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Pharmacology (Fach) / Pharmacogenetics (Lektion)

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• Def. Pharmacodynamics "What the drug does to the body" --> Drug action (specific to drug)
• Def. Pharmacokinetics "What the body does to the drug" --> Drug handling (non-specific)
• ADME scheme Absorption - outside of body to the blood Distribution - from the blood to the tissues Metabolism - from the blood into metabolites  Excretion - from the blood to outside of the body 
• Enteral formulations 1. Tablets - compressed, 5-10% active drug, 90% fillers (binders, lubricants, disaggregants), enteric coating, sustained/extended/modified release (osmotic core, permeable coating)  2. Capsules - gelatinous capsules, controllable disintegration speed (slow- and fast.dissolving particles) 3. Liquid/Syrup - possible faster absorption  4. Suppository - vomiting patients
• Parenteral formulations (injectable) 1. Liquid - Vials/ampules/cartridges, pre-filled syringes 2. Lyphilised (freeze dried)- dry powder which needs to be reconstituted with liquid
• Topical formulations (local) 1. Cutaneous - cream, ointment, gel, paste  2. Inhaled 3. Others - Eye drops, nasal sprays, vaginal/urethral suppositories 
• Ways of administering a drug (3) 1. Enteral formulation (oral or by the gut) 2. Parenteral formulation (injectable) 3. Topical formulations (local)
• Oral route of administration 1. Gastric emptying - for most drugs the greatest absorption is in the intestine --> gastric phase delays the absorption  2. Hepatic portal circulation - Oral medication --> intestinal tract --> portal vein to liver --> hepatic vein to systamic circulation via heart + lungs --> Hepatic artery  --> First-pass metabolism
• Distribution of drugs - short distances: via diffusion (within a body compartment) - long diatnces: through the bloodstream --> depends on perfusion of the organ
• Well-/Poor-perfused tissues 1. Well-perfused: Liver, Lungs, Kidneys, Brain, Heart 2. Poorly perfused: Fat, Bone, Muscle 
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• blood circulation oxygen-rich blood and oxygen-poor blood (Ways) 1. From heart:   a) Systematic circulation: Aorta to head and arms/stomach and intestines/lower body and legs, hepatic artery to liver, renal artery to kideys  b) Pulmonary circulation: Pulmonary artery to lungs and pulmonary vein back to heart  2. Back to heart: a) Lower body and legs/Kidneys (renal vein)/Stomach an intestines (hepatic portal vein) to liver,  to inferior vena cava (terminates in the heart) b) Head and arms into superior vena cava (terminates into heart) --> Superior and inferior vena cava join 
• Plasma protein binding after IV dose - Reversible binding to plasma proteins (Albumin - acidic drugs; alpha-1 acid glycoprotein - basic and lipophilic drugs) --> can't cross membranes and pharmacologically inactive  - as free plasma levels fall, more bound drug is released from the complex 
• Def. Vd "The volume of body fluids into which the drug appears to have distributed" --> fixed characteristic of each drug and independent of dose  - C = mass/volume - C(plasma) = drug dose/Vd - Vd = drug dose/C(plasma) --> drug remains in plasma = high C; drug in plasma + interstitium = lower C, more diluted ; drug in plasma, interstititum, intracellular = low C, diluted 
• Problems with the Vd - uneven drug distribution due to absorption by any compartment which isn't necessarily the targeted one can lead to large Vd --> plasma concentration doesn't reflect the tissue concentration 
• Blood-Brain barrier (BBB) - excludes large, water-soluble molecules from the brain --> only small, lipid.soluble molecules can access it - maintained by tight junctions and astrocytes 
• Drug metabolism - Inactivation of toxins by making them more water-soluble in the liver and excretion by the kidneys --> major source of inter-patient variability
• First-pass metabolism (oral drugs) 1. degradation stomach/gut lumen/gut wall  2. Absorption into capillaries and transport to liver via hepatic portal vein  3. Transport to general circulation via hepatic vein --> repeated passing of the liver (2nd/3rd/... pass metabolism)
• Phases Hepatic metabolism Phase 1: Oxidation, reduction, hydrolysis,... of the drug into derivatives (Inactivation) --> catalysed by cytochrome P450 isoenzymes in SER of hepatocytes  Phase 2: Conjugation with glucoronide/... of the derivatives (Solubilisation) for renal excretion by secondary enzymes in hepatocyte cytoplasm 
• Consequences of metabolism (4) 1. Conversion of drugs into less active metabolites  2. Conversion of inactive drug (pro-drugs) into active drugs 3. Generation of toxic metabolites  4. Affection of pharmacogenetic differences
• Examples pharmacogenetics differences (2) 1. Metaprolol and CYP2D6 - 5-10% of the population have different CYP2D6 genes and different rates of metabolism of metaprolol (beta-bocker) 2. Alcohol : Ethanol -->(Alcoholdehydrogenase - ADH) Acetaldehyde -->(Aldehydedehdrogenase - ALDH) Acetale  --> in the far east 80% fast ADH and 50% slow ALDH
• Parents route of administration - avoids 1st-pass metabolism 1. Intravenous (IV) - instantaneous acces, high peak concentration 2. Intramuscular (IM) - intermediate onset 3. Subcutaneous (SC) - very slow onset 4. Others - Intraarterial (IA), intraosseous, epidural,etc. 
• Topical route of administration 1. Transdermal - very slow onset, prolonged action --> requires highly lipophilic drug 2. Inhaled - rapid delivery, local action
• Drug Absorption (how drugs cross membranes) - drug absorption into the general circulation generally requires a dissolved drug to penetrate lipid membranes and epithelial barriers  1. Lipid-soluble drug - diffusion through lipid membrane 2. Water-soluble drug (mol. weight <200) - diffusion through acqueous channels or carrier (if it ressembles a natural molecule) 3. Water.soluble drug (mol. weight >200) - diffusion through intercellular junctions
• Fick's Law of Diffusion - simple (passive) diffusion across a membrane depends on: 1. Concentration gradient (C2-C1) 2. Area (A) of available membrane 3. Thickness (T) of membrane 4. Permeability of membrane Diffusion = ((C1-C2) x A x P)/T --> ionic charge and pH can also play a role!
• Influence of ionisation on absorption 1. Acid drugs are best absorped in acidic environment --> mainly non-ionised  --> absorped in stomach 2. Basic drugs are best absorped in basic environment --> mainly non-ionised  --> absorped in intestine
• Bioavailability (F) of drugs - F always between 0-1/0-100% --> F(IV) = 1 - Bioavailable dose = D x F --> 10mg x 0,6 = 6mg bioavailable D= administered dose 
• Factors influencing the oral bioavailability 1- Extend of drug solubility 2. Extend of drug binding to gut content 3. Extend of drug degradation (gut, liver) 4. Extend of drug absorption 
• Routes of drug elimination (Oversight) 1. Drug Volatile --> Exhaled  Water soluble --> Urine Lipid soluble --> Metabolism (solubilisation) 2. Metabolite Small --> Urine Large (<500Da) --> Bile
• Routes of Excretion - Lungs - Volatile compounds only --> gaseous general anaestetics, alcohol  - Elimination dependent on: Extend of distribution to other organs, rate and depth of ventilation, air-blood partition
• Route of drug excretion - Bile - Large drugs (<500Da) and glucoronide drug conjugates which are eliminated in bile mixed with bile salts - Elimination dependent on release of bile from the gale bladder
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• Route of drug elimination (Kidney) Basic stept in urine formation: 1. Filtration  - small molecules (wanted substances, unwanted substances) are filtered into nephrons --> large drugs aren't 2. Reabsorption - wanted substances and lipophilic get reabsorbed into the circulation (diffussion through the tubule membrane) 3. Secretion additonal waste can be actively secreted by tubular transporters into tubules (e.g. drug metabolites conjugated with glucoronide) 4. Excretion - unwanted substances are left in urine and excreted
• Drug elimination of lipophilic drug - metabolism in liver, gut wall, lung etc., followed vy excretion in urine or bile
• Pharmacodynamic interactions - often wanted to enhance a wanted effect --> e.g. codeine (opoid) and paracetamol (NDAID) to reduce pain (synergistic action)
• Pharmacokinetic interactions (4) - interference of one drug with the ADSE of another, altering the concentration and thus the activity  1. Interaction affecting Absorption - Antacids: neutralise stomach pH --> alter absorption of some drugs (e.g. weak acids which will be ionised) - Drugs that increase/decrease gut motility --> alter gut transit time of drugs 2. Interaction affecting Distribution - Plasma protein binding: drugs compete for binding sites leading to a higher free concentration of one or both drugs 3. Interaction affecting Metabolism - CYP450 induction and inhibition: a) Induction: Drug A induces CYP gene expression -->increased CYP metabolism of drugA and of other drug b) Inhibition: Drug A inhibits CYP metabolism of drug B (or both are inhibited) --> Inhibition of the warfarin metabolism (antocoagulant) after taking the H2 antihistamine Cimetidine (inhibits many CYP450 oisoenzymes) --> Increase of clotting time (bleeding) 4. Interaction affecting Excretion - altered by pH in the kidney tubule  - e.g. alkalinising the urine increases the excretion of weak acid drugs (are ionised in alkaline pH and not reabsorbed into blood)
• Drugs likely to cause interactions 1. Inducers - Ethanol, Phenobarbitone & Phenytoin (antiepileptics) 2. Inhibitors - Cimetidine (H2 antihistamin), Nicotine, Omeprazole (proton pump inhibitor), Grapefruit juice 3. Substrates  - Theophylline (asthma), Warfarin (anticoagulant),...
• Calculation Bioavailable dose (D) D = F x drug dose  --> 0,6 x 30mg = 18mg of the given drug dose is bioavailable
• Calculation Vd referred to patient's weight Distribution into total body water = Vd x kg --> 0,6l/kg x 60kg = 36l 
• Elimination - Zero order kinetics - rate of elimination of a drug is constant regardless of Cp (i.e. constant amount of drug eliminated per unit time) --> Cp decreases linearly with time --> e.g. ethanol (1 unit (8g)/h), aspirin, heparin, warfarin 
• Elimination - First order kinetics - For most drugs, the same proportion of drug concentration falls in each unit of time (not the same amount!) --> exponential elimination curve  --> C(drug) high = high rate of drug elimination (clearance volume contains a lot of drug) --> C(drug) = low rate of drug elimination (clearance volume contains less drug)
• Clearance (CL) - The volume of blood from which the drug is cleared per unit of time (ml/min) in a particular organ - Calculation:  CL(total) = CL(Liver) + CL(Kidney) + CL(Lungs) + CL(n)
• Calculation Rate of elimination Rate of elimination (mg/h) = Clearance (CL in l/h) x Plasma concentration (Cp in mg/l)
• Steady-state plasma concentration (Css) - Increase of Cp until drug has fully distributed through its Vd --> Css --> Rate of drug elimination = rate of drug infusion
• Variations in Cp Bolus doses 1. Single fixed dose - single peak in Cp followed by a continuous decline 2. Repeated fixed dose (oral) - oscillations in Cp  3. Dose-interval relation - a bigger dose at a longer interval doesn't change the Css, only the soze of oscillation around the Css
• Dose rate - Dose-rate (mg/h) = Dose (mg)/Interval (h) --> determines the Cp --> too frequent is unconvenient for the patient, too long intervals cause bigger variations in Cp
• Calculation maintenance doses (oral/IV) - Rate of dosing (mg/h) = CL x Css = Rate of elimination  - CL x Css = (D x F) / T
• How long to each Css? 3 T1/2 = time to reach 88% of Css (ca. 90) 4 T1/2 = 94% (ca. 90) 5 T1/2 = 95% (ca. 95)
• Calculation Loading dose - for drugs with long half lives (<24h), the time to achieve desired Cp may be unacceptable long. That's why a large first dose (loading dose) can be given, followed by the usual maintenance dose at usual intervals  - Loading dose x F = Vd x Css 
• Def. prodrug "Inactive precursor thats metabolised in one or more active metabolites"
• Adverse effects/Side effects/Medical errors 1. Adverse effects - harmful or undesiredeffect of a drug  2. Side effect - adverse affect thatÄs judged to be secondary to the main effect 3. Medical error - administration of an incorrect drug or unsuitable dose 

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