2016-01-11 acem primary pharmacology - acem primary pharmacology (1) Flashcards
What is potency?
the amount of drug required to produce an effect of given intensity.
Potency is measured by the ed50 which is the amount (dose) of drug required to produce 50% of the drug’s maximal effect
What is efficacy?
measure of the maximum clinical respose to the drug regardless of dose
What is the ec50?
the dose at which 50% of people exhibit a quantified effect.
What is td 50?
The dose required to produce a toxic response in 50% of subjects (LD 50 has same definition but the toxic response is death)
What is the therapeutic index?
TD50/EC50 ratio
Give examples of lipid soluble ligands that cross the membrane and act on intracellular receltors?
steroids such as corticosteriods, sex steroids and vitamin D
These bind to the nucleus to stimulate transcription of genes and make new proteins- therefore the lag is 30 minutes to hours while the proteins are being made.
They persist in their effect over days when the agonist concentration goes to zero due to slow turnover of most enzymes and proteins
Give examples of substances that trigger ligand gated ion channels?
How does this work?
acetylcholine, gaba, excitatory amino acids
Receptor alters transmembrane conductance of ions and thereby alters electrical potential across the memebrane
Describe the nicotinic acetylcholine receptor?
pentamer made up of 5 polypeptide units (2 alpha, 2 beta, 1 gamma) which each cross the lipid bilayer 4 times and form a cylindrical structure. Binding of ach causes structural change that opens sodium channel. Occurs in milliseconds.
Give examples of substances that bind to a transmembrane receptor that stimulates a tyrosine kinase.
Insulin, PDGF, ANF
How do tyrosine kinase receptors work in general?
Receptor polypeptide consists of a hormone binding domain (extracellular) and an enzyme domain (cytoplasmic) which are connected through the membrane. Hormone binds with extracellular receptor, resulting conformational change that brings together the protein tyrosine kinase domains that become enzymatically active.
What are the three mechanisms by which a drug/ligand binding to a transmembrane protein can cause change?
- The transmembrane receptor contains an ion channel which changes shape e.g. gaba, ach
- The transmembrane receptor has a tyrosine kinase on the insidene.g. insulin, pdgf, anf
- Transmembrane receptor stimulates a g-protein- the activated g-protein changes the activity of a receptor element (usually an enzyme or an ion channel)
What is the advantage of signalling via g-proteins?
Signalling via G proteins allows effect to persist long after the extracellular receptor has dissociated from its agonist molecule
What do Gs G-proteins do?
increase adenylyl cyclase, causing increased cAMP
Give example of Gs G-proteins?
Beta adrenergic amines, glucagons, histamine, serotonin.
What do Gi G-proteins do?
Give examples of these?
decrease adenylyl cyclase, causing decreased cAMP Open cardiac potassium channels causing decreased heart rate
Alpha2 adrenergic amines, acetylcholine (muscarinic only), opioids, serotonin
What do Gold g-proteins do
Stimulate adenylyl cyclase causing increased cAMP.
stimulated by odourants
What do Gq G-proteins do?
Give examples of these?
Increase adenylyl cyclase causing increased cAMP Increase phopholipase C resulting in increased IP3, diacylglycerol and cytoplasmic calcium.
Acetylcholine (muscarinic), serotonin
What is the structure of g-protein coupled receptors?
serpentine receptors- polypetide chains which cross the membrane 7 times.
How does cAMP work?
G protein stimulates membrane adenylyl cyclase that converts ATP to cAMP. cAMP exerts most effects by stimulating cAMP dependent protein kinases.
How does calcium and phospholipase second messaging work?
G protein stimulates membrane enzyme phospholipase that hydrolyses PIP2 to DAG and IP3. DAG is confined to the membrane and activates protein kinase C.
IP3 diffuses through the cytoplasm to trigger release of calcium from internal stores. Calcium binds to calmodulin, which regulates calcium dependent protein kinases.
How are DAG and IP3 inactivated?
DAG inactivated by phosphorylation back to phospholipid.
IP3 rapidly inactivated by dephophorylation.
How does cGMP work?
small role -mainly intestinal mucosa and vascular smooth muscle. G protein stimulates membrane guanylyl cyclase which converts GTP to cGMP. cGMP exerts most effects by stimulating cAMP dependent protein kinases.
What is the volume of distribution?
What are the units?
It relates the amount of drug in the body to its concentration in blood or plasma- depends what it is soluble in/binds to.
Vd=Amount of drug in body /concentration. Most commonly expressed in units of litres per kilogram
Give an example of a drug that is distributed in the total body water?
What is the volume of distribution?
ethanol and other small water soluble molecules
0.61L/kg (42L)
Give an example if a drug that is distributed in the extracellular water?
What is the volume of distribution?
Mannitol, gentamycin
larger water soluble molecules
0.2l/kg
14 L
What is the volume of distribution of blood?
0.08l/kg= 5.6L
Give an example if a drug that is distributed in plasma? (and explain why it is largely confined to plasma)
What is the volume of distribution?
Heparin
0.04l/kg
Bound to a plasma protein
Give an example if a drug that is distributed in fat?
What is the volume of distribution?
DDT (insecticide)
0.2-.35l/kg (14-24l)
Give an example if a drug that is distributed in bone?
What is the volume of distribution?
0.07l/kg
(4.9L)
lead and flouride
What drugs cannot be removed by dialysis?
drugs with large volumes of distribution
Give examples of drugs with large volumes of distribution? (5-10L/kg)
Antidepressants
Phenothiazines
Propanolol
Verapamil
Give examples of drugs with small volumes of distribution? (
Theophylline Salicylate Phenobarbitone Lithium Phenytoin Heparin Warfarin
What is the half life of a drug?
Time required to change the amount of drug in the body by 1/2 during elimination or during a constant infusion
T1/2=0.7xVd / CL
Half life can refer to the drug itself or the active metabolites of the drug
What is allosteric action?
drugs that bind to the same receptor but do not prevent binding of the receptor molecule, may enhance or inhibit action
How is the action of transmembrane receptors terminated?
ligand binding often causes acellerated endoscytosis of reception followed by the degradation of the receptors and their bound ligands
Why are volumes of distribution greater than actual volumes found in the human body?
because it is the volume apparently necessary to contain the concentration found in blood, plasma or water
Drugs with very high volumes of distribution have much higher concentrations in the extravascular compartment then in the vascular compartment- i.e. not homogenously distributed.
Drugs that are completely retained within the vascular compartment have a minimum volume of distrubution
What is drug clearance?
Rate of elimination/concentration, this is additive when more than one organ clears it
i.e. CL(liver)= rate of elimination by liver/C
kidney generally excretes unchanged drug while liver metabolises
What is the rate of elimination?
CLx C when clearance is first order
calculated using the area under the time concentration curve (dose/AUC)
When is rate of elimination not first order?
capacity limited elimination e.g. phenytoin and ethanol, aspirin
also known as dose/concentration and saturatable elimination
cannot use auc to measure rate of elimination
rate of elimination = vmax x c/ km x c
What is flow-dependent elimination?
relevant for drugs that are cleared mainly on the first pass and therefore elimination depends on blood flow to the organ
What is bioavailability?
The fraction of the drug reaching the systemic circulation following administration by any route- IV has greatest bioavailability because it avoids first pass metabolism, extent of absorption (liphophilicity, reverse transporter associated with p glycoprotein)
How do your calculate the dosing rate for a drug?
CL x target concentration (TC)
How do you calculate the maintenance dose?
Drugs are usually administered in order to achieve a steady state where dosing equals elimination.
Dosing rate=CL X target concentration (TC)
Maintenance dose=dosing rate x dosing interval
When is a loading dose needed?
How does one calculate the loading dose?
Loading doses are required if the half-life of a drug is prolonged and the time taken to reach steady state would otherwise be prolonged
If the target concentration is known the clearance will determine the dosing rate
Loading dose=Vd X TC(target concentration)
Give a formula for systemic clearance of a drug?
Clearance can pertain to each organ and is additive in effect CLrenal+CLliver+CLother=CLsystemic.
What is another work for capacity limited clearance?
zero order kinetics
Describe how zero order kinetics works?
Drug elimination pathway becomes saturated at high concentration of drug. Elimination is proportional to concentration of the drug at low concentrations but at high concentrations elimination is constant.
e.g. Aspirin, Phenytoin, Ethanol
What is first order clearance?
First order clearance = clearance proportional to concentration
What are some drugs that exhibit flow dependent elimination? Give 3 examples?
Extraction is chiefly dependent on blood flow through the organ and the drug is almost completely extracted by the organ on first pass
Morphine Lignocaine Propanolol
What are some limitations to drug absorption in the gut?
Lipophilic (acyclovir) versus hydrophilic (atenolol) drugs
Bacterial metabolism within the gut (digoxin) Absorption abnormalities in small bowel.
What is the extraction ratio?
Extraction ratio defines the degree of first pass metabolism.
ER=CL liver /Q
(Q is hepatic blood flow = 90l/h)
Where does first pass elimination occur?
Can occur in gut wall, portal blood, or by excretion in bile. Most important is metabolism by liver.
What is the formula for systemic bioavailability?
Systemic bioavailability (F) =extent of absorption (f) X (1-ER)
How do you avoid hepatic first pass metabolism?
Hepatic first pass metabolism can be avoided by sublingual, transdermal and to a lesser extent, rectal administration
What is biotransformation?
Biotransformation is the metabolism of drugs that allows for the renal excretion of lipophilic, un-ionised or partially ionised drugs that would otherwise fail to be effectively excreted and have a prolonged duration of action.
Biotransformation transforms a lipophilic molecule into a more polar and therefore more readily excretable product.
Where does biotranformation occur
Biotransformation can occur in GIT (eg clonazepam, penicillin), lungs, skin, kidneys, but most important site is liver.
What are the two phases of biotransformation reactions?
Phase 1 reactions Convert the parent drug to a more polar metabolite by introducing or unmasking a functional group such as OH, NH2, SH.
Phase 2 reactions The introduced functional group combines with an endogenous substrate to form a highly polar conjugate. Enzymes for phase 2 reactions may be located in microsomes or in the cytosol. Phase 2 reactions can sometimes precede phase 1 reactions.
How do phase 1 reactions work?
Phase 1 reactions utilise mixed function oxidases located on the ER of liver cells and other tissues.
Require oxygen and NADPH to function. Mixed function oxidases include NADPH-cytochrome P450 reductase and cytochrome P450.
How many major CYP450 isoforms are there? What is the most important one?
Different P450 isoforms are responsible for metabolism of different drugs. 7 main isoforms account for most metabolism. CYP3A4 is the largest component, responsible for 60% of clinically prescribed drugs metabolised by the liver.
Where do phase 1 and 2 reactions occur?
Whase 1 occur on the ER, Phase 2 occur in microsomes and the cytosol
What are some genetic factors that affect biotransformation?
Suxamethonium - genetic defect in
pseudocholinesterase, causes suxamethonium to remain active for prolonged periods. Other examples - oxidation of ethanol, acetylation of isoniazid
What are some environmental factors that affect biotransformation?
Enzymes may be induced or inhibited by environmental factors.
Charcoal - induction
grapefruit juice -inhibition of CYP3A4 (responsible for 60% of drug metabolism)
What dies phenytoin do to digoxin metabolism?
Phenytoin enhances digoxin metabolism
What do barbituates do to warfarin metabolism?
Barbiturates enhance warfarin metabolism
The metabolism of what drugs does cimetidine affect?
Cimetidine inhibits warfarin and diazepam metabolism
The metabolism of what drugs is affected by cardiac disease?
Cardiac disease can affect drugs that are flow-limited
e.g. Morphine, Verapamil
What are the physical barriers to drug distribution? list 4
- Aqueous diffusion -generally determined by fixed law though if a drug is charged its flux will be influenced by electrical fields.
- Lipid diffusion - most important limiting factor for drug permeation. Lipid:aqueous partition coefficient determines how readily the molecule moves between acid aqueous and lipid media. The abililty of weak acids and bases to move between aqueous and lipid mediums depends on pH.
- Special carriers (active transport/facilitated diffusion) - for molecules that are too large or too insoluble - eg peptides, amino acids, glucose
- Endocytosis and exocytosis for very large molecules -eg vit B12, iron
What is fick’s law of diffusion
Passive flux of molecules down a concentration gradient equals the difference in concentration across the membrane (C1- C2) multiplied by the area of the membrane and the permeability coefficient, divided by the thickness of the membrane
conc grad x sa x perm coeff /thickness
Define weak acid?
a neutral molecule that can readily dissociate into an anion and a proton
Define weak base?
A neutral molecule that can combine with a proton and form a cation
What is the pKa?
pKa =the pH at which the concentrations of ionized and and inionized forms are equal
When are weak acids and bases more likely to be in a lipid soluble form?
More of a weak acid will be in a lipid soluble from at an acid pH.
More of a weak base will be in a lipid soluble form at an alkaline pH
This is important for excretion of drugs by the kidney.
What is the henderson hasselbach equation?
pH = pKa + log [base]/[acid]
What is the general structure of local anaesthetics?
Consist of a lipophilic group, ester or amide chain and ionisable group (usually a tertiary amine)
What are the two types of local anaesthetics?
Esters: Cocaine (procaine) (benzocaine)
Amides: Lignocaine Bupivicaine Prilocaine (etidocaine)
Define local anaesthetics?
Agents which reversibly block impulse conduction along nerve axons, thereby reducing pain sensation- usually do this by blocking voltage gated sodium channels
Where do local anaesthetics act on the sodium channel?
Blockade occurs at the intracellular end of the sodium channel
What are the pharmacodynamics of local anaesthetics?
Activated channels have higher affinity for drug therefore drug effect is more marked in rapidly firing fibres.
Progressive increase in drug concentration causes increased threshold, reduced action potential amplitude, then failure to produce an action potential.
What ion concentration changes increase and decrease the effects of local anaesthetics?
Local anaesthetic effect is increased by hyperkalaemia and decreased by hypercalcaemia
How does fibre type (size and myelination) affect how local anaesthetics work on the nerves?
Large diameter fibres less sensitive than small diameter fibres. (3 successive nodes required for blockade, nodes are further apart in large fibres).
Myelinated fibres of the same diameter as unmyelinated fibres tend to become blocked first.
Why are sensory nerves more sensitive to local anaesthetics?
Sensory fibres tend to have a fast firing rate and long action potential therefore are more sensitive to blockade.
How does the position of a nerve in the bundle affect how sensitive it is to local anaesthetics?
Peripheral nerves exposed first -motor nerves tend to be peripheral in large trunks.
What are the safe doses for lignocaine with/without adrenaline?
2mg/kg IV, 3mg/kg SC, 5mg/kg with adrenaline.
What is 1% solution of drug?
10mg/ml
What is the safe dose of bipivicaine and prilocaine?
Bupivacaine 2mg/kg SC
Prilocaine 3-5mg/kg IVRA
What are the relative potencies of the local anaesthetics, say lignocaine = 4
(if procaine = 1) Cocaine =2 Lignocaine =4 Bupivacaine = 16 Prilocaine = 3
What is the CNS toxicity of local anaesthetics?
Drowsiness, visual and auditory disturbance, restlessness, nystagmus, shivering, convulsions, CNS depression.
How do you manage convulsions caused by local anaesthetics?
If convulsion occurs, the patient should be hyperventilated to induce respiratory alkalosis as this lowers extracellular potassium and favours rested, low affinity sodium channels
Which local anaesthetics cause the most CNS and CVS toxicity?
Bupivacaine>lignocaine> prilocaine
Bipivicaine is most cardiotoxic -Although all local anesthetics potentially shorten the myocardial refractory period, bupivacaine avidly blocks the cardiac sodium channels, thereby making it most likely to precipitate malignant arrhythmias.
What are the cardiovascular effects of local anaesthetics?
Depression of cardiac pacemaker activity, excitability and conduction. Negative inotropic effect and decreased peripheral resistance.
How is cocaine different from other local anaesthetics in its cardiovascular effect?
noradrenaline uptake blockade and subsequent vasoconstriction and hypertension.
What haemotological toxicity do local anaesthetics have?
Prilocaine in high doses liberates the 0-toluidine metabolite that causes methaemoglobinaemia.
Which drug interract with local anaesthetics?
Fentanyl and midazolam utilise same microsomal enzymes in liver
Halothane, cimetidine and beta blockers decrease hepatic blood flow and therefore reduce metabolism
Enzyme inducers such as phenytoin may increase metabolism
Are local anaesthetics acid or base?
most are weak bases, potency depends on how liphophilic it is and therefore depends on the pH of the tissue
What is the active form of local anaesthetics? Is this the form that gets into the tissues?
Most are in a charged, cationic form and this is the active form at the receptor site, but the uncharged form is required for penetration - hence poor penetration in acidic (infected) tissue
How protein bound are local anaesthetics?
bupivicaine 95%, prilocaine 50%
What affects systemic absorption of local anaesthetics?
What does local effect depend on?
dose, vascularity of site of injection, drug-tissue binding, presence of vasoconstrictors (more effective for short acting highly lipid soluble drugs), chemical properties of the drug.
Local effect is proportional to the amount of drug that penetrates the nerve fibre
What is the comparative duration of action of the common local anaesthetics?
Cocaine -medium
Lignocaine -medium
Bupivacaine - long (up to 12 hours for peripheral nerve blocks)
Prilocaine - medium.
Why do ester local anaesthetics have a very short plasma half life?
Rapidly metabolised by pseudo- cholinesterase therefore half life less than 1 minute.
How are amide local anaesthetics metabolised?
Slowly hydrolysed by liver enzymes and excreted by kidney: Dosage reduction required in liver disease and reduced hepatic blood flow
Prilocaine metabolised most rapidly, lignocaine intermediate, bupivacaine slowest: Prilocaine metabolism produces O- toluidine
What are guedel’s stages of anaesthesia?
Stage of analgesia
Stage of excitement
Stage of surgical anaesthesia
Stage of medullary depression
What are the 5 factors that affect the brain uptake of an inhaled anaesthetic?
- Partial pressure of inspired anaesthetic agent
- Solubility (blood:gas partition coefficient)
The more soluble an agent the longer it takes for its partial pressure in blood to rise therefore the slower the onset of anaesthesia. - Pulmonary ventilation Increases the rate of induction of anaesthesia for drugs with high solubility - little effect on drugs with low solubility
- Pulmonary blood flow
Increased flow decreases the rate of induction with
soluble agents, little effect with poorly soluble agents. - Arteriovenous concentration gradient (tissue:blood solubility coefficient)
Gradient between arterial and mixed venous blood determined by uptake of agent by highly perfused organs such as brain, heart, liver, kidneys and gut. Drugs with high tissue:blood solubility coefficient take longer to reach equilibrium.
Define the MAC (minimal alveolar concentration).
Give an example of a drug with a high MAC?
What are the limits to using MAC?
The partial pressure (% concentration) of an agent which results in immobility of 50% of patients undergoing a surgical incision.
For nitrous oxide, MAC>100% means that even if the partial pressure of nitrous oxide is 760mmHg, incomplete anaesthesia is achieved.
There may be vast individual differences and the MAC gives no indication where the other 50% lie on the curve.
Why is steady state alveolar concentration a useful measure of potency?
When steady state is achieved, the partial pressure of an inhaled anaesthetic in the brain equals that in the lung, therefore measurement of steady state alveolar concentration gives a measure of potency
How do inhaled general anaesthetic agents work?
Increase in cellular threshold to firing with subsequent decreased spontaneous and evoked neuronal activity.
Ionic basis of effect includes activation of potassium currents to cause hyperpolarisation and opening of cation channels to decrease synaptic transmission.
Research suggests that agents interact with lipid membranes to cause distortion of ion channels.
What are the cardiovascular effects of general anaesthetic agents?
Dose related variable reduction in mean arterial pressure and myocardial oxygen demand. Effects may be masked by nitrous oxide which causes sympathetic stimulation
Nitrous oxide causes minimal depressant effects
Halothane sensitises the myocardium to catecholamines and is arrhythmogenic.
What are the respiratory effects of general anaesthetics? List 5
- Respiratory depression due to reduced TV and inadequate increased rate. (except nitrous oxide)
- Increase apneic threshold to pCO2.
- Decrease ventilatory response to hypoxia.
- Decrease mucociliary function leading to atelectasis.
- Most have bronchodilator action.
What are the CNS effects of general anaesthetics?
Increase metabolic rate and blood flow to brain due to reduced cerebrovascular resistance. Hyperventilation reduces this effect.
What are the GI and GU effects of general anaesthetics?
GUS
Reduced renal blood flow and GFR. Uterine relaxation (minimal with nitrous oxide)
GIT
Reduced hepatic blood flow.
Describe the acute and chronic toxicity of general anaesthetic agents?
Halothane -1 in 35000 cases of fatal hepatic necrosis.
Methoxyflurane -fluoride related nephrotoxicity.
Malignant hyperthermia -tachycardia, hypertension, acidosis, hyperkalaemia, muscle rigidity, hyperthermia ,more common if suxamethonium also used -treated with dantrolene.
Chronic exposure to Nitrous oxide is associated with megaloblastic anaemia
What is the MAC of the common anaesthetic agents?
Nitrous oxide >100
Isoflurane - 1.4
Halothane - 0.75
Methoxyfluorane - 0.16
What are the solubilities and the brain:blood partition coefficients of the common anaesthetic agents?
Solubility (blood:gas partition coefficient) : Nitrous oxide - 0.47 Isoflurane -1.4 Halothane - 2.3 Methoxyfluorane - 12
Brain:blood partition coefficient Nitrous oxide ␣ 1.1 Isoflurane - 2.6
Halothane - 2.9
Methoxyfluorane - 2.0
Give some examples of IV general anaesthetics?
Barbiturates Benzodiazepines Opioids Propofol Ketamine
Give examples of barbituate general anaesthetics?
Phenobarbitone
Thiopentone -ultra short acting barbiturate intravenous anaesthetic
How do barbituates work? (3 mechanisms)
- Barbiturates bind to components of the GABA receptor and facilitate its action by increasing the duration of chloride channel opening.
- At high concentrations GABA may directly stimulate the receptor.
- Also depress actions of other excitatory neurotransmitters and have non-synaptic membrane effects.
What is the structure of the GABA receptor in the CNS?
GABA receptor consists of 5 alpha, beta and gamma membrane-spanning proteins which can form different pentameric combinations.
What are the indications for barbiturates in humans?
What is the dose of thiopentone?
Phenobarbitone - neonatal seizures.
Thiopentone -anaesthesia
Dose Thiopentone 3-5mg/kg
What are the adverse effects of thiopentone?
Toxicity CVS Depression at high doses.
Dose dependent decreased blood pressure, stroke volume and cardiac output.
Respiratory depression.
Decreased cerebral metabolism and blood flow. Nystagmus.
Reduces hepatic and renal blood flow.
Dizziness, fatigue, amnesia, blurred vision. Tolerance. Dependence.
What interactions do barbituates have with other drugs?
Effects are potentiated by other sedatives such as alcohol or other sedatives-may cause fatal CVS depression.
Induction of liver enzymes - decreases effect of warfarin, anticonvulsants, digoxin.
What are the contraindications for barbiturates?
Precaution with liver failure. Readily crosses placenta and enters breast milk. Porphyrias
What is the absorption and distribution of thiopentone and phenobarbitone?
Phenobarbitone -Orally active, rapidly absorbed. 50% protein bound.
Thiopentone - intravenous
Highly lipid soluble and rapidly distributed to brain, then redistributed to other tissues. Redistribution from CNS to skeletal muscle and adipose tissue is important process that contributes to termination of CNS effects.
Initial redistribution to brain and viscera, then to lean tissues and then to fat
Metabolised slowly in liver to water- soluble inactive metabolites that are excreted in urine.
What are the half lives of thiopentone and phenobarbitone?
Phenobarbitone plasma half life 4 hours, excretion half life 4-5 days (therefore has a tendency to accumulate)
Thiopentone Produces hypnosis in one circulation time. Plasma:brain equilibrium occurs rapidly (
How much of thiopentone and phenobarbitone is excreted unchanged?
Phenobarbitone 20% excreted unchanged.
Thiopentone - 1% excreted unchanged, metabolised at 12- 16% per hour.
What is propofol?
Phenol derivative.
Short acting intravenous anaesthetic agent.
Presented as an oil in water emulsion.
How does propofol work?
Potentiates the action of inhibitory neurotransmitters including GABA and glycine.
What is the dosage of propofol?
Sedation 0.5-1mg/kg Usually given in 20mg increments
Induction of anaesthesia 2-2.5mg/kg Usually given in 40mg increments.
Dose can be repeated as required.
What are the adverse effects and contraindications of propofol?
- Marked hypotension (15- 25%) due to reduced peripheral vascular resistance (direct effect of propofol). Potent negative inotropic effects. No compensatory increase in heart rate.
- Potent respiratory depression. Brief apnoea common. Infusion produces decreased tidal volume. Some bronchodilation due to direct effect on smooth muscle.
- Rapid, smooth induction and clear headed recovery. Cerebral blood flow and ICP decrease slightly.
- General Pain in injection in 25%.
Contraindications: Acidosis and possible neurological sequelae in children therefore contraindicated under 3 years.
Given as an intravenous fat emulsion - previous vehicle cause hypersensitivity reactions.
Onset, distribution and elimination of propofol?
What is the volume of distribution and why?
Rapid onset (30 seconds) and recovery
Distribution half life (t1/2 alpha) : 2-8 minutes,
Elimination half life (t1/2 beta): 30- 60 minutes.
90% protein bound. Small volume of distribution.
Where and how quickly is propofol metabolised?
What determines the distribution of effect of propofol?
Rapidly metabolised in liver (10 times faster than thiopentone) and excreted in urine.
Duration of effect largely determined by redistribution.
Less than 1% excreted unchanged.
What is ketamine and how does it work?
Short acting non-barbiturate intravenous anaesthetic agent. Chemically related to PCP
Action may involve blockade of glutamic acid (NMDA) receptors.
Mechanism of action largely unknown
What kind of anaesthesia does ketamine produce?
Characteristic
dissociative anaesthesia :amnesia, profound analgesia, normal or slightly increased muscle tone without loss of consciousness or loss of protective reflexes.
What is the IV dose of ketamine?
1-4mg/kg Administer slowly over 60 seconds to avoid respiratory depression and pressor response
What is the onset and offset of ketamine?
Onset 30 seconds, duration of action 5- 10 minutes. Additional doses can be given without accumulation
(Intramuscular 6.5-13mg/kg
Onset 2 minutes, duration 20 minutes)
What are the organ effects and toxicity of ketamine?
- CVS: Increased heart rate, blood pressure and cardiac output via inhibition of noradrenaline reuptake -peaks 2-4 minutes after injection, declines after 20 minutes.
- RS: May increase or decrease respiratory rate for several minutes. Upper airway tone is maintained.
- CNS Marked increase in cerebral blood flow and intracranial pressure. Nystagmus
- Emergence phenomena in 12% -disorientation, sensory and perceptual illusions and vivid dreams. Less incidence in children and elderly.
Reduced by minimising verbal, tactile and visual stimuli during recovery Interactions
Avoid hypertensive agents
Contraindications Uncontrolled hypertension, severe cardiovascular disease
Where does ketamine distrubute to and how is the effect of ketamine terminated?
Distribution Highly lipid soluble.
Rapid distribution to all tissues.
Termination of effect due to redistribution from brain to peripheral tissues
What is the metabolism of ketamine?
Metabolised by liver to 4 different metabolites including norketamine which has one sixth the potency of ketamine
Metabolites excreted in urine.
What is the structure of muscle relaxants?
What are the 2 types of muscle relaxants?
Structure: All bear a structural resemblance to acetylcholine
Depolarising Suxamethonium= 2 acetylcholine molecules linked end-to-end.
Non- depolarising (NDPMRs) Isoquinolone, tubocurarine, atracurium.
Steroid: pancuronium, vecuronium, rocuronium.
How do depolarising muscle relaxants work?
- Binds with the nicotinic receptor at the neuromuscular junction to cause the sodium channel to open and the end plate to depolarise. This results in generalised disorganised contraction. Suxamethonium is not metabolised effectively at the synapse, therefore depolarised membranes remain depolarised and unresponsive to subsequent impulses.
- Phase 2 block (Desensitising): depolarisation gradually decreases and the membrane becomes repolarised. Membrane cannot become repolarised while suxamethonium is present- essentially this is the same as non-depolarising blockade.
How do non-depolarising muscle relaxants work?
Reversible blockade, act predominantly at nicotinic receptors. Prevents opening of the sodium channel, may also enter ion pore at higher does and cause blockade.
What are the doses of suxamethonium and verocuronium?
Suxamethonium 1-1.5mg/kg (children relatively resistant) May be given IM
Vecuronium 0.1mg/kg
What are the adverse effects of depolarising and non-depolarising muscle relaxants?
- CVS: Pancuronium causes a moderate increase in heart rate and cardiac output due to vagolytic action.
Vecuronium, rocuronium (and most others) have little or no cardiovascular effects - Suxamethonium stimulates all autonomic cholinoceptors to some extent.
Bradycardia and negative inotropic effects at low doses and especially after a second dose.
Prevented by premedication with atropine and by giving a minimum dose. - Hyperkalaemia Due to exaggerated release of potassium from extra- junctional nicotinic receptors. There is an exaggerated release with burns, renal failure.
- Raised intraocular pressure Raised intragastric pressure Raised intracranial pressure
- Muscle pain This is the most common side effect
Malignant hyperthermia: Tachycardia, tachypnoea, rigidity
Contraindications to muscle relaxants?
Personal or family history of malignant hyperthermia Muscular dystrophy
Absorption and distribution of muscle relaxants?
All are highly polar and inactive orally.
Non-depolarising : Rapid initial distribution, small volume of distribution.
Metabolism and excretion of depolarising muscle relaxants?
What defects in excretion are there and what effect can this cause? Is there a test for this?
Onset of action 30s, duration of action 5-10 minutes due to rapid hydrolysis by pseudo- cholinesterase.
This limits the amount of drug reaching the synaptic cleft. Very little plasma cholinesterase at end plate neuromuscular blockade is terminated by diffusion away from the endplate into extracellular fluid.
95% of the population will have a normal pseudo- cholinesterase response. 5% will have prolonged apnoea up to 10 minutes.
Metabolism and excretion of non depolarising muscle relaxants?
Onset of action 2-3 minutes Route of elimination correlates with duration of action.
Renal excretion is slow, hepatic excretion fast.
Steroid -metabolised to 3 hydroxy, 17 hydroxy and 3,17 hydroxy metabolites that also have clinical effect and may persist.
Vecuronium - duration of action 20-35 minutes, minimal cardiovascular effects, hepatic elimination - 85% eliminated into bile.
Pancuronium -duration of action 35minutes - 1 hour, mainly excreted by kidney.
Rocuronium - very rapid onset of action.
What is the fastest onset non-depolarising muscle relaxant?
rocuronium
Mechanism of action of dantrolene?
Acts on the sarcoplasmic reticulum of skeletal muscle
Causes reduced release of calcium from the sarcoplasmic reticulum
What is malignant hyperthermia?
Malignant hyperthermia can be triggered by general anaesthesia and neuromuscular blockade and is a hereditary impairment of the ability to sequester calcium in the sarcoplasmic reticulum
Trigger results in massive release of calcium with prolonged muscle contraction, lactic acidosis and hyperthermia
What are the classes of antipychotics?
- Phenothiazine derivatives: Chlorpromazine
- Thioxanthene: Thiothixene
- Butyrophenone derivatives : Haloperidol
- Miscellaneous: Clozapine, Rispiradone, Olanzapine
Mechanism of action of antipsychotics?
Dopamine antagonist ␣ antipsychotic action related to dopamine receptor blockade in mesolimbic and mesofrontal systems.
Chlorpromazine Alpha1=5H T2>D2>D1 Haloperidol D2>D1=D4>Alpha1> 5H T2 Clozapine Alpha1 =D4 >5HT2> D2=D1 Rispiridone D2=5HT2 Olanzapine 5HT2>D2=D1=Alpha1> H1
Potency of various antipsychotics?
Chlorpromazine -low Thiothixene - high Haloperidol - high Clozapine - medium Rispiradone - high Olanzapine - high
Dosing of antipsychotics?
Haloperidol Oral 1-15mg/day in divided doses. IM - 2-30mg IV - 1-5mg
Chlorpromazine PO/IM 25-50mg tds
Olanzapine 10mg PO/IM
CNS Toxicity of antipsychotics?
Toxicity CNS Extrapyramidal effects Extrapyramidal toxicity related to high D2 affinity; manifest as parkinsonism, akathisia, acute dystonic reactions, tardive dyskinesia.
Chlorpromazine -high Thiothixene - medium Haloperidol - very high Clozapine - very low Rispiradone - low Olanzapine - very low
Sedation: esp chlorpromazine
Clozapine -2% incidence of seizures (can also occur with other antipsychotics)
ANS Toxicity of antipsychotics?
Autonomic effects Antimuscarinic actions. Loss of accommodation, dry mouth, difficulty urinating, constipation : Alpha1 antagonist actions.
CVS Toxicity of antipsychotics?
Tachycardia, reduced stroke volume, decreased peripheral resistance, orthostatic hypotension
Thioridazine causes T wave abnormalities and is associated with prolonged QT, ventricular arrhythmias and sudden death
most- chlorpromazine, least: olanzapine and haloperidol
What is NMS and how is it treated?
Neuroleptic malignant syndrome Muscle rigidity, reduced sweating, fever, autonomic instability, leukocytosis
Marked increases in CK may result in renal failure -use bromocriptine
Endo, haem effects of antipsychotics?
Amenorrhoea, galactorrhoea, increased or decreased libido, impotence -secondary to blockade of dopamine induced tonic inhibition of prolactin secretion.
Clozapine, chlorpromazine may cause agranulocytosis
Chlorpromazine - corneal and lens deposits
Absorption and distribution of antipsychotics?
Orally active. Readily but incompletely absorbed.
Chlorpromazine Significant first pass metabolism :bioavailability 30%. Half life 30 hours.
Others- Moderate first pass metabolism : bioavailability 65%
95% protein bound, lipid soluble, high distribution volumes
Presentation of antipsychotic overdose?
Drowsiness, coma, neuromuscular excitability, convulsions. Miosis and loss of deep tendon reflexes. Hypotension and hypothermia.
Activated charcoal effective.
Supportive therapy.
Avoid adrenaline and lignocaine.
Mechanism of action of lithium? 3 broad effects
- Closely related to sodium -inhibits sodium exchange across membranes but no effect on sodium/potassium or sodium/calcium exchange.
- Effects on neurotransmitters Enhances the action of serotonin. Decreases noradrenaline and dopamine turnover. Augments the synthesis of acetylcholine.
- Effects on second messengers. Inhibits enzymes responsible for recycling of inositol compounds, resulting in depletion of PIP2, IP3 and DAG.
Usual maintenance dose of lithium
dose 500mg-1g/day
Interractions of lithium?
Renal clearance reduced by diuretics and some NSAIDs.
Increased extrapyramidal effects when used with antipsychotics (except newer drugs) May increase the duration of muscle relaxnants.
Lithium toxicity?
Tremor (alleviated by propanolol), choreoathetosis, motor hyperactivity, ataxia, dysarthria, aphasia.
Mental confusion, drowsiness and seizures at higher levels.
Endocrine: Reversible reduction in thyroid function.
GUS: Nephrogenic diabetes insipidus, chronic interstitial nephritis, minimal change glomerulonephritis.
CVS: Nodal depression and T wave flattening.
General Oedema and weight gain.
Lithium in pregnancy?
Clearance increases during pregnancy and falls following delivery.
??dysmorphogenesis - unsettled.
Lithium toxicity in newborns characterised by lethargy, cyanosis, poor suck and reflexes
Absorption and distribution of lithium?
Orally active, completely absorbed in 6-8 hours, peak levels 30 minutes. 100% bioavailability.
Distribution Total body water, slow entry into intracellular compartment. Some sequestration into bone.
Excretion of lithium?
Not metabolised. Excreted into urine at 20% of the rate of creatinine clearance.
Elimination half- life 20 hours.
Presentation and management of lithium overdose?
anorexia, nausea, vomiting, diarrhoea, muscle weakness, lack of cooordination
No specific antidote.
Clearance increased by osmotic diuresis and urinary alkalinisation. Readily removed by haemodialysis.
Give four examples of antidepressant classes?
tricyclincs- amytriptilline, imipramine
Heterocyclics:
SSRI:
MAOI’s
Tricyclics Imipramine
Amitriptyline
Heterocyclics
Second generation: Maprotiline (tetracyclic) ,Buproprion
Third generation: venlafaxine
SSRIs
fluoxetine
MAOs: Phenelzine, Moclobamide
How do tricyclic antidepressants work?
Adverse effects?
Blockade of amine (serotonin»_space;noradrenaline) reuptake pumps.
Antimuscarinic actions Alpha1, H1, H2 antagonist
> 1000mg toxic
CNS Sedation, seizures, psychosis, coma Antimuscarinic effects very common Tremor, insomnia
CVS Orthostatic hypotension Tachycardia and minor T/ST changes very common Conduction defects (long PR, wide QRS>0.1s, long QT and ST) and arrhythmias also common.
GIS Nausea, raised liver enzymes
How do heterocyclic antidepressants work?
Adverse effects?
Buproprion alters noradrenaline neurotransmission by an unknown mechanism. Third generation heterocyclics have additional antagonist of 5HT receptors.
Same as TCAs though less pronounced.
How do MAOI’s work?
Adverse effects?
Blockade of MAO mediated amine degradation. MAO-A metabolises noradrenaline and serotonin, MAO-B metabolises dopamine.
Initial increase in amine leads to down-regulation of receptors.
Adverse effects of SSRI?
Anxiety, insomnia, tremor, nausea, rash (may lead to severe vasculitis), decreased libido. SSRI use in combination with MAO may lead to toxic build up of serotonin and serotonin syndrome
What is serotonin syndrome?
TCAs and SSRIs Serotonin syndrome if characterised by hyperthermia, muscle rigidity, myoclonus.
Antidepressant interactions with other drugs?
Phenothiazines displace TCAs from protein binding site and potentiate action.
Nefazodone can inhibit P450-3A4 and block the metabolism of terfenadine and cisapride.
F luoxetine and paroxetine are potent inhibitors of P450-2D6 -desipramine, nortriptiline and flecainide are dependent on same enzyme system for clearance.
MAOs : Accumulation of tyramine (fermented foods and drinks) results in hypertension. Moclobamide is relatively short acting compared with older drugs therefore this effect is rare
Absorption and distribution of tricyclics?
Incompletely absorbed. Slow gastric emptying due to antimuscarinic effect. Significant first pass metabolism (bioavailability 30- 70%)
80-90% protein bound. High lipid solubility. Large Vd
Absorption and distribution of tetracyclics?
Incompletely absorbed. Significant first pass metabolism (bioavailability 30- 70%)
80% protein bound. High lipid solubility. Large Vd
Absorption and distribution of SSRI’s?
Well absorbed orally. Moderate first pass metabolism (bioavailability 50- 70%) 95% protein bound.
High lipid solubility. Large Vd
Absorption and distribution of MAOI’s?
Well absorbed orally.
Metabolism of tricyclics, tetracyclics, MAOI’s?
Tricyclics: Metabolised in liver to active metabolites. Half life 10-40 hours
Heterocyclics: Metabolised in liver to active metabolite. Half life 10-40 hours
SSRIs Metabolised in liver. Fluoxetine forms an active metabolite, nil with paroxetine. Half life 24-96 hours.
MAOs: Metabolised in liver. Acetylation of phenelzine varies between individuals and may persist for several weeks.
Antidepressant overdose?
Severe antimuscarinic response is common Extension of toxic effects listed plus respiratory depression, metabolic acidosis, heart failure, cardiac arrest
Give 4 examples of anticonvulsants that are sodium channel blockers/membrane stabilisers?
Phenytoin
Carbamazepine Sodium valproate Lamotrigine
Give 4 examples of anticonvulsants that are GABA modulators?
Benzodiazepines Gabapentin Vigabatrine Phenobarbitone
What kind of antiarrhythmic is phenytoin?
class 1b
Mechanisms of phenytoin?
Membrane stabiliser - preferentially binds to inactivated sodium channel and maintains inactivated state and therefore blocks sustained high frequency repetitive firing of action potentials.
Reduces calcium permeability therefore inhibits calcium related secretory processes.
May potentiate the effects of GABA
Inhibits release of serotonin and noradrenaline, promotes uptake of dopamine.
Inhibits monoamine oxidases.
Uses of phenytoin?
Prophylaxis and treatment of partial seizures and generalised tonic clonic seizures.
Fast atrial and ventricular arrhythmias resulting from digoxin toxicity.
Trigeminal neuralgia.
Dosing of phenytoin?
10-15mg/kg not exceeding 50mg/minute then 100mg orally every 8 hours
(slow administration due to propylene glycol diluent which may induce cardiac arrhythmias
Toxicity of phenytoin?
Dose related CNS: Nystagmus and loss of smooth ocular pursuit. Diplopia and ataxia. Sedation.
CVS: Cardiovascular collapse (diluent effect if rapid administration)
Idiosyncratic: Chronic use frequently leads to gingival hyperplasia and hirsutism, coarsening of facial features, diminished tendon reflexes and osteomalacia.
Rash, fever, rare agranulocytosis.
Interractions of phenytoin with other drugs?
Protein binding : Phenytoin is displaced by highly protein bound drugs such as sulphonamides, calcium channel blockers. Hypoproteinaemia causes increased free drug.
May confuse thyroid function tests due to affinity for TBG.
Enzyme inducers: Phenytoin induces liver enzymes and affects the metabolism of other drugs such as warfarin, opioids, neuromuscular blockers, beta blockers
Other inducers may reduce phenytoin levels - anticonvulsants, rifampicin, ciprofloxacin
Enzyme inhibitors Erythromycin, cimetidine
Absorption and distribution of phenytoin?
Orally active. Intramuscular absorption unpredictable. 90% bound to plasma proteins.
Maximal effect after IV dose occurs after 30-60 minutes and may persist for 24 hours
Accumulates in endoplasmic reticulum of brain, liver, muscle and fat.
Therapeutic concentration 10- 20ug/l
Where is phenytoin metabolised and what kind of kinetics does it display?
Metabolised by liver, excreted in bile, reabsorbed and excreted in urine.
Variable order kinetics: Elimination rate is dose dependent - at low doses there is first order kinetics but metabolism is saturated at therapeutic concentrations and small increases in dose quickly lead to toxicity.
Half life and steady state of phenytoin?
Half life 12-36 hours -much higher at high concentrations.
5-7 days to reach steady state.
Overdose of phenytoin
Overdose Toxicity varies between individuals CNS effects predominate though bradycardia and heart block can also occur
Mechanism of carbamazepine?
Membrane stabiliser - preferentially binds to inactivated sodium channel and maintains inactivated state and therefore blocks sustained high frequency repetitive firing of action potentials.
Also acts pre-synaptically to decrease synaptic transmission.
Inhibits reuptake and release of noradrenaline.
Interacts with adenosine receptors - ?significance
Toxicity of carbamazepine?
Skin rash common.
Diplopia, ataxia - often mild and reversible.
Drowsiness at high concentration.
Hyponatraemia and water intoxication rarely.
Rare agranulocytosis , leukopenia is common and just requires monitoring.
Interractions of carbamazepine?
Induces liver enzymes and affects own metabolism : half-life is typically halved from 40 to 20 hours with continuous therapy.
Phenytoin, carbamazepine, barbiturates and lamotrigine induce liver enzymes and reduce levels of each other.
Reduces effectiveness of benzodiazepines, pethidine, and warfarin.
Pharmacokinetics of carbamazepine?
Orally active
Rate of absorption variable but complete
Slow distribution. 70% protein bound.
Metabolised in liver -metabolite may have some clinical activity.
What is the active constituent of sodium valproate?
Fully ionised at body pH therefore active constituent is the valproate ion.
Mechanism of sodium valproate?
Membrane stabiliser - preferentially binds to inactivated sodium channel and maintains inactivated state and therefore blocks sustained high frequency repetitive firing of action potentials.
Increases levels of GABA - likely insignificant
Increases membrane potassium conductance
Toxicity of sodium valproate?
Dose related nausea vomiting and abdominal pain.
Sedation (particularly if used with phenobarbitone)
Tremor, weight gain, hair loss.
Idiosyncratic hepatotoxicity -may be fatal, more common in children under 2 years, usually occurs within 4 months of starting the drug.
Inerractions of sodium valproate?
Dose related nausea vomiting and abdominal pain.
Sedation (particularly if used with phenobarbitone)
Tremor, weight gain, hair loss.
Idiosyncratic hepatotoxicity - may be fatal, more common in children under 2 years, usually occurs within 4 months of starting the drug.
Absorption and distribution of sodium valproate?
Orally active. 80% bioavailability. 90% plasma protein bound. Distribution confined to extracellular water due to ionised status and protein binding.
Metabolism and excretion of sodium valproate?
Clearance is dose dependant - it inhibits its own metabolism at low doses. At higher doses there is increased free valproate.
20% excreted as a direct conjugate of valproate. 80% metabolised in liver and excreted in urine.
Half life 9-18 hours.
What does lamotrigine resemble in structure?
Phenytoin
Mechanism of lamortigine
Membrane stabiliser - preferentially binds to inactivated sodium channel and maintains inactivated state and therefore blocks sustained high frequency repetitive firing of action potentials.
Indication for lamictal
Partial seizures. Usually used in add- on therapy but increasingly used alone.
What is valproate best for?
Absence seizures. Generalised tonic- clonic seizures
Inerractons of lamortigine
`Phenytoin, carbamazepine, barbiturates and lamotrigine induce liver enzymes and reduce levels of each other.
Reduces effectiveness of benzodiazepines, pethidine, warfarin.
Side effects of lamrtigine
rash- if rash then cease lamortigine as linked to SJS, aseptic meningitis, leukopaenia, dizzyness, headache diplopia
Absorption and excretion of lamotrigine?
Orally active. 50% protein bound.
Linear kinetics. Metabolised by liver and excreted by urine.
Half life 24 hours, reduced to 15 hours if taking enzyme inducing drugs.
Mechanism of vigabatrine?
Absorption and excretion of vigabatrine?
Reversible inhibitor of GABA aminotransferase which degrades GABA. GABA levels are therefore increased. Indicated for partial seizures.
Orally active. Renally excreted. Short (5-8 hour) half life)
Toxicity of vigabatrine?
Dizziness, drowsiness and weight gain. Agitation and confusion rare
Structure and action of gabapentin?
Indications in epilepsy?
Amino acid analogue of GABA.
Despite structural relationship to GABA, does not act on GABA receptors but may alter GABA metabolism.
Partial seizures. Usually used in add- on therapy but increasingly used alone.
Interractions of gabapentin?
Does not induce liver enzymes. No significant interactions.
Absorption and excretion of gabapentin?
Orally active. Not protein bound.
Renally excreted. Short (5-8 hour) half life)
Mechanism of action of benzodiazepines?
Bind to GABA receptor in CNS
Benzodiazepines bind to the gamma subunit and in association with GABA, triggers chloride channel opening and subsequent hyperpolarisation.
Benzodiaepines increase the efficacy of GABAergic synaptic transmission -they do not cause chloride channel opening alone.
Structure of the GABA receptor in the CNS
GABA receptor consists of 5 alpha, beta and gamma membrane-spanning proteins which can form different pentameric combinations.
Dose of diazepam and midazolam used for sedation:
Diazepam Oral, IV or PR
Adult 5-40mg Child 0.1-0.3mg/kg
Midazolam
IV/IM 0.03-0.2mg/kg (higher dose used for induction of anaesthesia)
Does tolerance occur to resp depression with benzo’s?
no
Do benzodiazepine cross breast milk and placenta?
yes
What interracts with benzodiazepines?
Effects potentiated by other sedatives such as alcohol - may cause fatal CVS and respiratory depression.
What does benzo absorption depend on?
Which benzodiazepines are best and worst absorbed?
Orally active. Absorption dependent on lipid solubility.
Diazepam most lipid soluble. Oxazepam, lorazepam and temazepam least lipid soluble. They are highly protein bound and CNS uptake dependent is also dependent on lipid solubility.
What is the timeline of sedation by temazepam
Peak sedation 15 minutes after IM injection, 4 minutes after IV injection
How are benzo effects terminated?
Redistribution from CNS to skeletal muscle and adipose tissue is important process that contributes to termination of CNS effects.
How are benzodiazepines metabolised?
Metabolised in liver to water-soluble metabolites that are excreted in urine.
Metabolites may be more active than parent drug (diazepam forms desmethyldiazepam which is transformed to oxazepam and temazepam)
What are the half lives of diazepam, temazepam and midazolam?
Diazepam -20-80 hours (metabolite persist much longer)
Temazepam -10-40 hours.
Midazolam 2-4 hours
Elimination may increase up to 6 times in elderly patients in ICU
What is the action of flumazenil?
Reversal of benzodiazepine induced clinical effect.
Reversal of respiratory depression is unpredictable.
Side effects of flumazenil?
Agitation, confusion, dizziness, nausea May precipitate severe withdrawal syndrome if existing physiological dependence.
Very likely to induce convulsions if patient has a known seizure disorder or in TCA overdose.
Absorption of flumazenil?
Undergoes significant first pass metabolism if administered orally.
Intravenous administration. Rapid onset.
50% protein bound. Small volume of distribution.
Metabolism of flumazenil?
Rapid hepatic metabolism to inert metabolites and excreted in urine.
Short half life 0.7- 1.3 hours. Infusion may be necessary.
What are the spinal and supraspinal sites of pain transmission?
Spinal
Dorsal horn pain transmission neurons of
spinal cord.
Pain transmission:
Ventral caudal thalamus
Diencephalon
Pain modulation:
Cortex
Midbrain periaqueductal gray area
Rostral ventral medulla
What is the mechanism of mu opioid receptors?
What are the subtypes?
Receptor binding causes closure of voltage gated calcium channels on presynaptic neurons and decreased transmitter release. Also causes opening of potassium channels on post synaptic neurons resulting in hyperpolarisation and formation of IPSPs
mu1, mu2
Action of mu opioid receptors?
Analgesia Euphoria Sedation Respiratory depression Tolerance and dependence
Agonists of mu opioid receptors
F ull: Morphine Pethidine Fentanyl
Partial: Codeine
Delta opioid receptors types and mechanisms?
delta 1 delta 2
Receptor binding causes closure of voltage gated calcium channels on presynaptic neurons and decreased transmitter release. This causes spinal analgesia.
Agonists of delta opioid receptors?
morphine and codeine are partial agonists
Subtypes and action of kappa opioid receptors
kappa 1, kappa 2 , kappa 3
Receptor binding causes closure of voltage gated calcium channels on presynaptic neurons and decreased transmitter release.
What are morphine, codeine and heroin classified as?
Phenanthrenes
What are the Phenylheptylamines?
methadone
What are Phenylpiperidines?
pethidine, fentanyl, loperamide
Can endogenous opioids cause release of exogenous opioids?
yes
What receptors does morphine act on?
mu, delta, kappa
What is paperveretum?
mixture of 253 parts morphine, 23 parts papaverine, 20 parts codeine - sometimes used as a premedication. Essentially identical actions as morphine though greater sedation and relief of anxiety.
Endocrine effects of opioids?
stimulates ADH, prolactin and somatotropin, inhibits LH
Histamine release- itching and urticaria
General effects of opioids on smooth muscles?
increase tone e.g.increased biliary smooth muscle contraction, increased GI smooth muscle contraction
Action of morphine in APO?
Reduced preload and afterload, reduced anxiety, reduced dyspnoea
Respiratory effects of opioids
respiratory depession
truncal rigidity- reduces thoracic compliance and increases work of breathing- likely supraspinal effect
Withdrawal to opioids?
rhinorrhea, lacrimation, yawning, chills, piloerection, hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhoea, and anxiety.
Onset 6-10 hours, Peak 36-48 hours, Lasts 5 days
Absorption of opioids?
Rapid absorption orally but high (and unpredictable) first pass metabolism therefore low bioavailability.
Variable protein binding.
Concentrates in highly perfused organs.
Structure determines how readily the drug crosses the blood/brain barrier -codeine and fentanyl cross quite readily, morphine less so.
Excretion of opiates?
Metabolised in liver and excreted in urine.
Morphine, codeine - metabolised in liver to active metabolites that may have greater activity than parent drug.
Excreted in urine. Small amount excreted in bile.
Metabolites may accumulate in renal failure.
Codeine mechanism?
Less efficacious - partial agonist at mu and delta receptors only.
Few side effects due to low potency. Constipation is prominent.
Absorption and metabolism of codeine?
The structure of codeine protects it from first pass effects and increases ability to cross the blood brain barrier.
10% is metabolised to morphine
Potency of pethidine?
One tenth as potent as morphine.
Metabolism of pethidine?
What interracts with this?
Metabolite 50% as active as parent drug - and is associated with seizures.
Halothane and enflurane decrease clearance by 50%.
Mechanism of fentanyl
highly selective mu agonist only
Toxicity of fentanyl:
CNS toxicity: Little hypnosis or sedation
Potent respiratory depression
Truncal rigidity
Marked muscle rigidity at high doses.
Peripheral toxicity:
Bradycardia with little effect on cardiac output or blood pressure.
Obtunds the cardiovascular response to intubation.
Minimal histamine release.
Halothane and enflurane decrease clearance by 50%.
Fentanyl potency, onset of action, duration of action?
IV or transdermal
33% bioavailability given PO
More lipid soluble than morphine therefore crosses the blood/brain barrier more readily.
Rapid onset of action.
50-80 times more potent than morphine.
Small dose has a shorter duration of action (1-1.5 hours) - larger doses 4-6 hours.
What is heroin metabolised to?
converted to morphine by tissue esterases
Tramadol mechanism?
Centrally acting analgesic with some opioid properties.
Not structurally related to opioids
Weak mu agonist actions
Noradrenaline inhibition and serotonin reuptake inhibition.
Dose of tramadol:
Mild to moderate pain
Dose PO/IV 50-100mg tds- rapidly orally absorbed
Side effects of tramadol?
Similar CNS and peripheral side effects
No respiratory depression except at high doses
No cardiac effects
No histamine release
Does not suppress opioid withdrawal symptoms
Increased risk of seizures
Avoid with SSRIs and MAOs due to actions on serotonin
Increased tramadol metabolism with enzyme inducers such as tramadol
Methadone potency?
Orally active, equivalent potency, longer duration of action
Tolerance and dependence develop and resolve more slowly and symptoms are milder.
Naloxone mechanism of action?
How does it act at the organ level?
Antagonist action at opioid receptors. More potent action at mu receptors than delta or kappa.
Inert if no agonist present. Antagonist action results in reversal of opioid induced effects in 1-3 minutes.
Duration of action of naloxone vs naltrexone?
naloxone: Extensive first pass metabolism therefore IV only. Short half life 1-2 hours (duration of action usually 20 minutes) therefore frequent dosing required in overdose
naltrexone: Longer half life than naloxone (10 hours) and will block the effects of injected heroin for 48 hours
Mechanism of ethanol?
No specific receptor.
Affects broad range of molecular processes including neurotransmission, enzyme action, electron transport chain, ion transport.
Enhances the action of GABA
Inhibits the action of glutamate
Oran effects of ethanol?
Intoxication. Myocardial depression. Smooth muscle relaxation.
Liver and GI toxicity of ethanol?
Increased alcohol metabolism leads to increased NADH/NAD+ ratio, resulting in reduced gluconeogenesis, hypoglycaemia, ketoacidosis and promotion of TG synthesis from FFA.
Accumulation of acetaldehyde promotes inflammation.
Nutritional deficiency is due to reduced intake and reduced absorption due to small bowel injury - reduces free radical scavengers such as glutathione
Increased gastric and pancreatic secretion, alteration of mucosal barriers resulting in gastritis.
Non-GI toxicity of ethanol?
CNS:
Nystagmus. Generalised symmetrical peripheral neuropathy. Gait disturbance and ataxia. Dementia. Wernicke-Korsacoff syndrome - paralysis of external ocular muscles, ataxia, acute confusion, memory loss.
CVS toxicity
Dilated cardiomyopathy, ventricular hypertrophy, fibrosis. Atrial and ventricular arrhythmias. Hypertension.
Blood:
Mild anaemia due to folate deficiency.
Immune system: Higher rates of infection
Foetal alcohol syndrome: Poor growth, microcephaly, poor coordination, flattened facial features, minor joint abnormalities, congenital heart defects.
Cancer: Mouth, pharynx, larynx, oesophagus, liver.
Interactions: Additive effect with other sedatives.
Acute use tends to inhibit enzymes, chronic use induces. Additive effect with hypoglycaemics and vasodilators.
Absorption and distribution of ethanol?
Small, water soluble molecule rapidly absorbed from GIT. Vd approximates TBW. Concentration in CNS rises quickly due to large blood flow.
Metabolism of ethanol?
90% metabolised by liver, 10% excreted by lungs and urine.
Metabolism follows zero order kinetics at approximately 1 standard drink per hour.
Ethanol converted to acetaldehyde by alcohol dehydrogenase in liver and stomach and by mixed function oxidase.
MFO activity increases in alcoholism.
Acetaldehyde converted to acetate by aldehyde dehydrogenase.
Acetete converted to carbon dioxide and water.
Mechanism of disulfram and the effect this causes with alcohol?
Inhibition of aldehyde dehydrogenase therefore aldehyde accumulates.
Flushing, throbbing, headache, nausea, vomiting, sweating, hypotension, confusion within a few minutes of alcohol consumption.
Interractions of disulfram with other drugs?
Interactions Inhibits the metabolism of phenytoin, warfarin, isoniazid.
Other drugs including metronidazole, cephalosporins may have disulfiram like effects.
Absorption and excretion of disulfram?
Orally active. Rapidly and completely absorbed
Slow elimination
How does methanol affect the human body?
No specific receptor. Affects broad range of molecular processes including neurotransmission, enzyme action, electron transport chain, ion transport.
Enhances the action of GABA. Inhibits the action of glutamate.
Symptoms of methanol consumption?
Visual disturbance predominates -may take 30 hours to be present. Formaldehyde may be detectable on breath.
Treatment of methanol intake?
Charcoal ineffective Supportive Intravenous ethanol- higher affinity for alcohol dehydrogenase therefore less formate.
Haemodialysis effective
Toxicity of methanol
Toxicity is probably related to the formation of formate. Visual disturbances (snowstorm sensation) is typical. CVS and CNS depression, metabolic acidosis.
Distribution of methanol?
Small, water- soluble molecule rapidly absorbed from GIT.
Vd approximates TBW. Concentration in CNS rises quickly due to large blood flow.
Treatment of ethylene glycol overdose?
Charcoal ineffective. Supportive.
Intravenous ethanol -higher affinity for alcohol dehydrogenase.
Consider alcohol dehydrogenase inhibitor - 4- methylpyrazole.
Haemodialysis effective.
Toxicity of ethylene glycol poisoning?
Transient excitation followed by CNS depression. Severe high anion gap metabolic acidosis after 4-12 hours.
Renal insufficiency due to deposition of oxalate.
Metacolism of ethylene glycol?
Converted to toxic aldehydes and oxalate by alcohol dehydrogenase.
Mechanisms of sodium chromoglycate?
Toxicity?
Alteration of function of chloride channels in cell membranes
Inhibition of mast cell degranulation
Likely inhibits mediator release from other cells
Used for asthma prevention through MDI or inhaler
toxicity: Reversible dermatitis, myositis or gastroenteritis in 2%
Theophilline structure and mechanism
Inhibits phosphodiesterase at high concentrations resulting reduced degradation of cAMP and high intracellular cAMP.
Increased intracellular cAMP leads to smooth muscle relaxation.
Increased cAMP in the heart leads to calcium influx and positive chronotropic and inotropic action
Inhibition of respiratory mucosal adenosine receptors which cause contraction of smooth muscle and histamine release
Blockade of cardiac adenosine receptors leading to increased catecholamine release
Possible anti-inflammatory action.
Dosing of theophilline in asthma?
Loading dose should be given slowly as rapid loading results in transient toxic plasma levels.
Dose Orally 3-4mg/kg tds
Tends to be avoided IV due to toxicities but can be given as an intravenous loading dose followed by infusion
Toxicity and interractions of theophilline?
Therapeutic and toxic effects closely related to blood level.
Therapeutic range 5-20mg/l
Anorexia, nausea, vomiting, headache at 15mg/l
Seizures or arrhythmias at >40mg/l
Interactions : Clearance enhanced by liver enzyme inducers -phenytoin, phenobarbitone.
Clearance reduced by propanolol, macrolides, cimetidine, OCP, calcium channel blockers.
Absorption and distribution of theophilline?
Absorption Well absorbed orally.
Distribution Volume of distribution is proportional to lean body weight.
Rapid intravenous loading causes transient toxic plasma levels
Metabolism of theophilline?
What type of kinetics does it display?
Metabolised by liver
(therefore reduced dose in liver disease, heart failure).
Variable order kinetics Elimination rate is dose dependent -at low doses there is first order kinetics but metabolism is saturated at therapeutic concentrations and small increases in dose quickly lead to toxicity.
Children clear theophylline most rapidly -poor in neonates and young infants
Mechanism of salbutamol at the molecular and cellular level?
B2 receptor agonists
Stimulation of adenylyl cyclase results in increased cAMP
Inhibits release of mediators
Bronchodilation due to smooth muscle relaxation. Inhibition of mediator release from mast cells. Inhibition of microvascular leakage. Increase mucociliary transport.
IV dosing of salbutamol?
Intravenous/SC
Adults Loading dose 200ug then 5-20ug/min
Children Loading dose 7.5ug/kg then 5ug/kg/hr
Toxicity of salbutamol
Predictable beta agonist actions
Tachycardia, palpitations, nausea, dizziness, tremor are common
May cause an initial reduced pO2 due to ventilation/perfusion mismatch
Hypokalaemia - especially high doses in combination with methylxanthines and diuretics
Hyperglycaemia and possible ketoacidosis in diabetics
Excessive use may result in tolerance
Metabolism of salbutamol
Metabolised by liver.
28% excreted unchanged by kidney
Half life 4 hours.
Salmeterol has long duration of action due to high lipid solubility rather than long duration of action
Mechanism of ipratropim
Muscarinic antagonist
Comtetitively inhibits the action of acetylcholine at muscarinic receptors
Toxicity of ipratropium
Predictable antimuscarinic effects though poor systemic absorption minimises this
Absorption and excretion of ipratropium
Absorption Poor systemic absorption
Quaternary ammonium structure leads to poor penetration into CNS.
10% of dose reaches airways, 90% swallowed.
Onset 1-3 minutes. Peak effect 1-2 hours.
90% excreted unchanged in faeces
Half life 3 hours.
List the common air pollutants
Carbon monoxide 52% Sulphur oxides 14% Hydrocarbons 14% Nitrogen oxides 14% Particles 4%
Toxicity of carbon monoxide?
Colourless, tasteless, odourless by product of incomplete combustion
Combines reversibly with haemoglobin to form carboxyhaemoglobin 220 times more avid binding than oxygen
An individual breathing air containing 0.1% CO (1000ppm) would have a carboxyhaemoglobin level of 50%
Treatment of carbon monoxide poisoning?
Removal of source ABC Oxygen
Room air at 1atm, elimination half life of CO 320 minutes
100% oxygen at 1atm elimination half life 80 minutes
100% oxygen at 2atm elimination half life 20 minutes
List 3 classes of insecticides and give examples?
Chlorinated hydrocarbons:
DDT Lindane
Organophosphates and carbamates:
Parathion Malathion
Naturally-derived insecticides:
Pyrethrum
Give an example of a herbicide
Paraquat
Give examples of commercially available cholinesterase inhibitors? list 3 types with examples
(Indirect-acting cholinoceptor stimulants)
Alcohols - edrophonium.
Carbamates - neostigmine, physostigmine
Organo- phosphates - parathion, malathion.
Interact with acetylcholinesterase and therefore blocks the hydrolysis of acetylcholine.
What are the mechanisms of the 3 types of cholinesterase inhibitors?
How long does the effect last for each of the 3 classes?
Alcohols - short lived reversible binding lasting 2- 10 minutes.
Carbamates -2 step hydrolysis to form a covalent bond, lasts 30mins-6hours
Organophosphates - initial hydrolysis results in a phosphorylated active site. This undergoes aging that involves strengthening of the phosphorus-enzyme bond that may last for hundreds of hours.
What are the effects of cholinesterase inhibitors at a molecular level?
Effects are similar to direct acting cholinomimetics. At the NMJ, therapeutic effects prolong and intensify the physiological action of acetylcholine resulting in increased strength of contraction.
Higher does may result in fibrillation.
What are the clinical indication for the 3 types of cholinesterase inhibitors?
Alcohols (edrophonium):
Diagnosis of myasthenia gravis = tensilon test.
Carbamates (neostigmine, physostigmine):
Reversal of non- depolarising neuromuscular blockade. Myasthenia gravis Glaucoma
Paralytic ileus Urinary retention
Organo-phosphates (parathion, malathion): Glaucoma
Side effects of cholinesterase inhibitors (describe muscarinic and nicotinic effects separately)
Muscarinic agonists: nausea, vomiting, diarrhoea, salivation, sweating, vasodilation, bronchoconstriction.
Nicotinic agonists: CNS stimulation, convulsions, coma, flaccid paralysis, hypertension and cardiac arrhythmias.
Organophosphates may also cause delayed neurotoxicity
Absorption and distribution of
1) carbamates?
2) organophosphates?
Carbamates - absorption poor due to permanent charge and lipid insolubility. Physostigmine has better absorption due to tertiary amine group.
Organophosphates - well absorbed from skin, lung, gut, conjunctiva and distributed into CNS.
Distribution:
Carbamates - distribution in CNS negligible. Physostigmine is widely distributed.
Organophosphates - widely distributed including the CNS.
Metabolism and excretion of
1) carbamates?
2) organophosphates?
Carbamates: majority of the dose is excreted in the urine.
Organo-phosphates: Malathion is rapidly metabolised to inactive products and therefore relatively safe. Parathion is metabolised less effectively and is therefore more toxic.
What are 2 naturally occuring antimuscarinic agents?
Atropine: found in Atropa belladonna (deadly nightshade) and datura stramonium
Hyoscine: found in hyoscyamus niger
What are the 2 types of synthetic antimuscarinic agents?
Tertiary amines - pirenzepine, tropicamide
Quaternary amines - propantheline, glycopyrrolate, ipratropium, benztropine.
How does atropine work?
Competitive antagonist of acetylcholine at muscarinic receptors. Reversible blockade.
No distinction between M1,2 and 3
Salivary, bronchial and sweat glands are the most sensitive.
What are the organ effects of atropine?
Mydriasis
Cycloplegia
Decreased lacrimal secretion
Tachycardia (note - may cause initial bradycardia at low dose)
Increased contractility
Arterial constriction (Dilation - high dose direct effect)
Venoconstriction (Dilation - high dose direct effect) Bronchiolar smooth muscle relaxation
Decreased mucus secretion
Gut relaxation
Contraction of sphincters
Decreased salivary, gastric and pancreatic secretion.
Bladder wall relaxation
Bladder sphincter contraction Uterus smooth muscle relaxation
Decreased sweating
Drowsiness, confusion, hallucinations, dysarthria
Clinical uses of antimuscarinic agents?
Bradycardia due to increased vagal tone, including cardiac arrest -Atropine
Cholinomimetic (direct or indirect) poisoning -Atropine
Mydriasis -Tropicamide, Atropine
Motion sickness -Hyoscine
Bronchodilation -Ipratropium
Diarrhoea - Atropine
Urinary urgency -Oxybutynin
Toxicity of antimuscarinic agents?
In adults, toxic effects are an extension of the clinical effect.
Children are sensitive to hyperthermic effects that are centrally mediated.
Produce very similar effects to LSD in high doses though delusions tend to be bizarre. Effects are very long acting (several days).
Delerium, fluctuating level of awareness, difficulty in thinking and marked loss of memory are particularly characteristic.
Contraindications Glaucoma.
Absorption and distribution of antimuscarinic agents?
Absorption
Naturally occurring agents: Well absorbed from gut, skin and conjunctival membranes.
Synthetic agents (quaternary amines) : only 10-30% absorbed orally.
Distribution:
Naturally alkaloid esters of tropic acid - widely distributed.
Synthetic antimuscarinic agents (quaternary amines) - mostly peripheral distribution.
Metabolism and excretion of antimuscarinic agents?
Metabolised in liver and excreted in urine
Half life 4 hours
What is pralidoxime?
Cholinesterase regenerator:
The Acetylcholinesterase enzyme has two parts to it. An acetylcholine molecule bound at both ends to both sites of the enzyme, is cleaved in two to form acetic acid and choline. In organophosphate poisoning, an organophosphate binds to just one end of the acetylcholinesterase enzyme [ the esteric site ], blocking its activity. Pralidoxime is able to attach to the other half [ the unblocked, anionic site ] of the acetylcholinesterase enzyme.It then binds to the organophosphate, the organophosphate changes conformation, and loses its binding to the acetylcholinesterase enzyme. The conjoined poison / antidote then unbinds from the site, and thus regenerates the enzyme, which is now able to function again.
After some time though, some inhibitors can develop a permanent bond with cholinesterase, known as aging, where oximes such as pralidoxime can not reverse the bond
What is pralidoxime?
Hydrolysis of phosphorylated acetylcholinesterase
Slows aging process
Pralodoxime is only effective if aging has not occurred
Dosing of pralidoxime?
Pralidoxime is initially administered intravenously in a dose of 1 to 2 g. Signs of recovery appear rapidly. If the symptoms reappear, then an infusion of 2.5% is infused at a rate of 0.5 g/hour.
What is paraqat and why is it toxic?
herbicide
Paraquat forms a potent free radical that accumulates in the lung: Oedema, alveolitis, progressive fibrosis
Lethal dose of paraqat
50-500mg/kg
Toxidrome of paraqat?
Initial gastrointestinal symptoms Delayed onset respiratory distress Death may occur after several weeks Oxygen aggravates pulmonary effects
How does arsenic affect tissues and what effects does this cause?
Inhibition of enzymes of oxidative phosphorylation
Shock Arrhythmias Encephalopathy Peripheral neuropathy Pancytopenia
How is arsenic absorbed and excreted?
absorbed: All mucosal surfaces Widely distributed
Excreted by kidney
How does lead affect tissues and what effects does this cause?
inorganic oxides: Inhibition of enzymes, interferes with essential cations, alters membrane structure
Inorganic oxides and salts: Anaemia, peripheral neuropathy, nephropathy, hypertension
Organic: Encephalopathy
How is lead absorbed and excreted?
Inorganic oxides and salts: Gastrointestinal and respiratory tracts
Organic: All mucosal surfaces
Excretion:
Organic -Metabolised by liver to lead, excreted in urine and faeces
How does mercury affect tissues and what effects does this cause?
Inhibition of enzymes and membrane alterations
Elemental:
Behavioural disturbance (erethism) Gingivostomatitis
Peripheral neuropathy
pneumonitis
Inorganic: (Hg+ less toxic than Hg2+)
ATN
Organic:
CNS effects, birth defects
How is mercury absorbed?
Elemental: Respiratory tract
Inorganic:
Gastrointestinal tract
Skin
Organic:
All mucosal surfaces
Tend to concentrate in soft tissues, especially kidney
How is mercury excreted?
Elemental: Converted to Hg2+
Excreted in urine and faeces
Inorganic: Excreted in urine
Symptoms of iron toxicity
Nausea Epigastric pain Abdominal cramps Constipation Diarrhoea
Black stools
Symptoms of iron overdose?
Seen commonly in young children (10 tablets can be lethal)
Necrotising gastroenteritis with vomiting, abdominal pain and bloody diarrhoea
Shock
Improvement followed by severe metabolic acidosis, coma and death
Treated with desferrioxamine
What is desferrioxamine?
Used for iron poisoning
Avidly binds to iron
Competes for iron binding with haemosiderin and ferritin
Iron-chelator complex is excreted in urine
Side effects of desferroxamine?
Flushing
Gastrointestinal symptoms
ARDS
Toxic dose of tricyclic antidepressants?
> 1000mg
Toxic side effects of tricyclic antidepressants?
- CNS: Psychosis, sedation, seizures, coma
Antimuscarinic
Sympathomimetic: Tremor, insomnia
2. CVS: Orthostatic hypotension Conduction defects (long PR, wide QRS>0.1s, long QT and ST), arrhythmias.
- Respiratory depression and apnoea.
- Metabolic acidosis
Toxicity of salycilates?
- Salicylism: tinnitus, reduced hearing, vertigo.
- Hyperventilation, fever, dehydration
- Metabolic acidosis due to salicylic acid dissociation, deranged carbohydrate metabolism and reduced renal function.
- Respiratory alkalosis due to central stimulation of respiratory centre Eventual renal and respiratory failure
Norml anion gap?
12-16meq/L
Na+ + K+) - (HCO3- + Cl-
What causes an increased anion gap metabolic acidosis?
Methanol Ethylene glycol Lactic acid Cyanide Carbon monoxide Salicylates Metformin
What is the osmolar gap and what are some causes of increased osmolar gap?
Alcohols: ethanol intoxication methanol ingestion ethylene glycol ingestion acetone ingestion isopropyl alcohol ingestion
Sugars:
mannitol
sorbitol
glucose (in those with insulin resistance, such as diabetics)
Lipids:
Hypertriglyceridemia
Proteins:
Hypergammaglobinemia (M. Waldenström)
What is the calculated osmolality?
2 x [Na mmol/L] + [glucose mmol/L] + [urea mmol/L]
Causes of increased anion gap metabolic acidosis?
Causes include:
lactic acidosis
ketoacidosis
chronic renal failure (accumulation of sulfates, phosphates, urea)
intoxication: organic acids (salicylates, ethanol, methanol, formaldehyde, ethylene glycol, paraldehyde, INH) sulfates, metformin (Glucophage) massive rhabdomyolysis
Causes of normal anion gap metabolic acidosis?
U - ureterosigmoidostomy S - saline administration (in the face of renal dysfunction) E - endocrine (Addisons, spironolactone, triamterene, amiloride, primary hyperparathyroidism) D - diarrhea C - carbonic anhydrase inhibitors A - ammonium chloride R - renal tubular acidosis P - pancreatitis
Is peritoneal dialysis an option for getting rid of drugs?
no, not effective for most drugs
What determines whether a substance is dialisable?
Molecular weight Water solubility Protein binding Endogenous clearance Volume of distribution (small)
What drugs is dialysis ineffective for?
Amphetamines, cocaine Benzodiazepines Phenothiazines Digoxin Opioids Quinidine Tricyclics
What drugs is dialysis effective for?
Ethylene glycol Methanol Salicylate Theophylline Procainamide
Features of benzo and barbiturate withdrawal?
Withdrawal - agents with short half lives produce rapidly evolving severe withdrawal. Longer half life produces gradual, less severe withdrawal. Withdrawal similar to alcohol - agitation, nausea and vomiting reduced seizure threshold, delirium, psychosis.
Mechanism of caffeine as a stimulant?
Inhibits phosphodiesterase at high concentrations resulting reduced degradation of cAMP in high intracellular cAMP. Possible inhibition of adenosine receptors.
Mechanism of nicotine?
Causes release of catecholamines from central and peripheral nerves.
Produces insidious onset central euphoriant effect. Withdrawal characterised by pronounced and long lasting craving.
Mechanism of cocaine?
Inhibition of dopamine and noradrenaline reuptake Produces marked increased mental alertness and euphoria then may progress to delusions and psychosis.
Short acting compared with amphetamines but magnified effect.
Mechanism of amphetamine?
Cause central increased catecholamine neurotransmitter release Produces marked increased mental alertness and euphoria then may progress to delusions and psychosis
Withdrawal - lethargy, increased appetite, depression
Methamphetamine - speed
Methyeledoxymethamphetamine - ecstasy
Mechanism and effects of LSD?
The psychedelic effects of LSD are attributed to its strong partial agonist effects at 5-HT2A receptors but exact mechanism unknown. LSD affects a large number of the G protein-coupled receptors, including all dopamine receptor subtypes, and all adrenoreceptor subtypes, as well as many others.
Mechanism unknown ␣ interacts with several serotonin receptor subtypes. Produces dizziness, weakness, tremors, nausea and prominent visual illusions and other perceptive abnormalities. Also causes pupillary dilation, tachycardia and increased blood pressure.
PCP mechanism and effects?
Related to ketamine.
May act at opioid, dopamine or glutamate receptors. NMDA antagonist, D2 partial agonist, nAchR antagonist.
Produces detachment, disorientation, distortion of body image, nystagmus (vertical and horizontal), sweating, tachycardia, hypertension. Overdose can be fatal (in contrast with LSD).
Effect of antimuscarinics (in drug abuse setting)?
Produce very similar effects to LSD in high doses though delusions tend to be bizarre.
Effects are very long acting (several days). Delirium, fluctuating level of awareness, difficulty in thinking and marked loss of memory are particularly characteristic.
Pharmacological profile of marijuana?
Where does it act?
Contains several cannaboids including tetrahydrocannabinol (THC). Stimulates a specific receptor located in basal ganglia, substantia nigra, globus pallidus, hippocampus and brain stem. May also have a non-specific membrane effect.
Produces euphoria and characteristic uncontrollable laughter, alteration of time sense, sharpened vision followed by extreme relaxation and dream like states. Tachycardia and conjunctival reddening are characteristic.
Therapeutic use likely to increase due to antiemetic and
analgesic actions
How does activated charcoal work as a decontaminant?
Large surface area available to adsorb many drugs and poisons. 1 gram has a surface area of 1000m2 Manufactured by heating charcoal under pressure. Most effective in a 10:1 ratio of charcoal to poison.
What substances is activated charcoal not effective for?
does not bind:
Ions - lithium, potassium, cyanide
Heavy metals - iron Hydrocarbons
Acids/alkalis
Alcohols: ethanol, methanol
What is whole bowel irrigation and what substances is it useful for?
Balanced polyethylene glycol-electrolyte solution: used for iron, enteric coated medications, foreign bodies.
Antidote to paracetamol?
acetylcysteine
Antidote for anticholinesterases? (organophosphates and carbamates)?
pralidoxime
Antidotes of tricyclic antidepressants and quinine?
bicarbonate
Antidote for iron salts?
desferrioxamine
Antidote for digoxin?
digibind, digoxin antibodies
Antidote for methanol and ethylene glycol?
rthanol
Antidote for benzodiazepines?
flumazenil
Antidote for beta blockers?
glucagon
Antidote for opioids?
naloxone
Antidote for carbon monixide?
oxygen
Antidote for antimuscarinics?
physostigmine
Mechanism of aspirin?
Reduced synthesis of eicosanoid mediators:
Irreversible inhibition of cyclooxygenase
Reduced synthesis of thromboxane A2 Reduced synthesis of prostaglandins
Central blockade of CNS response to IL1 in causing fever
Effects of aspirin and how long does it last?
Antiplatelet
action lasts for the lifespan of the platelet - thromboxane A2 stimulates platelet aggregation and granule release
Antiinflammatory Analgesic Antipyretic
Effects of aspirin at therapeutic, anti-inflammatory and toxic range?
- Therapeutic range
0-10mg/kg
Gastritis, ulceration Impaired haemostasis - Anti-inflammatory range 50mg/kg
Salicylism: tinnitus, reduced hearing, vertigo. - Toxic range 50-150mg/kg hyperventilation, fever, dehydration, metabolic acidosis
- Serious intoxication >150mg/kg
Respiratory alkalosis due to central stimulation of respiratory centre
Renal compensation for respiratory alkalosis. Metabolic acidosis due to salicylic acid dissociation, deranged carbohydrate metabolism and reduced renal function.
Eventual renal and respiratory failure
Interactions of aspirin with other drugs?
Displaces from protein binding (phenytoin, methotrexate)
Decreased activity of spironolactone
Decreased tubular secretion of penicillin
Absorption and distribution of aspirin?
Orally active Rapidly absorbed. Acidity of stomach keeps aspirin in nonionised form that is more readily absorbed
Bound to albumin in low doses. As serum concentration rises, increasing fraction is unbound
Metabolism and excretion of aspirin?
Hydrolysed to acetic acid and salicylate by blood and tissue esterases.
Salicylate conjugated by liver and excreted by kidney.
Demonstrates variable order kinetics ␣ metabolism is saturable and small further increases in aspirin dose results in large rise in salicylate levels.
Half life 3-5 hours at low dose, 12 hours at anti- inflammatory doses
Alkalinisation of the urine increases rate of excretion of free salicylate
Haemodialysis indicated in severe toxicity
Mechanism of nsaids?
Reduced synthesis of eicosanoid mediators
Reversible inhibition of cyclooxygenase (COX1, COX2 or both)
Reduced synthesis of thromboxane A2 Reduced synthesis of prostaglandins
Prostaglandins are important mediators of inflammation
Inhibition of mediator release from leukoctes
Decreased sensitivity of vessels and pain sensors to bradykinin and histamine
Central blockade of CNS response to IL1 in causing fever
Toxocity of ibuprofen?
Gastritis, ulceration and minor gastrointestinal disturbance
Impaired haemostasis
Nephrotoxicity and reduced renal function in those with renal disease
Hepatotoxicity and increased liver enzymes in those with hepatic disease
Oedema, especially if pre- existing heart failure
Visual disturbances
Aseptic meningitis
What does ibuprofen interact with?
Warfarin: risk of fatal haemorrhage due to displacement from albumin
Lithium/digoxin: increased plasma levels Antihypertensives: reduced effect
Contraindications of ibuprofen?
NSAID/aspirin sensitive asthma
3rd trimester of pregnancy: may cause closure of the fetal ductus arteriosus, fetal renal impairment, inhibition of platelet aggregation and delay labour and birth
Absorption of ibuprofen?
Orally active
Rapidly absorbed.
Absorption slowed by food
Highly protein bound
Metabolism and excretion of ibuprofen?
Metabolised by liver to inactive metabolites.
Excreted in urine and bile
Half life 2 hours
Dising of naproxen and toxicity of naproxen?
10mg/kg in 2 divided doses slow release formulation available
may impair feritlity
Excretion of naproxen
Mostly excreted unchanged Half life 12 hours
Mechanism of indomethasin, ketoprofen and diclofenac?
Indomethacin, ketoprofen and diclofenac inhibit lipoxygease and therefore reduce formation of leukotrienes
ketoprofen Half life 2 hours
Mechanism of mefanamic acid?
May antagonise the actions of prostaglandins PGE2 and PGF2alpha at uterine receptors
Is indomethacin more or less potent than aspirin?
Most effective absorption?
Potent prostaglandin inhibitor 28 times more potent than aspirin
PR more rapid
T 1/2 4 hours
Indications for indomethacin?
Patent ductus arteriosus
Gout
Preterm labour (though may cause closure of the ductus, renal toxicity, delayed labour, impaired haemostasis
Dose 50-200mg/day in 2- 3 divided doses
Indications and dosing for kerolac?
Short-term management of post operative pain
Equally effective as 10mg morphine/100mg pethidine IM or panadeine forte
Dose 10-30mg IM every 6 hours for a maximum of 5 days
Mechanism of paracetamol?
Para-aminophenol derivative
Weak prostaglandin inhibitor
Probably has COX3 antagonist actions in the CNS
Symptoms of paracetamol toxicity/overdose?
What doses typically cause this?
Toxic symptoms include vomiting, abdominal pain, hypotension, sweating, central stimulation with exhilaration and convulsions in children, drowsiness, respiratory depression, cyanosis and coma.
Hypokalaemia and ECG changes have also been noted
In adults, hepatotoxicity may occur after ingestion of a single dose of paracetamol 10 to 15 g
25 g is potentially fatal.
Symptoms during the first two days of acute poisoning by paracetamol do not reflect the potential seriousness of the intoxication.
Major manifestations of liver failure such as jaundice, hypoglycaemia and metabolic acidosis may take at least three days to develop.
Medications which interact with paracetamol?
Alcohol and enzyme inducers :increased risk of toxicity
Absorption of paracetamol?
Orally active
Peak blood levels 30- 60 minutes Food intake delays paracetamol absorption. Partially protein bound
Metabolism of paracetamol?
Metabolised in liver In adults at therapeutic doses, paracetamol is mainly conjugated with glucuronide or sulfate.
Also metabolised to a toxic metabolite (cyp3a4 and cyp2a1) that is detoxified by conjugation with glutathione
Excreted in the urine
Elimination half- life varies from one to three hours.
Overdose Activated charcoal IV fluids
If 15g or more ingested, acetylcysteine
Mechanism of paracetamol toxicity?
Paracetamol is metabolised in the liver, mainly by conjugation with glucuronide and sulfate. It is also metabolised by cytochrome P450 to form a reactive, potentially toxic, metabolite.
This metabolite is normally detoxified by conjugation with hepatic glutathione, to form nontoxic derivatives.
In paracetamol overdosage, the glucuronide and sulfate conjugation pathways are saturated, so that more of the toxic metabolite is formed.
As hepatic glutathione stores are depleted, this toxic metabolite may bind to hepatocyte proteins, leading to liver cell damage and necrosis.
Mechanism of NAC in paracetamol toxicity?
Acetylcysteine is a sulfydryl (SH) group donor, and may protect the liver from damage by restoring depleted hepatic reduced glutathione levels, or by acting as an alternative substrate for conjugation with, and thus detoxification of, the toxic paracetamol metabolite.
Dosing of NAC in paracetamol overdose?
8 hours or less since overdose ingestion.
Initial dose 150 mg/kg over 15 minutes, followed by continuous infusion of 50 mg/kg in glucose 5% 500 mL over four hours and 100 mg/kg in glucose 5% 1 L over 16 hours.
If more than eight hours have elapsed since the overdosage was taken, the antidote may be less effective.
Rumack-Matthew nomogram gives indication of likelihood of toxicity as a function of time since ingestion and plasma levels
NAC toxicity and contraindications?
Nausea and vomiting
Allergic reactions
Tachycardia, chest pain
Contraindications: Asthma, renal and hepatic failure - administer with caution
Mechnism of colchicine?
Binds to intracellular tubulin, therefore inhibiting leucocyte migration and phagocytosis (also anti- mitotic)
Inhibits formation of leukotriene B4
Inhibits urate crystal deposition
Dosing of colchicine?
Acute gouty arthritis
Dose 0.5-1mg then 0.5mg every 2 hours until pain is relieved or diarrhoea occurs
Do not exceed 8mg
Toxicity of colchicine?
Diarrhoea (80% in 8-12 hours)
Nausea and vomiting
Bone marrow suppression (especially in overdose) inhibition of B12 absorption
Contraindications of colchicine?
Hepatic or renal disease
Cardiac disease
Gastrointestinal disease
Toxicity of colchicine? Describe the dose and the two phases of toxicity
Toxic dose >0.5mg/kg
Latent period- 2-12 hours:
Burning throat pain, bloody diarrhoea, dehydration
Second phase 24-72 hours: Shock, renal failure, muscular weakness and ascending paralysis, bone marrow suppression, DIC, multiorgan failure
Absorption and distribution of colchicine?
Rapidly absorbed
Bioavailability 25- 50%
Metabolism of colchicine?
Metabolised by liver, excreted in bile and urine.
Some enterohepatic circulation
Half life 4 hours
Management of colchicine overdose
Activated charcoal
Supportive measures
Mechanism of alloprinol?
Xanthine oxidase inhibitor
Urate formed from amino acids and purines
Xanthine oxidase is required for formation of urate therefore its inhibition will decrease production
Toxicity of allopurinol?
May precipitate acute gout unless given with colchicine or probenicid Rash Nausea and vomiting Bone marrow depression Impaired renal function Impaired hepatic function
Absorption of allopurinol?
Metabolism of allopurinol?
80% absorbed not bound to plasma proteins
Metabolised by xanthine oxidase which it also inhibits
Half life 1-2 hours
Describe the anatomy of sympathetic pre and post ganglionic fibres?
Sympathetic preganglionic fibres terminate in ganglia in paravertebral chains.
Post ganglionic fibres then pass to the organs
Describe the anatomy of parasympathetic pre and post ganglionic fibres?
Parasympathetic fibres: some terminate in parasympathetic ganglia (ciliary, pterygopalatine, submandibular, otic, pelvic), majority terminate in organs.
Where is acetylcholine found as a neurotransmitter?
All pre-ganglionic autonomic
All parasympathetic post-ganglionic
All somatic motor
How is acetylcholine made? Where do the components come from?
What can block this production?
Acetylcholine synthesised in cytoplasm from acetyl-CoA (made in mitochondria) and choline (transported from extracellular fluid by sodium dependent carrier) - enzyme=choline acetyltransferase.
Hemicholiniums block choline carrier
Where is acetycholine stored?
What can block the storage?
Acetylcholine transported from cytoplasm to storage vesicle by proton antiporter.
Vesamicol blocks antiporter.
What causes acetylcholine release?
What proteins are involved?
What blocks this?
Calcium influx causes the vesicle to fuse with the terminal membrane and release acetylcholine into the synaptic cleft.
Synaptobrevin, SNAP and syntaxin required.
Botulinum toxin blocks release by enzymatic removal of 2 amino acids from synaptobrevin.
What terminates the action of acetylcholine?
Acetylcholine degraded by acetylcholinesterase into acetate and choline.
Where is noradrenaline found?
Most post-ganglionic sympathetic
How is noradrenaline synthesised?
What inhibits this?
Tyrosine carried into cell by sodium dependent carrier.
Converted to DOPA by tyrosine hydroxylase.
DOPA converted to Dopamine by DOPA decarboxylase.
Metyrosine inhibits action of tyrosine hydroxylase.
What blocks the storage of dopamine in vesicles?
Dopamine transported into vesicle by a carrier. Reserpine blocks carrier.
What is the mechanism of noradrenaline release into the synapse?
What drugs potentiate this? What drugs block this?
Calcium influx causes the vesicle to fuse with the terminal membrane and release noradrenaline into the synaptic cleft. ATP and dopamine beta hydroxylase are also released into the cleft.
Tyramine and amphetamines are capable of noradrenaline release by a displacement process that is not calcium dependent.
Release can be blocked by bretylium and guanethadine
What terminates the action of noradrenaline at the synapse?
What stops this termination?
Noradrenaline diffuses away from the cleft or is transported back into the cytoplasm or into the post-junctional cell.
Noradrenaline is then metabolised by MAO and COMT.
Reuptake is blocked by cocaine and tricyclic antidepressants.
Where are muscarinic M1 receptors found?
CNS, sympathetic postganglionic, some pre-synaptic
What is the result of M1 muscarinic receptor binding?
IP3, DAG, increased calcium
Where are M2 muscarinic receptors found?
heart, smooth muscle, endothelium, some pre- synaptic
What is the binding result if M2 muscarinic receptors?
Inhibit adenylyl cyclase, open potassium channels, stimulates release of EDRF.
Where are M3 muscarinic receptors found and what is the result of receptor binding at M3 receptors?
Exocrine glands, vessels, eye, lungs, GIT, bladder
IP3, DAG, increased calcium
Where are nicotinic N receptors bound and what does binding result in?
Postganglionic neurons, some pre-synaptic cholinergic terminals
Open sodium and potassium channels, depolarisation
Where are nicotinic M receptors found and what is the result of activation of these receptors?
Skeletal muscle endplates
Open sodium and potassium channels, depolarisation
Where are alpha 1 adrenoceptors found and what is the result of binding to these?
mostly smooth muscle IP3, DAG, increased calcium
Where are alpha 2 adrenoceptors found and what is the result of binding to these?
pre-synaptic terminals, platelets, lipocytes, smooth muscle inhibition of adenylyl cyclase, reduced cAMP
Where are beta 1 adrenoceptors found and what is the result of binding to these?
heart, brain, lipocytes plus presynaptic stimulation of adenylyl cyclase, increased cAMP
Where are beta 2 adrenoceptors found and what is the result of binding to these?
heart, lungs, smooth muscle stimulation of adenylyl cyclase, increased cAMP
Where are beta 3 adrenoceptors found and what is the result of binding to these?
lipocytes stimulation of adenylyl cyclase, increased cAMP
What receptor dilates the pupil
i.e. constricts radial (pupillary dilator) muscle of iris?
A1
What receptor constricts pupil?
i.e. constricts circular (pupillary constrictor) muscle
M3
What receptor contracts the ciliary muscle?
M3
What receptor increases aqueous humour?
B
What receptors increase and decrease heart rate at the sa node?
B1, B2 (acellerate)
M2 (decellerate)
What receptors increase cardiac contractikity?
B1, A1, B2 (increase)
M2 (decrease)
What receptor contracts Skin, splanchnic blood vessels?
A1
What receptor relaxes skeletal muscle blood vessels?
B2
What adrenoceptor aggregates platelets?
A2
What adrenoceptors relax and contract gut wall?
relax a2, b2
contracts M3
sphincters contract a1, relax m3
What adrenoceptor increases secretions (salivary, gastric, pancreatic)?
M3
What adrenoceptor causes
- gluconeogenesis?
- glycogeniolysis?
- Lipolysis?
- Decreases lipolysis?
- B2, A
- B2, A
- B3
- A2
What adrenoceptor increases renin release at the kidney?
b1
What adrenoceptor causes
- bladder wall contraction?
- Bladder wall relaxation?
- Bladder sphincter contraction?
- Bladder sphincter relaxation
- B2
- M3
- A1
- M3
What adrenoceptor causes uterine contraction and relaxation?
relax: b2
contract: A, M3
What adrenoceptor causes
1) piloerection in the skin?
2. Increased sweating?
1) A1
2) A, M
Describe the 2 classes of cholomimetic drugs with examples?
Centrally mediated alerting action, tremor, emesis, convulsions.
Choline esters: Acetylcholine (both), Methacholine (muscarinic), Carbachol (both), Bethanecol (muscarinic)
Alkaloids: Pilocarpine (muscarinic), Nicotine (nicotinic), Lobeline (nicotinic), Muscarine (muscarinic).
Indications for cholomimetic drugs?
- Glaucoma: pilocarpine, methacholine, carbachol.
- Paralytic ileus: bethanechol
- Urinary retention: bethanechol
- Antimuscarinic drug intoxication.
Absorption and distribution of choline esters and alkaloids?
Choline esters: Poorly absorbed orally.
Alkaloids: Well absorbed orally and transcutaneously.
Distribution: Choline esters Hydrophilic therefore poorly distributed in CNS
Alkaloids: Nicotine very lipid soluble therefore widely distributed in CNS
Metabolism and excretion of choline esters and alkaloids?
Choline esters: Hydrolysed in GIT (acetylcholine more than others, carbachol and methacholine negligible)
Alkaloids: Renally excreted, increased by acidification of the urine.
What are the 2 types of direct acting sympathetomimetics?
Give examples of these?
catecholamine and non-catecholamine
Catecholamines:
Adrenaline, Noradrenaline, Isoprenaline, Dopamine Dobutamine
Non-catecholamines:
Ephedrine
Phenylephrine, Amphetamine
Indirect acting sympathomimetics:
Cocaine
Tyramine
Give an example of an alpha 1 agonist and antagonist.
agonist: Phenylephrine A1>A2»»>B
antagonist: prazocin
Give an example of an alpha 2 agonist and antagonist?
Agonist: Clonidine A2>A1»»>B
antagonist: Yohimbine
Give an example of an beta 1 agonist and antagonist?
agonist: Dobutamine B1>B2»»A
antagonist: Betaxolol
Give an example of an beta 2 agonist and antagonist?
agonist: Terbutaline/Salbutamol (B2»B1»»A)
antagonist: Butoxamine
What is a mixed beta agonist and antagonist?
agonist: isoprenaline
antagonist: propranolol
What receptors does dopamine activate?
D1=D2»B»A
How are adrenoceptors regulated and what is the mechanism of this?
Number and function of adrenoceptors may be regulated to modify physiological response. Desensitisation may occur after exposure over a period of time and results in lesser response to further stimulation.
Mechanisms:
- Receptor sequestration -rapid and transient event decrease in receptor availability.
- Down-regulation -reduced receptors due to reduced synthesis.
- Receptor phosphorylation - resulting in impaired binding
What is the general structure of sympathomimetic drugs?
What happens if you substitute at the
1) benzeine ring?
2) amino group?
3) alpha carbon?
Sympathomimetic drugs are based on a benzene ring structure with an ethylamine side chain. Substitutions made on the terminal amino group, benzene ring or the alpha or beta carbons modify the affinity of binding at specific receptors.
Catecholamine formed by substitution with hydroxy groups on the benzene ring this increase potency but decreases bioavailability and decreases duration of action by making the drug subject to inactivation by COMT.
Substitution on the amino group increases beta receptor activity. Substitution at the alpha carbon blocks oxidation by MAO. Substitution on the beta carbon is important for storage.
What are the catecholamine sympathomimetics?
Adrenaline, Noradrenaline, Isoprenaline, Dopamine, Dobutamine.
What are the non-catecholamine sympathomimetics?
Ephedrine, Phenylephrine, Amphetamine.
Mechanism of:
- adrenaline?
- Isoprenaline?
- Noradrenaline
- Dopamine
- Dobutamine
Adrenaline: Non-selective alpha and beta- adrenergic agonist.
Noradrenaline: Non-selective alpha agonist, B1 greater than B2.
Isoprenaline: Selective beta agonist Potent beta agonist, little alpha agonist effect.
Dopamine: D1 and D2 agonist with beta and alpha actions at high doses.
Dobutamine: B1 selective agonist.
(Dobutamine is a racemic mixture -the positive isomer has B1 agonist and A1 antagonist actions, the negative isomer has A1 agonist actions - the net effect is positive inotrope action with little peripheral effect hence less reflex tachycardia)
Phenylephrine mechanism?
Relatively pure alpha agonist with limited beta action
Ephedrine mechanism?
Some direct non-selective action on adrenoceptors, also causes release of stored catacholamines.
Amphetamine mechanism?
Causes release of stored catecholamines
Methyldopa and clonidine mechanism?
Methyldopa - centrally acting A2 agonist.
Clonidine - centrally acting A2 agonist).
causes centrally mediated reduction in TPR (clonidine also causes bradycardia)
Cardiovascular effects of adrenaline and noradrenaline?
Adrenaline: Rise in systolic blood pressure due to positive inotropic and chronotropic effects via B1 receptors. Total peripheral resistance and hence diastolic blood pressure may fall due to vasodilation mediated by B2 receptors. Bolus doses tend to have mainly peripheral vasoconstrictor effect whereas infusions have the effect described above
Noradrenaline: Rise in systolic blood pressure due to positive inotropic and chronotropic effects via B1 receptors. Total peripheral resistance and diastolic pressure also increase due to alpha effect and lack of B2 mediated vasodilation
Cardiovascular effects of isoprenaline and dopamine?
Isoprenaline: Marked increase in cardiac output due to positive inotropic and chronotropic effect mediated by B1 receptors. Total peripheral resistance and diastolic blood pressure fall due to vasodilation mediated by beta receptors. Systolic pressure typically falls by a small amount though may rise.
Dopamine: Reduction in TPR mediated by D1 receptors on blood vessels and pre-synaptic D2 receptors that result in reduced noradrenaline secretion. Most important effects are renal vasodilation. At higher doses, dopamine acts on beta receptors then alpha receptors to cause vasoconstriction and has an adrenaline-like action.
Dose: Renal 0.5-2ug/kg/min
Beta 2-10ug/kg/min
Alpha >10ug/kg/min
Cardiovascular effects of dobutamine?
Increased stroke volume and cardiac output mediated by B1 receptors. Less chronotropic effects. Mild vasodilation, sometimes vasoconstriction.
Cardiovascular effects of phenylephrine and ephedrine and adrenaline?
Phenylephrine: Marked increase in peripheral vascular resistance and decrease in venous capacitance mediated by alpha receptors and resulting in hypertension, and reflex vagally-induced mild bradycardia.
Ephidrine: Mainly used as a nasal decongestant, mild central stimulant effect.
Amphetamine: Marked central stimulant effect on mood and alertness. Appetite suppressant. Some efficacy in ADHD. Most have marked central stimulant effect, especially amphetamine.
Catecholamine absorption, distribution and excretion?
Poor bioavailability after oral administration due to catechol structure and subsequent inactivation by COMT found in gut and liver
Poor distribution to CNS due to catechol structure.
Metabolised by COMT and MAO and excreted in the urine.
Non catecholamine sympathomimetic absorption, distribution and excretion?
Orally active, longer duration of action.
Readily enters CNS, especially amphetamine.
Significant fraction excreted unchanged.
Weak base therefore excretion enhanced by acidification of the urine.
Give an example of an indirectly acting sympathomimetic?
What does this do
Cocaine
Inhibition of noradrenaline reuptake at noradrenergic synapses
Widely distributed and readily enters CNS, short duration of action
Give 3 examples of alpha antagonists and their structure?
Phentolamine imidazoline derivative.
Phenoxy- benzamine
Prazosin (Piperazinyl quiazoline)
What are the receptor selectivities of
- Phentolamine?
- Phenoxybenzamine?
- Prazosin?
- Phentolamine: Non selective mixed A1 and A2 antagonist.
Reduction in peripheral vascular resistance mediated by blockade of alpha receptors. This may result in a reflex tachycardia. Antagonism of pre- synaptic A2 receptors may cause noradrenaline release. (Also inhibits response to 5HT and H1/H2) - Phenoxybenzamine: A1 selective antagonist. (also blocks Ach, H1, 5HT). Blockade of catecholamine induced vasoconstriction.
- Prazosin: Potent A1 antagonist. Decreased total peripheral resistance due to relaxation of arterial and venous smooth muscle mediated by alpha 1 blockade.
Toxicity of
- Phentolamine?
- Phenoxybenzamine?
- Prazosin?
Phentolamine: Reflex tachycardia due to greater release of noradrenaline and its action on beta receptors
Phenoxybenzamin: Postural hypotension and reflex tachycardia. Inhibition of ejaculation, fatigue, sedation.
Prazosin: Less reflex tachycardia
1st dose hypotension
Tends to cause salt and water retention
Dizziness Palpitations Headache No effect on lipids
Absorption and distribution of
- Phentolamine?
- Phenoxybenzamine?
- Prazosin?
Phentolamine: Poorly absorbed orally. Duration of action determined by half life and rate of dissociation from the receptor.
Phenoxybenzamine: Well absorbed orally.
Prazosin: Well absorbed orally Highly protein bound
Metabolism and excretion of prazocin?
Extensively metabolised by liver
50% bioavailability. Half-life 3 hours.
Mechanism of
- Propanolol?
- Metoprolol?
- Atenolol?
- Esmolol?
- Labetolol?
- Carvedilol?
- Propanolol: Non-selective beta antagonist No action at alpha or muscarinic receptors
- Metoprolol: B1 selective
- Atenolol: B1 selective.
- Esmolol B1 selective
- Labetolol: Mixed B1 antagonist and alpha antagonist
- Carvedilol: Mixed non-selective beta blocker and alpha antagonist
Which beta blockers also have local anesthetic actions?
The following beta blockers also act as membrane stabilisers by sodium channel blockade
Acebutolol Betaxolol Labetolol Metoprolol Pindolol Propanolol
CVS, respiratory, eye and metabolic effects of beta blockers?
CVS
Negative inotropic and chronotropic effect on the heart. (including slowed AV conduction and increased PR interval)
Increased peripheral vascular resistance due to unopposed alpha effects. Antagonism of the release of renin (B1) resulting in reduced TPR
RS
Increased airway resistance (largely avoided by B1 selective agents but not completely).
Eye
Decreased aqueous humour production leading to reduced intraocular pressure.
Metabolic and endocrine: Inhibition of catecholamine induced lipolysis and glycogenolysis via B2 receptors.
Impair the recovery from hypoglycaemia as this is usually mediated by catecholamines.
Masking of clinical signs of hypoglycaemia and impaired recovery from hypoglycaemia
Increased VLDL, decreased HDL
Metoprolol and propranolol CNS side effects?
Sedation, sleep disturbance, depression, psychotic episodes.
What do beta blockers interract with?
Calcium antagonists - leading to severe hypotension, bradycardia, congestive cardiac failure
Absorption and distribution of beta blockers?
Absorption Well absorbed orally.
Distribution Large volume of distribution.
Propanolol: Lipid soluble Readily crosses BBB
Metoprolol: Moderate lipid solubility
Atenolol: Low lipid solubility
Esmolol: Low lipid solubility
Metabolism and excretion of propranolol?
Extensive first pass metabolism Excreted in urine Variable between individuals
Low bioavailability
Half life 3-6 hours
Dose reduction required in hepatic failure
Metabolism and excretion of
- metoprolol?
- atenolol?
- esmolol?
- Metoprolol: Extensive first pass metabolism
Low bioavailability, Half life 3-4 hours - Atenolol: Less extensive first pass metabolism Low bioavailability. Half life 6-9 hours
- Esmolol: Rapidly hydrolysed by esterases in red blood cells. Half life 10 minutes.
What does Trimethaphan do?
ganglion blocking agent: Competitive antagonist at nicotinic cholinoceptors on sympathetic and parasympathetic postganglionic neurons.
Causes pooling of blood in capacitance vessels.
Abandoned due to side effects ␣ sympathoplegia (excessive orthostsaic hypotension, sexual dysfunction) and parasympathoplegia (constipation, urinary retention, glaucoma, blurred vision, dry mouth)
IV administration
Mechanism of Guanethidine?
Inhibitor of noradrenaline release from postganglionic sympathetic neurons: Guanethidine is transported across the nerve membrane by uptake 1. Concentrated in transmitter vesicles where it replaces noradrenaline causing depletion of noradrenaline stores.
Causes reduced cardiac output due to bradycardia and relaxation of capacitance vessels.
Postural hypotension common. Overdosage may result in severe hypotension or shock. May induce hypertensive crisis in those with phaechromocytoma due to release of noradrenaline. Effects are attenuated when TCAs are coadministered due to their effect on blocking reuptake.
Very large volume of distribution and long half life.
Mechanism of reserpine?
Reserpine blocks carrier mediated transport of dopamine into the vesicle. Results in depletion of dopamine, noradrenaline, and serotonin in central and peripheral neurons.
Causes antihypertensive effect by reduction in cardiac output and total peripheral resistance.
Effects are largely irreversible and last for several days.
For methyldopa state the:
- Mechanism?
- Organ effects?
- Clinical use?
- Centrally acting alpha agonist. Inhibition of dopa decarboxylase and depletion of noradrenaline
A2 actions greater than A1 - Centrally mediated reduction in total peripheral resistance with variable reduction in heart rate and cardiac output.
- Mild to moderate hypertension.
Pregnancy induced hypertension
Dose 0.5-3g/day in divided doses 0.25-1g IV over 20 minutes.
For methyldopa state the:
1. Toxicity and interactions
CVS
May cause postural hypotension and bradycardia.
CNS
Sedation and loss of concentration Depression Nightmares.
Endocrine: Lactation -mediated by inhibiting action on dopaminergic mechanisms in the hypothalamus.
Other: Positive Coombs test is 25%.
Interactions May result in lithium toxicity if co-administered
For methyldopa state the:
- Absorption and distribution
- Metabolism and excretion
- Absorption Orally active. Occasional IV use occasional.
Distribution Active transport into brain - Extensive first pass metabolism.
Metabolised in liver ␣ likely production of an active metabolite.
Most is renally excreted.
Antihypertensive effect in 4-6 hours, clinical effect may last 24 hours due to active metabolite.
For clonidine state the:
- Mechanism?
- Organ effects?
- Clinical use?
- Centrally acting partial agonist at alpha receptors, causing reduced sympathetic tone and increased parasympathetic tone. Preference for A2
- Reduction in blood pressure and mild bradycardia.
- Hypertension
For clonidine state the:
1. Toxicity and interactions
Sedation, dry mouth. Depression. Reactive hypertensive crisis if rapidly withdrawn.
For clonidine state the:
- Absorption and distribution
- Metabolism and excretion
Orally active, bioavailability 75%.
Distribution Lipid soluble and rapidly enters the brain.
Half life 8-12 hours
For acetazolamide state the:
- Mechanism?
- Organ effects?
- Clinical use?
- carbonic anhydrase inhibitor: Carbonic anhydrase most prominent in the luminal membrane of the PCT
- Profound depression of bicarbonate reabsorption in the proximal tubule
Reduced production of bicarbonate by the ciliary body - Glaucoma Urinary alkalinisation Metabolic alkalosis Acute mountain sickness
Epilepsy
Dose 250mg-1g/24hours
For acetazolamide state the:
1. Toxicity and interactions
Toxicity: Hyperchloraemic metabolic acidosis
Renal stones
Renal potassium wasting
Skin reactions
Interactions :
Salicylates - increased risk of metabolic acidosis Phenytoin - reduced excretion of phenytoin resulting in toxic levels
Contraindications:
Hepatic failure - acetazolamide will decrease the urinary loss of ammonia.
For acetazolamide state the:
- Absorption and distribution
- Metabolism and excretion
Well absorbed orally Increased urinary pH within 30 minutes
