Pharmacology

Explain the fluid mosaic model of plasma membrane

Flexible phospholipid bilayer with embedded proteins + cholesterol providing structural integrity

3 types of transport mechanisms in cell membranes

• passive diffusion: no membrane proteins → down conc gradient

• Facilitated diffusion: use membrane protein → down conc gradient

• Active transport: against conc gradient + requires ATP

What is the most important membrane transport mechanism in the control of intracellular Na/K+ conc

Na-K ATPase - pumps 3Na out + 2K+ in for every ATP molecule

How is cell volume regulated

Na+, K+, Cl- are osmotically active ions so water will follow

IV fluid prescribing (adults)

• water: 25-30ml/kg/day

• Na/K/Cl: 1mmol/kg/day

• Glucose: 50-100g/day

Crystalloid

Aqueous sol composed of water + electrolytes/glucose

Can be isotonic, hypo or hypertonic

Advantages of crystalloids

• cheap

• Non allergic

• Coagulation not effected

Crystalloid disadvantages

• higher vol needed

• Short time in intravascular space

Examples of crystalloids

• 0.9% saline

• Hartmann’s (closest composition to plasma)

• Glucose

• Ringer’s lactate

What is fluid resuscitation used for

• maintains intravascular vol in hypotensive/shock

• Replaces large fluid loss

How do colloids work

Large molecular weight particles cannot pass through capillary membrane → creates osmotic gradient

water remains in intravascular space (high oncotic pressure)

Colloid disadvantages

• expensive

• Risk of anaphylaxis

• Coagulopathy

Colloid examples

• albumin

• Gelaspan

Dehydration vs volume loss

Dehydration = loss of total body water

Vol loss = reduced ECF

Symptoms of reduced ECF

Thirst

Muscle cramps

Nausea/vomiting

Confusion

Postural dizziness/hypotension

Clinical features of increased ECF

• peripheral/pulmonary oedema

• Ascites

• Raised JVP

• Basal crackles

What is a ligand + examples

A molecule that reversibly binds to a receptor

Exogenous: drugs

endogenous: neurotransmitters, hormones

What is the difference between a receptor and acceptor

Receptors Specialised proteins dependent on ligand binding

Acceptors can be functional independently

What are agonists

Drugs that bind to receptors + produce a response

Types of receptors

• ionotropic

• GPCR (metabotropic)

• Enzyme-linked

• Intracellular

Examples of ionotropic receptors

• Cholinergic nicotinic

• GABAa

• 5-HT3

Types of cholinergic receptors

• muscarinic

• Nicotinic

Muscarinic receptors

5 types:

• M1,3,5 → GPCR (Gq) mediated by inositol lipid signaling

• M2,4 → use Gi to open K+ channels = hyperpolarisation

Locations of muscarinic receptors

• M1 - CNS+PNS parietal cells (neural receptors)

• M2 - cardiac

• M3- glandular + smooth muscle

• M4/5 - CNS

How do nicotinic receptors work

• Ligand gated ion channel

• Ach binds to N terminal → conformational change

• Channel opens so Na+ in/K+ out (depolerisation)

How do GCRP work (metabotropic)

• Activate intracellular guanine nucleotide binding protein

• Bind to GDP when inactive - GTP when active

• Adrenoceptors → respond to catecholamines

• Muscarinic → respond to ach

Enzyme/kinase linked receptors

• hormones, growth factors, cytokines

• Extracellular ligand binding site

• Intracellular catalytic domain → phosphorylates substrate

What is the significance of autophosphorylation

Receptor remains active until phosphate group is removed

So able to interact with other proteins → signalling

Intracellular receptors

Typically act on DNA → eg genetic expression of: enzymes, cytokines, receptor proteins

Examples of drugs that interact with intracellular receptors

• sex hormones

• Thyroid hormones

• Mineralcorticoids

• Vitamin D

Steps of cell signalling pathway

1) reception

2) transduction

3) response

Explain receptor mediated endocytosis process (eg LDLs + transferrin)

1) ligand binds to receptor in clathrin coated pits

2) invaginates + buds off from plasma membrane → vesicle

3) vesicle fuses with endosome → separates ligand from receptor (uses ATP)

4) receptors recycled back to CSM + ligand vesicle digested by lysosome

How do local anaesthetics work

• bind to voltage-gated Na+ channels (intracellular side of receptor)

• No Na+ entry = no AP generated

G-protein couple receptor structure

• seven-pass trasmembrane receptor

• Single polypeptide chain

• Extracellular N terminal + intracellular C terminal → activates G protein

G protein structure

• alpha, beta and gamma subunits

• 3 types q,i,s

• Inactive = bound to GDP, Active = bound to GTP

Examples of drugs that target GPCR

• bronchodilators

• Beta blockers

• ARB

• Antihistamines

• Naloxone

What enzyme does Gq activate +function

Phoshoplipase C: cleaves PIP2 → IP3+ DAG

• IP3 = opens Ca2+ channels in endoplasmic reticulum so increased conc inside cell

• DAG = phosphorylates protein kinase C

What enzyme does Gs stimulate + function

Adenylyl cyclase: converts ATP → cAMP

CAMP: binds to regulatory subunit of protein kinase A → catalytic subunit phosphorylates target proteins

What enzyme does Gi effect

INHIBITS adenylyl cyclase →Gs negative feedback

Examples of Gs-coupled receptors

• beta adrenoceptors

• D1 dopamine

• H2 histamine

Examples of Gi-coupled receptors

• alpha2 adrenoceptor

• D2 dopamine

• Opioid

Naloxone

Short acting opioid antagonist

Used to treat respiratory distress in opioid overdose

Opioids mechanism of action

• Mu, delta + kappa receptor agonists (brain, spinal cord, GI tract)

• Pre-synaptic: Ca+ channels inhibited so less Ca+ = decreased neurotransmitters

• Post-synaptic: K+ channels open so K+ efflux = hyperpolarisation

Opioid side effects

• nausea

• Constipation

• Miosis (Pupil constriction)

• Respiratory distress

How is Ca2+ gradient formed + maintained

• PMCA + Na+/ca2+ exchanger

• Ca2+ buffers

• Intracellular Ca2+ stores

• Closed VOCC at resting membrane potential

Plasma membrane Ca2+ ATPase (PMCA) mechanism

• high intacellular [Ca2+] → calmodulin to binds to Ca2+

• Ca2+-calmodulin binds to PMCA → removes Ca2+

• High affinity, low capacity

How do Ca2+ buffers work

• binding proteins that limit ca2+ diffusion

• Decrease intracellular conc by binding to excess ca2+

Mechanism of action of sodium channel blockers as antiarrhythmic

• Block Na+ channel so no influx

• Reduced phase 0 slope = reduced magnitude of AP + slow rate

• A- moderate, B- weak, C-strong

Examples of sodium channel blockers

• Class A: disopyramide, quinidine

• Class B: lidocaine, mexiletine

• Class C: encainide, flecainide

Beta blocker mechanism of action

• block cardiac beta1-adrenoceptors = no catecholamine binding

• Decreased SANS activity +cAMP

• Decrease phase 4 slope + increase PR interval

• slows AV conduction = less contractility

Examples of beta blockers

• selective: atenolol, bisoprolol

• Non-selective: propanolol, Timolol

Potassium channel blocker mechanism of action

• channel blocked = no k+ efflux

• Increased phase 2 + delays phase 3

• Prolongs AP → increased absolute refractory period

Examples of potassium channel blockers

• amiodarone

• Ibutilide

• Droneradone

Calcium channel blocker mechanism of action

• blocked channel = no Ca2+ influx

• Decreased phase 0 + 4 slope, increased PR interval

• Slows AV conduction = slower velocity + decreased contractility

Examples of calcium channel blockers

• verapamil

• Diltiazem

What are antagonists

molecule that blocks binding site + inhibits response → affinity but no efficacy

Can be reversible or irreversible competitive, or non-competitive

Pharmacodynamics

mechanism + effects of a medication binding to receptors on the body

What is drug potency + how is it measured

• amount of drug required to elicit pharmacological effect

• EC50 = drug conc producing 50% of max effect

• On graph more potent drug = left (lower dose)

How is the safety of a medication measured

therapeutic index

TD50 (dose that causes toxic side effects in 50% pop)/ ED50

Narrow complex (ratio closer to 1)→ greater danger

What is drug efficacy

measures strength of drug action once bound to receptor

what is drug affinity + how is it measured

measures the tendency of a drug to bind to receptors

Dissociation constant - conc of drug at which half the receptors are occupied (low Kd = higher affinity)

What is a partial agonist

molecule that binds to receptor but elicits a weaker response (reduced efficacy)

What is an allosteric modulator

substance that binds to secondary site on receptor + changes agonist binding site (orthosteric)

Can increase or decrease affinity

How do inverse agonists differ from antagonists

IA produces the opposite effect to an agonist

antagonists block the effects of both

Define tachyphylaxis + tolerance

Tachyphylaxis: rapid decrease of drug effect following repeated administration

Tolerance: gradual decreased response to drug

Define refractoriness + resistance

Refractoriness: loss of therapeutic efficacy

Resistance: loss of efficacy of chemotherapeutic agents

What mechanisms can cause a reduced drug response

• conformational change in receptor

• Translocation of receptors

• Increased metabolic degradation

• Physiological adaptation

What is bioavailability + what can affect it

Proportion of administered drug (non-IV) that reaches systemic circulation

• solubility

• GI absorption

• Hydrolysis by acid or enzymes

Examples of enteral drug administration

Drug entering via GIT

• oral

• Rectal

• Buccal (between cheek)

• sublingual (under tongue)

Examples of parenteral administration

Bypasses GIT directly into systemic circulation

• Intravenous

• Subcutaneous

• Intramuscular

What is first pass metabolism of enteral drugs

• blood from GIT is directed to liver

• Drug metabolised before reaching systemic circulation = reduced efficacy

Define pharmacokinetics + steps (ADME)

Movement + modification of drugs within the body

• Absorption

• Distribution

• Metabolism

• Excretion

Examples of drugs affected by first pass metabolism (NIL By Mouth)

• nitrates

• Imipramine

• Lidocaine

• Beta blockers

• Morphine

Nitroglycerine mechanism of action

• oral/sublingual for rapid absorption + relief (angina)

• Nitrite converted to NO → diffuses into SM cells of arteries + veins = vasodilation

• Veins: peripheral blood pooling = decreased preload

• Arteries: decreased vascular resistance = decrease afterload

Natural corticosteroid (hydrocortisone) MoA

• binds to glucocorticoid receptors

• Inhibits phospholipase A2, NF-kappa B, inflammatory transcription factors

• Decreased vasodilation + capillary permeability → anti-inflammatory

Reasons to use parenteral drug administration

• drug poorly absorbed by GIT

• Significant first-pass metabolism

• GIT not in use

Common sites of IM injections

• deltoid

• Rectus femoris

• Gluteus medius

IM muscle contraindications

• allergy

• Myopathy

• Muscular atrophy

• Infection at administration site

Haloperidol mechanism of action

• antipsychotic used for schizophrenia

• D2 antagonist → competitively blocks post-synaptic receptors

• IM administration = higher bioavailability, oral = maintenance

Intrathecal administration

Drug injected into spinal canal - eg spinal anaesthetic

Fine needle injects local into subarachnoid space

Delivered directly to CSF

How does an epidural differ from intrathecal administration

Epidural diffuses from dura to CSF

Given cervical, thoracic or lumbar → Catheter placed in epidural space

Examples of narrow therapeutic index (NIT) drugs

• digoxin

• Warfarin

• Lithium

• Theophylline

• Levothyroxine

Therapeutic drug monitoring (TDM) + significance

measuring drug conc in blood at timed intervals to maintain a constant conc in circulation

Important to achieve therapeutic effect + avoid toxicity

Direct oral anticoagulant (DOAC) mechanism of action

• Direct thrombin or factor Xa inhibitors

• Prevents thrombus formation

• Eg apixaban

What are the advantages of DOACs to warfarin

warfarin has narrow therapeutic index so requires INR monitoring

Pharmacokinetics: Absorption

passage of a drug from site of administration into the plasma

What are the factors affecting drug absorption?

• food (enhance or impair)

• Formulation

• Route of administration

Pharmacokinetics: Distribution

Movement of a drug from circulation to body tissue + relative proportions of drug in the tissue

What are the factors affecting drug distribution?

• plasma protein binding competition

• Drug receptor sites

• Regional blood flow + vascularity (brain, liver, kidney)

• Lipid solubility (cross membranes easier)

Plasma protein binding

• drugs will bind to plasma proteins eg albumin → limited to plasma so essentially inactive

• Unbound drugs are free to act at receptor site + diffuse into tissue

What are the factors which can increase the fraction of unbound drug?

• renal impairment → high blood urea + plasma proteins can be filtered out

• Low plasma albumin levels → chronic liver disease, malnutrition

• Late pregnancy → decreased albumin production + increased blood volume= dilution

Volume of distribution (Vd)

theoretical vol that accommodates all the drug distributed in the body

Vd = dose administered (mg)/ plasma concentration of drug (mg/L)

High vs Low volume of distribution

• high Vd = higher dose needed to reach target plasma conc, as more distribution to tissue

• Low Vd = lower dose required, tends to remain in plasma

Object + precipitant drug

• object: used at dose lower than no. Albumin binding sites (eg warfarin)

• Precipitant: used at doses greater than no. Of binding sites so displace object drug (eg aspirin)

Pharmacokinetics: Metabolism

biochemical modification of drug into +/- active metabolite - primarily in liver

• phase 1: Oxidation, reduction and hydrolysis via CYP450, form more soluble + reactive products

• Phase 2: Conjugation, usually form inactive + readily excretable products

What are the factors affecting drug metabolism?

• first pass metabolism

• Hepatic blood flow

• Age

• Genetics

• Liver disease

• Other drugs → hepatic enzyme inhibitors/inducers

Loading dose

• initial higher dose given at start of treatment (single bolus)

• Eventually drops down to lower maintenance dose

• Useful for drugs with long half life when rapid effect desired

Half life

time required for drug conc in plasma to be reduced by 50%

Zero order kinetics

Constant rate of drug elimination per unit of time

Eg warfarin, aspirin

First order kinetics

Rate of drug elimination is directly proportional to plasma concentration Common in most drugs

Exponential decrease → helps to determine half life