Principles of pharmacology Flashcards
What is pharmacology:
The effects of drugs on the function of living tissues (Greek: Pharmakos=drug, Logos= study)
What are drugs:
Chemicals that alter the physiological function of cells in a specific way
What is pharmacodynamics
- The study of the biochemical and physiologic effects of drugs on the body
- Describes what a drug does to the body
What can the relationship between drug and body be broken down into
- Drug: the interaction between drug and receptor
- Biochemical and physiological effects on the body i.e response to drug
- Relationship between the dose of drug and therapeutic response
How do most drugs exert their effects
By binding to specific target protein molecules
What are examples of target protein molecules
- Classic receptors e.g muscarinic receptors
- Enzymes
- Transmembrane transport proteins
- Ion channels
What are two actions drugs can do:
- A drug can either stimulate its target to produce a desired response i.e acting in the same way as a normal molecule operating in the body to achieve that effect (agonist)
- Or block the target to prevent binding of the natural agonist i.e naturally occurring molecule that would normally achieve the desired biological or physiological response (this type of drug is termed an antagonist)
What is an agonists
Drugs that interact with target and stimulate target to produce desired response
What is an antagonists:
Drugs that block target to prevent binding of another naturally occurring molecule
Examples of receptor drug targets:
- Beta adrenergic
- Alpha adrenergic
- Histamine
Examples of ion channels drug targets:
- Sodium channels
- Calcium channels
Examples of enzymes drug targets:
- Sodium channels
- Calcium channels
Examples of transporters drug targets:
- Na+ K+ ATPase
- Na+ K+ Cl- cotransporter
What are the most common drugs:
Those that act on adrenergic nervous system
What are the two different types of receptors:
Beta and alpha
What is beta adrenergic:
Beta blockers – treatment of glaucoma and cardiovascular disease
What is antihistamine used for:
Allergic eye conditions and other allergic condition e.g hay fever
What are histamine receptors used for:
Production of gastric acid
What are topical anesthetics:
- Interact with na+ channels in nerves in ocular surface
- This inhibiting conduction of action potential along sensory nerves
What are calcium channels used for:
Treatment of blood pressure – ca channel blockers
What is carbonic anhydrase used for:
Production of aqueous humor and endothelial pump in cornea
What is cyclooxygenase:
- Non steroidal anti inflammatory drugs – ibuprofen, neurofin
- Block Cyclooxygenase enzymes and
What are the three sources of drugs and explain them and examples of each:
- Natural e.g. alkaloids
- Semi-synthetic - prepared by chemical modification of natural drugs
- Synthetic: prepared by chemical synthesis in pharmaceutical laboratories
Give an opthalmic example of natural i.e alkaloids source of drug and its use:
Atropine = cycloplegic agent i.e derived from plants = naturally occuring
Give an opthalmic example of semi synthetic source of drug and its use:
- Cyclopentolate
- Came about cause they wanted to alter chemical structure of naturally occurring compounds
Give an opthalmic example of synthetic source of drug and its use:
Latanoprost = treating glaucoma
What is side effect of atropine:
Long acting so dilates pupil and achieves cycloplegia but takes many days to wear off
Why did cyclopentolate come about:
- Due to atropine being long acting dilating pupil taking many days for it to wear off
- So they altered chemical structure of atropine in a way to maintain its effect on pupil and ciliary body but to shorten its action
What are two ways drugs can work:
- Stimulate receptors (agonists)
- Or bind to receptors without stimulating thempotentailly blocking the receptor (antagonists) preventing binding of the natural agonist
What are two forms of antagonsits:
- Competitive i.e compete with naturally occurring agonist
- Non-competitive
What should a drug ideally show:
- Ideally a drug should show a high degree of specificity in terms of its binding site and target
- However, specificity is rarely absolute
What can increasing the dose of the drug cause:
The drug to affect targets other than the principal one, which can lead to side effects
What causes more unwanted side effects and how can you minimsie that:
- The lower the potency of the drug and lower the amount that’s needed to achieve its therapeutic response , the higher the dose needed
- And so the greater likelihood of unwanted effects
- Want to minimise dose to maximise therapeutic response but keep the dose of drug at level below that would achieve an adverse drug reaction i.e unwanted effect
What relationship do drugs have and what is this represented by:
- A relationship between the dose of the drug and its pharmacologic effect
- Represented by the ‘Dose Response Curve’
Describe the ‘Dose Response Curve’:
- Y axis = therapeutic response to drug
- Initially = no response = no effect range = at that level conc of drug so low doenst stimulate sufficient number of target receptors to achieve measurable therapeutic response
- As dose increases = increasing effect
- All of drug targets fully occupied = maximum effect range = drug levels off
What is definition of drug toxicity and what is it also reffered as:
- Also called adverse drug reaction (ADR) or adverse drug event (ADE)
- Defined as the “manifestations of the adverse effects of drugs administered therapeutically i.e in normal range or in the course of diagnostic techniques”
What is the therapeutic index and what is it used for:
- The ratio between the toxic dose of drug and the therapeutic dose of a drug as a fraction
- Used as a measure of the relative safety of the drug for a particular treatment
What happens in a narrow therapeutic index and what do we ideally want:
- Ideally want therapeutic dose of drug to be relatively low and toxic dose of drug to be high
- But if theres little difference between toxic dose of drug and therapeutic dose of drug then that type of drug has narrow TI
- So a drug with a narrow therapeutic index needs to be prescribed with care because of the close relationship between toxic and therapeutic dose of drug
Give and explain use example of drug with narrow therapeutic index:
- Digoxin
- To treat cardiac arrythmias or epilepsy
- It has a narrow therapeutic index = make sure dose of drug maintained in therapeutic range to reduce side effects
What can cause inter-individual drug responses:
- Due to pharmacokinetic or pharmacodynamic variation
- Genetic heterogeneity also appears to be a source of variability in the response to drugs (pharmacogenetics)
What is meant by variation on drug response:
- Any given drug can be therapeutic in some individuals but ineffective in others
- And some individuals experience adverse drug effects whereas others are unaffected
- So make sure drug achieves desired response and minimises adverse effect
What causes drug to vary in response:
- Drugs can vary between individuals because of the way the body handles drug i.e absorbed, disturbed around body and excreted
- Or inter individual differences in interaction between drug and its target
- Some is genetic determined = related to observed variability in response to drugs
What is meant by pharmacokinetics:
- What the body does to the drug
- Study of the absorption, distribution, metabolism and excretion of drugs
When is understanding of drugs pharmacokinetics important:
When choosing an appropriate route of administration of a drug
When can pharmacokinetics factors cause:
Inter-individual variability in therapeutic response
What are the different routes of drug administration and examples of them:
-In most cases the oral route (enteral) is preferred – e.g. tablets = absorbed across GI system = slower
- Perenteral (non-oral) is chosen if a drug is poorly absorbed from the gut or causes gastrointestinal irritation = injection = if want drug to be absorbed more rapidly
- Local administration e.g. ophthalmic drugs or inhaled drugs to treat asthma
- Rectal = if want drug to act more quickly
- Percutaneous = pass through skin e.g injection into skin
- Intravenous = injection into vein
- Intramuscular = injection into muscle
- Intrathecal = injecting into CSF through injection into spine
- Inhalation – lung disorders treatment
Pathway of drug:
- Drug enters plasm via different routes
-Once in plasma, it passes through liver
-Liver = metabolism of drugs - Distribute drug to target = therapeutic response
- Drug eliminated
How are most drugs excreted and eliminated:
- By kidney through urine mostly
- Also by gut and faeces
Why do pregnant and breast feeder people have to be careful with drugs:
- If pregnant drugs can pass from plasma into breast milk
- Can cross blood placental barrier and pass through fetus
What needs to happen for a drug to reach its target tissue:
It must first be absorbed from its site of administration
How easily are drugs abosrbed:
- Non-polar (unionised) drugs readily penetrate cell membranes, i.e penetrate easily because they are lipophilic, can cross cell membranes readily
- However, most drugs are weak acids or bases i.e have mixture of polar and non polar characteristics, which can exist in ionised or unionised forms
- In this way they are in state of equilibrium between ionised form of drug or unionised form of drug = this will determine how the drug is absorbed
- The ratio of these two forms i.e balance between ionised and unionised form is determined by the surrounding pH and the dissociation constant (pK), of the drug which represents the pH at which the drug is 50% ionised and 50% unionised
What is form of most drugs:
Weak acids or bases
What is meant by weak acid or base:
Mixture of polar and non polar characteristics, which can exist in ionised or unionised forms
What is pK of drug:
- The dissociation constant of the drug which represents the pH at which the drug is 50% ionised and 50% unionised
- So the ionized form of drug and unionised form of drug are in equilibrium
- That equilibrium is determined by dissociation constant of drug i.e pk
What does pK of drug determine:
Balance between ionised and unionised form which is determined by surrounding ph
What is the degree of ionisation calculated from:
Henderson-Hasselbalch equation
This is the relationship between pH of drug and its pk and log of ratio between ionised(A-) and non ionised (HA) from of drug
What does position of equilibrium i.e ionized and non ionized form of drug depend on:
pH
What happens in an orally administered drug - how does pH of drug vary once absorbed:
- First pass into stomach
- Stomach is very acidic due to gastric acid = low ph
- Drug leaves stomach and passes into small intestine = it will be in alkaline environment as ph in small intestine rises
- So have two different environments in terms of ph and change from acid to alkaline
What happens to the drug reaction in an acid environment for a weak acid:
- The reaction will shift to the left
i.e. the non-ionised form (H+ ) which is present in a higher concentration and more readily absorbed - So weak acid is well absorbed in acid environment and more readily absorbed across lining of stomach
What happens to the drug reaction in an alkaline environment for a weak acid:
- The reaction will shift towards the right
i.e. the ionised form (A-) which is present in a higher concentration so more readily absorbed across membranes - So drug have weak absorption in alkaline environment
What happens in a weak acid in an acid solution:
Will be mainly in its un-ionised form.
What happens in a weak acid in an alkaline solution:
Will be mainly in its ionised form.
Summarise absorption of weak acidic drug in alkaline and acidic environment”
The result is that an acidic drug will be concentrated and absorbed in a compartment where there is an acid environment and absorbed more readily and it will be concentrated and less well absorbed in a compartment with a high pH
What happens to the drug reaction in an acid environment for a weak base:
- The reaction will shift towards the right
- Due to high concentration of H+ ions
- Ionised form
- IONISED FORM OF DRUG CONCETRATED AND NOT ABSORBED
What happens to the drug reaction in an alkaline environment for a weak base:
- The reaction will shift towards the right
- Non ionised form
- IONISED FORM OF DRUG WELL ABSORBED
Summarise absorption of weak base drug in alkaline and acidic environment:
- A basic drug in an alkaline solution will be non-ionised and have a greater ability to cross lipid membranes.
- However, in an acid environment it will be trapped, as it is ionised. The result is that an alkaline drug will be concentrated in a compartment with a low pH so wont be absorbed in the stomach but will be readily absorbed across intestine
Summarise absorption of weak base drug in alkaline and acidic environment:
- A basic drug in an alkaline solution will be non-ionised and have a greater ability to cross lipid membranes.
- However, in an acid environment it will be trapped, as it is ionised.
- The result is that an alkaline drug will be concentrated in a compartment with a low pH so wont be absorbed in the stomach but will be readily absorbed across intestine
Absorption of weak acid:
- A weak acid is more likely to be absorbed from the stomach = unionised form
- Low pKa
Example of weak acid and its pH:
Aspirin low pKa= 3.5
Absorption of weak base:
- A weak acid is more likely to be absorbed from small intestine
- High pKa
Example of weak base and its pH:
Pethidine high pKa= 8.6
What is drug absorption from the intestine determined by:
Ionisation and lipid solubility
Which drugs are least and most well absorbed:
- Strong bases (pK>10) and strong acids pK<3 are poorly absorbed since they are fully ionised
- Drugs that are best absorbed are weak acids and weak bases
How long does it take for drug to be absorbed:
Typically 75% of an orally administered drug is absorbed within 1-3 hours
What several factors affect absorption of drug:
○ Gut mobility = how rapidly drug moving through gut
○ Splanchnic blood flow = level of blood flow in gut. Higher blood flow = takes drug away
○ Drug Formulation
○ Physiochemical factors
○ A drug taken after a meal is often more slowly absorbed since progress to the small intestine is delayed
○ Drugs can be formulated specifically to delay absorption e.g. capsules, tablets with resistant coatings where drug needs to be absorbed and broken down before drug released
Example of a poorly absorbed drug:
Tetracyclines e.g doxycyclines
Describe tetracyclines and their side effects:
- They bind strongly to calcium and calcium rich foods (especially milk or antacids
- Preventing their absorption of drug
- Used in treating indigestion = people who are put on these antibiotics should limit calcium containing food
- Contraindicated in pregnancy and lactation since they affect tooth and bone formation as they can cross blood placental barrier to reach foetus and blood can go from plasma into breast milk.
- These drugs bind to calcium and interfere with tooth and bone formation
- Tetracyclines (as with other antibiotics) also reduce the absorption of oral contraceptives (patient advised to use alternative forms of contraception during treatment)
What is meant by bioavailability:
The fraction of the dose that proceeds unaltered from the site of administration and becomes available at the site of action
What does bioavailability depend on:
The rate of absorption
What is involved in orally administered drugs:
Other factors e.g. first pass metabolism
What is first pass metabolism and what can it show:
- Represents the breakdown of a drug by biotransformation by enzymes within the gut wall or liver before it reaches the plasma compartment
- i.e breakdown of drug after it becomes absorbed
- First pass metabolism may show marked inter-individual variation
- Explains why glyceryl trinitrate (GTN), a drug used for the treatment of angina, is effective sublingually but not when swallowed
- Drugs get altered in this process
What is an example of a drug that goes through first pass metabolism:
Glyceryl trinitrate (GTN)
Drug orally:
- Drug absorbed across gut wall and is transformed by enzymes in gut wall
-It then passes by vascular system to liver where further metabolism occurs
What do all orally drugs needs to go through before entering the plasma:
First pass metabolism
Why is first pass metabolism important in phthalmic drugs ( drops or ointments ):
- Because target is in eye but the risk is absorbed into general circulation
- Because the drug passes down into nasolacrimal duct into nasal pharynx and absorbed across mucosa
Explain first pass metabolism for glyceryl trinitrate (GTN), a drug used for the treatment of angina:
- As angina occurs when coronary arteries are narrow such that on exertion, cardiac muscle gets insufficient amount of blood causing chest pain
- Chest pain alleviated through taking vasodilatory drugs e.g. GTN
- If this drug was tablet = broken down through first pass metabolism
So cant be orally given
To prevent that is by delivering it in different ways- patch so delivered through skin or into mouth but held under tongue so absorption takes place under oral mucosa and then gets directly into vascular system into plasm and then target
What is distribution of drug:
Transit from site of absorption through to its target
What happens after absorption of drug:
Distribution of a drug and how much drug gets to target
Why is distribution of a drug and how much drug gets to target not uniform:
- Physicochemical properties of the drug
- Differences in blood flow between tissues
- Degree of “leakiness’ of the blood vessels within a particular tissue
- A drug may have an affinity/binding for a particular tissue component e.g. melanin or fat.
- Plasma protein binding is another important variable e.g gobulin
How does richness of vascular supply tissue effect distribution of drug:
Rich vascular supply tissue = greater proportion of drug compared to poor blood supply
What is leakiness of vessels in brain and retina:
Are impermeable and tight – not leaky
Example of drug distribution in eye:
- Cyclopentolate – high affinity for melanin
D- ark pigmented iris – takes longer for drug to work because of binding of drug in iris compared to less pigmented iris
How do drugs travel:
In the plasma, partly in solution (unbound drug), or bound to plasma proteins (bound drug)
What do drugs bind to:
- Albumin binds mainly acidic drugs e.g. warfarin( anti coagulant ) and non-steroidal anti-inflammatory drugs (NSAID)
- ß-globin and a acid glycoprotein, bind mainly basic drugs e.g. propanolol ( beta blocker )
What does protein binding do:
- Potentially reduces the availability of the active form of the drug and protein-bound drugs show a restricted tissue distribution and slow elimination
- Drugs that have excess of protein binding = lower bioavailability due to binding and would influence elimination of drug from body
How does the elimination of drugs from the body occur:
- By metabolism (biotransformation) and excretion
- Most drugs are metabolised first before excretion
- Some drugs, such as aminoglycoside antibiotics are polar compounds highly charged and are excreted by the kidneys without being metabolised first because polar compounds are excreted well
- Non polar compounds excreted by kidney so tend to be poorly secreted because are reabsorbed by kidney tubules so metabolism important in elimination of non polar compounds
- The body has evolved a variety of mechanisms to detoxify foreign chemicals, which are utilised in the biotransformation of drug molecules
What does metabolism involve:
The enzymatic conversion of the drug into another chemical entity
Where does drug metabolism mostly take place:
In liver by enzymes
What does drug metabolism involve and why:
- Two types of chemical transformation, which are termed phase I and phase II reactions
- The purpose of this is to make the drug more polar/ionised (hydrophilic) to hasten its secretion by the kidneys
Phase I reactions:
- Involve adding or unmasking a functional charged group onto molecule e.g. –OH, -NH2, -SH.
- Oxidations are the most common reactions and are usually carried out by a family of microsomal enzymes known as cytochrome in liver P450 (CYP) = make it more polar
Phase II processes:
- Often termed conjungation
- Involve the attachment of a substituent charged component group e.g. glucuronyl, acetyl, methyl or sulphate.
- These reactions make the drug more polar so that it can be excreted by the kidneys
Example of aspirin metabolism:
- Non polar
- Few exposed charged groups = poorly excreted – just reabsorbed in kidney and back into vascular system
- Two phased system = biotransforming aspirin molecule
- Phase 1 = adding OH group = more polar
Phase 2 = adding sugar molecule to OH = multiple OH groups = taken non polar original aspirin and made it more polar = more readily excreted by kidney in this form
How are most drugs excreted:
- Through kidney
- Most drugs leave the body in the urine either unchanged or as polar metabolites
- Other drugs are secreted into bile via the liver followed by loss of the drug via the faeces
Rate of renal clearance:
Is variable - some drugs are lost in a single transit through kidney whilst others are cleared more slowly
What happens with those drugs that are excreted without biotransformation without metabolism and what does this mean:
- Drug action can only be terminated by renal elimination.
- These drugs therefore need to be prescribed with special care in the elderly as elderly have poorer renal function and in those with altered renal function and liver disease
Example of drug that increases the activity of drug metabolizing enzymes:
Some drugs increase the activity of drug metabolizing enzymes e.g. barbiturates
Example of drug that decreases the activity of drug metabolizing enzymes:
Erythromycin, ethanol
What can lead to inter-individual variation in drug metabolism:
- Genetic polymorphisms
- Age: neonates may have an immature drug metabolizing mechanism. The elderly may have impaired hepatic metabolism of drugs and also show an impaired glomerular filtration rate reducing renal clearance
