Expert Prescribing Guidance | The Tradies Guide to Medicine

Medication Summaries and High Yield Content

From Doc Nolan and his second year appreno "It ain't much, but it's honest work"

Rehashing the Building Blocks

The effects of a drug are influenced by various factors. Pharmacokinetics refers to the study of how a drug moves through the body, essentially describing how the body processes the drug. This includes absorption, distribution, metabolism, and elimination. On the other hand, pharmacodynamics examines how the drug affects the body, focusing on its mechanism of action, therapeutic outcomes, and potential side effects .When drugs are used in combination with other substances, interactions can occur that either amplify (synergistic effect) or diminish (antagonistic effect) the drug's impact. These effects often involve the regulation of enzymes like cytochrome P450, which are crucial for metabolising medications. A thorough understanding of both pharmacokinetics and drug interactions is essential in selecting the best route of administration, such as oral, topical, or intravenous (IV). For instance, drugs processed by the liver can accumulate to toxic levels if liver function is impaired, increasing the risk of adverse effects. Similarly, medications excreted by the kidneys must be carefully managed in patients with renal dysfunction to avoid toxic buildup. Before Prescribing a Drug Revisit the Fundamentals Outlined Below.

Pharmacokinetics (LADME: an acronym for the important phases of pharmacokinetics)

Liberation
Absorption
Distribution
Metabolism
Excretion

Pharmacodynamics

Receptor types and their interaction with the drug
Dose-response relationship

Clinical trials: phases of drug development, testing, and regulatory approval (occur after preclinical studies)
- Do you know how to assess whether what you’re about to prescribe is safe? Capacity is a two way street!

Pharmacokinetics

(What the body does to the drug)

Liberation

Various routes of administration are used to introduce drugs into the body, each chosen based on the desired effect, drug properties, and patient’s situation.

Common Routes

Injection: The drug is delivered directly into the bloodstream (intravenous) or into tissues (intramuscular, subcutaneous)
Inhalation: The drug is absorbed through the lungs
Per oral administration: The drug is taken by mouth and absorbed through the digestive system
Dermal (topical) administration: The drug is applied to the skin for localized or systemic effects
Rectal administration: The drug is introduced via the rectum, often using suppositories

Less Common Routes

Buccal: The drug is placed between the gums and cheek, where it dissolves and is absorbed into the bloodstream
Sublingual: The drug is placed under the tongue for rapid absorption
Intra-articular administration: The drug is injected directly into a joint for localized treatment

Absorption

The process by which the drug reaches the bloodstream. The following factors affect drug absorption

Bioavailability

Describes the rate and concentration at which a drug reaches systemic circulation
Expressed as a percentage of the dose that was initially administered
Drugs administered intravenously have a bioavailability of 100%
Can be calculated using the area under curve (AUC) of the plotted graph concentration versus time: (F) = (AUCoral/AUCIV) x 100
Bioavailability is affected by two mechanisms:
- The ability to pass through lipid membranes: Dependent on the nature of the substance)
- First Pass Effect: Orally administered drugs are absorbed in the GI tract and reach the liver via portal circulation In the liver they undergo first pass metabolism before they enter systemic circulation → ↓ bioavailability of the drug (F < 100%) Rectal or sublingual administration bypasses first pass metabolism, as the drug is absorbed directly into the bloodstream

Nature of the Substance: Lipophilic substances can easily diffuse across the lipid bilayer of the cell membrane. These drugs can be administered topically and can freely diffuse across the blood-brain barrier. Lipophilic drugs generally undergo biotransformation in the liver to become more hydrophilic in 2 possible phases. Without biotransformation, lipophilic molecules may be excreted via biliary elimination.

AUC: Metric used to evaluate the ability of a screening or diagnostic test to correctly predict the probability of a binary outcome (e.g., disease vs. no disease). A receiver operating characteristic (ROC) curve with an area under the curve (AUC) close to 1.0 indicates that the test has high combined sensitivity and specificity, while a ROC with an AUC closer to 0.5 indicates that the test has poor discriminative ability.

Distribution

Distribution coefficient: Measures the hydrophobicity/hydrophilicity of a drug

Corganic / Cwater (The drug is introduced into a mixture of water and a hydrophobic, organic solvent. The concentration of the drug is then measured in the two liquids; the smaller the distribution coefficient, the more hydrophilic the drug). Corganic = drug concentration in an organic solvent. Cwater = drug concentration in water

Volume of distribution:

Vd = M/Cplasma

Vd = volume of distribution (usually expressed in liters/kg body weight). The volume of water that would contain the total amount of the substance within the body at a concentration equal to that present in plasma. Reflects the tendency of a drug to be distributed in body tissue rather than plasma. Drugs that are restricted to the intravascular compartment tend to have a low volume of distribution (< 0.2 L). Vd = total drug amount / drug concentration seen in plasma.
M = amount of drug in the body at a specific time
Cplasma = plasma concentration of the drug at a specific time
The theoretical volume a drug would occupy if it was distributed evenly in fluids at plasma concentration
Provides information about a drug tendency to distribute in other compartments (e.g., muscle or adipose tissue) rather than in the plasma
Drugs can be distributed in more than one compartment.
The Vd of plasma protein-bound drugs may be increased in patients with renal and liver disease due to loss of plasma proteins (the proteins in the serum, which include albumin (60%), clotting factors, globulins, transferrin, haptoglobin, and lipoproteins. With the exception of globulins, all serum proteins are produced in the liver and are reduced in liver failure "Plasma proteins" refer to serum proteins without the clotting factors)
Binding to plasma proteins: Different drugs have different affinities to bind to plasma proteins (e.g., albumin). Only the unbound fraction of the drug has a pharmacological effect. Different drugs may compete to bind to plasma proteins
Redistribution (pharmacology): Transfer of a drug between the different compartments within the human body. Lipophilic substances (e.g., inhalation anesthetics) are redistributed from plasma into fat tissue → initially decreased action of the applied drug. The drug is stored but over time is released again from fat tissue into plasma → delayed elimination and prolonged action of the specific drug
Changes in advanced age: Hydrophilic drugs (e.g., digoxin) ↓ total body water → ↓ Vd. Acidic drugs ↓ albumin → ↓ binding. Lipophilic drugs (e.g., propofol) ↑ body fat content → ↑ Vd
After the drug reaches the bloodstream, it is initially distributed in the most vascularized organs. Renal and liver disease can increase the apparent volume of distribution of drugs bound to plasma proteins.

Metabolism (Biotransformation)

Chemical alteration of substances (e.g., drugs) within the body by the action of enzymes and mainly takes place in the liver. This works to Detoxify drugs and facilitates their elimination.

Types of Drug Kinetics

Zero order kinetics: The rate of metabolism and/or elimination remains constant and is independent of the plasma concentration of a drug at steady state (Cp decreases linearly over time). Zero-order is a capacity-limited elimination. Examples include ethanol, phenytoin, aspirin (at high concentrations)
First order kinetics: The rate of metabolism and/or elimination is directly proportional to the plasma concentration of the drug (Cp decreases exponentially over time). First-order is a flow-dependent elimination. Applies to most drugs

Phases of Biotransformation

Phase I reaction: A drug is transformed into a polar, water-soluble metabolite by cytochrome P450 via one or more of the following reactions: Oxidation (most common reaction), Reduction, and Hydrolysis
Phase II reaction: A drug is conjugated and thereby transformed into a very polar metabolite (can be excreted renally) via one or more of the following reactions: Glucuronidation (most common coupling reaction), Acetylation (e.g., isoniazid), Sulfation, Methylation

Clinical significance

Detoxification: In most cases, the drug is inactivated and modified into a hydrophilic metabolite, allowing excretion of the drug via the kidneys or in bile
Activation: Certain drugs are transformed in the liver from their inactive prodrug state into active forms (e.g., the ACE inhibitor enalapril is transformed through ester hydrolysis into the active form enalapril)
Formation of toxic metabolites: (e.g., the breakdown of paracetamol gives rise to toxic metabolites that may cause severe liver damage in large doses)
In individuals who are slow drug acetylators, the decreased rate of metabolism increases the risk of side effects (e.g., isoniazid)

Changes in advanced age: ↓ metabolisation (due to ↓ hepatic mass and ↓ hepatic blood flow)

Because phase I metabolism decreases (affecting drugs like diazepam), drugs predominantly metabolized in phase II (e.g., acetaminophen, lorazepam) are considered safer
Consequently, lower therapeutic doses should be considered in elderly individuals

Excretion

Excretion Drug clearance (CL): A measure of the rate of drug elimination.

It is defined as the plasma volume that can be completely cleared of the drug in a given period of time (e.g., creatinine clearance)

CL = Vd x Ke = rate of drug elimination/plasma drug concentration
Vd = volume of distribution
Ke = elimination constant
CL = rate of elimination / plasma concentration
CL can be impaired in patients with cardiac, hepatic, or renal dysfunction

Half-Life (t½): The time required for the plasma concentration of a drug to reach half of its initial value

Steady state:

Dynamic equilibrium
Drug concentration stays constant because the rate of drug elimination equals the rate of drug administration

First-order kinetics

It takes 1 half-life to reach 50% of the steady-state level, 2 half-lives to reach 25%, 3 half-lives to reach 12.5%, and 4 half-lives to reach 6.25%
Complete steady-state attainment takes 4–5 half-lives for drugs infused at a constant rate; 90% of steady-state level is reached after 3.3 half-lives

Effective half-life

It takes 1 half-life to reach 50% of the steady-state level, 2 half-lives to reach 25%, 3 half-lives to reach 12.5%, and 4 half-lives to reach 6.25%
Complete steady-state attainment takes 4–5 half-lives for drugs infused at a constant rate; 90% of steady-state level is reached after 3.3 half-lives
The time it takes for a drug's plasma concentration to reach 50% of its initial value during the most clinically important phase of its kinetics
For drugs with atypical kinetics (e.g., those with a high volume of distribution), the effective half-life may be shorter than the terminal elimination half-life but more predictive of the drug's duration of effect and accumulation
Defects in renal, hepatic, or cardiac function can impair drug clearance
After 4 half-lives, more than 90% of the drug will be eliminated

Drugs and/or their metabolites are excreted from the body in one or more of the following ways:

Renal elimination: mostly hydrophilic drugs. Main renal elimination mechanisms include, Glomerular filtration, Tubular secretion, and Tubular reabsorption
Ionised substances cannot cross renal tubular membranes and are cleared quickly
Weak acidic drugs (e.g., phenobarbital, methotrexate, aspirin) are trapped in a basic environment
Overdoses with these drugs can be treated via alkalinisation of urine (sodium bicarbonate)
Weak basic drugs (e.g., tricyclic antidepressants, amphetamines) are trapped in an acidic environment
Overdoses with these drugs can be treated via acidification of urine (ammonium chloride)
RNH3+ (trapped form) ⇄ RNH2 + H+ (lipid soluble)
The elimination of tricyclic antidepressants, which are basic, can be increased by acidification of urine, but toxicity is generally treated with sodium bicarbonate
Neutral substances can be reabsorbed

Biliary elimination

Lipophilic and hydrophilic substances
Lipophilic substances that have undergone biliary elimination may be reabsorbed from the gut and then secreted again in bile (enterohepatic circulation)

Pulmonary elimination: Primarily in inhaled anaesthetic drugs

Changes in advanced age:

↓ Tubular secretion and ↓ GFR → ↑ concentrations of drugs that are eliminated renally
Consequently, lower therapeutic doses should be considered in elderly individuals

Anaelgesia

The definition of anaelgesia is misleading to it's use in medicine. The meaning of the word, being, 'the absence of pain' is a harmful and untenable (big word for the appreno) way to approach prescribing. As a general rule of thumb, for both practice and exams, pain relief involves a multimodal approach utilising the WHO anaelgesia step ladder. The WHO analgesic ladder has five key principles:

Starting from and with the Bottom:

Oral administration of analgesics should be used whenever possible
Analgesics should be given at regular intervals with the duration and dose of medication supporting the patient’s level of pain
Analgesics should be prescribed according to the pain intensity characterised by the patient (this should be free from judgement from the clinician)
Dosing of pain medication should be adapted to the individual, starting at the lowest dose and duration possible but titrating accordingly to response
Consistent administration of analgesics is vital for effective pain management
Step 3 is straight bullshit and not used in clinical practice. For obvious reasons, the first being, opioids are highly enjoyable. If a patient with a tiny laceration to their finger requests oxycodone because their pain is 10/10, obviously you will get in shit if you prescribe this.

Regardless of pain severity make sure you have a baseline of regularly charted paracetamol and an NSAID (there are some caveats to this, such as poor kidney function, liver disease, and allergies). However, in general put these down on the medication chart as a regular medication before adding anything stronger. These are sometimes charted on the front of the medication chart in ED departments if the patient is expected to be admitted.

Charting Paracetamol:

Route of administration, usually PO, can also be charted IV or PO/IV as dosages don't change between the two. The dose, usually 1 gram.
Frequency, usually written as QID (4 times daily), you can change this as long as there is 4 hours in-between each 1gram dose.
Max 24 hour amount, 4 grams.
Consider lowering this if the patient has deranged liver function or known liver disease.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

There are two general types of NSAIDs available: non-selective and COX-2 selective. Most NSAIDs are non-selective and inhibit the activity of both COX-1 and COX-2. These NSAIDs, while reducing inflammation, also inhibit platelet aggregation and increase the risk of gastrointestinal ulcers and bleeds. COX-2 selective inhibitors have fewer gastrointestinal side effects, but promote thrombosis, and some of these agents substantially increase the risk of heart attack. These differential effects are due to the different roles and tissue localisations of each COX isoenzyme. By inhibiting physiological COX activity, NSAIDs may cause deleterious effects on kidney function, and, perhaps as a result of water and sodium retention and decreases in renal blood flow, may lead to heart problems. In addition, NSAIDs can blunt the production of erythropoietin, resulting in anaemia, since haemoglobin needs this hormone to be produced. The most prominent NSAIDs are aspirin, ibuprofen, and naproxen; all available over the counter (OTC) in most countries.

Ibuprofen Charting: 200 mg orally every 4 to 6 hours; may increase to 400 mg orally every 4 to 6 hours as needed. Maximum dose: 1200 mg/day.

Naproxen (IR): 250 mg to 500 mg orally twice a day

Controlled Release: 750 mg to 1000 mg orally once a day.

Delayed Release: 375 mg to 500 mg orally twice a day.

Celecoxib: 100mg to 200 mg orally, usually twice per day. For acute pain 400 mg PO can be given as an initial starting dose. Monitor renal function, especially in older patients.

Opiates

Codeine: is a prodrug that is metabolized in the body by the enzyme cytochrome P450 2D6 (CYP2D6) into morphine, which is largely responsible for its pain-relieving effects. Variations in the CYP2D6 enzyme, of which there are over 100 known types, result in a wide range of metabolic activity. The effectiveness and safety of codeine depend heavily on whether an individual is an ultrafast or poor metaboliser of this enzyme. Ultrafast metabolisers can produce high concentrations of morphine after taking codeine, increasing the risk of side effects, including severe or fatal overdoses, especially in children and breastfeeding infants. A small percentage of individuals, varying by ethnic group, fall into this category. On the other hand, poor metabolisers may experience limited or no pain relief from codeine due to insufficient conversion to morphine. Clinically, codeine's first-pass metabolism in the liver is limited by a methyl group on the 3-carbon, which allows for greater bioavailability after oral administration. Unlike other opioids such as morphine, the difference between oral and parenteral doses of codeine is relatively small. There are serious safety concerns, particularly in cases where ultrafast metabolisers take codeine postpartum and expose infants to potentially dangerous levels of morphine through breastfeeding.

Panadeine (Paracetamol + Codeine) Paracetamol: 500 mg - Codeine: 8 mg. 1-2 tablets, per oral, every 4 hours, maximum of 8 tablets every 24 hours (4 grams of paracetamol is the limiting aspect here, anymore will potentially cause a paracetamol driven toxidrome).

Panadeine Forte (Paracetamol + Codeine) Paracetamol 500 mg - Codeine: 30 mg. 1-2 tablets, per oral, every 4-6 hours, maximum of 8 tablets every 24 hours (4 grams of paracetamol is the limiting aspect again, anymore will potentially cause a paracetamol driven toxidrome). May be a better option for patients who are at greater risk from continuous high amounts of paracetamol.

Mersyndol (Paracetamol + Codeine + Doxylamine) Paracetamol 450 mg - Codeine: 9.75 mg - Doxylamine: 5 mg. 1-2 tablets every 4 to 6 hours as needed for relief. Do not exceed 8 tablets in a 24-hour period (again it’s the paracetamol that is limiting the maximum per 4 and 24 hours that can be prescribed. If you are prescribing near or at the maximum amount it’s probably time to consider prescribing something funner). Never prescribed this myself, not much difference when compared with the above two medications, however, the doxylamine addition doesn’t sound to smart. This drug is an antihistamine based medication with strong anti-cholinergic properties. Given opiates already cause constipation, doesn’t seem like a good idea to include this in the mix. Doxylamine can be sedating and reduce nausea and vomiting, there are other drugs that can achieve this, it seems pointless prescribing something which increases adverse effects when the desired therapeutic effect can be achieved through prescribing alternatives.

Nurofen Plus (Ibuprofen + Codeine) Ibuprofen: 200 mg - Codeine: 12.8 mg. 1 to 2 tablets every 6 to 8 hours. Maximum dose, no more than 6 tablets (i.e., 1200 mg ibuprofen and 76.8 mg codeine) in 24 hours.

Anticoagulation

INR/PT and PTT: Prothrombin time (PT) and partial thromboplastin time (PTT) are tests used to evaluate coagulation, or the clotting of blood. While both measure how quickly blood clots, they have distinct purposes. The PT test, also known as the PT/INR test, looks at the extrinsic pathway of coagulation (meaning coagulation that occurs after blood escapes a blood vessel). The PTT test looks at the intrinsic pathway of coagulation (meaning coagulation that occurs within a blood vessel). When looked at individually and together, the PT and PTT can reveal a bleeding disorder and your risk for severe blood clots. It can also show how well your blood clots in advance of surgery and how well you are responding to anticoagulant therapy ("blood thinners").

Prothrombin: Evaluates ability to clot through measuring how long it takes for a blood clot tot form based on a protein produced by the liver called prothrombin. Also known as clotting factor II (or 2), is one of 13 substances known as ‘’clotting factors’’ that are involved with coagulation. How fast blood clots depends on how much of each clotting factor is in the blood. How the test works? Once blood is drawn, a substance called a tissue factor is added to the test tube. Tissue factor, also known as clotting factor 3, activates the sample in a way that illustrates how blood would clot if there is bleeding (the extrinsic pathway). Once activated, the PT test is measured in seconds. The time is then compared to the reference range of values (meaning the time span in which blood clotting is considered normal). With the PT test, the reference range is between 11 to 13.5 seconds if you are not on anticoagulants. A number higher than the reference range means your blood is taking longer than usual to clot. A number lower than the reference range means that your blood is clotting faster than normal. There are many possible reasons why these might occur. One of the key reasons is that you may have too much or too little vitamin K in your blood, which your body uses to build clotting factors.

INR: Ensures that results from a PT test are the same from one lab to another. The PT test is sometimes referred to as the PT/INR test. The INR refers to the international normalized ratio, a calculation that helps ensure test results are standardized from one lab to the next. Because there are variations in the different types of tissue factor used for the PT test, the INR calculation ensures that the clotting time is accurate based on the body of test results from tissue factor manufacturers worldwide. INR values are important because they help determine how well a person is responding to warfarin, one of the most commonly prescribed anticoagulants used to prevent blood clots. For people on warfarin, the reference range of values for PT/INR is 2 to 3 seconds.

High and low INR values are interpreted as follows: Low INR values mean that you may be at risk of blood clots. High INR values mean that you may be at risk of bleeding. Based on the values, a doctor can decide if the warfarin dose needs to be adjusted or if other interventions are needed.

Partial Thromboplastin Time (PTT): Determines if blood-thinning therapy is effective. The partial thromboplastin time (PTT) test also measures the speed of clotting but differs from the PT test in that it aims to establish how blood clots within a blood vessel (intrinsic pathway). This is based in part on an enzyme called thromboplastin (clotting factor 11) that converts prothrombin into its more active form, called thrombin. How the test works? The processes involved in the PTT test are similar to the PT test, but instead of using tissue factor, the blood sample is activated with minerals or acids that show how blood clotting occurs when something is introduced into the blood. With the PTT test, the reference range is between 25 and 33 seconds. As with the PT test, a higher PTT number means your blood is taking longer than usual to clot. A lower PTT number means that your blood is clotting faster than normal. There are several reasons why this might occur.

Activated Partial Thromboplastin Time (APTT): Test of blood coagulation used to investigate the clotting factors of the intrinsic pathway. The major reason of the APTT test is to do screening of bleeding capacities and to monitor patients on heparin therapy. This test has replaced the older version of the PTT test. APTT is considered as a more sensitive version of the PTT test. The deficiencies of the coagulation factors like Factors V, VIII, IX, X, XI, and XII elevates the APTT. Decalcified blood is used for the APTT test. An activator is used in this test to make the clot faster. The normal APTT value is 35 seconds.

Beginning Therapeutic Anticoagulation (Follow local guidelines): For treatment of venous thromboembolism, LMWH or UFH are typically used initially. When transitioning to warfarin, give heparin in combination (as early as day 1) and continue until INR is in target therapeutic range on 2 consecutive days. Start warfarin at 5–10mg given at 18:00 on days 1 and 2, then check INR. On day 3 (it takes 48–72h for anticoagulant effect to develop). Adjust subsequent doses according to the INR, which needs to be measured on alternate days until stable, then weekly or less often. When transitioning to a DOAC switch from heparin (i.e. do not co-administer DOAC and heparin). DOACS and warfarin may both be initiated as monotherapy in chronic AF (DOACS also in less extensive thromboembolism).

Antidotes

UFH overdose: Stop infusion. If there is bleeding, protamine sulphate counteracts UFH - discuss with a haematologist.

Warfarin: Vitamin K may take several hours to work and can cause prolonged resistance when restarting warfarin, so should be avoided, if possible, when long-term anticoagulation is needed. Prothrombin complex concentrate contains a concentrate of factors II, VII, IX, and X and provides a more complete and rapid reversal of warfarin than FFP

DOACS: Challenging and evolving area (including monoclonal anti-drug antibodies eg idarucizumab for dabigatran)—discuss with haematologist.

Therapeutic vs Prophylactic: Therapeutic = Venous Thromboembolic Disease: DVT and PE. Prophylactic = prevention of DVT/PE in high-risk patients, e.g. post-op. Prevention of stroke, e.g. in chronic AF or prosthetic heart valves.

Heparin, Warfarin and DOACs

Low-Molecular-Weight Heparin – LMWH

The preferred option in the prevention and initial treatment of venous thromboembolism. Inactivates factor Xa (but not thrombin) t½ is 2- to 4-fold longer than standard heparin, and response is more predictable: only needs to be given once or twice daily SC, and laboratory monitoring is usually not required. Some examples include, dalteparin, enoxaparin, and tinzaparin. LMWH accumulates in renal failure - decrease the dose for prophylaxis use and switch to unfractionated heparin if therapeutic treatment is required.

Mechanism of action: LMWHs exert their anticoagulant effect by targeting factor Xa, a pivotal player in the coagulation cascade. By inactivating factor Xa, LMWHs impede the formation of thrombin, thereby preventing the conversion of fibrinogen to fibrin and ultimately halting the clotting process.

Indications: One of the defining characteristics of LMWHs is their extended duration of action Compared to UFHs. This prolonged activity translates into less frequent dosing requirements, enhancing patient convenience and compliance. LMWHs have a reduced risk of certain adverse effects, such as osteoporosis and heparin-induced thrombocytopenia (HIT), making them more appropriate than UFHs in certain patient groups such as in pregnant women.

LMWH May be Preferred in Certain Scenarios, such as: Acute treatment of VTEs, including DVTs and PEs and Prophylaxis of VTEs in hospitalised patients undergoing surgery or with medical illnesses. Treatment and prevention of VTE in pregnant women or individuals with cancer.

Dosing: The dosing of LMWHs varies based on the indication and patient factors such as weight, renal function, and concomitant medications. For the treatment of DVT and PE in uncomplicated patients, LMWHs are often used to bridge the gap until oral anticoagulation can be established or long-term, depending on the patient’s circumstances. Common dosing for treatment is: 1.5mg/kg enoxaparin SC or 200 units/kg dalteparin SC

For thromboprophylaxis in hospitalised patients a lower dose is typically used and will vary slightly depending on the reason for admission. In medical patient’s typical doses are: 40mg enoxaparin SC once daily or 5000 units dalteparin SC once daily. The exact dosing and timing of doses around surgical procedures will vary, depending on the procedure being carried out and the patient’s individual risk factors.

Unfractionated Heparin (UFH)

Administered IV or SC. Binds antithrombin (an endogenous inhibitor of coagulation), increasing its ability to inhibit thrombin, factor Xa, and IXa. Rapid onset and has a short t½. Monitor and adjust dose with APTT.

Mechanism of Action: UFH enhances the activity of antithrombin, leading to the inhibition of coagulation factors IIa (thrombin) and Xa. The inhibition of those coagulation factors prevents the conversion of fibrinogen to fibrin, thereby impeding clot formation.

Indications: UFH is preferred over LMWHs in patients with a higher risk of bleeding or renal impairment due to its shorter half-life and reversibility. UFH is indicated in the following: Acute treatment of VTEs, including deep vein thrombosis (DVT) and pulmonary embolism (PE). Prophylaxis of VTE in hospitalised patients undergoing surgery or medical patients

Dosing: Depends on the indication. For the treatment of DVT, initial administration is typically an intravenous loading dose of either 5000 units or 75 units/kg followed by 18 units/kg/hour as a continuous intravenous infusion or 15000 units subcutaneously twice daily. For thromboprophylaxis in medical patients, the dose is usually a subcutaneous injection every 8-12 hours at a dosage of 5000 units. For surgical patients, a single pre-operative dose of 5000 units is usually administered subcutaneously, followed by 5000 units every 8-12 hours postoperatively

Side Effects: Bleeding (e.g. at operative site, gastrointestinal, intracranial), heparin induced thrombocytopenia (HIT), osteoporosis with long-term use. HIT and osteoporosis are less common with LMWH than UFH. Beware of hyperkalaemia.

Contraindications: Bleeding disorders, platelets <60≈109/L, previous HIT, peptic ulcer, cerebral haemorrhage, severe hypertension, neurosurgery.

Warfarin

Used PO, OD as long-term anticoagulation. The therapeutic range is narrow, varying with the condition being treated and effects are reflected in the INR. Warfarin inhibits the reductase enzyme responsible for regenerating the active form of vitamin K, producing a state analogous to vitamin K deficiency.

Warfarin Target INR Levels: Pulmonary embolism and DVT - aim for INR of 2–3; 3.5 if recurrent PE or DVT whilst anticoagulated. Atrial fibrillation: for stroke prevention) Target INR 2–3. Prosthetic metallic heart valves: for stroke prevention - target INR 2–3 if aortic valve or 2.5–3.5 if mitral valve.

Duration of anticoagulation in DVT/PE: First episodes of DVT or PE require at least 3 months of anticoagulation. Consider extending this to 6 months in patients with more extensive, life-threatening clot at presentation, for those with transient but persistent risk factors (e.g. prolonged immobility) or if evidence of persistent clot at 3 months. For those with recurrent unprovoked emboli or underlying thrombophilia, consider bleeding risks against benefits of indefinite treatment.

Contraindications: Peptic ulcers, bleeding disorders, severe hypertension, pregnancy (teratogenic) Use with caution in elderly and those with past GI bleeds.

Direct Oral Anticoagulants (DOACS)

Rivaroxaban, apixaban (factor Xa inhibitors) and dabigatran (a direct thrombin inhibitor) do not require regular monitoring and dose adjustment; just a quarterly assessment and annual blood test. They offer an attractive alternative to warfarin (particularly where monitoring and maintaining a therapeutic INR is difficult)

Dabigatran dosing: Atrial fibrillation (indefinite duration) (110-150mg BD). Acute VTE (150mg BD, usually after 5-10 days of LMWH)*. Secondary prevention of VTE (150mg BD). Stable coronary artery disease or peripheral artery disease (not applicable)

MOA: Direct factor IIa inhibitor, 80% renal clearance

Half-life: 7-17 hours (Creatine clearance >50 ml/min (increases significantly with reduced renal function)

Rivaroxaban dosing: Atrial fibrillation (indefinite duration) 15 or 20mg BD. Acute VTE (15mg BD, for initial 21 days then 20mg OD). Secondary prevention of VTE (10-20mg OD). Stable coronary artery disease or peripheral artery disease (2.5mg BD with daily lose dose aspirin)

MOA: Direct factor Xa inhibitor, 33% renal clearance

Half-life: 7-11 hours (Creatine clearance >50 ml/min (not significantly impacted with reduced renal function)

Apixaban dosing: Atrial fibrillation (2.5-5mg BD). Acute VTE (10mg BD for first 7 days then 5mg BD). Secondary prevention of VTE (2.5-5mg BD). Stable coronary artery disease or peripheral artery disease (not applicable)

MOA: Direct factor Xa inhibitor, 25% renal clearance

Half-life: 8-12 hours (Creatine clearance >50 ml/min (not significantly impacted with reduced renal function)

Contraindications: Severe renal/liver impairment; active bleeding; lesion at risk of bleeding; reduced clotting factors

Interactions: heparin, clopidogrel

Others: Fondaparinux is a pentasaccharide Xa inhibitor and is used in acute coronary syndrome or in place of LMWH for prophylaxis.

Blood Products

Haematology Blood transfusion and blood products: Blood should only be given if strictly necessary and there is no alternative. Outcomes may be worse after an inappropriate transfusion. Know and use local procedures to ensure that the right blood gets to the right patient at the right time. Take blood for crossmatching from only one patient at a time. Label immediately. This minimizes risk of wrong labelling of samples. When giving blood, monitor TPR and BP every ½h. Use a dedicated line where practicable (or dedicated lumen of multilumen line)

Group and Save (G&S): Group and Save is the sample processing that determines the patient blood group (ABO and RhD) and screens for any atypical antibodies. The process takes around 40 minutes and no blood is issued. If patient blood has atypical red cell antibodies, the laboratory will do additional tests to identify them. Know your local guidelines for elective surgery. Having crossmatched blood may not be needed if a blood sample is already in the lab, with group determined, without any atypical antibodies (i.e. G&S). The process takes around 40 minutes, and no blood is issued If patient blood has atypical red cell antibodies, the laboratory will do additional tests to identify them

When is Group and Save Required? Group and Save is recommended if blood loss is not anticipated, but blood may be required should there be greater blood loss than expected. Usually, patients undergoing planned surgeries that may require transfusion, ideally have samples for group and save taken at preadmission clinics

Pink Blood Bottle: The one used to send blood samples to the transfusion laboratory, for G&S and X-Match requests

Cross Match (X-Match): A crossmatch is the final step of pretransfusion compatibility testing, to request blood from the laboratory. Crossmatching involves physically mixing of patient’s blood with the donor’s blood, in order to see if any immune reaction occurs. After ensuring that donor blood is compatible, the donor blood is issued and can be transfused to the patient. This process takes around 40 minutes, in addition to the 40 minutes required to G&S the blood. It is not possible for the laboratory to provide crossmatched blood without having processed a G&S sample first

When is Crossmatch required? Crossmatch is performed if blood loss is anticipated – the surgeon will usually inform about this

Products

Whole Blood: The only option for the first 250 years of transfusion history, but now rarely used. Red cells: (Packed to make haematocrit ~70%.) Use to correct anaemia or blood loss. 1 unit increases Hb by 10–15g/L. In anaemia, transfuse until Hb reaches at least 80g/L

Platelets: (Usually only needed if bleeding or count is 20 ≈ 109 /L. Usually only needed if bleeding or count is 20 ≈ 109 /L). 1 unit of platelets should increase the platelet count by >20 x10^9/L

Fresh frozen plasma (FFP): Used to correct clotting defects, warfarin overdosage where vitamin K would be too slow; liver disease; thrombotic thrombocytopenic purpura. It is expensive and carries all the risks of blood transfusion. Do not use as a simple volume expander

Human Albumin Solution: Produced as 4.5% or 20% protein solution and is used to replace protein. 20% albumin can be used temporarily in the hypo-protein aemic patient (e.g. liver disease; nephrosis) who are fluid overloaded, without giving an excessive salt load. Also used as replacement in abdominal paracentesis

Cryoprecipitate: (a source of fibrinogen); coagulation concentrates (self-injected in haemophilia); immunoglobulins

Complications of Transfusion

Early (within 24h): Acute haemolytic reactions (eg ABO or Rh incompatibility); anaphylaxis; bacterial contamination; febrile reactions (e.g. from HLA antibodies). Allergic reactions (itch, urticaria, mild fever); fluid overload; transfusion-related acute lung injury (TRALI, i.e. ARDS due to anti-leucocyte antibodies in donor plasma)

Delayed (after 24h): Infections (eg viruses: hepatitis B/C, HIV; bacteria; protozoa. prions); iron overload; GVHD; post-transfusion purpura—potentially lethal fall in platelet count 5–7d post-transfusion requiring specialist treatment with IV immunoglobulin and platelet transfusions.

Massive blood transfusion: This is defined as replacement of an individual’s entire blood volume (>10U) within 24h. Complications: low platelets; low Ca2+, reduced clotting factors; increased K+, hypothermia. Seek early and ongoing support from haematologist and blood bank who should advise on products and monitoring. In acute haemorrhage, use crossmatched blood, if possible, but if not, use ‘universal donor’ group O Rh-neg blood, changing to crossmatched blood as soon as possible

Transfusing Patients with Heart Failure: If Hb <50g/L with heart failure, transfusion with packed red cells is vital to restore Hb to a safe level, e.g. 60–80g/L, but must be done with care. Give each unit over 4h with furosemide (e.g., 40mg slow IV/PO; don’t mix with blood) with alternate units. Check for raised JVP and basal lung crackles; consider a CVP line

Autologous Transfusion: There is a role for patients having their own blood stored pre-op for later use. Erythropoietin can increase the yield of autologous blood in normal people. Intraoperative cell salvage with retransfusion is also being used more often, especially in cardiac, vascular, and emergency surgery. Cost-analysis shows that it may be worthwhile on an economic basis alone.

Some Liver Function Considerations for Paracetamol & Other Drugs

AST 90 U/L (<41 U/L)
GGT 110 U/L (<51 U/L)
ALP 90 U/L (30–120 U/L)
Bilirubin 12 µmol/L (<25 µmol/L)
Albumin 42 g/L (35–50 g/L)

So be wary of c**ts like Nollsy, who have been sinking piss from the age of 6, presenting to hospital with a low ALT, low albumin, and an elevated GGT, ALP, and raised bilirubin. This indicates that Nollsy has killed off enough of his liver cells, probably from putting a slab a day away with Stevo, that the hepatocytes left aren't even enough to raise ALT if there is damage. Low levels of albumin may indicate that the livers synthetic function is working as about as well as a one handed first year appreno brick layer. This protein is produced by the liver, and important in most systems.

Bilirubin is processed in the liver following the breakdown of haemoglobin into globulin chains, haem and iron , the haem portion contains two Os ( two Os = 02) easy way to remember that haem carries oxygen around the body. When haemoglobin breaks down it breaks into, wait for it... haem and globin. Haem is then oxidised by haem oxygenase into biliverdin. Haem oxygenase promotes haem degradation through breaking down the haem ring through by a reductive reaction which draws on oxygen. This produces ferric iron (FE+3) and biliverdin. Unconjugated bilirubin is then created by biliverdin reductase and transported to the liver by carrier proteins to be transferred into conjugated bilirubin through bilirubin UDP glucuronyl transferase. Unconjugated bilirubin remains water soluble until it reaches the liver and cant be transferred into conjugated (non-water soluble bilirubin), which is stored in the gallbladder and released into the small intestine as bile beforehand.

GGT (Gamma-glutamyl transferase) is an enzyme in blood that transports molecules around the body and to the liver to be metabolised. Raised levels may indicate a more chronic type picture of liver damage. This is due to the primary production location being the bile ducts. Damage to the bile ducts tends to take longer than other causes of liver injury. For example, Nollsy drinking a bottle of terps after the bottelo closes.

Transport of unconjugated bilirubin is done through binding with albumin (remember albumin is a protein produced by the liver, so if the livers f***ed and there's less albumin, there's less transport of water soluble bilirubin in the blood stream to the liver. This is partly the reason why Nollsy's eyes are f***ing yellow, got to much water soluble bilirubin in his blood because a) he produces f**k all albumin and b) when the albumin carrying bilirubin arrives his liver is that f**ked he can't metabolise it into conjugated bilirubin. Conjugation occurs through a process involving glucuronate, through a process of hydrogen exchanging facilitated by bilirubin glucuronyl transferase. This is then excreted in the bile. To have functioning glucuronyl transferase, UDP–glucose is converted to UDP–glucuronate through the donation of Hydrogen ions by NADH2, making glucuronate residues that allow bilirubin to be solubilisied for

In Nollsy's liver, however, he has f**ked so many of his hepatocytes that their are not enough hepatocytes to restore the required UDP-glucuronate as less cells = less cellular metabolic activity and less ATP dependent pathways available for re-oxidation of NADH. Less NADH+H2 will be available for UDP-glucoronate production because glucuronate dehydrogenase requires... well Hydrogen. Less UDP-glucoronate means less conjugated bilirubin which means more unconjugated bilirubin which means Nollsy looks like a Simpsons character. Because Nollsy has been hitting the sauce so hard for so long, his hepatic glucose stores are also reduced, and those cells containing glucose (glycogen) are more reluctant to spare their coin through a process known as glycogenolysis. His liver is also predisposed to store fat, rather than storing glucose as glycogen for future use. Therefore, Nollsy's liver is what we refer to as a 'Jeffrey Epstein' type of liver. He might get away with the damage for a while, but eventually the Clinton Foundation is going to f**k him from every angle.

An entire Section on Adrenaline Dosing

This page is only necessary because some absolute w**ker decided it would be a good idea to stock hospitals with vials of adrenaline differing in strength by 10x. It f***king grinds my gears how straight up stupid this is. To summarise this f**ck fight, one vial contains adrenaline diluted in the amount of 1:1000 per 1 ml. The second vial of contains a concentration of 1:10,000 adrenaline per ml. Meaning 1ml of the first vial = 1mg of adrenaline and 1ml of the second vial = 0.1mg of adrenaline. what a f**cking joke.

1:1000 means there is 1gram in 1000mls
This is the same as 1g per 1 litre (or 1000mg per 1000mls)
Taking this down to actual therapeutic doses that are used in real life clinical practice we ‘divide by 1000’ – so there will be 1mg per 1ml
There is 1mg per 1ml in a standard 1:1000 vial of Adrenaline

The second vial of adrenaline contains a 1:10,000 concentration.

1:10000 means there is 1g in 10000ml
In other words there is 1000mg in 10000ml
Take off the zeros and you are left with 1mg in 10mls
Alternatively, simply remember that 1:1000 Adrenaline is 1mg/1ml and divide by ten as 1:10000 is ten times more dilute than the 1:1000 Adrenaline.

1ml of 1:1000 = 1mg of adrenaline

1 ml of 1:10,000 = 0.1mg of adrenaline

But wait, there's more. The 1:10,000 solution comes pre-prepared in 10mls. This means that if someone is doing up a dose of adrenaline for a young child with anaphylaxis using the 1 in 10,000 vial, and draw up 1ml, they will be giving about half of the amount needed to treat this highly reversible life ending condition. Alternatively, if they give the entire 1:1000 adrenaline vial, which also comes pre-prepared in 1ml. The same patient will receive potentially x3-x4 more than the required dose. This is made even more confusing given the dose of adrenaline for patient's in cardiac arrest is 1mg.

If you're losing your sh*t trying to work this out when managing a patient in anaphylaxis.

Find a vial that say's 1:1000
If the patient look's old enough to smoke in Bali (12+), draw up half a vial into a syringe and deliver intramuscularly.
If the patient doesn't look old enough to buy a pack of darts in Bali (f**k not the best example, 5 year olds could probably get away with buying a carton of winnie golds over there) if they look like they might still be wearing a nappy, draw up 1/3 to 1/4 of the vial into a syringe and jab them intramuscularly.
Re-assess and give the same dose in 5 minutes, or until Nollsy arrives.

Click on the link for a less tradie type of explanation.

https://emergencypedia.com/2014/01/07/the-solution-to-dilution/