NSC2500 Pharmacology and Pathophysiology in Health

Parental (fast)

-Injections (IM, SC, IV, IP) -Inhaled

4 families/classes of receptor

-Ligand-gated ion channels -G protein-coupled receptors -Kinase linked receptors -Nuclear receptors

How do drugs work?

-Transport systems: eg. ion channels, carriers • Eg. Xylocaine (lidocaine) to block voltage-gated sodium channels • Enzymes: eg. block/prevent enzyme activity • Eg. Viagra (sindenafil) to block phosphodiesterase type5 (PDE5) • 'non-specific': eg. chelation, antacids, osmotics • Eg. Desirox (deferasirox) to reduce chronic iron overload

Variability in drug response - examples (2)

1) Geriatric Patient • Decreased cardiac output • Decreased renal function • Decreased brain mass • Decreased total body water • Decreased body fat • Decreased serum albumin • Decreased respiratory capacity 2) Pregnant Patient• Increased cardiac output • Increased heart rate • Increased blood vol. (up to 45%) • Decreased protein binding • Decreased hepatic metabolism • Decreased blood pressure • Placental barrier permeability /lactation (effects on child

Drug interaction with the body (a drugs life cycle) 5 steps, what are they?

1. Administration - getting the drug in 2. Absorption - drug gets into bloodstream 3. Distribution - blood carries drug to tissues 4. Drug action - eg. drug binds & affects cells 5. Termination of effect, metabolism and/or elimination steps 2,3,5 = Pharmacokinetics, step 4 = Pharmacodynamics

Shapes of bacterial cells (morphology)

1. Coccus (plural cocci = berries) - spherical 2. Bacillus (plural bacilli = little staffs) - rod shaped 3. Spirillum (plural spirilla) - spiral forms

5(+) 'Rights' of Safe Administration

1.Right patient 2.Right drug 3.Right dose 4.Right time 5.Right route 6.Right to refuse 7.Right documentation 8.Right education 9.Right assessment/reason 10.Right evaluation/response

One drug, many names (3), what are they?

Chemical name • Identifies the chemical elements and compounds that are found in the drug - most important to chemists, pharmacists and researchers who work with the drug at a chemical level. • Generic name (non-proprietary) • The universally accepted name of a drug. It appears on all drug labels, resource guides and publications. Generic names often follow similar patterns for drugs of the same class or mechanism (eg. lidocaine, procaine) • Brand or trade name (proprietary) • The copyrighted and trademarked name given by the drug company - restricts the use of the name.

Important implications for drug+receptor interaction

Drugs are a ligand and act on receptors that are already present in, and expressed by, a cell. Therefore: • drugs can potentially alter the rate of any bodily/brain function • drugs cannot impart entirely new functions to cells • drugs do not create effects, only modify ongoing ones • drugs can allow for effects outside of normal physiological range

Routes of administration: "the path by which a drug, fluid, poison, or other substance is taken into the body.

Enteral (Systemic) Oral Buccal Rectal • Drug reaches the target via the GI tract • Oral: majority of drugs, but least reliable o First-pass metabolism (gut & liver) Parenteral (systemic) Intravenous Intramuscular Subcutaneous Intradermal Transdermal Inhalational Transtracheal • Does not involve the GI tract • Direct delivery to plasma • Rapid effect • Avoids first-pass metabolism • Pain, infection, etc Topical (local) Skin Eyes Ears Intranasal Vaginal Urethral • Direct local effect (mainly)

Antifungal drugs

Fungi are eukaryotic but cell membranes contain sterols • Azoles: • Inhibit synthesis of sterols by inhibiting enzymes (have greater affinity for fungal enzymes than human enzymes) • Polyenes: • Combine with a major sterol component (ergosterol) in cell membrane leakage of cell contents cell death (amphotericin B, nystatin) • Inhibit ergosterol biosynthesis (allylamine drug group - but toxic to human cells as combine with cholesterol)- good for topical treatments, sometimes oral • Inhibit -glucan synthesis in cell wall (new group - echinocandins) - effective in treating candidiasis (mucosal, invasive) and aspergillosis (invasive)

Bacterial virulence factors: ability to attach to

Glycocalyx and capsule • Outer sticky covering composed of polysaccharides and glycoproteins • Capsule or slime layers (depending on its structure and function) • Prevents desiccation Pili and fimbriae • Hairlike appendages for attachment • Adherence to surfaces and host cells eg E. coli causing urinary tract infection • DNA exchange through sex pili via conjugation (cause antibiotic resistance). Slime Layer /biofilm • Composed of glycoproteins and polysaccharides • Thinner and less tightly bound to wall than a capsule • Prevents desiccation, traps nutrients, binds cells together and attach to host calls and surface (eg plant roots, teeth, medical devices) • Contributes to the formation of biofilms

Disruption of nucleic acid synthesis

Inhibit precursors and/or DNA or RNA replication • Sulfonamides: interfere with synthesis of precursor for purines and pyrimidines needed for nucleic acid formation; in elderly may cause exfoliative dermatitis, rarely fatal suppression of bone marrow; may cause nausea • Quinolones: specifically inhibit action of bacterial enzymes needed to unwind DNA prior to replication (eg norfloxacin (UTI and GIT infections); ciprofloxacin (active against Pseudomonas aeruginosa)) • Rifamycins: bind RNA polymerase mRNA not produced (greater affinity for bacterial enzyme than human enzyme); interact with a number of different drugs (anticoagulants, corticosteroids, hypoglycaemic agents, oral contraceptives) • Nitroimidazoles: antibacterial and antiprotozoal actions (eg Helicobacter pylori, Giardia lamblia, Trichomonas vaginalis); may cause nausea, intolerance to alcohol

The enteral route - first pass metabolism, what happens?

Most of drugs absorbed from the GI tract enter the portal (liver) circulation before they are distributed to the systemic (general) circulation • The drug will be metabolized in the liver before reaching the target organ, decreasing drug efficacy. • eg: nitroglycerin is 90% cleared during a single passage through the liver (this is why nitroglycerin is administered sublingual, rather than oral)

Examples of Enteral (slow)

Orally (swallowed) • Rectally (suppository) • Through mucus membranes • Oral Mucosa (e.g. sublingual) • Nasal Mucosa (e.g. insufflated) • Transdermal (slow; parenteral; through skin) • Topical (slow; through skin)

The 2 main arms of pharmacology?

Pharmacodynamics (PD) - "what the drug does to the body" • The biochemical, physiologic, and molecular effects of drugs on the body • chemical interactions, receptors, signal transduction, etc Pharmacokinetics (PK) - "what the body does to the drug" • The movement of a drug into, through, and out of the body) • liberation, absorption, distribution, metabolism, excretion • Half-life (t½), bioavailability, etc

The difference between Prokaryotic and Eukaryotic Cells?

Prokaryotic: Unicellular and Very simple structure Eukaryotic: Unicellular (protozoa, yeasts) OR Multicellular (algae, fungi, more complex plants and animals)

Disruption of protein synthesis

Protein synthesis basically the same in prokaryotes and eukaryotes BUT... Prokaryotes have different ribosomes (70S made up of 50S & 30S subunits) compared to eukaryote cells (80S made up of 40S and 60S subunits ) and so the ribosomes themselves are targeted • BUT... the mitochondria in eukaryotes have 70S ribosomes and so are also affected • Aminoglycosides: not absorbed in GIT so IM administration; some may cause ototoxicity, nephrotoxicity • Tetracyclines: broad spectrum (treatment of PID, cholera, some pneumonias, intracellular chlamydiae /mycoplasmas and active against Neisseria gonorrhoea); may cause liver damage and in young children can cause yellow discolouration of teeth, may interfere with formation of bone • Macrolides: broad spectrum against Gram+ve and Gram-ve aerobes (but NOT Gram-ve rods) eg Leigonella, Chlamydia, Bordetella pertussis (whooping cough); • Oxazolidinones, streptogramins and lincosamides: binds 50S subunit; penetrate tissue (bone, joints) may cause diarrhoea • Chloramphenicol: binds 50S subunit (including human mitochondria); now synthetic; toxicity may occur (bone marrow suppression, suppression of erythrocyte production in bone marrow (rare toxicity), toxic to neonates as lack liver enzymes to eliminate) • Fusidic acid: complexes with growing protein chain and stops protein being completed

Schedule of drugs (9) what are they?

Schedule 1: (not used) Schedule 2: Pharmacy medicine Schedule 3: Pharmacist only medicine Schedule 4: Prescription only medicine Schedule 5: Caution Schedule 6: Poison Schedule 7: Dangerous poison Schedule 8: Controlled drug Schedule 9: Prohibited substance Schedule 10: Dangerous substances (prohibited)

Antimicrobial agents

The diverse microbial world • Bacteria: prokaryotic • Viruses: Not living cells - require a host to carry out metabolic processes • Fungi: Yeast and filamentous fungi • Parasites: • Helminths and arthropods • Protozoa: Unicellular eukaryotic organisms • Algae: Aquatic organisms - limited disease • Chemotherapy • Introduction of specific chemical compound/drug to the body to elicit a desired response preferably without causing harm • Antibiotic/antimicrobial • Compound that in small amounts exhibits microbiostatic or microbiocidal properties • Microbiostatic - inhibits reproduction • Microbiocidal - kills microbes • Naturally occurring • Fungi, actinomycetes, bacteria (Streptomyces) • Synthetic and semi synthetic • Chemically modified

EMQ1 Questions and answer:

The study of drug absorption, distribution, metabolism and excretion = Pharmacokinetics The fraction of unchanged drug reaching the systemic circulation following any route of administration = Bioavailability Describes the delivery of a drug by a means other than via the GI tract = Parental The time taken for the plasma concentration of that drug to fall to half of its original value = Half life The separation of the active ingredient from the excipient (vehicle) = Liberation A substance that binds to a specific receptor and activates the receptor to cause a physiological response = Agonist The process(es) by which a drug is cleared from an organism, either in an unaltered form or as a metabolite = Excretion The means through which endogenous ligands and drugs exert a biological effect = Receptor A method of drug nomenclature based on the atomic/molecular structure of the drug = Chemical names The comparison of the concentration at which a drug becomes toxic and the concentration at which the drug is effective = Therapeutic Index

Infectious Diseases

Types of infections • Localised: eg infected wound (mainly bacteria), cutaneous fungal infection • Disseminated: • Pathogen escapes from initial site of infection to infect another area of body • eg Streptococcus pneumoniae (pharyngitis) to ears (otitis media) or lungs (pneumonia) • Bacteria in circulation lodges in susceptible location • eg ends of growing bones (osteomyelitis) or defective heart valves (endocarditis) • Systemic disease occurs when pathogen enters body and affects several organs or tissues in the body • eg Clostridium tetani causes anaerobic infection, produces neurotoxin which circulates in blood and causes severe muscle spasms

pharyngitis -bacterial

aka strp throat s.pyogenes gram pos pathogen able to cause many diseases common in 5-15years old tx os necessary can lead to rheumatic fever and rheumatic heart disease

what is a drug?

any substance that brings about a biological change or effect on the body

vaccinations

biological substance that evokes an immune response without causing disease createa clone of memory cells types: live attenuated (life long immunity) inert (kills whole cells or inactivates them)

sepsis

bodys response to bacterial infection risk factors trauma burns decreaed immune system chronic illness wounds invasive medical procedures

infections

contact air vehicle (food, water, drugs and body fluids) vector (mosquitos, flies, rats or vermin)

epiglottitis symptoms

drooling difficulty in swallowing difficulty in breathing stridor child has to sit up to breathe poor ventilation leads to increased CO2, causing confusion rapid inflammation can cause airway obstruction and death complete obstruction in 3-6hrs for severe cases haemophilus influenzae type b (Hib) most common cause tx: vaccination - haemophilus infuenzae and streptococcus pneumonaie therapeutic - endotracheal tube tracheostomy and ABs

acute otitis media

ear ache, fever, vomitting, lethargy diagnosis will require examination of the ear ABs tx reduces pain in 24hrs in 5% of pts resolve spontaneously complications of tearing tympanic membrane

Disruption of cell wall synthesis

lactams (have a -lactam ring structure) • Effective in growing cells, disrupt synthesis of unique bacterial cell wall • Some allergies can develop (?-lactam ring joining with plasma proteins inflammatory reaction?) • Natural penicillins (from Penicillium chrysogenum): • penicillin G (benzylpenicillin) inactivated by stomach acid (administer IM, IV) • penicillin V is acid stable so can take orally (but not well absorbed, excreted quickly) • Semi-synthetic penicillins: • Eg Clavulanic acid (from a streptomycete) inhibit -lactamase enzymes produced by some bacteria • Cephalosporins (from marine fungus, Cephalosporium): • Currently 4 generations (but Ceftriaxone (3rd gen) can form precipcitates if administered with calcium-containing solutions) • Carbapenems (synthetic): concerning emergence of metallo--lactamase which inactivate these • Monobactams (not inactivated by -lactamases... at the moment..) • Others: glycopeptides (eg vancomycin, teicoplanin)

lower respiratory tract infections (LRTIs)

lower trachea bronchi lungs bacterial LRTIs whooping cough lung abscesses tuberculosis pneumomia (typical, atypical and aspiration)

bacterial infections in the nervous system

occurs in bloodstream, ears, sinuses or peripheral nerves : meningitis and tetanus

whooping cough

pertussis droplet transmission invective agent bordetella pertussis

What is Pharmacology?

the branch of medicine concerned with the uses, effects, and modes of action of drugs. what they do and how they do it

Tuberculosis (TB)

top of 10 deaths can be dormant for years mycobacterium TB difficult to grow (upto 6weeks on agar) gram stain (waxes in cell walls) treat (standard 6mnth course of 4 antimicrobial drugs)

Bacterial infection example: Staphylococcus aureus

• 'Golden staph' • At least 1/3 people carry Staphylococcus spp. in their nose (nares) or on the skin (groin, axilla) • A gram-positive cocci bacterium • Is predominantly associated with skin infections (boils, impetigo) • Can also cause: • pneumonia, sinusitis, meningitis, osteomyelitis, endocarditis, toxic shock syndrome (TSS), bacteraemia and sepsis • Methicillin-Resistant Staphylococcus aureus (MRSA) is a major issue in hospitals especially in bone infections (osteomyelitis) and surgical sites • Surgery can provide a route of entry • Treatment • Most staphylococci respond to flucloxacillin • Vancomycin drug of choice for MRSA • Antibiotics generally not required for skin infections

Four (6?) principles (ADME or LADMET)?

• (Liberation) • Absorption • Distribution • Metabolism • Elimination • (Toxicity)

Receptor-mediated action of drugs

• A receptor is: "any biological molecule that receives chemical signals and is responsible for transducing extracellular signals into intracellular responses" • Binds to receptor, initiates intracellular signal, resulting in a response/effect • For a drug to have an effect, the target must have the right receptor! • Note: a ligand is any molecule binding to a receptor (a drug is a ligand!)

Drugs can be Agonists OR Antagonists

• AGONISTS have: • AFFINITY for the receptor (they bind to it) • INTRINSIC ACTIVITY (binding elicits a response) • ANTAGONISTS (aka receptor blockers or inhibitors) • have AFFINITY (bind the receptor) • LACK intrinsic activity (no response)

Absorption, what is it?

• Absorption refers to how medicines enter the bloodstream (plasma) • Rate is dependant on route of administration

Mechanisms of Pain

• Activation of peripheral nociceptors by noxious stimuli • Mechanical - pressure, tumour growth, incision • Thermal - hot, cold • Chemical - ischaemia, inflammation, infection • Polymodal - excited by both noxious and non-noxious cutaneous or visceral stimuli • Transduction and transmission • A- (A-delta) fibres • Small diameter, myelinated, faster conduction velocity, sharp and well-localised intense pain, associated more with mechanical and thermal nociception • C fibres • Smaller diameter than A- fibres, unmyelinated, slower conduction velocity, dull throbbing/burning slow pain which is poorly localised • Modulation of signal • Attenuation (usually) of signal by intrinsic inhibitory pathways in the peripheral and central nervous systems before perceived as unpleasant • Sometimes signal is AMPLIFIED rather than attenuated • eg Pathologic pain: • Peripheral sensitisation: spontaneous ectopic activity in injured nerves and dorsal root ganglion cells; increased sensitivity to mechanical, thermal, chemical nociception • Central sensitisation: increased sensitivity of pain signalling neurons in CNS due to repeated and prolonged activation of afferent nociception fibres

Middle ear infections

• Acute Otitis Media (AOM) •Predominantly small children, esp 6-18 months (often recurrent) •Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, respiratory syncytial virus (RSV), rhinoviruses, influenza viruses and adenoviruses •Much higher infection rates in Indigenous populations

Cellulitis

• Acute bacterial infection usually superficial but can spread to subcutaneous tissues and blood (via lymphatic system) • Infected tissue becomes hot, painful, swollen • Fever, chills, lymph node enlargement may occur • Streptococcus pyogenes or Staphylococcus sp.

Drug effectiveness: Affinity, Potency & Efficacy

• Affinity - the ability of a drug to bind to its receptor by direct chemical interactions (electrostatic, hydrophobic etc.) with the receptor binding site. • Potency - the ability of a drug to produce a tissue response. The lower the concentration of the drug needed to give a specified response (mostly a 50% response; EC50) the more potent the drug. • Efficacy - the ability of a drug, once bound to its receptor, to activate that receptor and initiate cellular signalling pathways leading to a tissue response.

What is pain?

• An unpleasant physical and emotional/psychological experience • Sensory and emotional components • Associated with actual or potential damage • Normal in life and vital as a warning sign of potential or actual damage (but can be in absence of tissue damage (ie phantom pain) • Can be: • Acute: usually from injury or inflammation (survival, minimising further injury) • Chronic: persisting beyond expected duration of tissue healing • Back pain most common, then severe headaches, arthralgia, neck pain

Pathogenic Microbes: protists/protozoa

• Animal-like protists • +5mm diameter • Single-celled, animal-like • Some diseases eg. Malaria, Giardiasis

Antibiotic resistant organisms

• Antibiotic resistance organisms may be responsible for many HCAIs • Use of large amounts of drugs selects for resistant strains • MRSA - multi resistant S. aureus • VRSA - vancomycin resistant S. aureus • GRGN - gentamycin resistant Gram negative bacteria • VRE - vancomycin resistant enterococci

Human Microbiota

• Bacteria (prokaryote): • very simple cells that are unicellular with no nuclear membrane, mitochondria, Golgi bodies or endoplasmic reticulum, reproduce by binary fission (can be every 20 mins!) • Archaea: • Lack nuclei (like prokaryotes), have unique membrane (unlike prokaryotes); able to live in extreme environments; ? Have a role in obesity? • Eukaryote (Microeukaryote) • Complex cells with membrane bound nucleus • Virus: • NOT a cell but a PARTICLE, genetic material DNA or RNA (not both); obligate intracellular parasite (takes over invaded cell's metabolic machinery)

Pathogenic Microbes: bacteria

• Bacteria (prokaryotes) • 100,000+ spp. (species) • Unicellular • Reproduce via binary fission (one cell splitting in two) • DNA but no discrete nucleus • Cell wall (capsule) • Gram reaction for differentiation

Bacterial movement

• Bacteria move by flagella • Simple flexing • Rotation/corkscrew type motion • Many Bacilli have flagella; most Cocci have no flagella • Taxis: movement toward or away from chemical or physical conditions • Chemotaxis: movement in response to chemical agents • Phototaxis: movement in response to light

Microbiology Basics

• Bacteria: prokaryotic • Viruses: Not living cells - require a host to carry out metabolic processes • Fungi: Yeast and filamentous fungi • Parasites: • Helminths and arthropods • Protozoa: Unicellular eukaryotic organisms • Algae: Aquatic organisms - limited disease?

Bacterial virulence factors: toxin production

• Bacterial toxins • Some are extremely potent at low concentrations (eg C. botulinum toxin) • 2 types • Endotoxins • LPS from Gram negative cell wall • Relatively weak, but large quantities can cause toxic shock • Exotoxins • Soluble and secreted • C. botulinum toxin Exotoxins • Neurotoxins (tetanus, botulism) • Enterotoxins (dysentery, cholera) • Cytotoxins (anthrax) • Haemolysins • S. pneumoniae (alpha (partial) haemolysis) • GBS, GAS (beta (complete) haemolysis)

Barriers to Drug Distribution

• Blood brain barrier • Usually only lipid soluble drugs can enter brain and CSF • Placenta • Allows passage of lipid and some water soluble drugs - eg opioids, antiepileptics • Enzymes in placenta will also inactivate some drugs

Drug Classes (3):

• By makeup: • Hormone • Carbohydrate • By action: • Beta blockers • ACE Inhibitors • By therapeutic affect: • Antiarrhythmic • Antianginal

Inhibitor of cell membrane function

• Cationic detergent action, disrupts cell membrane phospholipids • With oral administration not readily absorbed and cause ototoxicity and nephrotoxicity • Topical mainly but may be parenteral for resistant bacteria as last resort

Antimicrobial sensitivity/resistance

• Choice of drug is dictated by several factors including: • Site of infection • Infecting organism/s • Route of antibiotic administration • Antimicrobial sensitivity • Microorganisms may become resistant to action of antibiotics/antimicrobials • Multiple resistance • Resistance transfer • Tests used • Disk diffusion test • Minimum inhibitory concentration test

Clearance

• Clearance (CL) reflects the elimination of the drug from the body & is related to the plasma concentration (Cp) and dose rate: 𝐶𝑝 = 𝐷𝑜𝑠𝑒 𝑟𝑎𝑡𝑒 𝐶𝐿 • Clearance (CL) is the collection of processes by which the body removes the drug from the body & occurs via two key ways: Metabolism & elimination • Clearance is a very important parameter as it defines how much drug should be administered, and how frequently to dose a patient (dose rate

Vibrio cholerae

• Comma-shaped Gram-negative bacteria • Causes acute infection of GIT in about 25% cases • Endemic in SE Asia, Africa, Central & South America • From drinking water, seafood • Epidemics often associated with natural disasters • Cholera toxins cause profuse diarrhoea and dehydration • Live, attenuated vaccine available

Antiparasitic drugs

• Complex life cycles of parasites so difficult to treat (need for selective toxicity) • Example: Malaria • At least 5 species of the Plasmodium protozoa infect human • Quinine used to be used for all infections but now is considered too toxic (only used in resistant strains) • Chloroquine used but resistance in many areas of the world • Mefloquine was used prophylactically but resistance now in many areas of the world • Primaquine used to eliminate protozoa from liver to prevent relapses

Scalded skin syndrome (or SSSS)

• Complication of impetigo • Staphylococcal Scalded Skin Syndrome (SSSS) • caused by strains of S. aureus that produce epidermolytic exotoxins (exfoliatins A and B) • Exfoliatins break down the desmosomes and skin layers come apart • Outer layers of skin shed exposing red inner layer • Septicaemia may result

Dose response & effective concentration (EC50)

• Depicts the relationship between drug dose and magnitude of drug effect • EC50 is the concentration which induces a response halfway between baseline and maximum • Drugs vary in effectiveness • Different sites of action • Different affinity, potency, efficacy • The effectiveness of a drug is considered relative to its safety (therapeutic index)

Factors altering drug response

• Drugs do not work the same every time, or have the same effect in every person! • Some factors affecting response include: • Age • Body mass • Gender • Time of administration • Pathologic state • Genetic factors • Psychological factors

Distribution & effect of protein binding

• Drugs reversibly & rapidly bind plasma (blood) proteins • (protein + drug ↔ drug-protein complex) • Proteins are large & sequester (trap) drugs in the blood • drug can't distribute to target receptors • thus protein bound drug is pharmacologically inactive • Therefore concentration of free drug in blood decreased • Thus less pharmacologically active drug • Only free drugs can bind to their receptors!

Therapeutic index (TI): a measure of drug safety

• Drugs with a narrow TI, there is little difference between toxic and therapeutic doses • Such drugs may have their dosage adjusted according to measurements of the actual blood levels achieved in the person taking it (therapeutic drug monitoring (TDM)).

The respiratory tract

• Entry for the greatest number of pathogens • Upper and lower both have moist epithelia • Upper has mucus, cilia and normal flora • Lower has alveolar macrophages and mucus in the bronchioles • Examples • Streptococcal sore throat • Meningitis • Diphtheria • Whooping cough • Influenza • Measles • Mumps • Rubella • Common cold • Fungi causing pneumonia infections: •Many microbial pathogens tend to be associated with specific sites on the host •Their incidence may also be influenced by: - Patient age - Underlying illness - Length of stay, if in hospital - History of smoking - Immunocompromised

Bacterial virulence factors: Evasion

• Evasion of host immune system • Hide from immune system • Proteases to prevent chemotaxis • Antigenic variation (serotypes) • Molecular mimicry (also creates autoimmune issues) • Prevent phagocytosis • Capsules • Escape from 'digestion' process • DNase to degrade Neutrophil Extracellular Traps (NETs) • Proteases which destroy phagocytes • Biofilm formation Structures formed by some bacteria for survival during adverse environmental conditions. • Resist high temperature, high UV irradiation, desiccation, chemical damage and antibiotic treatment • Protected by several sets of membranes and contains dehydrated cytoplasm • Most spore-forming bacteria are G+ve rod-shaped belonging to the genera Bacillus and Clostridium (especially soil bacteria). • Genetic regulation to control expression of virulence factors depending on the stage of infection • Coagulase - Forming plasma clot • Streptokinase - Dissolving clots But also need susceptibility... • True pathogens • Opportunistic pathogens • Commensals • Age • Immune status • Genetic factors • Surgery • Pre-existing disease • Chemo/immunosuppressive drugs • Other infections • Stress

Therapeutic use of antimicrobials

• Factors need to be considered before a drug is prescribed • Antimicrobial sensitivity • Treatment of infections • Pharmacokinetics • Prophylaxis • Limitations of an antimicrobial • Development of drug resistance • Prescribing principles taken into account • Sensitivity testing • Absorption rate • Oral, IM, IV, blood-brain barrier • Patient status • Immune dysfunction (bactericidal drugs prescribed), organ integrity • How drugs are metabolized and excreted in a person • Drug interactions • Cost • Pharmacokinetics • Dose must lead to effective concentration of drug at the site • Rate of elimination = half life

Pathogenic Microbes: fungi

• Fungi • 100,000+ spp. (species) • Filamentous (mycelial), walled, heterotrophs • Some are disease causing eg. Candida, Cryptococcus, Aspergillus

Healthcare associated infections (HAI) and non-healthcare associated infections

• HAI: • Infection that is not apparent or incubating at the time of admission but appears at least 48 hours post admission or within a specified time after discharge • Causative agents: Bacteria (most), fungal, then viruses • Sites of infection generally include: Urinary tract; Surgical wounds; Lower respiratory tract; Skin; Blood • Influenced by: Person's age; Operation type and site; Degree of immunosuppression; Catheterisation or cannula insertion (length of time) • Non-HAI (community acquired) • Can be from endogenous infection; Transient microflora; True pathogen; Opportunistic pathogen; Environmental influences; Secondary infection; transmission from surfaces, community, water etc • Can be exacerbated by overuse and inappropriate use of broad spectrum antibiotics (may antibiotic resistance)

Normal microbiota

• In a healthy human, the internal tissues, eg blood, brain, muscle, are not usually inhabited by microorganisms • But surface tissues, ie skin and mucous membranes, are colonised harmlessly by a mix of microbes (~10X the number of human cells) • These mixtures of bacteria sometimes form a BIOFILM (eg plaque on teeth) • Bacteria are the most abundant components of the normal microbiota • Microbiota can be resident or transient; aerobic, anaerobic, microaerophilic

Bacterial skin infections

• Intact skin acts as a structural barrier to microbes • Has high salt, low pH, lysozymes (in secretions), fatty acids & antibiotic peptides • Normal microbiota defend against pathogens But minor and major trauma may lead to skin infections • Systemic infections may result from skin invasion • Some infectious agents provide their own passageways using digestive enzymes or bites, such as: • Staphylococcus aureus • Streptococcus pyogenes • Neisseria gonorrhoeae • Rabies virus

Bacterial GIT infections

• Intestinal infections are a major world health problem, esp in developing countries • Microbes are continually ingested but only few cause intestinal disease • Most are circumvented by Stomach acidity, Digestive enzymes, Bile salts, Peristalsis, Indigenous microbes, Immune defences • Most intestinal pathogens localised in GIT • Some invade GIT tissues and become systemic • Others grow on food and secrete exotoxins • Most GIT infections cause acute diarrhoea

Bacterial virulence factors: Invasion

• Invasion • Few bacteria are able to colonise host surfaces • Degrade cells using proteases and plasminogen binding proteins • Trick cell into internalising using fibronectin binding proteins

Selective toxicity

• Kill or inhibit disease causing microorganism, with little or no damage to host cell • Exploits differences between microorganism and host cells: • Identify a reaction or structure unique to the target organism • ie one that does not occur in the host cell • Must prevent replication or cause cell death • Need to be monitored • Interfere with processes in host cell

Antimicrobial therapy

• Kill or inhibit growth of microorganism or produced toxin • Antibacterial • Antifungal • Antiviral • Antiprotozoal • Antitoxin • Selective against particular cellular components • Broad spectrum antimicrobials • Active against many different microorganisms • Narrow spectrum antimicrobials • Limited range of activity

The drug + receptor complex

• Lock and key concept: • drug acts as key, receptor as lock, combination yields response • dynamic and flexible interaction Note: a ligand is any molecule binding to a receptor (a drug is a ligand!)

Host-microbe interactions

• MRSA/Golden staph (Staphylococcus aureus) • Pneumonia (probably Streptococcus pneumoniae) • Thrush (Candida albicans) • HIV (Human Immunodeficiency virus) • Genital herpes (Herpes Simplex Virus Type 2) • Syphilis (Treponema pallidum) • Glandular fever (Epstein Barr virus) • TB (Mycobacterium tuberculosis) • Meningococcal meningitis (Neisseria meningitidis) • Chicken pox/shingles (Varicella zoster virus)

Metabolism

• Metabolism is the irreversible conversion of one chemical compound into another • Most metabolism of drugs occurs in the liver, but also in the gut wall, lungs, and blood plasma • First-pass effect allows the liver to metabolise or deactivate medicines and potentially harmful substances before they are distributed throughout the body • Liver hepatocytes contain the necessary enzymes for metabolism • The main enzymes involved belong to the cytochrome P450 group

What binds to the receptors?

• Most receptors have naturally occurring (endogenous) molecules that bind to them • Exogenous (foreign) molecules can be designed to bind to the same receptor rational drug design • Example: • Endorphins (endogenous) opiate receptors • Morphine (exogenous) opiate receptors

Antiviral drugs

• Nucleoside analogues • Antiretroviral • Nucleoside analogue reverse transcriptase inhibitors (NRTIs) • Non-nucleoside inhibitors (NNRTIs) • Protease inhibitors (PIs) • Integrase inhibitors • Entry inhibitors • Antiretroviral therapy • Anti-influenza drugs • Interferons

Growth requirements

• Oxygen • Moisture • Temperature • pH • Nutrients • Some microorganisms can survive extreme environments

The gastrointestinal tract

• Pathogens contained in food, drink and other ingested substances • Adapted to survive digestive enzymes, mucosa and pH changes, such as: • Salmonella spp. • Shigella spp. • Certain strains of Escherichia coli • Giardia lamblia

Drug sources? There is 6

• Plants: eg. Digitalis (foxglove) -> digoxin, belladonna -> atropine • Animals: Glandular products, eg. Pregnant Mare Urine = Premarin (estrogens for menopause) • Microorganisms (fungi, bacteria): antibiotics, eg. penicillin (penicillium notatum, a mould) • Minerals: eg. lithium carbonate (an antipsychotic), MgSO4 (a laxative), • Synthetic: Laboratory produced, eg. Sulfonamides (antibacterials) • Recombinant proteins: Proteins produced by expression of cloned genes in recombinant cells, bacteria, etc. eg. Insulin (human gene in bacteria)

What are receptors?

• Receptors are macromolecules that mediate a biological change following ligand (drug) binding • Most receptors are proteins with: • 1° aa sequence • 2° regular sub-structures • 3° 3-D structure • sometimes 4° multi-protein complexes • Are located on the surface of or within cells

Excretion

• Refers to how the body gets rid of a medicine or its metabolites • Main routes of elimination: 1. Excretion by kidneys: • The liver transforms drug into compounds which are more readily excreted by kidneys • Excretion by kidneys directly into the urine 2. Excretion in faeces: • Metabolised drug is secreted by the liver in bile and enters small intestine where it is either reabsorbed into the bloodstream or eliminated in faeces

Emergence of resistance to antimicrobials

• Selective pressures lead to a change in DNA • Mutation • Reduced [drug] inside bacterial cell • Over-prescription • Genetic transfer of resistance factors • Conjugation, transduction, transformation • Bacterial enzymes that destroy or inactivate drugs • Beta-lactamase • Drug impermeable to changed bacterial cell membrane • Bacterial alteration of target sites • Metabolic synthesis via different pathways than the one designed for the drug

Classification of Pain States

• Somatic and visceral pain: • Somatic: localised; injury/disease of skin, musculoskeletal/joints; tissue stimulation lead to binding of receptors (ie nociceptors) • Visceral: no clear loci (often referred pain); internal organ dysfunction (eg myocardial ischaemia, renal calculi, functional disease) • difference in densities and types of nociceptors in viscera and convergence with afferent somatic pathways in spinal cord Neuropathic, nociceptive and mixed pain • Neuropathic: somatosensory system affected (eg post-herpetic neuralgia) • Nociceptive: injury of skin, muscle, tendons, ligaments, bones, joints • Mixed: eg cancer - tumour and/or treatment sequelae (eg surgery, chemotherapy, radiation) • Dysfunctional pain • Amplification of pain signal with no inflammation or injury (eg fibromyalgia, irritable bowel syndrome, interstitial cystitis) (exact pathophysiology still to be elucidated)

Escherichia coli

• Some strains cause infections of GIT and other organs • Enterotoxigenic E.coli (ETEC): both heat labile and heat stable enterotoxins and have fimbriae • Enterohaemorrhagic E.coli (EHEC) • May cause haemolytic uraemic syndrome (HUS) especially strains O157 & O111 • Enteropathogenic E.coli (EPEC): colonise intestinal epithelial cells • Enteroinvasive E.coli (EIEC): use adhesins to enter intestinal cells • Enteroaggregative E.coli (EAEC): destroy cells by enterotoxins and cytotoxins

Limitations

• Suppression or elimination of resident microbiota • Compromised clearance • Adverse side effects • Hypersensitivity • Ototoxicity • Nephrotoxicity • Bone marrow suppression • Risk versus benefits • Emergence of resistance • Oral/parenteral availability

Therapeutic index (TI): a measure of drug safety

• TI is the ratio of the dose that produces toxicity to the dose that produces an effective response: • The TI provides an indication of safety of a drug: higher (wider) is better

Bioavailability - the fraction absorbed

• The fraction of an (orally or enteral) administered dose that reaches the systemic circulation as intact drug, taking into account both absorption and local metabolic degradation (first-pass) • By definition, the fraction following IV administration = 1 (or 100%) • Why is bioavailability important? • High bioavailability, dose same for IV and oral routes • eg metronidazole, fluconazole, amoxicillin • Low bioavailability, lower dose for parenteral than oral routes • eg morphine: 10 mg s/c or IM = 30 mg po

Distribution

• The reversible transfer of a drug from the bloodstream to the tissue • drug moves between different body compartments • drug reaches the site of action (receptors) • The degree of distribution of a medicine depends on its physical and chemical properties • For a drug to reach it's target it must be distributed into interstitial and intracellular fluids

Pharmacodynamics

• The study of the mechanisms by which specific drug dosages act to produce biochemical or physiological changes in the body. • The biochemical, physiologic, and molecular effects of drugs on the body • Often referred to as "what the drug does to the body" • In short, what the drug does

Body fluid compartments & volume of distribution

• There are several physiological fluid compartments into which drugs can distribute • plasma, interstitial, intracellular • (~70kg man approx. 42L total volume) • The volume of distribution (VD) is the theoretical volume necessary to contain the total amount of drug in the body at the same concentration as that in the plasma

Virulence Factors & Biofilms

• To cause disease, a microbe must: • Gain entry to host • Attach to host tissue • Multiply • Mechanisms that help • Bacterial virulence factors • surface structures & toxins • antibiotic resistance • Viral specificity & ability to become latent • Yeast - pseudohyphae enhances invasion • Protozoa, flukes & helminths - suckers allow attachment to host cell wall • Survival • Evade host defences • Host and environmental influences - pathogenesis • Health, nutritional status, age, gender

How do drugs work?

• Transport systems: eg. ion channels, carriers • Enzymes: eg. block/prevent enzyme activity • 'non-specific': eg. chelation, antacids, osmotics

Clearance & kinetic order

• Two types of kinetics, related to the plasma concentration of a drug, describe the rate at which a drug leaves the body: • Zero-order kinetics: • Rate of elimination is constant. • Rate of elimination is independent of drug concentration. • Constant amount eliminated per unit of time. • Example: Alcohol • First-order kinetics: • A constant fraction of drug is eliminated per unit of time. • When drug concentration is high, rate of disappearance is high.

Absorption & drug solubility • Solubility is a major factor affecting drug absorption

• Water-soluble • Ionized (have electrical charge) • Crosses through pores in capillaries, but not cell membranes • Lipid(fat)-soluble • Non-ionized (no electrical charge) • Crosses pores, cell membranes, blood-brain-barrier

What is an URTI?

•RTIs classified as URTI or LRTI •URTIs generally associated with: - Throat - Pharynx - Middle ear - Sinuses - Epiglottis

Urogenital tract

•Urinary and reproductive systems •Predominantly sexually transmitted diseases/infections (STDs/STIs) •Enter skin or mucosa of penis, external genitalia, vagina, cervix, urethra •Defences include normal microbiota (not all sites), pH, sphincters as mechanical barriers and mucus • Examples • Syphilis • Gonorrhea • Genital warts • Chlamydia • Herpes