Pharmacology, Prescribing And Therapeutics Flashcards
What is clinical pharmacology?
Science of drugs + their use in humans
What is a drug?
A molecule which has a physiological effect when ingested or otherwise introduced into the body; size + chemical nature of modern drugs can vary greatly (e.g. small compounds ~500Da -> Abs ~150,000Da)
Define bioavailability.
The proportion of administered drug which reaches the systemic circulation unchanged + is thus available for distribution to the site of action
What is the bioavailability of intravenous (IV) injection? Why?
100% because all the drug reaches the systemic circulation unchanged
What are the pros and cons of intravenous (IV) injection?
Pros: rapid + powerful action
Cons: inconvenient for long-term therapy
Why is the bioavailability of the oral route? Why?
< 100% due to:
- Exposure to pH, enzymes + microbial activity in gut
- Exposure to 1st pass metabolism
What are the pros and cons of the oral route?
Pros: popular, often safest, most convenient + economical
Cons: absorption depends on rates of GI transit + requires patient compliance
What different mucosal routes can drugs be administered by?
Sublingual/buccal Nasal Eye Vaginal Rectal
Why are mucosal routes of drug administration good?
Achieves rapid transit to systemic circulation
Avoids 1st pass metabolism
Drug stability as pH in mouth is neutral compared to acidic stomach
What can the inhalation route of drug administration be used for?
Aerosols for airway disease
Lipid soluble anaesthetics
Why is the inhalation route of drug administration good?
Rapid absorption
Avoids 1st pass metabolism
What is the problem with the transdermal route of drug administration? How can this problem be avoided?
Outer skin layer influences rate of absorption
Low input rates can be useful instead for e.g. HRT (oestrogen/progesterone)
How does subcutaneous injection work?
Consistent absorption from small volumes e.g. insulin in which there is passive diffusion into bloodstream via absorption across capillary walls
Why are intramuscular injections a good route of drug administration?
Large blood in muscles of upper arm
Reliable + suitable for irritant drugs
Good for depot preps (long lasting)
Rapid absorption of larger volumes in contrast to subcutaneous injection
Absorption is perfusion limited i.e. increased with exercise
Define pharmacokinetics (PK).
The study of drug movement within the body i.e. what the body does to a drug
Define pharmacodynamics (PD).
The study of drug effects + mechanisms of action i.e. what the drug does to the body
What are the 4 phases of pharmacokinetics (PK)?
- A: absorption
- D: distribution
- M: metabolism
- E: excretion
Explain the first phase of pharmacokinetics (PK)?
Absorption: crossing of the GI tract + avoidance of metabolism by the liver/GI tract - most drug absorption happens via PASSIVE + in SI (lipid solubility affects absorption rate)
What is the equation for rate of diffusion?
Permeability x SA x concentration difference
What factors affect GI drug absorption rates?
SA/blood flow
GI motility; affected by drugs or pathophysiological/psychological states
Malabsorptive states e.g. coeliac disease
Food type; meal composition (fat intake delays gastric emptying) + specific drug-food interactions (e.g. dairy + tetracycline)
Define first pass metabolism.
The extent of metabolism occurring before the drug enters the systemic circulation
What organs and tissues are involved in first pass metabolism?
Gut lumen e.g. gastric acid
Gut wall enzymes
Liver (MOST IMPORTANT)
Why is insulin not taken orally?
Inactivated by gastric acid + proteolytic enzymes of the gut lumen
What occurs in first pass metabolism?
Drugs enter digestive system, hepatic portal system + liver where they can be rapidly metabolized by enzymes - can greatly reduce levels reaching systemic circulation + thus, bioavailability
Explain the second phase of pharmacokinetics (PK).
Distribution: process by which drug is transferred from systemic circulation into tissues
What factors determine the rate and extent of drug distribution?
Ability of drug to pass through tissue membranes
Lipid solubility of drug i.e. increases distribution
Binding of drug to plasma proteins
Active transport of some drugs across cell membranes
Presence of other drugs in the body
Perfuse rate limitations i.e. regional blood flow
Explain how drug binding to plasma proteins can affect its distribution in the body.
Drugs can reversibly + non-specifically bind to plasma proteins e.g. albumin w/o significant effects on protein function
But, only non-protein-bound drug traverses membrane to gain access to cells
So changes in protein binding can lead to changes in drug distribution (high protein binding can increase drug T1/2)
What is the criteria for plasma protein binding significantly altering drug distribution?
Protein-bound drug constitutes 90% of total drug in plasma
Extent of distribution of drug to tissues must be small
Give an example of why plasma protein binding of drugs is important.
Warfarin is taken long-term + is normally 99
% protein-bound
Aspirin is also a high protein binder that displaces warfarin from proteins
So increased plasma levels of unbound warfarin which increase its biological effects + can pose risk (withdrawal of aspirin will have opposite effect also posing risk)
What is the major site of drug metabolism? Where else does this occur?
LIVER
GI tract, kidneys, skin
What are the 2 phases of drug metabolism? Describe them.
Phase 1 e.g. oxidation, reduction, hydrolysis: products produced chemically more reactive + often more toxic than parent drug
Phase 2 e.g. conjugation: conjugates are chemically polar + readily cleared by kidneys or excreted in bile
What is the difference usually between the drug metabolites and the drug itself?
Drug metabolites exhibit less biological activity + more easily removed from plasma than the original form of the drug
What are the 3 fates of drugs that go through drug metabolism?
- Conversion to inactive compounds (most common) - if this occurs in liver, it promotes excretion via kidneys
- Become active pro-drugs with altered absorption kinetics - prevents adverse effects + improves distribution
- Active metabolites e.g. codeine (inactive) -> morphine (active)
What factors affect drug metabolism?
Liver disease
Age
Genetic polymorphisms in drug metabolising enzymes (pharmacogenetics)
Competition between different drugs for the same metabolising enzyme
What is the major route of drug excretion? What others exist?
KIDNEYS
GI: bile into intestine (may be reabsorbed via enterohepatic circulation) OR faecal
Lungs, sweat, tears, saliva + breast milk too
Whats special about drugs like digoxin in terms of excretion?
Excreted unaltered
Define half-life (T1/2).
The time it takes for the plasma [drug] to halve irrespective of the starting dose
Why is it important to understand drug half-life (T/12)?
Guide to time it takes for a drug to be eliminated from body
Guide to rate of accumulation of drug in body during multiple dosing; time to steady state (may be altered in kidney impairment)
Guide to calculating loading dose during treatment
What conjugation reactions can be involved in phase 2 drug metabolism?
Sulphonation
Gluocoronidation
Methylation
Acetylation
What are the 4 ways in which drugs can exert their effect on the body?
- Direct effects on cellular receptor function
- Action on ion channels
- Action of membrane transport processes
- Enzyme inhibition
What are receptors?
Specific proteins with distinct binding sites + signal transduction properties situated in cell membranes (fast responses i.e. secs) or within cell cytoplasm (slower responses i.e. hrs/dys)
What different types of ligands exist for receptors?
Agonists
Antagonists
Partial agonists
How can drugs exert their effect by acting on ion channels?
Ion channels influence movement of ions (e.g. Na+, K+, Ca2+ & Cl-) in + out of cell across membrane which influences polarisation of excitable cell membranes + IC signalling cascades so drugs acting on ion channels affect neural transmission + SM contractility
What are some examples of drugs that target ion channels?
- Na channel blockers in local anaesthesia e.g. lidocaine
2. Ca channel blockers to slow HR e.g. verapamil
How can drugs exert their action by targeting transporter function?
Transporters mediate movement of specific endogenous signalling molecules + nutrients in + out of cells e.g. neurotransmitters + glucose
What is an example of a drug that targets transporter function?
The SSRI fluoxetine (Prozac) blocks the neuronal SERT leading to retention of 5-HT in neural synaptic cleft
What are some examples of drugs that target enzymes?
- ACE inhibitors block ACE
2. NSAIDs block COX-2
What are the 2 effects drugs can have on enzymes?
- Reaction
2. Inhibition
