Pharmaco-dynamics/Kinetics Flashcards
When perscribing a drug what variables are we thinking about? Also what patient specific variables do we need to think about when perscribing a drug?
Perscriptions - medicine, dose, route, frequency, duration.
Patient-specific variables - age, sex, genetics, interacting diseases, interacting drugs, patient preferences
What is definition of pharmacology? How does this differ from clinical pharmacology?
Pharmacology is the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes.
Clinical pharmacology is the study of drug action in man providing the scientific basis for rational, safe and effective prescribing for humans –> more focused on drugs and their impact on the human body
What is the definition of therapeutics?
Therapeutics is the application of the principles of clinical pharmacology to the use of drugs as medicines to treat human disease.
It should be noted that, although drug therapy is a major part of ‘therapeutics’, it represents only of a variety of modalities of treatment - others including fluid treatment, physiotherapy, and psychotherapy.
Defintion of perscribing?
A written order, which includes detailed instructions of what medicine should be given to whom, in what formulation and dose, by what route, when, how frequently, and for how long
Side note - perscriptions can be viewed as an experiment - each individual will respond differently.
What is pharmacodynamics?
Pharmacodynamics is the study of:
- The biochemical and physiological effects of drugs on the body
- The mechanisms of drug action
- The relationship between drug dose (or concentration) and drug effect
Drugs effect on the body- Pharmacodynamics is pivotal to our understanding of how drugs exert both their beneficial and adverse effects on the body.
What do drugs normally target?
Drugs normally target receptors
Receptors tend to be glycoproteins which respond to endogenous ligands –> Receptor that is occupied by a ligand drives conformational change which in turn drives downstream responses in target cell - Process called signal transduction
Note – this is a reversible reaction (most cases) – binding & dissociation – equilibrium – concentration of receptors occupied will depend on ligand concentration and affinity (important to keep in mind as you need to compete/take this into account)
What are the four main types of receptor?
Different types of receptors that drugs may be acting on
- Channel-linked receptors – receptor coupled with an ion channel - nicotinic acetylcholone receptors
- G-protein coupled receptors - G-protein receptors are coupled to intracellular G-proteins that transduce the signal - e.g. muscarinic cholinergic receptor, adrenoceptors and opioid receptors.
- Enzyme (kinase) linked receptors – results in a cascade of phosphorylation - e.g. tyrosine kinase receptors - insulin receptor
- Nuclear receptors – receptors located within the cytosol – accounts for many hormones – glucocorticoids and sex hormones
What are some examples for each of the 4 receptor types?
What are the four different targets that are targetted by drugs?
- Receptors - discussed on other cards
- Ion channels - different types of ion-channels exist - includes - ‘Ligand-gated channels’ - allow the passage of common ions such as sodium, potassium, chloride, calcium and protons
- Enzymes - proteins that catalyse biochemical reactions, either inside or outside cells - target them in order to alter their activity.
- Transporters - are specialised proteins, spanning cell membranes, that assist in the movement of ions, peptides, small molecules, lipids and macromolecules across the membrane - two types of transport active and passive - Drugs can influence this process by either binding and inhibiting the transport function of the protein or competing with the substrate for transport
What are examples of drugs that target each of the four types of drug target (condition - hypertension)?
- Atenolol is a beta-adrenoceptor antagonist (‘beta-blocker’) that acts by inhibiting the stimulation of these receptors by catecholamines
- Amlodipine is a calcium channel blocker that inhibits the entry of calcium ions into contractile cells in the blood vessel wall.
- Ramipril is an angiotensin-converting enzyme inhibitor (‘ACE inhibitor’) that inhibits the production of the vasoconstrictor angiotensin II.
- Bendroflumethiazide is a thiazide diuretic that inhibits the transport of sodium ions back into the body in the renal tubule - reduce blood volume and thus pressure
What is the drug-response curve?
Normally plot on a log 10 scale – forms a sigmoidal curve
Emax - Maximum response
Ed50 – effective dose 50 – concentration required to achieve 50% of the maximal effect
Dose relationship with response changes – intially small increase in dose leading to big change in response v.s. big increase in dose leading to a small change in response
Effective dose range - most of the change in response occurs over a relatively narrow part of the overall range of concentramon - straight line segment of the curve.
It should be noted that, in reality, it is ligand concentration that affects response, rather than the dose.
What is meant by the therapeutic index?
Therapeutic index - The ratio between the doses causing adverse effects and those required to produce beneficial effects
Therapeutic window - calculated by looking at the difference in concentration at the ED50 level between the two dose response curves (beneficial and adverse)
Note that adverse effect can also be plotted in a dose-response fashion – desirable that the this curve is shifted to the right - increased safety
In this example - 100-fold increase in drug dose (or concentration) is required to elicit the adverse effects compared to the beneficial therapeumc effects.
Note - that the dose-response curves will vary in a population - not homogenous.
What are agonists and antagonists?
Agonists - illicit the same response as natural ligand
Antagonist – blocks/competes with natural ligand - (competitive - binds at the same location are natural ligand and non-competitive inhibition - binds to alternative site) – binds but does not drive downstream signaling
With non-competitive inhbition - increasing the concentration of the agonist, even to very high levels, cannot overcome their effects and so the maximum response to the agonist (Emax) is reduced.
What effect does an competitive antagonist have on the dose-response curve?
Introduction of an antagonist – drives the dose response curve to the right – higher concentrations required to achieve desired response
What are some examples of competitive antagonist drugs?
What is meant by drug potency and efficacy?
Pharmacologists and prescribers often need to compare the pharmacodynamic effects of different drugs
Efficacy is the term used to describe the extent to which a drug can produce a response when all available receptors or binding sites are occupied - This corresponds to Emax on the log dose–response curve.
Potency is a term used to describe the amount of a drug required to produce a given response - More potent drugs produce biological effects at lower doses (or concentrations), so that they have a lower ED50 - corresponds to ED50
Drug potency is related to affinity for the receptor - indicates how readily the drug– receptor complex is formed.
In this example, Drug C is the most potent
because drug responses are achieved at 10-fold lower doses than Drug A and 100-fold lower doses than Drug B.
What is meant by drug selectivity?
Looking at the differential effect of drugs at different sites - e.g. different receptor sub-types
Heart receptors are more sensitive to noradrenaline when compared to the lungs – difference at the receptor level
What does the desensitization to a drug refer to?
Desensitisation refers to the common situation in which the biological response to a drug diminishes when it is given continuously or repeatedly taken
The term tachyphylaxis is used to describe desensitisation that occurs very rapidly, sometimes with the initial dose.
The term tolerance is conventionally used to describe a more gradual loss of response to a drug that occurs over days or weeks.
No clear distinction between the two but the timescale imply that different mechanisms may be involved.
Note that in some cases, the tissues may become completely refractory to its effect - complete lack of responsiveness
What are some pharmacodynamic & pharmacokinetic causes of desensitisation?
Pharmacodynamic
- Reduction in receptor number – a process often described as receptor ‘down-regulation’
- Changes in receptor structure or function resulting from a chemical modification, such as phosphorylation of receptor proteins
- Exhaustion of mediators such as signalling molecules like intracellular secondary messengers or exhaustion of stored neurotransmitters
- Physiological adaptation – where repeated exposure to a drug leads to counteracting physiological responses that diminish its clinical effects
Pharmacokinetic
- Increased drug metabolism – where repeated exposure to a drug increases the capacity of the liver to metabolise it, …… or
- Increasing capacity to actively remove the drug from cells
What are some examples of desensitization?
Opioids - Mechanism involves receptor downregulation and modification
Benzodiazepines - Reduced activity of the intrinsic GABA pathways
Ethanol - Tolerance due to increased metabolism but is also due to ‘learned’ behaviour
Apart from the molecular changes, what other factors to consider when thinking about a reduced drug response?
Big one - Reduced adherence – 50% of drugs are only taken in accordance with the prescribed treatment regime
What are the four phases/processes that pharmacokinetics can be divided into?
Four phases
1. Absorption
2. Distribution
3. Metabolism
4. Excretion
Abbreviated as ADME
What are the different routes of drug administration?
Different routes of administration
- Oral passes through the liver via portal circulation and subsequently enters systemic circulation)
- Intravenous - bypasses gastrointestinal absorption and liver (1st pass metabolism)
- Intention to get the drug at the required concentration at the site of action
When providing a oral drug - what factors do we need to think about?
Only a proportion of a drug dose that is administered by the oral route eventually becomes bioavailable for distribution to the body tissues
Multiple levels where it may be lost –> but most important factor - first pass metabolism in the liver - cytochrome p450 system
The cells of the intestinal wall also contain a large number of enzymes capable of metabolising drug molecules passing through them & are able to pump them back into th lumen.
What other GI routes can be used that skip first pass metabolism?
Buccal administration involves the tablet being placed between the upper lip and gum and held there until it dissolves.
Sublingual administration involves placing a tablet beneath the tongue and holding it there until it dissolves.
Both the buccal and sublingual routes involve drug molecules being absorbed into the capillaries of the oral circulation from where they drain into the superior vena cava before returning to the heart and entering the systemic circulation.
Rectal drug administration is particularly useful for patients who cannot swallow or who are vomiting, where there is no suitable injectable formulation (e.g. paracetamol), or where a rapid effect is necessary in an unconscious patient, in whom intravenous access is uncertain
What are the advantages and potential concerns associated with intravenous administration?
Where a drug has a low therapeutic index (i.e. a narrow range between the lowest effective dose and the highest safe dose), a high drug concentration in plasma may not be desirable. In this case, an intravenous infusion may be preferred so that the dose can be administered over a longer period - reducing peak concentrations
What are drug concentration time curves?
Shows the changes drug concentrations in the blood plasma over time
The area under the curve (AUC) for the oral administration is significantly smaller than for the intravenous curve indicating reduced bioavailability.
It is also notable that the peak concentration is lower and delayed after oral administration.
Intravenous administration is preferred for very ill patients for whom the pharmacological effects of the drug are required more urgently.
Why is drug distribution important to think about and how can we divide the body to conceptualise this?
For a drug to exert its desired pharmacodynamic effects it must reach the site of action in sufficient concentration.
Will depends on the rate and extent of the distribution of drug molecules around the various fluid compartments of the body.
Divide up the body into a series of compartments - plasma, the interstitial fluid (extracellular) and the intracellular fluid (+fat stores)
Drugs will divide themselves into the different compartments - this will establish an equilibrium - obviously this is not maintained as drugs are metabolized and excreted –> biochemical properties of the drug will ultimately determine the proportion of the durg in each compartment.
How do drugs move across the cell membrane?
Different types of movement across membranes…
1. Passive diffusion
2. Pore-mediated diffusion
3. Pinocytosis
Why is protein binding of drugs in the plasma important to consider?
Many drugs are bound to proteins in plasma.
Weak acids bind to albumin and weak bases to alpha1-acid glycoprotein, whereas steroids bind to globulins.
This creates a protected depot of drug in the blood – bound drug molecules cannot leave the plasma because the molecules carrying them are too large to cross the capillary walls, nor can they be metabolised or excreted.
This will influence the amount of drug that is free to act at the site of interest
What is the equation to calculate the volume of distribution?
Volume of distribution can be calculated knowing prescribed concentration and plasma concentration
The volume of distribution (Vd) is a pharmacokinetic parameter representing an individual drug’s propensity to either remain in the plasma or redistribute to other tissue compartments.
Vd = A (administered) / Cp (plasma concentration)
Look at the level of sequestration
Influences the time taken to load up patients with drug
The volume of distribution (Vd) is expressed either as an absolute volume in a 70 kg adult or as the volume per kilogram.
What is the main site of drug metabolism?
The principal organ of drug metabolism is the liver, which is well-perfused and contains a high concentration of metabolising enzymes in the smooth endoplasmic reticulum.
These are often referred to as the cytochrome P450 system, a superfamily of enzymes containing haem as a cofactor.
The combination of the metabolism of drugs in the small bowel mucosa and liver is often referred to as first-pass metabolism
What is the purpose of phase I and II drug metabolism?
Most drugs have to be lipid-soluble in order to be absorbed, cross membranes, move around the body and reach their site of action - However, in preparation for excretion - metabolism has to reduce this lipid solubility
Two phases…
- Phase I (non-synthetic) reactions involve oxidation, reduction or hydrolysis that alters the structure in a way that often prevents or reduces the pharmacological activity of the molecule.
- Phase II (synthetic) reactions involve conjugation with a natural endogenous constituent, such as glucuronic acid, glutathione, sulphate, acetic acid, glycine or a methyl group, resulting in a product that is more soluble and easy to excrete.
Broadly speaking, what does the cytochrome P450 do?
Each cytochrome enzyme contains a haem-bound iron at the active site, responsible for binding with oxygen and the drug substrate, enabling the transfer of one atom of oxygen to the substrate (a mono-oxygenase reaction) in the presence of NADPH, which provides the reducing equivalents to facilitate the reaction.
How is the cytochrome p450 family divided into?
The superfamily of CYP enzymes is divided into four families (CYP1, CYP2, CYP3 and CYP4)
Each of which is further divided into five subfamilies (A to E).
Individual enzymes (isoforms) within each subfamily are also numbered.
The most important subfamilies are CYP1A, CYP2B, CYP2C, CYP2D, CYP2E and CYP3A.
CYP3A is the most abundant hepatic subfamily, responsible for the metabolism of more drugs than any other.
Important to consider that the cytochromes are under genetic control – different alleles
What is the role of phase II metabolism?
Phase II reactions involve conjugation of the metabolite formed in a phase I reaction with natural endogenous constituents to form glucuronide, sulfate, acetyl and methyl conjugates.
These products are water-soluble and therefore suitable for excretion either in urine or bile.
Note – there is variation – some drugs will solely pass phase I and can be excreted
What determines the duration and intensity of pharmacological action? What are some examples of external factors that influence drug metabolism?
The duration and intensity of pharmacological action of most lipophilic drugs are determined by the rate at which they are metabolised to inactive products, most commonly by the cytochrome P450 system.
What are the different routes of excretion?
Kidney (main) which is primarily responsible for the excretion of low molecular weight compounds into the urine
The bile is responsible for excreting large molecular weight compounds (above 400–500 Da) into the bile which subsequently leave the body in the faeces.
The lungs allow some volatile anaesthetic gases and small amounts of other compounds such as ethanol to leave the body in exhaled gases.
Other routes of excretion for a small number of drugs are the tears and sweat
Breast milk is an important site of drug excretion for small amounts of many lipid-soluble drugs, which may be ingested by the infant.
Why is water-solubility important for excretion?
For any drug, or drug metabolite, to be excreted from the body, by any route, it must be water-soluble.
Example - urine –> As the drug is filtered into the urine it becomes more concentrated - if it were to be lipid soluble it would simply move back into the body down the concentration gradient.
What are the different mechanisms that contribute to renal excretion?
- Glomerular filtration carries water, ions and most molecules of low molecular mass across the fenestrated glomerular membrane into the renal tubule.
Extent that drugs or their metabolites are filtered depends on renal blood flow and the degree of binding to plasma proteins.
Note - this does not depend on lipid/water-solubility.
- Tubular secretion - The tubular cells contain specialised transporter molecules that enable the active transport of acidic and basic drugs into the tubular lumen.
Drugs using the same transporter may interact by competing for binding and excretion.
- Passive tubular reabsorption (not common) has a very important influence that reduces the excretion of many drugs and metabolites if they are sufficiently lipid- soluble to diffuse from the tubular fluid down their concentration gradient back into the body.
Important to consider pH of urine as this will influence the lipid solubility of molecules in the urine - alter their charge
Desrcribe the role of biliary excretion.
- Large molecular weight (>300 Da) drugs with a degree of polarity
- Conjugated metabolites (e.g. glucuronides) - faciliatates biliary excretion
- Active transport into bill cannaliculi against a concentration gradient
- Specialised transport molecules (e.g. P-glycoprotein)
- Potential for saturation of transport and competition between drugs
Enterohepathic circulation - Once excreted into the gut, molecules that are sufficiently lipid-soluble can be re-absorbed. – microbes can remove the glucuronide moiety – allowing the drug to re-enter circulation
What is the relationship between drug concentration and time (single dose)?
First order kinetics – concentration will reduce in accordance with the drugs ½ life
Based on the law of mass action - rate of a chemical reaction or process is directly proportional to the concentrations of the reactants.
With regard to pharmacokinetics….
This implies that the rate of metabolism of drugs in the cytochrome P450 system in the liver will be proportional to their concentration.
The amount of drug excreted by glomerular filtration will be proportional to the concentration of the drug in the plasma.
What are the implications of first order kinetics?
The importance of this relationship to prescribers is that it means that the effect of increasing doses on plasma concentration is predictable.
If a dose is doubled or trebled then this will lead to a doubled or trebled plasma concentration at all time points after dosing - also results in a faster rate of elimination
Nevertheless, the elimination of each dose takes the same length of time - metabolism/elimination is usually not a limiting factor
What is zero-order (saturation) kinetics?
For some drugs, especially if given at higher toxic doses, the availability of the metabolising enzymes may be exceeded. When this happens, the rate of elimination will remain constant even if the dose increases, a situation that is described mathematically as zero-order or saturation kinetics.
What problem do we encounter when we administer a single dose of a first order kinetic drug?
Necessary concentration that exceeds the minimum effective concentration is only maintained for a limited time - known as the duration of action - before the plasma concentration falls to sub-therapeutic levels.
Hence, there is a continuous need to be given to maintain the plasma concentration in the therapeutic range.
Note - some drug companies have altered their drugs (modified release) so that they have a delayed release in the small bowel so that absorption occurs over longer period and
provides a much smoother increase and slower subsequent decline in plasma concentration - increasing the half life
How do we overcome the ‘duration of action’ problem?
Multiple doses are provided until a steady state is reached - the rate of elimination of the drug is equal to the rate of administration.
The rate at which the plasma drug concentration increases, and time taken to achieve steady state, are determined by the drug half-life.
By convention, it is generally considered that, for practical purposes, steady state is achieved after 5 half-lives.
What is the difference between short and long half-lives drugs in terms of reaching steady-state?
For drugs with a long half-life, how can we acheive desired plasma concentrations before 5 half lives?
For drugs with long half-lives, the only way to achieve a target plasma concentration safely before five half-lives have elapsed is to give an initial loading dose
