Pharmacology Flashcards
What are the 2 routes of administration of a drug?
Systemic and local
What are the 2 branches of systemic administration of a drug?
Enteral (GI tract) and Parenteral (not GI tract)
What are the different types of local routes of administration?
Topical e.g. topical steroid creams for eczema
Intranasal
Eye drops
Inhalation - can also be systemic depending on drug e.g. salbutamol only affects airways but anaesthetic drug sevoflurane is also given by inhalation but has systemic effects)
Transdermal - can also be systemic depending on drug
What is systemic administration of a drug?
Covers the whole system
What is local administration of a drug?
Targets a specific area of pathology, without exposing the rest of the system to drugs unnecessarily
What are the different types of systemic enteral administration?
Oral (PO)
Rectal (PR)
Sublingual
What are the different types of systemic parenteral administration?
IV/IM/SC
Inhalation
Transdermal
What are pharmacodynamics?
Action of the drug on the body (its use!)
What are pharmacokinetics?
Action of the body on the drug (how it’s broken down)
How do drugs cross membranes?
Passive diffusion
Facilitated diffusion
Active transport
Endocytosis
By what route of administration is a drug absorbed the quickest?
IV - directly into bloodstream and no membrane crossing or first pass metabolism
How are drugs absorbed into the bloodstream?
Unless given straight into the bloodstream (IV), drug will need to pass though membranes
How are water soluble drugs absorbed?
Water soluble molecules move through membrane by diffusion
How are lipid soluble drugs absorbed?
Lipid soluble drugs can cross phospholipid membrane directly
How are larger drugs absorbed?
Larger drugs might need facilitated diffusion from carrier proteins in the membrane, ATP dependent active transport, or are engulfed by the cell through endocytosis
What is absorption dependent on?
Solubility of drug Size of molecules pH Surface area Perfusion
What happens to a drug if it is taken orally?
If taken orally, not all of the drug taken gets to the bloodstream – the gut and liver will both start metabolising it first before reaching circulation
When is bioavailability assumed to be 100%?
It is assumed to be 100% if a drug is given IV, but lower if given orally
How is bioavailability calculated?
AUC oral / AUC IV x 100
What is bioavailability?
Rate and extent to which an administered drug reaches the systemic circulation
Fraction of drug that reaches systemic circulation unaltered
What are the drug target types?
Cellular receptors
Enzymes (ACE inhibitors)
Membrane ion channels (lidocaine)
Membrane transporters (PPIs)
What does drug distribution depend on?
Blood flow to area Permeability of capillaries Binding to proteins (albumin = slower) Lipophilicity Volume of distribution
Give an example of how blood flow to an area affects distribution.
Drug will get to the brain (if can pass through BBB) faster than the skin
How does permeability of capillaries affect drug distribution?
Some capillaries have slit junctions that allow drugs through – many in the liver (allows metabolism), none in the brain so harder to get through
How does binding to protein affect drug distribution?
Drugs may also travel in the blood bound to albumin, which slows the process of distribution as the drug must be FREE FROM ALBUMIN to cross membranes
How does lipophilicity affect drug distribution?
Lipophilic drugs can penetrate the cell membrane easily
How does volume of distribution affect drug distribution?
Higher volume of distribution = drug more in tissues, less in plasma, need to give higher concentration
Where can drug targets be found?
Cellular receptors but not all drug targets are receptors on cells (e.g. ramipril, lidocaine, proton pump inhibitors)
What is ramipril?
An ACE inhibitor which blocks the angiotensin converting enzyme
What is lidocaine?
Blocks sodium ion channels and is a local anaesthetic
What are proton pump inhibitors?
Inhibit membrane transporters
Give an example of a proton pump inhibitor.
Omeprazole
Why is the liver key in the excretion of drugs?
Kidney can’t excrete lipid soluble drugs so liver converts lipid soluble drugs into water soluble drugs so they can be excreted by the kidney (2 stages)
Summarise the first phase of drug excretion.
Make drug hydrophilic (cytochrome p450 catalyses)
Summarise the second phase of drug excretion.
If still too lipophilic, add something else to make it polar so the drug can’t be absorbed - e.g. acetylation/adding glutathione)
How do drugs affect cytochrome P450 enzymes?
Drugs can alter the activity of cytochrome P450 enzymes, and therefore alter the rate of metabolism of other drugs
How does alcohol abuse affect drug excretion?
Alcohol abuse, both chronic and acute can mess up the P450 system
What is a CYP450 inducer?
Increases cytochrome P450 activity, and speed up metabolism of other drugs – may result in sub-therapeutic dose
What is a CYP450 inhibitor?
Decreases cytochrome P450 activity, reduce metabolism of other drugs – may result in toxicity
Give some examples of CYP450 inducers.
Anti-epileptics: phenytoin, carbamazepine Rifampicin St John's Wort Chronic Alcohol intake Smokers (CYP1A2)
Give some examples of CYP450 inhibitors.
Abx: ciproflaxacin, erythromycin Isoniazid Amiodarone Allopurinol Anti-fungal: ketoconazole, fluconazole SSRI: fluoxetine, sertraline Sodium Valproate Acute Alcohol
By what type of kinetics are most drugs eliminated?
Most drugs are eliminated through first order kinetics
What is first order kinetics?
Catalysed by enzymes, rate of metabolism directly proportional to drug concentration
The capacity of the elimination system is higher than the concentration of the drug
What is zero order kinetics?
Enzymes saturated by high drug doses, rate of metabolism is constant, e.g. ethanol, phenytoin
When might doses of drugs need to be altered?
Renal failure
Other than the kidneys, how else can drugs be excreted?
Some also excreted by the liver in the bile and then faeces
What is signal transduction?
Binding of drug to extracellular or intracellular receptor
How does signal transduction occur?
Via a variety of receptors: ligand-gated ion channels, G protein-coupled receptors etc
What does signal transduction lead to?
Amplification or down-regulation of signals
What is an agonist?
Binds to receptor and activates it by mimicking the endogenous substance
What response does an agonist induce?
Can be full (causes same response as endogenous substance) or partial
Give an example of an agonist.
Salbutamol (asthma) is beta 2 agonist
What is an antagonist?
Binds to receptor and prevents its activation - can also bind at another site to the main active site (allosteric site)
What type of reaction takes place when an antagonist binds to a receptor?
Can be reversible or irreversible (if a covalent bond forms)
Give an example of an antagonist.
Propranolol (hypertension) is a beta blocker
Beta blockers like bisoprolol
What do beta blockers do?
Block the adrenergic receptors of the sympathetic nervous system
When should beta blockers be avoided?
Avoid beta blockers in asthmatic patients
Use cardio-selective ones (bisoprolol) if absolutely necessary, rather than propranolol (non-selective)
What is efficacy?
How well the ligand (drug) activates the receptor – e.g. full or partial agonist?
What is potency?
Binding affinity of the drug for the receptor
What is first pass metabolism?
Metabolism of the drug by the gut and liver before it reaches the bloodstream
What does a narrow therapeutic range indicate?
Increased risk of toxicity, decreased chance of effective dose
Give some examples of drugs with a narrow therapeutic range.
Digoxin Theophylline Lithium Phenytoin Gentamicin, Vancomycin
What happens to paracetamol following a therapeutic dose?
Paracetamol is mostly converted to non-toxic metabolites via Phase II metabolism
What happens to paracetamol during phase II metabolism?
Here, it conjugates with sulfateand glucuronide, with a small portion being oxidized via thecytochrome P450 enzyme system
What do the cytochromes do to a small fraction of paracetamol during its metabolism?
CytochromesP4502E1and3A4convert approximately 5% of paracetamol to a highly reactive intermediate metabolite, N-acetyl-p-benzoquinone imine (NAPQI)
What happens to NAPQI under normal conditions?
NAPQI is detoxified by conjugation with glutathioneto form cysteine and mercapturic acid conjugates.
What happens to the phase II metabolic pathways after a paracetamol overdose?
The phase II metabolic pathways become saturated, and more paracetamol is shunted to the cytochrome P450 system to produce NAPQI
What happens as a result of increased NAPQI concentration from a paracetamol overdose?
Hepatocellular supplies of glutathione become depleted, as the demand for glutathione is higher than its regeneration
What happens once there is not enough glutathione to detoxify NAPQI after a paracetamol overdose?
NAPQI therefore remains in its toxic form in the liver and reacts with cellular membranemolecules
What can paracetamol overdose result in?
Widespread hepatocytedamage and death, leading to acute liver necrosis
What is the first treatment considered for a paracetamol overdose?
Activated charcoal should be considered if patient presents within 1 hour of ingestion of >150mg/kg paracetamol
What treatment is given for patients where paracetamol overdose has occurred within the last 8 hours?
You should wait until 4 hours from ingestion then measure plasma level and send for urgent analysis.Await result before deciding whether treatment is required.
What is given if results suggest acute liver injury from paracetamol overdose?
Double-check history of paracetamol ingestion, especially the timing, and consider treatment with intravenous N-acetylcysteine.
What treatment is given if a patient has taken a staggered overdose of paracetamol?
The treatment nomogram in unreliable and instead based on paracetamol levels and further blood tests
What is classed as a staggered paracetamol overdose?
Paracetamol taken over a period of more than 1 hour
What might be needed if damage to the liver becomes severe from a paracetamol overdose?
Liver transplant
What is the need for a liver transplant from a paracetamol overdose?
Low blood pH, highblood lactate, poor blood clotting, or significant hepatic encephalopathy
What is the prognosis of paracetamol overdose with early treatment?
Liver failure is rare and death only occurs in about 0.1% of cases
What is the nervous system divided into?
CNS and PNS
What is the CNS?
Brain and spinal cord
What is the PNS?
All the nerves that connect the centralnervous system to the muscles and organs
What is the PNS divided into?
Somatic nervous system and autonomic nervous system
What is the somatic nervous system?
Controls skeletal muscles
What is the autonomic nervous system?
Further divided into thesympatheticand the parasympathetic and controls internal organs
What are cholinergic receptors?
Receptors on the surface of cells that bind acetylcholine (ACh)
What are the 2 types of cholinergic receptors?
Muscarinic and nicotinic
What do preganglionic and postganglionic neurons release in the sympathetic nervous system?
Different neurotransmitters
What do preganglionic neurons do in the sympathetic nervous system?
Release theneurotransmitter ACh, which binds tonicotinic receptors on thecell membrane of postganglionic neuroncell bodies
What do postganglionic neurons do in the sympathetic nervous system?
Most postganglionic neurons release theneurotransmitters adrenaline (epinephrine) andnoradrenaline (norepinephrine) which bind toadrenergic receptors on theplasma membrane of the target organ cells.
What do preganglionic neurons do in the parasympathetic nervous system?
TheACh released bypreganglionic neurons binds tonicotinic receptors on postganglionic neuroncell bodies
What do postganglionic neurons do in the parasympathetic nervous system?
ReleaseACh and it binds to themuscarinic receptors on the target organ cells
What are cholinergic drugs divided into?
Cholinergic agonists and antagonists
What are cholinergic agonists?
Drugs that mimic or enhance the action of ACh at the neuromuscular junction
What are the effects of cholinergic agonists?
Increases GI and GU tone, increases bronchial tone and respiratory secretions. Enhances PSNS activity
What are cholinergic antagonists?
Drugs that inhibit the action of ACh
What are the effects of cholinergic antagonists?
Blocks the ability of acetylcholine to initiate involuntary muscle movements in the lungs, GI tract and GU tract. Balances production of dopamine. Enhances SNS activity
What is the mechanism of direct-acting cholinergic agonists?
Mimic ACh and bind to ACh receptors
Give some examples of direct-acting cholinergic agonists and their therapeutic use.
Carbachol (constrict pupil)
Bethanechol (increase smooth muscle tone in GI and GU tract)
Pilocarpine (stimulate saliva secretion)
What is the mechanism of indirect-acting cholinergic agonists?
Inhibit enzyme AChE, increasing the concentration of ACh available at the synapse
(Reversible)
Give some examples of indirect-acting cholinergic agonists and their therapeutic use.
Neostigmine, Pyridostigmine (myasthenia gravis, reverse anesthesia)
Donepezil, Rivastigmine, Galantamine (boost cholinergic activity in Alzheimer’s)
What is the mechanism of nicotinic antagonists?
Compete with ACh for binding to the nicotinic receptor
Give some examples of nicotinic antagonists and their therapeutic use.
Curare, Pancuronium (relax skeletal muscles during surgery)
What is the mechanism of muscarinic antagonists?
Compete with ACh for binding to the muscarinic receptor
Give some examples of muscarinic antagonists and their therapeutic use.
Atropine, Scopolamine, Belladonna alkaloids (treat bradycardia, diarrhoea, bladder spasms; dilate bronchi, reduce secretions, dilate pupils; as sedatives, respectively)
What are the catecholamines?
Adrenaline and noradrenaline
What are adrenergic receptors?
Receptors on the surface of cells that get activated when they bind a type of neurotransmitters called acatecholamine
What are catecholamines involved in?
Stimulation of our organs by thesympathetic nervous system (fight or flight)
What type of receptor is an adrenergic receptor?
One type ofG-protein coupled receptors or GPCR, because they work directly with intracellular proteins calledguanine nucleotide-binding proteins or G proteins
What do adrenergic receptors bind to other than catecholamines?
They bind to aguanosine diphosphate or GDP molecule when they’re inactive, and to aguanosinetriphosphate or GTP molecule when they’re active.
What are the different types of adrenergic receptors?
⍺₁, ⍺₂, β₁ and β₂
What do ⍺₁ adrenoreceptors do?
Vasoconstriction Increased peripheral resistance Increased blood pressure Mydriasis Increased closure of internal sphincter of the bladder
What do ⍺₂ adrenoreceptors do?
Inhibition of noradrenaline release
Inhibition of acetylcholine release
Inhibition of insulin release
What do β₁ adrenoreceptors do?
Tachycardia
Increased lipolysis
Increased myocardial contractility
Increased release of renin
What do β₂ adrenoreceptors receptors do?
Vasodilation Decreased peripheral resistance Bronchodilation Increased muscle and liver glycogenolysis Increased release of glucagon Released uterine smooth muscle
What do α-agonists do?
Bind to α-receptors on vascular smooth muscle and induce smooth contraction and vasoconstriction, thus mimicking the effects of sympathetic adrenergic nerve activation to the blood vessels.
Give an example of an alpha-1 agonist.
Decongestants (phenylephrine)
Give an example of an alpha-2 agonist.
Centrally-acting vasodilators e.g. clonidine, ⍺-methyldopa
Give an example of a beta-1 agonist.
Inotropes (epinephrine, dopamine, dobutamine)
Give an example of a beta-2 agonist.
SABA/LABA
Give an example of an indirect agonist.
Cocaine
Amphetamine
Give an example of an alpha-1 antagonist.
Tamsulosin
Doxazosin
Give an example of an alpha-2 antagonist.
Yohimbine
Give an example of a beta-1 antagonist.
Selective/Non-selective beta-blockers
Give an example of a beta-2 antagonist.
Non-selective beta-blockers
What do alpha-blockers (alpha-1 adrenergic receptor antagonists) do?
Bind to and inhibit type 1 alpha-adrenergic receptors and thus inhibit smooth muscle contraction
What do beta lactams contain?
Beta-lactam ring in their molecular structure
Give some examples of beta lactams.
Penicillin derivatives,cephalosporins, monobactams andcarbapenems
How do beta lactam antiobiotics act?
Inhibiting the synthesis of thepeptidoglycanlayer of bacterialcell walls