Pharmacokinetics - Charlie Birts

Excretion

The drug molecule is expelled in the body's liquid, solid or gaseous waste

Where is 5-HT found in the diet?

bananas

Where is tyramine found in the diet?

cheese

Metabolism

required for elimination of lipid soluble drugs as they are hard to eliminate to to their lipophilic properties. Allows a lipid-soluble drug to be converted to a water-soluble molecule Water-soluble molecules are much more readily eliminated from the body in the urine

variables affecting metabolism

species genetic environment age disease

What factors need to be considered before administering a drug?

- Age - Sex - Genetic differences - Dietary factors - Other drugs taking - Genetic predisposition - Disease

Renal excretion - pH dependent reabsorption

- All lipid soluble compounds are reabsorbed from the tubule and returned to the circulation until they are metabolised to water-soluble products -Urine has a normal pH of 6 compared with plasma at pH 7.4 - Drug concentrates in the fluid in which it is most ionised (pH. partioning) - Weak acids can be reabsorbed into the plasma - Weak bases are excreted in the urine - NaHCO3 increases urine pH (alkalinases) and enhances elimination of acids - NH4Cl reduces urine pH (acidifies) and enhances elimination of bases

Blood Brain Barrier

- BBB is a homeostatic mechanism allowing a constant CNS environment - ensures brain is not exposed to polar components in plasma - acts as a barrier as far as drugs are concerned brain endothelial cells joined by tight junctions so molecules cannot pass through - one area of brain has no BBB 'area postrema'

Rate of elimination

- Rate of elimination conforms to the First-order reaction kinetics - The rate of change in concentration is proportional to the concentration - high drug conc. = fast rate - low drug conc. = slow rate

Renal excretion - glomerular filtration

- Small molecules are filtered through pores 7-8nm diameter - The glomerular filtrate contains 20% of the plasma volume delivered to the glomerulus and so 20% of all water-soluble, low-molecular-weight compounds. - Protein-bound drug is not filtered, but some dissociates when water is reabsorbed from the tubule, and the "new" free drug is filtered the next time it is carried back to the kidney

Parkinson's disease

- decreased levels of dopamine - exogenous dopamine cannot cross BBB as not lipophilic - treatment = levodopa - precursor of dopamine - levodopa converted into dopamine in body - levodopa looks like an aa and so aa-transporters will transport it across BBB into brain where it'll be turned into dopamine by dopadecarboxylase. - dopadecarboxylase converts levodopa into dopamine in plasma before it crosses BBB - solution = carbidopa - carbidopa inhibits dopadecarboxylase in plasma, allowing levodopa to cross BBB and then dopadecarboxylase can convert levodopa into dopamine in the brain.

Routes of Administration

- oral DOESN'T PASS LIVER: - IV - sub-lingual (under tongue) - rectal

chronic administration - loading dose

-For drugs with long half-lives, the delay in the time to steady-state concentrations may be unacceptable - The delay can be avoided by giving a large first dose (loading dose) which has the effect of "topping-up" the apparent volume of distribution IV Loading dose = Css x V ORAL Css x V/F

Renal excretion - renal tubular secretion

-There are different transporters for acids and bases - An active process that can strip a drug from protein binding sites - Many drug conjugates are substrates for active secretion

Routes of excretion - kidneys

1. Bowmans capsule filters unbound drug into nephrons. 2. active secretion of drug through proximal tubule by active transporters - drug moved across membrane out of blood and into urine 3. reabsorption of drug back into blood through loop of Henle (dependent on pH of urine and pKa of drug)

What is pharmacokinetics important for understanding?

1. Time of onset of action 2. Intensity and duration of effect 3. Accumulation 4. Inter-individual differences 5. Intra-individual differences 6. Drug interactions 7. Inter-species differences

What does rate of distribution depend on?

1. diffusion rate across membranes 2. perfusion rate of tissue that take up the drug

Renal excretion

1. glomerular filtration 2. pH dependent reabsorption 3. renal tubular secretion

What are factors that affect absorption?

1. lipid solubility (Rapid from gut, slow from intra-muscular) 2. ionisation (Poor for ionic drugs from gut) 3. formulation (May limit rate of absorption May limit extent of absorption) 4. gastro-intestinal function (May limit rate of delivery to site of absorption, May limit time available for absorption) 5. First-pass metabolism (May limit extent of absorption)

What are commons for low bioavailability?

1.Decomposition in the gut lumen 2.First-pass metabolism in the gut wall 3.First-pass metabolism in liver 4.Not absorbed from the gut lumen 5.Tablet does not completely dissolve

Metabolism - phase 2 (sulphation)

A sulphate group -SO3- replaces the H in R-OH, ArOH, ArNH2, ArNHOH to give very water soluble inactive - usually - excretory products catalysed by Sulpho-transferase which is found in cytosol liver and gut.

How to measure bioavailability (F)

AUC (plasma conc. time graph) IV = AUC Oral = F = AUC(oral) AUC (iv)

AUC

AUC = the total amount of drug that has entered the general circulation units = conc. x time

What are the key pharmacokinetic processes?

Absorption Distribution Metabolism Excretion

Metabolism - phase 2 (acetylation)

Acetate CH3CO- replaces the H in -NH2, -SO2NH2, -NHNH2 - inactivates the functional group - but no real increase in water solubility Requires activation of acetate (AcetylCoA) N-acetyl transferase transfers the acetate to the drug

metabolism reactions

Aim - make drug molecule more water-soluble for excretion phase 1 reactions = oxidation reactions phase 2 = conjugation reaction (covalently bonding phase 1 metabolite produced and endogenous product in the body for excretion)

plasma clearance

CL = dose x F AUC - the volume of plasma cleared of drug per minute (or per hour) e.g. ml/min or L/h - is the parameter that best reflects the relationship between the blood and the organs of elimination - depends on how good the body is at eliminating that drug - is a specific value for each drug CLplasma = CLmetabolic + CLrenal

Routes of drug excretion

DRUG: - volatile -> exhaled - water soluble -> urine - lipid soluble -> metabolism METABOLITE: - Volatile -> exhaled - small -> urine - large -> bile

oral administration

Delay in absorption due to gastric emptying. Less lipid soluble = slow absorption more lipid soluble = fast absorption F = variable: - first pass metabolism

bililary excretion

Drugs are eliminated in bile mixed with bile salts Main route of excretion for large drug molecules Elimination depends on the release of bile from the gall-bladder - The drug may be reabsorbed from the intestine and carried back to the liver via the hepatic portal vein in entero-hepatic circulation Entero-hepatic circulation of the drug helps to maintain concentrations in the systemic circulation

metabolism factors - age

Elderly: •Size of liver and blood flow decreases with age •Reduced phase 1 metabolic reactions especially relevant when prescribing lipid soluble drugs (undergo extensive phase 1 metabolism) Young: •Drug metabolising enzymes are immature in the neonatal liver - glucuronidation •First-pass metabolism is low

F equations

F - is the fraction of an oral dose which reaches the systemic circulation as the parent compound SAME IV AND ORAL DOSE F = AUC(oral) AUC(iv) DIFFERENT IV AND ORAL DOSE F = AUC(oral) x Dose(iv) AUC(iv) Dose(oral)

Metabolism - phase 2 (glucuronidation)

Glucuronic acid C6H9O6 replaces the H in -OH, -COOH, -NH2, -SO2NH-, -SH to give water soluble inactive products Requires activation of carbohydrate (UDPGA) - diphopshateglucuronic acid UDPGT 'UDP-Glucuronyl transferase' will transfer UDPGA on to phase 1 metabolite

What determines the shape of the concentration-time curve?

IV - gradient = rate of distribution - eqm = extent of distribution - terminal phase gradient = elimination blue drug = rapid distribution ORAL - gradient = rate of absorption - peak plasma conc. = extent of absorption - terminal phase gradient = elimination

phases of drug distribution on a plasma conc. time graph

IV dose so no absorption

What is an important interaction in first pass metabolism?

Important interactions are when inhibition of an enzyme increases the bioavailability of a drug e.g Mono-amine oxidase: -MAO breaks down amines in gut wall -MAOI's (antidepressant) inhibit MAO's -amines (tyramine) levels increase and affect cardiac function - drug increasing F of another drug

Rate of elimination equation

K units = min-1 The terminal rate of decrease in plasma concentrations after either an oral or i.v. dose k = CL V The rate of elimination is inversely proportional to the half-life (t½)

Non-P450 oxidations enzymes

MAO Alcohol Dehydrogenases

multiple dosing

Maintain a constant concentration in the blood, by repeated oral dosing Css = Dose x F dose interval x CL

How is a drug absorbed?

Membrane pores - small drugs with low Mr or small ions Diffusion through membrane - lipid soluble molecules Carrier mediated - drug must resemble natural ligand or substrate in order for carrier protein to transport it.

Routes of Administration with F

Oral - F = variable IV - F=1 Subcutaneous - F=1 Intramuscular - F=1 Inhalation - high F Trans-dermal - low F Nasal - high F

General plasma proteins

Plasma albumin binds acidic (and basic) drugs a1-acid glycoprotein binds basic drugs

first pass metabolism

Point 5. of factors affecting absorption Orally administered drug: 1. passes into stomach (low pH) 2. gastric emptying means drug now in intestine - lumen of gut filled with enzymes that can change chemical structure of drug e.g. esterases 3. drug needs to pass gut wall to reach hepatic portal vein (gut wall has more enzymes) 4. drug reaches hepatic portal vein and enters liver (more enzymes in liver) 5. drug passes from liver to hepatic vein and into circulation

procaine to procainamide

Procaine is acted upon by ESTERASES, FAST acting = rapid hydrolysis and short duration of action Procainamide is acted upon by AMIDASES , SLOW acting = slow hydrolysis and longer duration of action

What is absorption?

Processes that take place between the site of administration and the site of measurement

What factors affect drug distribution?

RATE - Rate of partitioning into tissues (how fast can drug diffuse into tissue) - organ blood flow - affected by cardiac output EXTENT - Plasma protein binding - Tissue composition of body

Distribution

RATE - Time taken between dosing and equilibrium of plasma:tissues EXTENT - Ratio of drug in tissues compared to plasma at equilibrium Tissue 2 has a faster rate and extent of distribution as the time taken to reach eqm. was faster than tissue 1 and the ratio of drug in the tissue at eqm was greater in tissue 2 than 1.

What is the rate and extent of pharmacokinetics?

Rate = rate of absorption - how quick is the drug absorbed? Extent = how much of the drug is being absorbed?

Elimination

Removal of the drug from the body and may involve: •Metabolism (where the drug is transformed into a different molecule) •Excretion (the drug molecule is expelled in the body's liquid, solid or gaseous waste)

What is drug distribution?

The rate and extent of movement of the parent drug from the blood into the tissues after administration and its return from the tissues into the blood during elimination

Apparent volume of distribution

V or VD low V = plasma bound - cannot cross membrane and distribute) high V = more lipophilic - easier to cross membrane so higher volume of distribution one compartment model: V = dose/C0 C0 = plasma conc. of drug after its been distributed two compartment model: V = dose/y-intercept - is dependent upon the physicochemical properties of the drug - is an indication of the extent of tissue uptake of the drug (A large/extensive distribution gives a large V) - is independent of dose - is the volume of plasma in which the dose appears to have been dissolved

What is V

Volume of distribution V depends on: total in tissues total in plasma or tissue binding plasma binding

two compartment model of distribution

a - is the initial rate of decrease in plasma concentrations after an i.v. bolus dose

Metabolism - phase 2

conjugation reactions Formation of a covalent bond between the PHASE 1 metabolite and an endogenous substrate

elimination slope on a plasma conc. time graph

distribution of drugs all different but the rate of elimination is the same.

drug binding equilibrium

drug + protein <---> drug-protein complex binding is: - general - low affinity - high capacity - saturable at high conc. - not involved in drug mode of action - acts as a depot or reservoir of drug

Metabolism - phase 1

enzymes involved = cytochrome P450 (all contain Fe) - membrane-bound enzymes found in liver so liver main site for metabolism - belong to general class of enzymes called monooxygenases - bind drug substrate to O2 or CO2 (catalyses oxidation of drug) - 30 families

hydrolysis reactions

esters amides enzymes - Plasma pseudocholinesterase - Tissue esterases - Tissue amidases

Distribution of drugs - free drugs

free drug = unbound drug free drug can be ionised or unionised only unionised free drug can pass a membrane

Chronic administration

long term administration - Continuous intravenous infusion - Maintain a constant/stable concentration at site of action - Plasma (and tissue) concentrations increase until the rate of elimination is equal to the rate of input (or dosage) when a "steady state" (Css) is reached. - Css is the steady state concentration Css = rate of infusion clearance rate in = rate out t1/2 x 5 = Css

Routes of excretion

lungs - volatile compounds only kidneys - urine 1. low Mr (20kDa) + water soluble = glomerular filtration 2. Active secretion + filtration of unbound drug = tubular secretion 3. reabsorption - affected by urine pH Bile 1. High Mr (>50kDa) 2. Biliary metabolites may be metabolised in gut lumen and reabsorbed

Ionisation of drugs

need to consider: pKa of drug pH of solution strong acid = low pKa strong base = high pKa 50% ionisation when pH = pKa

Consequences of drug metabolism

once the drug has been metabolised it will be a different compound and will have: - no activity - similar activity - different activity - toxological action Phase 1 metabolites: - normally inactive - normally undergo phase 2 metabolism prior to excretion Phase 2 metabolites - nearly always inactive - much more water soluble

Routes of drug administration

oral - has to pass liver and so undergoes metabolic changes intravenous - directly into bloodstream so bypasses liver and kidneys Inhalation - e.g. steroids in inhaler - liver and kidneys very good at eliminating drugs

reduction enzymes

p450 reductase in liver gut flora

formulation

point 3. of factors affecting absorption - Drug needs to dissolve to be absorbed conventional formulation - repeated dose sustained formulation - sustains in therapeutic range for longer period of tike

gastro-intestinal function

point 4. of factors affecting absorption Gastric emptying - relies on process of food moving from stomach into intestine factors affecting gastric emptying: - temperature - food - high fat content - calories in meal

half-life

t1/2 = how long for drug conc. to half t1/2 = 0.693 k k = rate of elimination

Drug entry into the brain

the more lipid soluble a drug is, the better it is as getting into the brain

Bioavailability (F)

the rate at and the extent to which a nutrient is absorbed and used IV administration: F=1

What is pharmacokinetics?

what the body does to the drug

What is pharmacodynamics?

what the drug does to the body