Prevents the inhibitory action of the vagus nerve on the heart ↑Discharge of SA-node conduction and ↑AV-node. Access of the drug to the tissues where the target is located and then elimination of the drug from the body. The ability of the drug to bind to and exert an effect on the target (related to pharmacodynamics).
Change in receptor conformation resulting in an inability to "activate" despite binding of the agonist. Ion channels in the NMJ change shape, resulting in tight binding of the agonist without opening the ion channel. Repeated administration of the same dose results in a progressively lower plasma concentration due to increased metabolic breakdown.
The blood pressure-lowering effect of thiazide diuretics is limited due to a gradual activation of the Renin-Angiotensin system.
Processes of Pharmacokinetics
What additional information is needed before an assessment of the Glomerular Filtration rate (GFR) can be made?
Estimate this patients GFR using the additional information you requested above
How would this deteriorating GFR influence the clearance of Vancomycin from the body?
How would this reduced clearance influence Vancomycin dosing?
What could be causing the deterioration in the patients renal function over the past few days?
You are working as an intern in the emergency department when a patient is brought in who has taken an overdose of paracetamol (forty X 500 mg tablets).
How much paracetamol did she ingest?
What is the bioavailability of the paracetamol?
What would have been her initial serum concentration?
How long will it theoretically take to clear the paracetamol?
What effect does the highly reactive intermediary have on the body?
Gi en that the bod s stores of glutathione are minimal, how can continued metabolism of the highly reactive intermediary be assured?
It is also often used to provide local anesthesia to an area to assist with minor surgery such as the removal of skin lesions a oo s e c. It comes in a variety of strengths and formulations, the most commonly used being 1% plain Lignocaine vials for injection. The lignocaine is supplied as the hydrochloride salt (Lignocaine HCl) which makes the compound highly water soluble, with the pH of 1% regular Lignocaine HCl being approximately 4.0.
Detail the kinetics involved in a dose of lignocaine HCl spreading from the point of injection to its site of action.
Detail the kinetics involved in a dose of lignocaine HCl spreading from the point of injection to its site of action?
What clinical factors can modify these kinetics?
With the above knowledge, explain the following clinical scenario
Binding specifically to prokaryotic ribosomal subunits causes misreading of mRNA and inhibits the synthesis of proteins vital to bacteria. Binds specifically to prokaryotic ribosomal subunits. Inhibits the binding of tRNA to mRNA. Inhibits the synthesis of proteins vital to bacteria. Therefore, selective toxicity is difficult, because you have to inhibit the host cell machinery to stop the virus.
They block proteins (enzymes) that bind to penicillin, inhibit the synthesis of the peptidoglycan layer of the bacterial cell wall. Ribosomal subunits Inhibit binding of tRNA to mRNA Inhibit synthesis of proteins vital to bacteria. Premature depolarization (after Repol, but before another AP would normally occur) Due to excessive intracellular Ca2+ and prolonged APs - (May be caused by DIGOXIN) Note: Accumulation of Na+ and Ca+ in the cell causes the membrane to rest more positive.
Where an impulse re-excites temporarily blocked regions of the myocardium after the refractory period is decreased. Continuous circulation of action potentials Ectopic beats.
Triglycerides (Fatty Acids + Glycerol) o Lipid Transport
Vessel Injury Endothelial Damage
Complicated Plaques
Substernal/Precordial chest pain due to myocardial ischemia No cell necrosis Myocytes switch to anaerobic metabolism. Lactic acid stimulates pain nerves. Stress on the heart Activation of neurohormonal mechanisms Preload & BP Extra stress on the heart. Activate adenosine receptors (in the AV node) Activate ATP-dependent K+ channels (KATP) Hyperpolarizes the AV node Prolongs the conductive AP-ve-dromotropic effect (slows down the AV node).
NB: Tends to shorten AP duration due to submaximal depolarization. Fewer VG-Ca+ channels open to maintain the plateau. Shorter plateau. Shorter action potential. NOTE: Although the AP is shorter, the refractory period of the VG-Na+ channel is still prolonged due to prolonged depolarization. NB: Sotalol, although a 'β-blocker', is classified as Class III due to VG-K+ blockade) o Mechanism of action:.
Block VG-Na+ Channels in SA/AV Node Slow Conduction Depolarization SA-Node Heart Rate & Slow Conduction through the AV Node HR).
Nitric oxide binds to guanylate cyclase (GuCy) in vascular smooth muscle cGMP closes Ca+ channels Intracellular [Ca+] Smooth muscle relaxation Vasodilation. Guanylate cyclase (GuCy) in vascular smooth muscle cGMP closes Ca+ channels Intracellular [Ca+] Smooth muscle relaxation Vasodilation. Binds irreversibly to bile acids (endogenous cholesterol) & dietary cholesterol in the intestine Prevents intestinal cholesterol reabsorption Bl d Ch le e l.
Nitric Oxide Binds to Guanylate Cyclase (GuCy) in Vascular Smooth Muscle cGMP Closes Ca+ Channels Intracellular [Ca+] Smooth Muscle Relaxation. MOA: Activates Corticosteroid (GRα) Receptors Activates transcription factors in the Nucleus Decreases expression of cytokines ↓Inflammation in sub-mucosa. MOA: Activates Corticosteroid (GRα) Receptors Activates transcription factors in the Nucleus Decreases expression of cytokines ↓Inflammation in sub-mucosa.
Selective Estrogen Receptor Modulators SERMs – (Competitive estrogen receptor antagonists, but they are not antagonists – Instead they are modulators because they cause a conformational change in the receptor.).
Afferent Signals to Emetic Centre (From Noxious Stimuli) 2. CNS send out efferent emetic signals
Coordinated Respiratory & Abdominal muscle Contraction; & GI Smooth Muscle Relaxation Vomiting
Deep Inspiration with Closure of Airways and Nasopharynx
Re erse Peristalsis AKA Retrograde Giant Contraction : Mobilisation of Small Intestine Contents to the stomach
Expiration and Contraction of Abdominal Muscles
Ejection of Gastric (& Duodenal) Contents
Increases ductal permeability. Digestive enzymes penetrate the walls of the pancreatic ducts into the pancreas and surrounding tissue. Inflammation of pancreatitis.
Systemic Inflammatory Response Syndrome
Treat malabsorption by replacing digestive enzymes (eg common in CF patients) Manage diabetes with exogenous insulin. NB: Administered as a pro-drug (Activated by acidic stomach environment) Irreversible inhibition of H+/K+ ATPA e P n P m. Esomeprazole, Lansoprazole, Pantoprazole, Rabeprazole) Side effects (uncommon):. It consists of Non-S l ble Yarn which is processed. Forms a large hydrated mass in the intestinal lumen Promotes peristalsis and improves fecal consistency.
Consists of poorly absorbed solutes. Increases intra-luminal osmolarity Traps fluid in the lumen of the intestine. A good background knowledge of the peripheral nervous system is crucial to understanding drugs, drug targets (ie receptors) and drug actions. Receptor types within the functional divisions of the PNS. and CNS) Useful with drug targets - Consequences of NT binding to receptors (Ie effector actions) Useful with drug actions.
Nociceptive Pathways are Specific (Spinothalamic & Reticulospinal Pathways) 99% of ascending 2nd order neurons synapse with the Thalamus in the brain.
R Receptors (Vanilloid Receptors Sensitive to H + /Capsaicin/Heat/Mech)
The Pre-Ganglionic Neuron
The Ganglionic Neuron
Hormone-producing cells of the adrenal medulla (sympathetic) o Therefore, most nicotine agonists are also ganglionic stimulants, ie. Thee Angina Peco i b HR Con ac ion - Thee Hea Fail e b HR Con ac ion Formerly used as antihypertensives (no longer) Glaucoma: (eye drops Pupil constriction).
Pre-Seizure Period
Tonic Phase
Clonic Phase
Post-Ictal Coma
However, it can occur several times a day. o NB: Decreased consciousness Little/no memory of an attack. NB: Like local anesthetics, it is use dependent. Therefore, the drug is selective for fast-acting neurons. Antidiuretic effect – (NB: of concern in elderly patients, or patients with mild cardiac disease – e.g. hypertension/angina pectoris/heart failure) Sedation.
NB: Like local anesthetics, it is use dependent - Therefore, the drug is selective for fast-firing neurons. Blocks Ca+ channels in thalamic relay neurons (which are implicated in absence seizures) Reduces the spread of seizure activity through the rest of the brain thalamus. If epilepsy does not respond to drugs, surgery is essential to prevent permanent progressive brain damage o NB: The risk of brain damage increases the longer the condition continues. o NB: Seizures beget more seizures.
NOTE: Accurate mapping of the epileptic focus is an essential prerequisite for surgery to ensure that removal will not leave the patient paralyzed/unable to speak/other seriously impaired.
Evaluate the Pain Experience (Pain-Scale)
Choose Appropriate Analgesic
Start with Lowest Dose Possible, then Titre Up to Desired Clinical Effects
I.e. Because platelets do not have a nucleus to resynthesize the COX enzymes, they are rendered useless). P o aglandin Podcion by inhibiting the enzyme Cyclo-Oxygenase-2 (COX-2). Prostaglandin-mediated hypersensitivity of nociceptive neurons. I.e. Decreased NT release, reduced nociceptive signaling) o On POST-Synaptic neuron: - Activation of non-VG-K+ channels:.
Side effect – Respiratory depression – But less than morphine) (Side effect – Constipation – But less than codeine). Weak µ-opioid receptor agonist (less potent than morphine) (Side effect – norpethidine, a toxic metabolite of pethidine is a proconvulsant and hallucinogen). Lipid solubility of the drug (Since the binding site is on the inside of the ion channel) Therefore, the more lipid soluble, the easier it can access the binding site.
Sympathetic activity (therefore often co-administered with adrenaline or a vasopressin) At high systemic amounts, the patient will experience a progression from restlessness Convulsions Respiratory depression Hypotension and possibly heart failure.
Volume Expansion
- Loss of Consciousness (With Amnesia)
- Muscle Relaxation
- Propofol Induction Agent 2. Fentanyl – Narcotic Analgesic
- Nitrous + Isoflurane + Oxygen Maintenance
- MAC = The Concentration/Partial-P e e of agen Re i ed fo -100% of Recipients to be Fully Anaesthetised
- Solubility of the Drug in Blood (Ie. Blood:Gas Coefficient)
- Partial Pressures of the Drug in Arterial Vs. Mixed-Venous Blood
- Rate of Blood Flow to the Organ/Tissue (Ie. Drug Delivery)
- Partial Pressures of the Drug in Arterial Blood Vs. Organs/Tissues
- Juxtaglomerular Cells
- Macula Densa
- Folate Antagonists
- Pyrimidine Analogues
- Purine Analogues
- Vinca Alkaloids
- Campothecins
Analgesic properties (ie if GA has intrinsic analgesic properties, there is less need for narcotic analgesics Risk of respiratory depression). 1MAC = Minimum dose/partial pressure of a specific drug required to prevent response in 50% of patients (ie 50% are completely anesthetized). 1 MAC equivalent = The plasma concentration of a specific injected agent required to prevent response in 50% of patients (ie 50% are completely anesthetized).
I mean The faster the gas leaves the brain, the faster you wake up). NB: The patient may appear to show Self-neglect (ie forgetting to take pills/eat/go to the toilet) but this is only a manifestation of the above symptoms. o The normal brain shows activity in the prefrontal, motor and parietal cortex. o The schizophrenic brain shows more activity in areas EXCEPT the prefrontal cortex. It stems from the fact that some drugs that modify dopamine release can mimic/exacerbate the symptoms of psychotic disorders (ie schizophrenia).
NO need for monitoring (Ie Pt can go home Frees up a hospital bed) (However, it is quite expensive). Bleeding – (But Vitamin-K is an antidote) NB: Many factors affect effectiveness:. Diet/Alcohol/Body mass/Other medicine/Alternative medicine/Comorbidity/genetics) Is TERATOGENIC – CONTRAINDICATED in pregnancy. COX-1 (and COX-2) is responsible for prostanoid synthesis [i.e. Prostaglandins, Thromboxane & Prostacyclin] from arachidonic acid and is expressed by all cells).
Anti-inflammatory 5000 mg/day (BUT now obsolete due to GI issues). NB: PDE normally inactivates cAMP). Used in Angioplasty (ie Dilation of a Narrowed/Obstructed Vessel – Typically Atherosclerotic) Potential Use in Prevention of Thrombus/Embolism Complications During Neurovascular Surgery. Typically in Pts with a normal/elevated plasma Renin I.e. Young/white people) o + Thiazide diuretic; OR calcium antagonist.
Inhibitors
Aromatase is responsible for conversion of androgens to estrogens in peripheral tissues, especially postmenopausal women) Therefore, inhibition causes marked reduction in estrogen (in postmenopausal women).
Inhibitors
Competitive Inhibition
Or: 2 Drugs compete for the active site of the same enzyme Me ab li m f Both. OR: The inhibitor is NOT a substrate for the enzyme, but interacts with the enzyme in a competitive manner (eg with a cofactor or regulator) to block its activity.
Non-Competitive Inhibition
Normally conjugated by glutathione. However, glutathione stores can become depleted. Accumulation of NAPQI Extremely HEPATOTOXIC.
Acetylcysteine (A Precursor for Glutathione) Or Methionine
Chronic due to hypokalemia/reduced renal function/drug interactions (eg Ca-Channel Blockers/Tamoxifen/Neuromuscular Blockers).
