCoA –> RNHC(=O)CH3 + CoASH - Sulphide conjugation
e.g. ROH + 3’-phosphoadenosine-5’-phosphosulphate –> ROS(=O)(=O)OH + 3’-phosphoadenosine-5’-phosphate - O, S, N-methylation
e.g. RXH + s-adenosylmethionine (X = O, S, N) –> RXCH3 + S-adenosine-5’-phosphate - Glutathione conjugation
e.g. Ar-Cl (GSH) –> Ar-SG + H+ + Cl-
What are 2 examples of Phase I reactions? (reductive)
- Azo reduction
e.g. RN=NR’ –> RNH2 + R’NH2 - Nitro reduction
e.g. RNO2 –> RNH2
What are some examples of Phase I reactions? (hydrolysis)
e.g. RC(=O)OR’ –> RCOOH + R’OH
e.g. RC(=O)NR’ –> RCOOH + RNH2
What are the steps involved in the metabolism of aspirin? Include phase I and II processes and the intermediates/products formed.
Ar-OCOCH3 (Phase I, hydrolysis) –> Ar-OH (Phase II, glucuronidation) –> Ar-O-(complex ring structure)
Intermediate = Salicylic acid
Product = Glucuronide
What are the steps involved in the metabolism of imipramine?
Imipramine (Phase I, either demethylation or dealkylation) –> Intermediate (Phase I, hydroxylation) –> Intermediate 2 (Phase II, conjugation) –> Product (urinary excretion)
What is cytochrome P450? Where is it found? What does it do?
- Enzyme that catalyses Phase I reactions
- Found in smooth endoplasmic reticulum (SER)
- Consists of family of structurally related proteins that catalyse oxidation, reduction and hydrolysis reaction
- 30-100 sub-types exist, different types have different specificities
- Binds molecular oxygen and drug and forms part of electron transfer chain (ETC)
- All reactions start with hydroxylation step catalysed by enzyme system
What is the first pass effect?
- When some drugs are extensively metabolised by the liver prior to systemic circulation
- So the dose is considerably less than that absorbed into the hepatic portal vein
- Clinically important for certain drugs e.g. aspirin, salbutamol
What happens when drug metabolism goes wrong i.e. a very reactive chemical is yielded
- Drug metabolism rarely yields a chemical so reactive it avoids Phase II conjugations and binds covalently to cellular macromolecules
- If macromolecule is essential for function of cell/tissue, severe adverse reactions may result e.g. paracetamol hepatotoxicity, sulfonamide-induced skin rashes
What are the main routes by which drugs are eliminated from the body?
- Kidneys
- Hepato-biliary system (network of organs and ducts that work together to produce, store, and release bile)
What are the 2 basic processes in the kidney for drug excretion?
- Glomerular filtration: allows all drug molecules with MW < 20000 to pass into glomerular filtrate. Plasma (MW 68000) and protein bound drugs are held back. Accounts for ~ 20% of drug passed through kidneys.
- Active tubular secretion: remaining drug passes to capillaries of proximinal tubule where non-selective carrier systems transport acidic and basic drugs into tubular lumen. Active process that works against electrochemical gradient, so carrier systems can reduce plasma drug concentration to 0.
What is pharmacodynamics?
Concerned with the result of interaction of drug and body at site of action (normally a protein e.g. receptor, enzyme or carrier protein) i.e. what a drug does to the body.
