drug therapy Flashcards
medication error:
primary care (71%),
→ which is where most medicines in the NHS are prescribed and dispensed.
pharmacokinetics:
rate of movement of drugs within biological systems
affected by the Absorption, Distribution, Metabolism, and Elimination of medications.
What the body does to medications
pharmacodynamics
what the medication does to the body
absorption:
how the drug enters the bloodstream.
- Oral
- Subcutaneous
- Intramuscular
- Other GI - Sublingual, rectal
- Inhalation
- Nasal
- Transdermal
NOTE: Intravenous - not absorbed
oral absorption
Tmax
→ the time to peak concentration
Cmax
→ the peak concentration
AUC
→ the area under the drug concentration-time curve
amount of drug that reaches systemic circulation and is available for biological action.
- Bioavailability
→ Amount of drug which enters the systemic circulation - Speed at which this happens
The more rapid the rate of absorption, the earlier the drug concentration peak.
therapeutic range/ index:
therapeutic range: concentration range in which a drug is active
Below it → insufficient or no pharmacological action
Above it → toxicity
therapeutic index - a measure of the range over which a drug is safe and active.
oral administration:
Dissolution → breakdown of tablet/capsule
Absorption → across the lipid membranes in the GI system
factors affecting oral absorption bioavailability:
[1] Formulation (capsule, tablet, solution.. etc.)
[2] The ability of drugs to pass physiological barriers:
- Particle size
- Lipid solubility
- Degree of ionisation
[3] Gastrointestinal effects
- enhanced/decreased Gut motility
- Food
- Illness
[4] First pass metabolism
→ rapid breakdown of the drug when given orally due to acid/enzymes in the GI system
how to determine the bioavailability of a formulation
compare it to the intravenous route.
intravenous - 100% bioavailability.
oral - bioavailability decreased
how do drugs transport across membranes:
- Passive diffusion
- Protein-mediated transport
- Filtration
- Bulk flow
- Facilitated diffusion
- Ion-pair transport
- Endocytosis
passive diffusion:
Drug diffuses across the membrane down a concentration gradient
- No active role of the membrane
key factors:
Molecular size
Lipid solubility
Polarity
Degree of ionization
pH of the environment
lipid soluble/ lipophilic drugs
Lipid-soluble drugs diffuse by dissolving in the lipoidal matrix of the membrane
Why don’t most drugs completely ionise in water?
most drugs are weak acids/ bases
the degree of ionisation depends on the pH of the environment.
membrane diffusion between ionised and un-ionised forms of drugs
ionised and un-ionised forms will be present.
→ ionised drug does not cross the membrane.
→ un-ionised form should distribute across the membrane until equilibrium is reached
– an equal concentration at each side.
filtration/ bulk flow
Filtration occurs through channels in the cell membrane.
a normal method of transport for water-soluble molecules with a molecular weight of 100 or less
a mechanism for drugs crossing capillary walls
lipid water partition coefficient:
ability of a drug to diffuse across a lipid barrier.
the ratio of the amount of drug which dissolves in the lipid and water phase when they are in contact.
active transport:
Energy-dependent transport across membranes against a concentration gradient.
drugs must resemble naturally occurring compounds.
drug is reversibly bound to a carrier system.
effect of gut motility, food and illness on drug absorption
Gut motility
The speed of gastric emptying affects the speed at which the drug reaches the site of absorption
(most drugs are absorbed in the small intestine)
Gut motility is affected by other drugs, food/drink and illnesses (especially pain).
Food
- Can enhance or impair the rate of absorption.
Illness
- Malabsorption (e.g. Coeliac disease) - increase or decrease the rate of absorption
- Migraine reduces the rate of stomach emptying and the rate of absorption of analgesic (painkiller) drugs.
first pass metabolism
metabolism of the drug prior to reaching the systemic circulation
There can be a limit on the oral route for some drugs
→ Oral route not useable (GTN, insulin)
Locations & Action:
- Gut lumen → (acid, enzymes)
- Gut wall → (metabolic enzymes)
- Liver → (cytochrome P450 enzymes)
avoid first-pass metabolism
[1] Use other routes of administration:
- Subcutaneous and Intra-muscular
- Inhalation and Nasal
- Sublingual absorption from the buccal mucosa
- Rectal
- Transdermal
[2] Use drugs that don’t undergo first-pass metabolism
drug distribution
the reversible transfer of a drug between the blood and the extravascular fluids and tissues of the body
e.g. fat, muscle, and brain tissue
drug distribution mechanisms
- Plasma protein binding
- Tissue perfusion
- Membrane characteristics
- Blood-brain barrier
- Blood-testes/ovary barrier
→ Lipid soluble drugs & Actively transported are more likely to pass
- Transport mechanisms
- Diseases and other drugs (esp. renal failure, liver disease, obesity)
- Elimination/Clearance
plasma protein binding
Many drugs (e.g. phenytoin, warfarin NSAIDs) bind to plasma proteins
e.g. albumin or a1-glycoprotein.
unbound drugs - biologically active & binding is reversible.
The amount of unbound drug (active drug) can be changed by:
- Renal failure
- Hypoalbuminaemia
- Pregnancy
- Other drugs
In order for a drug to be active it must be free in the plasma. A drug is not active when bound to plasma protein.
If a drug is 96% protein bound then only 4% of the drug is free and available for action.
If the unbound drug level changes to 6% then plasma levels of free drug will increase by 50% which will result in toxicity.
Apparent Volume Of Distribution (Vd)
the volume of plasma that’s necessary to account for the total amount of drug in a patient’s body
if that drug were present throughout the body at the same concentration as found in the plasma.
Vd = drug mass/conc
drugs move away from the blood into the organ systems, we tend to measure a higher Vd as the concentration in the blood goes down.
So a higher Vd = more amount of drug moving into tissues
i.e. less in the blood
So a lower Vd = less amount of drug moving into tissues
i.e. more in the blood
vd should be 42L
clearance
- Clearance is defined as the theoretical volume from which a drug is completely removed over a period of time.
- Measure of drug elimination.
- Measured in units of time (ml/min).
renal and hepatic clearance:
renal - Dependent on drug concentration and urine flow rate
hepatic - Dependent on metabolism and biliary excretion
- Disease states and age (young and elderly) will reduce hepatic and renal clearance
half life t12 of a drug
the time taken for the drug concentration in the blood to decline to half of the current value.
→ Help us to work out how often a drug needs to be administered.
e.g. if it takes 4 hours for the concentration of a drug in the bloodstream to drop
from 10mg/L to 5 mg/L then the half-life is 4 hours
depends on the volume of distribution and rate of clearance.
If we know the volume of distribution and clearance we can show that the half-life
t1/2 = 0.693 x Vd/Cl
prolongation of a drugs half life
increase plasma levels and hence toxicity of a drug.
→ due to reduction in renal/hepatic clearance
→ due to a large volume of distribution
therapeutic benefit - drugs need to be given chronically
Plasma levels of a drug take many doses before they stabilise, usually 4-5 half-lives.
drug levels into the therapeutic range - loading dose may be necessary.
drug elimination
removal of active drugs and metabolites from the body.
determines the length of action of the drug.
[1] Drug Metabolism (liver)
[2] Drug Excretion (kidney but also biliary system/gut, lung, and milk)
drug excretion:
Three principal mechanisms are used:
* Glomerular filtration
* Passive tubular reabsorption
* Active tubular secretion
glomerular filtration rate
glomerulus filters 190 litres of fluid a day.
All unbound drugs will be filtered at the glomerulus
→ as long as their molecular size, charge or shape are not excessively large.
Any factor that reduces the glomerular filtration rate will reduce the clearance of a drug
- lead to prolongation of the half-life and increasing blood levels, leading to toxicity.
e.g. renal disease, hypovolaemia, hypotension
active tubular secretion
Some drugs are actively secreted into the proximal tubule
(acidic and basic compounds)
→ The most important system for eliminating protein-bound cationic and anionic drugs.
passive tubular reasbsorption
As the filtrate moves down the renal tubule any drug present is concentrated as water is reabsorbed.
Passive diffusion along the concentration gradient allows the drug to move back through the tubule into the circulation.
→ Passive diffusion occurs in the distal tubule and collecting duct.
→ Only un-ionised drugs such as weak acids are reabsorbed
biliary secretion
liver secretes 1 litre of bile a day.
→ Drugs are passively or actively secreted into the bile.
Biliary secretion accounts for 5-95% of drug elimination for many drugs.
entero-hepatic circulation - drugs that are reabsorbed from the bile into the circulation.
It continues until the drug is metabolised in the liver or excreted by the kidneys.
drug conjugation
Drug Metabolism in the liver
- leads to the conjugation of the drug to make it more water-soluble.
The conjugated drug is not reabsorbed from the intestine
liver damage leads to toxicity
reduces the rate of conjugation and biliary secretion
leads to the build-up/ reabsorption of the drug with resultant toxicity.
prodrugs
drugs that increase in activity, more active metabolites, following drug metabolism.
drug metabolism
biochemical modification of pharmaceutical substances by living organisms through specialized enzymatic activity.
lipid soluble, nonpolar compounds → water soluble and polar
allows them to undergo excretion, whereas lipid-soluble substances are passively reabsorbed into the blood.
- Liver
- Lining of the gut
- The kidneys
- The lungs.
drug metabolism effects
[1] Loss of pharmacological activity.
[2] Decrease in activity, with metabolites that show some activity.
[3] Increase in activity, more active metabolites.
→ Activation of a prodrug.
[4] Production of toxic metabolites.
- Direct toxicity
- Carcinogenic.
- Teratogenic
enzymes
they have a wide substrate specificity
individual drugs can be metabolised by more than one enzyme
Enzyme induction leads to increased metabolism of drugs
- leads to ineffective treatment.
Some enzymes are:
→ regulated at several levels
→ expressed constitutively, constantly.
→ expressed in the presence of a particular substrate
metabolism is divided into 2 phases
phase 1 - oxidation, reduction, hydrolysis
leads to drug activation/ inactivation
phase 2 - glucuronidation
leads to the conjugation products
phase 1
[1] Hydrolysis, oxidation, reduction
[2] Increasing the polarity of the drug by adding a polar group
(provides an active site for Phase 2 metabolism)
[3] Metabolising enzymes: Cytochrome P-450
- Drug specificity is determined by the isoforms of the cytochrome P-450.
- Specificity tends to be relative rather than absolute.
isoforms of cytochrome P-450
[1] CYP3A4
→ major constitutive enzyme in the human liver
→ also found in the gut and is responsible for the pre-systemic metabolism of several drugs
- Example drugs – diazepam, methadone, simvastatin, CCBs.
[2] CYP2D6
→ responsible for the metabolism of some antidepressants, antipsychotics
and the conversion of codeine to morphine.
[3] CYP1A2
→ induced by smoking and is important in the metabolism of theophylline.
5-10% of the population are fully/partially immune to the analgesic(painkilling) actions of codeine
Because the reduced or absent expression of CYP2D6 is found in 5-10% of the population.
factor that affect metabolism
- Other drugs/herbals/natural substances
- Genetics
- Hepatic blood flow
- Liver disease
- Age
- Sex
- Ethnicity
- Pregnancy
phase 2 metabolism
[1] Conjugation
[2] Increases water solubility and enhances excretion
Conjugation involves the attachment of glucuronic acid, glutathione, sulphate or acetate to the metabolite
- generated by Phase 1 metabolism.
Conjugation results in inactivation - a small number of drug metabolites may be active.
smokers require a higher dose of theophylline than non-smokers
smokers have higher levels of CYP1A2 - induced by smoking.
And that isoform of cytochrome P-450 is involved in the metabolism of theophylline
enzyme induction
increased enzyme synthesis
- therefore increased activity.
drug metabolising enzymes can be induced by other compounds
- Increased metabolism of drugs by that enzyme
→ Resulting in loss or decrease in drug effect.
e.g.
Indinavir & John’s wort
enzyme inducers
alcohol and smoking
enzyme inhibition
Drugs, herbal medicines, and foodstuffs may inhibit drug-metabolising enzymes.
Common culprits include:
cimetidine, valproate, erythromycin, clarithromycin, ketoconazole, CCBs, and grapefruit juice.
e.g.
Effects of grapefruit juice on felodipine pharmacokinetics and pharmacodynamics
pharmocogenetics affect treatment
Wide variability in the response to drugs among individuals
- Consequences may be a therapeutic failure or an adverse drug reaction
Drug metabolising enzymes are expressed in multiple forms (Genetic Polymorphism) within the same individual and between different individuals
→ therefore inter-individual differences in gene expression are common.
Gene mutations result in excess or deficiencies or complete absence of a particular metabolising enzyme activity
→ eventually may lead to toxicity or insufficiency, depending on the condition
GI
ph, bacterial flora, git motility
ph affect gi tract absorption
Changes in pH lead to changes in the degree of drug ionisation
H2 antagonists, proton pump blockers and antacids reduce H+
- increase the pH
changes in GI bacterial flora affect absorption in the GI tract
Bacterial flora are usually found in the large bowel
→ Broad-spectrum antibiotics destroy normal gut flora
This may lead to failure of oral contraceptives or digoxin toxicity
GI motility affects absorption in the GI tract
oral medicines - absorbed in small intestines
Gastric emptying - rate limiting step
[1] drugs delay gastric emptying - delay absorption
e.g. anticholinergics, tricyclic anti-depressants, opiates
[2] drugs increase gastric emptying and accelerate absorption
i.e. migraine treatment with paracetamol and metoclopramide
Rifampicin and st John wort increase the metabolism of Ciclosporin by inducing CYP3A4
→ prevents transplant rejection
Digoxin and Lithium are toxic agents
they have a narrow therapeutic index which are eliminated by the kidney
→ Verapamil/diltiazem inhibits digoxin excretion
→ Loop diuretics increase the tubular reabsorption of lithium
(increase causing toxicity)
types of pharmacodynamic interactions
Direct
Indirect
Antagonistic
e.g. using both atenolol and salbutamol
→ atenolol causes bronchoconstriction while salbutamol causes bronchodilation
Synergistic / Agonistic
When two drugs with the same pharmacological effect acting on different receptors are given together
→ additive or multiplicative
indirect agonism
benzodiazepines and tricyclics/ alcohol
- sedation
warfarin and nsaids
- bleeding
atenolol and verapamil
- bradycardia
indirect antagonism
[1] NSAIDs increase blood pressure
(opposite of what is needed in antihypertensive medication)
[2] NSAIDs increase water retention
(opposite of what is needed in heart failure
Predisposing Factors for Adverse Drug Reactions:
[1] Multiple Drug Therapy
→ Incidence of ADRs increases exponentially with the number of medications
→ Polypharmacy Increases Potential for Drug Interactions
[2] Inter-current Disease
→ Renal and hepatic impairment
[3] Race and Genetic Polymorphisms
[4] Age
→ Elderly and neonates
[5] Sex
→ ADRs more common in women
surveillance methods for adrs
Yellow card system
→ Online reports made for all medicines including vaccines, blood factors and immunoglobulins, herbal medicines and homoeopathic remedies, and all medical devices.
Green-card system
suspensions
dispersions of coarse drug particles in a liquid phase.
→ dose can be contained in a small volume
→ Good for drugs which are insoluble & unpalatable as they are better tolerated
Solutions and Suspensions
delivery systems used to administer drugs to the young, elderly and patients who can’t swallow tablets or capsules.
May be given via a nasogastric or PEG tube
→ Absorbed extremely rapidly
- Absorption depends on {{c2::gastric emptying}} and is most rapid from the {{c2::small intestine}}
modified tablets - enteric coating
delays the disintegration of the tablet until it reaches the small intestine
Tablets are enteric-coated to:
→ Protect the drug from stomach acid
- Omeprazole
→ Protect the stomach from the drug
- Aspirin
