Pharmacology notes PDF

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Weekly Summary from lecture notes and practicals MD1
Essential learning for weekly test. This one is specifically on pharmacology. ...

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DRUGS  Time after dose: absorption, distribution, elimination (hepatic metabolism or renal excretion)  AUC (exposure to a drug measure) curve  Determinants of availability: - Oral bioavailability- fraction absorbed (portal vein), if not- travels out through the stool (what proportion is absorbed by the GIT). Parts of the drug dissolved in GIT fluids - Calculate bioavailability: calculate hepatic clearance (formula)- Oral is about 30% of the intravenous (ie. Intravenous dose= oral dose*bioavailability OR oral dose= intravenous/bioavailability) (ie. Oral dose always greater than intravenous. Bioavailability is always 1 or less) 

PK concept: volume of distribution - Not a real volume (simply relates to the drug dose to the concentration observed in the blood) - Key function is to reflect the extent to which a drug will distribute out of the bloodstream - Half-life= (0.693XVolume of distribution)/Systemic clearance

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Metabolism and elimination - A small proportion is eliminated unchanged but majority of the dose is metabolised and then excreted

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Two major types: functionalisation (adding of a hydroxyl group or removing methyl or ethyl group, to unmask an amine or hydroxyl group- it will be more polar and therefore water soluble. Therefore reduce amount reabsorbed and more is excreted.) and conjugation (transferases- involve the covalent linkage of a suitable functional group present in the molecule with a polar endogenous compound to increase the metabolism and enable it to be excreted)

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Passive Reabsorption (Negatively Contributes). Filtration & Active Secretion (Positively Contributes) are the three renal elimination processes)

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Estimating organ clearance: CLs(systemic)= CLr (renal)+CLh(hepatic)+CLo(other). You can estimate CLr from fraction of dose excreted unchanged in urine (fe): CLr=CLs*fe

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High hepatic clearance: >60L/hr

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Impact of changing Clint- ie changing enzyme activity differs between high hepatic versus low hepatic drugs. It’s bioavailability vs clearance.

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Bioavailability- high CLh drug. The fraction of drug that escapes first pass metabolismthe same absolute change in CLint has a large effect on how much drug gets into the body

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Low hepatic clearance: induce the enzymes to increase the clearance. The focus is the volume of blood that is cleared of drug per unit of time.

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Bioavailability- low CLh drug: the focus is on the fraction of drug that escapes first pass metabolism

Drugs can induce or inhibit the clearance of other drugs (tobostatin)

Pharmacodynamics Learning Objectives SUMMATIVE- pharmacodynamics LO1: Describe the relationships between dose concentration at the receptor, and response to an agonist. 

Amount of dose administered is determined as: dose= concentration x volume

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Molecular aspects of absorption: needs to be lipophilic (ie. Like fat), diffusion through a lipid, diffusion through an aqueous channel, or through a carrier.

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Lipophilicity and charge are also determinants of absorption: -

Ideally drugs are lipophilic, but not so lipophilic that they get “stuck” in the transmembrane region

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Ideally drugs remain uncharged to be absorbed better. Hence, for those with high charges, they need to be administered via IV to be absorbed.

LO2: Explain the processes by which drugs may behave as reversible or irreversible competitive antagonists, or agonists, of receptors for endogenous ligands. 

Reversibile inhibition: metabolic reactions require both binding of the substrate (governed by affinity) and catalysis (governed by efficacy) to produce a metabolite. Therefore inhibitors can either impede binding or catalysis.

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Competitive inhibition is the most common type of inhibition of drug metabolising enzymes and it is when two drugs compete for binding to the enzyme catalytic site. This impedes the binding of the substrate.

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Non-competitive or uncompetitive inhibition is when the inhibitor binds to a distinct site on the enzyme other than the active site. Ie. For CYP this is usually the heme. Therefore, binding of the inhibitor impedes catalysis, but not necessarily substrate binding.

Effect on metabolism: 

Induction of enzyme activity in metabolism results in excessive formation of the active metabolite and leads to toxicity.

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Inhibition of enzyme activity causes an opposite effect- reduces formation of the active metabolite and can lead to therapeutic failure.

Effect on bioavailability: 

Can result from altered absorption or first pass elimination due to: -

Disease states

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Drug interactions

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Genetics

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May alter the rate OR extent of availability

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GI expression of CYP3A4 can have a major effect on bioavailability

LO3: Explain the concept of bioavailability in relation to route of administration. 

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Routes of administration include: -

Oral or rectal- absorption tends to occur in the SI. At the liver, depending on the extent and rate of metabolism, a proportion of the drug absorbed from the GIT will enter the systemic circulation (fH). Ie. FH=1-EH (where Eh is the extraction ratio- the proportion of the drug entering the organ that is extracted or cleared by the organ). Disadvantages include that some is not absorbed and some is inactivated by the liver.

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Percutaneous (skin) (these three are parenteral dosing: systemic administration of a drug by a route other than GIT) Ie. Injection to one of these three common sites.

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Intravenous

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Intramuscular

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Intrathecal (CSF)

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Inhalation

The intestine also contains a large number of transport proteins which also affect the intestinal absorption of the drug. -

The P-glycoprotein is involved in the ATPbinding cassette and expressed in many tissues (GIT, liver, kidney, brain)

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The overexpression of this can result in multidrug resistance

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Many CYP3A substrates are substrates for Pgp. It can be induced to increase bioavailability or inhibited to reduce bioavailability.

Bioavailability is essentially the proportion of administered dose which reaches the systemic circulation intact. It is dependent on:

1. The proportion of dose absorbed from the GIT (fg) 2. The proportion of the drug entering the liver that is not extracted in 1 st pass metabolism (fH) -

It essentially indicated the “effective” dose of a drug/formulation.

LO4: Give definitions and understand concepts of bioavailability (F), volume of distribution (VD), clearance (CL) and elimination half-life (t1/2) and how to calculate each from basic pharmacokinetic data. 

Distribution- once a drug reaches systemic circulation, it can be distributed to various sites within the body. This is defined as the reversible transfer of a drug between two compartments within the body. (usually the fluid compartments) -

Ie. Extracellular, intracellular, transcellular fluid or fat

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Drugs typically bind to proteins in the blood (ie. Acidic drugs to albumin, basic to alpha-1-acid glycoprotein)

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The extent of binding depends on affinity of the drug for the protein (some are highly bound, some to a low extent)

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The Volume of distribution: VD= total amount of drug in the body/ blood or plasma concentration

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Along with clearance, Vd is a major determinant of half life (the duration to which an individual is exposed to a drug)

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Clearance: this is essentially the volume of blood cleared irreversibly of a drug per unit time. As organ clearances are additive, systemic clearance can be calculated by summing the clearances of individual organs; using the abovementioned equation.

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Half-life: this is essentially the time taken for the blood/plasma concentration to be reduced by ½. -

The time to steady state is usually 3x to 5x halflives

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You essentially continue to add the drug at certain time points post dose to ensure it remains within the therapeutic range. Dose rate= CLs x Css (steady state)

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Attained rapidly: fentanyl- 1-2 hours, attained slowly: amiodarone (2 months)

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The volume of distribution is Vd= total amount of drug in the body/ blood or plasma concentration.

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Hence, to achieve the steady-state more rapidly, a ‘loading dose’ which fills up the volume of distribution may be used. The loading dose= VD x ‘target’ concentration.

LO6: Explain the concept and significance of high and low hepatic drug clearance as it relates to bioavailability and systemic clearance. -

The clearance can be calculated on the basis of blood concentration using a standard pharmacokinetic approach. Ie. For a drug administered intravenously, clearance is calculated as the dose/AUC, whereas for a drug administered orally, it is simply the dose/AUC and then multiplied by the bioavailability.

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Estimating organ clearance: CLS= CLr (which you can estimate as a fraction of the dose excreted unchanged in the urine (fe)- CLr=CLsxfe)

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In terms of renal clearance, this also incorporates three processes: glomerular filtration, secretion and reabsorption. Hence: -

Hepatic extraction is a little more complex:

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Limiting cases for hepatic clearance: 1. Low hepatic clearance (means capacity limited clearance) 2. High hepatic clearance (availability limited clearance)

- This is essentially based on the capacity of the enzymes in the liver to clear a drug which is delivered to them

Effect on enzyme activity

Low clearance drug

High clearance drug

Clearance (CLh)

Bioavailability (F)

Clearance (CLh)

Bioavailability (F)

Induce

Increase

Not much change

No change

Decreases

inhibit

decrease

No change

No change

Increases

 You can change the enzymes to alter the clearance and therefore the bioavailability  For a high hepatic clearance drug, if you inhibit metabolism then the AUC curve increases (the height) but the slope down is unaltered because the clearance is the same  If you change the clearance of a low hepatic clearance drug bioavailability isn’t altered, but the clearance slope rate will increase (induce the enzymes)- take longer to be reduced LO5: Describe the primary mechanisms of drug elimination with respect to hepatic metabolism and renal excretion. 

Drug metabolism can include detoxification/termination of activity (the products have less biological activity than the parent drug), clearance (where it is converted to another compound), enhances elimination (the products of metabolism are more readily excreted by the kidney), minimizing oral exposure (usually a protective barrier against exposure to toxic orally ingested chemicals).

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Majority of drugs undergo metabolism to a significant extent as this results in the formation of a more readily eliminated product, or “metabolite.” The two main types of drug metabolism reaction include: 1. Functionalization (phase I) reactions (adding of a hydroxyl group or removing methyl or ethyl group, to unmask an amine or hydroxyl group- it will be more polar and therefore water soluble. Therefore reduce amount reabsorbed and more is excreted.) The most important functionalization enzymes include the P450s, or CYPs- they are heme containing enzymes of approximately 500 amino acids. They bind the substrate molecule to the oxidised form of the CYP enzyme. This is then reduced by NADPH cytochrome P450 and then a proton is added to cause the cleavage of the O-O bond. Hence, water is released. -

CYP450 exist as a family of enzymes which are all independently regulated and metabolise drugs in a unique way.

2. Conjugation (phase II) reactions (transferasesinvolve the covalent linkage of a suitable functional group present in the molecule with a polar endogenous compound to increase the metabolism and enable it to be excreted). Ie. They catalyze the transfer of a polar endogenous substrate containing a suitable acceptor group. -

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The most common conjugation rxn= glucuronidation. Catalysed by UDPglucuronosyltransferase (or UGT) and usually involves covalent linkage of glucuronic acid to a substrate bearing a suitable functional group according to an SN2 mechanism.

The LIVER contains the highest abundance of drug metabolizing enzymes.

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Elimination by the kidney: -

Clearance value of drug is essentially that amount of drug which is eliminated unchanged

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Elimination by the kidney involves filtration, active secretion and passive reabsorption. Ideally you want the kidney to be increasing active secretion and filtration of the drug, but reducing the passive reabsorption.

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Filtration occurs in the glomerulus: only the drug not bound to protein is filtered and enters the renal tubule. GFR can also be estimated on the basis of creatinine clearance.

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Renal transport mechanisms: occur at the proximal and distal tubules and the LOH, and can facilitate drug transport either into or out of the nephron- passive, passive with transporter mechanisms and active.

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Determinants of reabsorption include: 1. Urine flow rate- if this is high, the urine is more dilute and there is a reduced concentration gradient, so less drug is reabsorbed. If flow rate is low, urine becomes concentrated so more drug is reabsorbed. 2. Lipophilicity- lipophilic drugs are almost completely reabsorbed, resulting in...