Modify physiological processes not create new ones - prevent, diagnose/treat disease - modify actions of other drugs - analyse mechanisms or functions of an organism Expressed in terms of altering a known fx or process - returns a fx to normal operation - changes fx away from normal condition

Pharmacology 1+2 - Drug Kinetics and Toxicity Flashcards by Naina K

Pharmacology

Effects of drugs on living systems

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Pharmacodynamics

Study of biochemical and psychological effects of drugs and their mechanism of action on body

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Pharmacokinetics

Absorption, distribution, biotransformation and excretion of drugs - effect of the body on the drug

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Toxicology

Adverse effects of drugs and chemicals

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Pharmacotherapeutics

Use of drugs in the prevention and treatment of disease

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Fx of drugs

Effects

Modify physiological processes not create new ones

prevent, diagnose/treat disease
modify actions of other drugs
analyse mechanisms or functions of an organism

Expressed in terms of altering a known fx or process

returns a fx to normal operation
changes fx away from normal condition

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Drug definition

Chemical substance of a known structure, which when given, produces a biological effect in a living organism

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3 aspects of drugs

Describe terms

Goal of therapeutics is

Specificity - only produces one effect
Selectivity - one effect predominates over a particular dose conc –> THERAPEUTIC WINDOW
Toxicity - usually occurs beyond therapeutic dose conc. Some show toxicity at higher end of therapeutic dose –> adverse effects

To achieve specificity

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General mechanisms

Deficiency

Excess action

Antagonists also

Physiochemical environment

Replacement therapy for conditions such as iron or hormone deficiency
Chemical antagonists can block or reduce the effects of XS activity of normal processes
block excess effects of exogenous substances e.g reversal of overdose
Drugs can alter the environment or characteristics of a cell or tissue, changing its activity

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Dose/concentration

Drug quantity in weight / volume

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Response/effect

Different effects

Change occurring after administration

Therapeutic - intended effect
Side - effect other than therapeutic
Toxic/adverse - harmful unexpected effects usually occurring at higher dose
Lethal - death caused by very high drug dose

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Acceptor

Substances drugs bind to without effect e.g plasma proteins

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Receptor

Cell component directly involved in reaction

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Receptors

Mechanisms on binding

Component of cell/organism which interacts with a drug and initiates chain reaction of events –> effect

Ligand binds to receptor

agonist - initiates response e.g NTS and hormones
antagonist - prevents agonist binding therefore no response

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Drug receptors as molecular targets

Types of receptors

Mechanism and name of it

Molecules on or in the cell that the drug molecule first interacts with and activates/blocks?

Membrane receptors, enzymes, ion channels, DNA, cytosolic proteins

Receptors convert drug molecule signal to a biochemical signal via effectors = TRANSDUCTION

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Receptor location

3 possible locations and examples

Cell membrane - transmitters/peptides

Nucleus - thyroxin and insulin sensitivity

Cytoplasm - steroids

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Classes of cell surface receptors

Ion channel linked
G protein linked
Enzyme protein linked

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Receptor subtypes

Action

Adrenoreceptors

β1, 2 and 3

Found in heart, lungs and bladder

Beta-agonists = bronchodilation due to muscle relaxation

β agonist will down regulate β -adrenoreceptor during tolerance

β antagonist will up regulate β adrenoreceptor during withdrawal

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Drug/receptor interaction terms

EC50

POTENCY

EFFICACY

AFFINITY

EC50 - drug concentration which produces 50% of the maximal effect

Potency - conc required to produce a particular effect - depends on E AND A

Efficacy - relationship between receptor occupancy and ability to initiate a response at molecular, tissue or cellular level

Affinity - ability to bind a receptor

drugs can have same affinity but different efficacy

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Receptor activation

full agonist or partial

antagonist

based on maximal pharmacological response that occurs when all the receptors are occupied

binds but doesn’t activate and are used to prevent agonist from binding

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Intracellular receptors

Binding sites for…

Steroids e.g hydrocortisone, betamethason, beclomethasone

Steroid - anti-inflammatory action

Inhibit prostaglandin production

glucocorticoids

Role in events

vascular
as inflammatory and immune mediators
as cellular population control

Reduce vasodilaton and reduce fluid exudation

Reduces production and action of cytokines

Reduces clonal expansion of T and B cells
Decreases action of cytokine-secreting T cells

NSAIDs

Function and mechanism

Inhibit enzyme activity (COX1 COX2)
Inhibit prostaglandin release

Diclofenac
Aspirin
Ibuprofen
Paracetamol

Benzodiazepines/barbiturates

Mimic GABA | Stimulate GABA receptors at allosteric sites therefore constant hyperpolarisation --> CNS depression

Transport ion channel

Ion channels can be blocked by substances such as LA | Nervous impulse transmission is blocked

Proton pump inhibitors

Irreversibly block the H+/K+ATPase gastric pump Fr prolonged inhibition of gastric acid Omeprazole Lansoprazole

Early therapeutic monoclonal antibodies Depends on

host defence mechanisms location of infection pharmacokinetics and dynamic properties of the antibacterial agent

Anti-infective agents Mechanism

Protein synthesis inhibitor in bacteria

B-lactam antibiotics Function

Disrupt synthesis of peptidoglycan layer of bacterial cell walls Destroy bacterium

Anti fungal Anti viral

e.g metronidazole inhibits DNA synthesis Inhibit DNA polymerase

Drug absorption mainly via MEMBRANE PENETRATION

G.I mucosa Capillary endothelium Blood-brain barrier Cell membrane Passes through via passive diffusion IV drugs will actt quicker

Gastric emptying

Essential for drug absorption | Most drugs absorbed from intestine due to greater SA

Bioavailability Definition Depends on

Fraction of unchanged drug reaching the system circulation following any route of admin Absorption First pass metabolism Food Differs between drugs

Distribution Physiochemical properties Physiological factors

molecular size oil/water miscibility protein binding degree of ionisation ``` organ/tissue size blood flow rate physiological barriers - blood cap membrane - cell membrane - specialised barriers ```

Plasma proteins... are involved in ...

Drug binding in blood Acid drugs --> albumin Basic drugs --> α1-acid glycoprotein Displacement of one acid drug by another ==> free drug concentration increase Free drugs will be eliminated faster

Guidelines for rate of drug distribution perfusion limited tissue distribution permeability rate limitations or membrane barriers

1. immediate equilibrium of drug in blood and in tissue 2. only limited by blood flow i.e PERFUSION 3. poor perfusion - skin, fat, bone, muscle 4. high perfusion - lungs, liver, kidneys, brain blood-brain barrier - extra layer blood-testis barrier placenta

Placenta barrier

Mother's blood --> foetus - sugars, fats and oxygen - passive immunity antibodies Foetus --> mother - Urea and CO2 Viruses can pass Toxins e.g drugs and alcohol can pass Lipid soluble toxic substances can pass to foetus

Drug metabolism De-activation Activation Excretion

Decrease of pharmacological effect Decrease of toxicity Increase pharmacological effect Increase toxicity Drug undergoes phase I --> primary metabolite --> excretion Phase II --> conjugate --> excretion

Phase I reactions

Drug --> primary metabolite Exposure of a polar group Metabolites may be excreted if sufficiently polar

Phase II reactions

Primary metabolite --> conjugation Drug --> conjugation Attachment of an endogenous molecule to a drug Produces less active compounds than phase I

Drug metabolism enzymes Phase 1 Phase II

Oxydation - cytochrome P450 - found in liver - varying substrate specificity Conjugation - transferases

Polymorphism

Occurrence of variant form of an enzyme/receptor through inheritance of drug metabolising enzymes e. g lack CYP2D6 - poor metaboliser for CV, psychiatric and opiate drugs

Biliary excretion - secreted by - important in - fate - composition of bile factors influencing secretion of drugs in bile where else can products end up

Hepatic cells of liver Digestion and absorption of fats 90% reabsorbed from intestine and transported back into liver Metabolites more excreted than parent drugs --> increased polarity - m.w - polarity - nature of biochange - gender, diseases, drug interactions Some pass into intestine Reabsorption from gut during process of enterohepatic recycling may prolong pharmacological effect of a drug

Drug elimination | Two types

Renal - water soluble - ionised Hepatic - lipid soluble - unionised e.g propanolol, cyclosporin Drugs high in water/ionised excreted renally Drugs lipid soluble or unionised will be hepatic ally processed

role of nephron

1. glomerular filtration - not much for protein bound drugs 2. active secretion - adds to tubular fluid - free and bound drug 3. passive reabsorption - only unionised drugs transfers back to blood

renal clearance formula what may affect it

excretion = (filtration + secretion) - reabsorption if > GFR = net secretion efficiency of renal excretion renal diseases

Therapeutic index

Greater = greater safety of drug Minimum toxic concentration is margin between therapeutic effects and toxic effects

Factors affecting metabolism when HIGH blood level - XS dose - decreased clearance

``` Normal variation Saturable metabolism genetic enzyme deficiency Renal/liver failure Age Enzyme inhibition ```

Factors affecting metabolism when LOW blood level - too low a dose - no effect - increased clearance

``` Normal variation Poor absorption High first pass metabolism Non-compliance Enzyme induction ```

Factors affecting drug metabolism

Environmental Disease Genetic Age Drug interaction

Saturable metabolism

Increase in the dose would result in a decrease in hepatic clearance and a more proportionate increase in the drug levels