General Principles In Pharmacology

GENERAL PRINCIPLES IN PHARMACOLOGY Maria Victoria M. Villarica RN, MD, DPPS, FPSECP Department of Pharmacology Our Lady of Fatima College of Medicine

Objectives: 1. Define Pharmacology and its branches 2. Discuss principles of pharmacokinetics and pharmacodynamics 3. Differentiate different types of agonists vs. antagonists 4. Discuss the 5 transmembrane receptor signaling mechanism 5. Discuss variations of drug responsiveness

Evolution of Pharmacology • 17th century – materia medica  precursor to

pharmacology - science of drug preparation and medical use of drugs • 18th – 19th century – Francois Magendie and Claude Bernard – developed methods of experimental physiology and pharmacology • 60 yrs ago ( 1950s) – concept of rational therapeutics - controlled clinical trials to evaluate therapeutic claims

Goal of therapeutics: Use of medicine to achieve a desired beneficial effect with minimal adverse effects Rational Drug Use (WHO conference of experts – Nairobi 1985) - key words: appropriate to clinical needs doses that meet clinical requirements adequate period of time lowest cost

• Alternative health care – promoted for health and not as a

drug - botanicals (herbs and plant extracts) • Complimentary medicine Critical thinking about public health issues Greater impurities in botanicals “ no artificial separation between scientific medicine” and “alternative” or “complimentary” medicine. - “ALL substances” should undergo the same standard of efficacy and safety

Basic Principles: PHARMACOLOGY AND ITS BRANCHES: • Pharmacology – study of substances

that interact with living systems to produce an effect - binds with regulatory proteins (inhibit or activate body processes)

• Pharmacotherapeutics/ Medical

Pharmacology / Clinical Therapeutics –drugs used in the diagnosis, treatment and prevention of diseases

• Toxicology – undesirable effects of

chemicals on living systems (individual cells to humans to complex ecosystem)

• Pharmacognosy – drugs in their

unaltered state

• Pharmacoeconomics – health economics; comparing the value of 1 pharmaceutical drug/therapy to another; “cost and effect” • Pharmacogenomics – “personalized medicine”

- study of genetic factors that underlie variation in drug response; recognition that more than 1 variant may contribute to variation in drug response - fate of drug in the body depends in certain cases upon a discrete genetic trait - decoding the genomes ( siRNAs, miRNAs, ANOs) - genome wide association studies - genetic variations in enzymes, transporters, immune system variations, polygenic effects - Clinical Pharmacogenetics Implementation Consortium

2 basic pharmacologic concepts • Pharmacokinetics • Pharmacodynamics

Basic Pharmacologic concepts: Pharmacokinetics – body → drug - “ dose - concentration” relationship 4 processes: A. absorption B. distribution C. metabolism D. elimination

1.

4 basic processes of pharmacokinetics A. ABSORPTION – rate → circulating fluids factors: drug solubility, drug concentration, local conditions, blood flow, surface area e.g. hydrophilic; lipophilic; P-glycoprotein reverse transporter

Routes of drug administration: a. enteral – oral , rectal b. parenteral – IV, IM, SC, intraperitoneal, intrathecal, intraarterial c. topical/percutaneous – inhalation, optic, otic

B. DISTRIBUTION – site of administration →site of action Permeation – how a drug transverses the plasma membrane - (A) aqueous diffusion (interstitial spaces, cytosol) – capillaries of the brain, the testes and other tissues; permit molecules as large as MW 20,000-30,000; driven by a concentration gradient - (B) lipid diffusion – lipid:aqueous partition coefficient of drug - (C) special carriers – too large or too insoluble in lipid (active transport and facilitated diffusion) - selective, saturable and inhibitable - (D) endocytosis (Vit B12 and iron) /exocytosis (neurotransmitters)

Ionization of weak acids and weak bases • Ionization of drugs may markedly reduce their ability to permeate

membranes • Weak acid – neutral molecule that can reversibly dissociate into an anion (-) and a proton (H+) - protonated form is lipid soluble - weak acid will be lipid soluble in an acidic pH • Weak base – neutral molecule that can form a cation (+) by combining with a proton - unprotonated form is the neutral form - basic drug will be lipid soluble in an alkaline pH - amine containing molecules (3 atoms: carbon and hydrogen – primary/secondary/tertiary –undergoes reversible protanation while quarternary – permanently charged;poorly lipid soluble)

Distribution: • Factors: size of the organ, blood flow, solubility, binding

• Factors affecting protein binding: affects total drug

concentration a. albumin concentration – phenytoin, salicylates, disopyramide b. Alpha1-acid glycoprotein concentration – quinidine, lidocaine, propanolol c. capacity-limited protein binding – saturation at higher concentrations; prednisolone, salicylates d. binding to RBCs – cyclosporine, tacrolimus Clinical importance of plasma protein binding is only to help interpretation of drug concentrations but does not really affect clearance

C. METABOLISM– biotransformation; (liver) Factors (individual differences): a. Genetic factors – polymorphisms b. Commensal gut microbiota c. Diet and environmental factors d. Age and sex e. Drug-drug interactions during metabolism: a. Inducer b. Inhibitor

f. Diseases

2 phases: 1. phase I – introduce or unmask a functional group (-OH, -NH2, -SH ) e.g. dealkylation, oxidation, reduction, hydrolysis, deamination, cytochrome p450 2. Phase II – formation of covalent linkage between the functional group on the parent compound; combines to form a highly polar conjugate ; cytosol e.g. glucoronidation, sulfation, acetylation OR “sequential biotransformation”

Phase I

Phase II

Metabolism of Drugs to Toxic products

D. EXCRETION – elimination; kidneys Factors: renal disease adjust urine pH to accelerate excretion of the drug

2 Basic Parameters of Pharmacokinetics 1.

Volume of distribution (Vd) – amount of apparent space in the body able to contain a drug (homogeneously in the blood, plasma, or water)

Vd = amt of drug in body / concentration (C) the higher the Vd, the higher is the concentration of a drug in the tissues and lower plasma concentration the lower the Vd, the lower is the concentration of a drug in the tissues but higher in plasma concentration

Clearance (Cl) – ability of the body to eliminate a drug - total systemic clearance (kidney, liver and other organs) - single most important factor determining drug concentrations CL = rate of elimination / C : for most drugs, clearance is constant over the concentration range …. → rate of elimination = CL x C “first order elimination” – a constant fraction of drug is eliminated/unit of time; not saturated - AUC

2.

Clearance: A. capacity-limited elimination –varies, depending upon concentration of the drug that is achieved; saturable; dose or concentration dependent; nonlinear or MichaelisMenten elimination e.g. phenytoin, ethanol, aspirin rate of elimination =

Vmax x C Km x C Vmax – maximum elimination capacity Km – drug conc. at w/c rate of elimination is 50% of Vmax “pseudo-zero order kinetics” – elimination is independent of concentration

B. Flow dependent elimination – dependent on the rate of delivery of the drug to the organ “high extraction” drugs (Table 4-7) - no effect in liver dysfunction but there’s an effect with cardiac and pulmonary diseases

- no effect in liver dysfunction but there’s an effect with cardiac and pulmonary diseases

Other parameters: • Half-life (t ½) – time required to change the amount

of drug by ½ t ½ = 0.7 x Vd CL

- indicates: a. time required to attain 50% of or decay 50% from steady state b. useful in designing drug dosage regimens (frequency)

• The volume of distribution and Cl of a subject is 80L and 4

L/hr. The half life is approximately: t ½ = 0.7 x Vd Cl = 0.7 x 80 L 4 L/hr = 14 hrs.

• Drug A is given to a 50 kg patient with history of palpitations.

The Vd of this drug is 30 L, the target concentration is 2 mg/L and the Cl is 5 L/hr. When will the concentration of Drug A be reduced to 50%? • T ½ = 0.7 X Vd Cl = 0.7 X 30 L 5 L/hr = 4.2/hr

• Drug C has a Vd of 80 L and a t ½ of 40 hrs. How much of

the drug is cleared per hour? • Cl ? • Half life (t ½) = 0.7 X Vd Cl so, to get Cl = 0.7 X Vd t½ = 0.7 X 80 L 40 hrs = 1.4 L/hr

Half-life: • 4 half-lives must elapse after starting a drug-dosing regimen

before FULL effects will be seen • Therefore, if dosing interval is shorter than 4 half-lives, drug accumulation will be detectable

STEADY STATE PLASMA CONCENTRATION, OR PLATEAU 1ST HALF LIFE = 50% 4th HALF LIFE: 94% 2ND HALF LIFE =75 % 5TH HALF LIFE “ 97 % 3RD HALF LIFE = 88% 6TH HALF LIFE: 99 %

• Drug accumulation – drug interval is shorter than 4 t ½ ,

accumulation is detectable Accumulation factor =

1 1 – fraction remaining

• Bioavailability – fraction of unchanged drug reaching the circulation; extent of absorption varies - common measure: Area under the curve (AUC) ( 1st order elimination) - affected by: a. extent of absorption b. first-pass elimination – extraction ratio c. rate of absorption –determined by site of administration and the drug formulation; zero order vs. first order kinetics

(systemic clearance is not affected by bioavailability but clearance can markedly affect the extent of bioavailability)

Reasons for diff. routes of drug administration • Convenience • Maximize concentration at the site of action and minimize it

elsewhere • Prolong duration of drug absorption • Avoid first-pass effect

Time course of drug effect Relationship of drug effects to plasma concentration •Immediate effects – drug effects are directly related to plasma concentration but does not necessarily mean effects simple parallel time course of concentrations - high initial concentration in relation to C50 (short t ½ but > 24hrs. effect); effect produced is related to the plasma concentration •Delayed effects – distribution/ dissociation from receptors / synthesis of new proteins / slow turnover of substances •Cumulative effects – intermittent vs infusion

Dosage Regimen • Loading dose

= Vd x desired plasma conc. - initial dose that is given in bolus (drugs with long t ½)

• Maintenance dose

= Cl x desired plasma conc. X time - dose that is given at regular intervals to maintain a steady state  (rate in (dosing rate) = rate out (rate of elimination)

• Intermittent dose:

peak – high pts. of fluctuations (toxic effects) troughs – low pts. of fluctuations (lack drug of effects)

Case A Ms X was admitted at Fatima Medical Center and was given an antibiotic for her pneumonia. The CL and Vd of Ms X are 80 ml/min and 40 L, respectively. What maintenance dosage should be administered every 6 hrs to obtain a steady state plasma conc of 4 mg/L? steady state : rate in = rate out dosage = plasma concentration x CL x time = 4 mg/L x 0.08 L/min = 0.32 mg/min = 0.32 mg/min x 60 min/hr x 6 hrs. = 115.2 mg/dose every 6 hrs.

Case B What is the loading dose to achieve the therapeutic plasma concentration of 4 mg/L? Loading dose = Vd x plasma conc. = 40 L x 4 mg/L = 160 mg

• What is the maintenance dose of drug A using the dosing

interval based on the half-life? ( Vd = 30 L • Cl = 5 L/hr; plasma conc = 3mg/L; t ½ = 4.2 hr ) • Maintenance dose = plasma conc. X Cl X time = 3 mg/L X 5 L/hr X 4.2 hr = 60 mg

Pharmacodynamic – action of drug to the body; “concentration –effect” relationship

Pharmacodynamic Principles • Drug (D) + Receptor-effector (R)  drug-receptor-effector complex effect • D + R drug-receptor (D-R) complex effector molecule

effect • D + R (D-R) complex

activation of coupling molecule effector molecule effect

• Inhibition of metabolism of endogenous activator

increased activator action increased effect

Receptors: • Largely determine the quantitative relations between dose or

concentration of a drug and pharmacologic effects • Responsible for selectivity of drug action • Mediate the actions of pharmacologic agonists and antagonists inert binding site – binds with a drug w/out initiating events leading to any of the drug’s effects; buffers concentration gradient that drives diffusion (albumin and α1-acid glycoprotein – non regulatory molecules) active site – recognition site; specific binding region that initiates drug effect • Effectors – molecules that translate the drug-receptor interaction into a

change in cellular activity

• (A) Agonist – bind and activate the

receptor • (B) Antagonist – bind to a receptor, compete with and prevent binding by other molecules • Allosteric – bind to the same receptor molecule (C) activator but do not prevent binding of the agonist or (D) inhibitor inhibit the action of the agonist molecule

• A receptor is postulated to exist in the Ri

(nonfunctional form) and Ra (activated form) • Constitutive activity (physiologic effect) – some exist in Ra, even in the absence of an agonist • Full agonist – activate the receptor to the maximum extent • Partial agonist – do not evoke a great response; do not stabilize the Ra-D configuration so that a significant fraction exists in Ri-D pool (low intrinsic efficacy)(ex: pindolol) • Neutral antagonist – presence of an antagonist at the receptor will block access of agonist to the receptor • Inverse agonist – drug has stronger affinity to Ri and stabilizes the Ri-D pool (ex: benzodiazepines)

Principles of receptor- effector interaction:

a.

Concentration effect curve – response to low dose increases in direct proportion to dose; however, as dose increases, the response increment diminishes that finally, doses may be reached at w/c no further increase in response can be achieved

Emax – maximal effect produced by a drug EC50 – concentration of a drug that produces 50% effect Bmax – total concentration of receptor sites Kd – equilibrium dissociation constant “If Kd is high, affinity for binding is low”

b. Receptor-effector coupling – transduction process that occurs between occupancy of the receptors and drug response

Receptors • spare receptors – do not have to bind with the drug to

produce a maximal effect; maximal effect is produced with less than maximal occupation of the receptors (Kd > EC50)

Pharmacologic agonist • full agonists - drugs that activate the receptor by binding

to it • partial agonists – drugs that bind with a receptor but produce a smaller effect at full dosage than a full agonist even when it has saturated the receptors - due to low intrinsic efficacy

Pharmacologic antagonists - drugs that bind with the receptor and prevents a drug agonist from binding and activating the receptor ; does not inactivate the receptor

•

classes: a. competitive antagonist – can be overcome by increasing the concentration of the agonist b. irreversible antagonist – cannot be overcome; unavailable; duration of action is relatively independent of its own rate of elimination and more dependent on rate of turnover of receptor molecule c. chemical antagonist – drug counters the effect of another by binding the drug and blocking its action; (dimecaprol and heavy metals; protamine and heparin) d. physiologic antagonist – drug counters the effect of another by binding to another receptor, causing opposing effect; (steroids and insulin; histamine and omeprazole)

Signaling mechanism and drug action 1. Intracellular receptors for lipid soluble agents – corticosteroids, mineralocorticoids, sex steroids, vitamin D 2. Ligand regulated transmembrane enzymes – insulin, epidermal growth factor, platelet derived growth factor, atrial natriuretic peptide, transforming growth factor 3. Cytokine receptor – growth hormone, erythropoietin, interferon 4. Ligand-gated channels – hypnotic-sedatives 5. G-proteins and 2nd messengers (cAMP, Ca, cGMP) - opioids, adrenoceptor blocking agents

Receptor Signaling Mechanisms

Transmembrane enzyme (2nd)

Cytokine receptor (3rd)

Ion-gated channels (4th)

Alpha 1 receptor α1 – Gq phospholipase C  IP3 and DAG  Ca dependent protein kinase ( IP3  inositol ; DAG stimulate tyrosine kinase (stimulate cell growth/proliferation through regulation of gene expression)

Relation between drug dose and clinical response A. Graded dose response – when the response of a particular receptoreffector system is measured against increasing concentrations of a drug (graph of the response vs. drug concentration or dose) pharmacologic potency – (EC50) – amount of a drug needed to produce a given effect maximal efficacy (Emax)– extent or degree of an effect that can be achieved by the patient

B. Quantal dose effect response – when the minimum dose required to produce a specified response is determined by each member of the population - margin of safety - indicates variability of responsiveness ED50,

LD50,

EC50,

TD50,

TI = TD50 ED50 Therapeutic window

Variations in drug responsiveness: - mechanisms involve alteration in concentration of a drug and changes in the receptor • Hyporeactive – intensity of effect is decreased • Hyperreactive – intensity of effect is increased • Tolerance - ↓ responsiveness due to continued drug administration • Tachyphylaxis – rapid, diminishing responsiveness after initial administration

Reasons for variations in drug responses: • Alteration in the concentration of the drug that

reaches the receptor • Variation in concentration of an endogenous receptor ligand • Alteration in number or function of receptors • Change in components of response distal to the receptor

Take home messages: • Rational drug design is the best way of discovering a new drug

• Pure, future active enantiomers would decrease adverse effects

relative to those produced by racemic mixtures • Critical thinking with regard to use of complimentary medicines should be done • Drug costs are affected by costs of drug development and marketing and return of profit to its shareholders

• t ½ is the most useful factor in designing drug dosage

regimen • All substances can under certain circumstances be toxic

In summary: 1. Define Pharmacology and its branches 2. Discuss principles of pharmacokinetics and pharmacodynamics 3. Differentiate different types of agonists vs. antagonists 4. Discuss the 5 transmembrane receptor signaling mechanism 5. Discuss variations of drug responsiveness

References: • Basic and Clinical Pharmacology 13th ed (Katzung) • The Pharmacological Basis of Therapeutics

12th ed (Goodman and Gilman)

Maraming Salamat